PROCEEDINGS of the Second Regional Pneumococcal …...emergence of resistant strains of pneumococcus...

Hotel Sofitel Sao PauloSão Paulo, BrazilDecember 13 – 14, 2006

PROCEEDINGS of the

Second Regional Pneumococcal Symposium

Acknowledgements

The Symposium Organizing Committee

wishes to thank the following organizations

for support of the Second Regional Pneumococcal Symposium:

Albert B. Sabin Vaccine Institute

GAVI’s PneumoADIP at Johns Hopkins

GlaxoSmithKline Biologicals

Pan American Health Organization

U.S. Centers for Disease Control and Prevention, Atlanta

Wyeth Pharmaceuticals

Proceedings of the Second Regional Pneumococcal Symposium iii

Table of Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

Keynote. The Value of Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2

Session I. Global Pneumococcal Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . .5Global Burden of Pneumococcal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

Global Antibiotic Resistance of Pneumococcus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

Session II. Pneumococcal Epidemiology in the Americas . . . . . . . . . . . . . . . . .8Pneumococcus in Latin America and the Caribbean: Review of the Evidence . . . . . . . . . . . . . . . . .8

Antibiotic Resistance in Latin America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10

SIREVA II: Latin America’s Surveillance Network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Measuring Vaccine Impact in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

Session III. Impact of Conjugate Pneumococcal Vaccines: Direct and Indirect Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15Real-time Impact in the U.S. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15

PCV Efficacy Against Invasive Disease and Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18

PCV Impact on Otitis Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20

Session IV. Pneumococcal Vaccine Development: Update & Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22Serotype Replacement in Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22

Wyeth: Existing and Upcoming Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23

GlaxoSmithKline: Two-at-a-Blow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24

sanofi pasteur: Protein Vaccine in Hand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

Instituto Butantan: Zeroing in on a Whole Cell Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26

Emerging Market Manufacturers: Their Rising Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28

Proceedings of the Second Regional Pneumococcal Symposiumiv

Session V. Opportunities and Challenges for PCV Introductions . . . . . . . . 30Cost-Effectiveness in High-Income Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

Cost-Effectiveness in the World’s Poorest Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32

Economic Burden of Pneumococcal Sisease in Latin America and the Caribbean . . . . . . . . . . . . .32

Cost-Effectiveness of PCV in Latin America and the Caribbean . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

Vaccine Financing Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34World Bank Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34

The GAVI Investment Case for Pneumococcal Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35

PAHO Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

Session V-A. Country Spotlights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Brazil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39

Mexico . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40

Chile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

Session VI. Next Steps in the Global Prevention of Pneumococcal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Round Table: Immunizations in High Risk and Vulnerable Populations

Brazil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43

Bolivia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44

Session VI-A. Implementation Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Session VI-?. Call to Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51

Closing Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54

Millennium Development Goal #4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54

List of Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55

List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .?

The Second Regional Pneumococcal Symposium,held in São Paulo, Brazil, in December 2006, followedby two years the First Symposium, held in MexicoCity. Participants in Mexico City had noted theurgent need to better understand the burden ofpneumococcal disease in Latin America and theCaribbean. For while it was clear that Streptococcuspneumoniae claimed the lives of many children andcaused extensive disease, rough estimates of itsimpact made it difficult for policy makers to makethe tough decisions, and commit the resourcesnecessary, for combating the disease.

Over two days in São Paulo, a dramaticallydifferent situation emerged. Presentationshighlighted the actual burden of disease, itsassociated costs, and the potential benefits thatwidespread use of conjugated pneumococcal vaccineswould bring to the region. One significant source ofthis data was a comprehensive report that reviewedall the literature in connection with pneumococcaldisease in the region of the Americas. The report wasthe result of an intense year of work by a team ofepidemiologists allied with the Albert B. Sabin

Vaccine Institute, working in collaboration with thePan American Health Organization, GAVI’sPneumoADIP at The Johns Hopkins University, andthe United States Centers for Disease Control andPrevention in Atlanta.

Many other contributors, from across the regionand the world, brought their unique national andglobal perspectives to bear as well, collectivelypresenting an in-depth understanding of thepossibilities and challenges ahead in the effort toalleviate the burden of pneumococcus. TheSymposium therefore brought to end a chapter ofresearch that lays the basis to accelerate PCVintroduction throughout the Americas, while alsoraising new questions and challenges.

We deeply thank all the researchers, epidemiol-ogists, economists, doctors, public health workers,members of industry, dedicated policy makers,donors and others who participated in shaping thisSecond Regional Pneumococcal Symposium, andwho will truly shape the future of the children in theAmericas.

Proceedings of the Second Regional Pneumococcal Symposium v

Foreward

Symposium Organizing Committee

Ciro A. de Quadros, MD, MPHAlbert B. Sabin Vaccine Institute

Cynthia Whitney, MD, MPHU. S. Centers for Disease Control and Prevention

Jon Andrus, MDPan American Health Organization

Orin Levine, PhDGAVI’s PneumoADIP

The World Health Organization (WHO) estimatesthat pneumococcal disease accounts for almost 1.6million deaths annually. Up to 1 million childrenunder five die from pneumococcal disease every year,and millions more suffer from pneumococcalpneumonia, otitis media (middle ear infections),meningitis, and sepsis (blood poisoning).

While pneumococcal disease can be controlled byantibiotics, they are often not available in developingcountries where the vast majority of child deathsoccur. And, where antibiotics are used, theemergence of resistant strains of pneumococcus ismaking treatment more difficult and costly.

Pneumococcal disease is caused by the bacteriumStreptococcus pneumoniae, of which there are over90 serotypes, each characterized by the molecules,called polysaccharides, on its outer coat. Some 23 ofthese serotypes are the most important humanpathogens, and they are included in a vaccine foradults. But the vaccine is useless in children, becauseof the immaturity of their immune systems. Hencethe need for a childhood vaccine attuned to thecapabilities of childrens’ immune responses.

A vaccine for children does exist. It is a pneumo-coccal conjugate vaccine (PCV), and it has been part ofthe universal childhood immunization program in theUnited States since 2000. But this vaccine is stillunavailable in most of the world, and is notably absentin poor- and middle-income countries, where thegreatest numbers of child deaths and disease occur.

The Second Regional Pneumococcal Symposium,

held in São Paulo, Brazil, in December 2006, tackledthe myriad of issues necessary to transform thissituation, and enable all countries to prevent a hugeburden of pneumococcal deaths and disease inchildren.

Symposium participants discussed a compre-hensive review of data on the regional burden ofpneumococcal disease and assessments of vaccinecost-effectiveness, evidence of vaccine efficacy inthe United States and in clinical trials worldwide,and new ways of assessing the value of vaccinesand building political support for vaccinationprograms.

Participants learned of new vaccine developmentsby both multinational pharmaceutical companies andemerging market manufacturers. Symposium partic-ipants heard the evidence regarding concerns such asserotype replacement and the problems and possiblesolutions to antibiotic resistant pneumococcus.

Throughout the two days of discussion, presentersand participants addressed recurrent themes ofequity, vaccine affordability and accessibility incountries in transition, and the need for targetedcommunication strategies.

New Evidence on the Value of VaccinesIn a keynote address, Dr. David Bloom, an economistwith the Harvard School of Public Health, presentednew economic data showing that childhood

Proceedings of the Second Regional Pneumococcal Symposium vii

Executive Summary

“Everybody thinks that education is the most powerful instrument of development.What is at stake now is the question of whether

we move health up to that same level.”—DR. DAVID BLOOM

Harvard School of Public Health, US

immunization programs can generate a rate of returnranging from 12% to 21%—making them competitivewith investments in primary and secondary educationas a stimulus to economic growth.

“Everybody thinks that education is the mostpowerful instrument of development. What is atstake now is the question of whether we move healthup to that same level,” said Bloom.

To do so will require re-analysis of previouseconomic evaluations of different vaccines, includingthose for pneumococcus and rotavirus, said Bloom.“We have been shooting ourselves in the foot byleaving out major components of the benefits ofvaccines over the years,” he said. These componentsconsist of additional indirect economic benefitsgenerated by vaccination—from the increasedsavings accrued by a healthier population tochildren’s improved cognitive abilities and higherearnings later in life.

This deeper understanding of the value ofindividual vaccines must be communicated to thepolicymakers who decide on vaccine introductions.Throughout the Symposium, discussion cued back tothe importance of targeted communications withministers of finance, ministers of health, centralbank governors, and other policymakers so that theycan understand and act on this knowledge.

“With the concrete information we have receivedthis week, we have enough data to start an importantdefense against pneumococcal disease in all countries,”said Dr. Ciro de Quadros, Director of InternationalPrograms of the Albert B. Sabin Vaccine Institute.

Impact in Latin America: Savethe Life of One Child Every Hour“Pneumococcus kills approximately two childrenevery hour in the Americas, or more than 18,000children every year,” said Dr. Elizabeth Gómez,

Director of Epidemiology and Statistics at theMinistry of Health of the Dominican Republic,reporting on the first comprehensive analysis of theburden of pneumococcal disease in Latin Americaand the Caribbean.

The analysis also found that pneumococcus causes1.6 million cases of disease. It incurs a totaleconomic cost of US$333 million across the region,and the equivalent of more than 600,000 Disability-Adjusted Life Years.

At the same time, universal vaccination with thecurrent PCV would prevent more than half of thedeaths and disease associated with pneumococcus,and be cost effective based on standard WHOmeasures. This translates into almost one life savedper 1,000 children vaccinated and one case ofpneumococcal disease averted per 80 childrenvaccinated.

The study found that even greater reductions indisease would be possible using vaccine formulationsthat include additional serotypes.

Other speakers documented the actual impact ofPCV7, especially in the United States, where it hasbeen in use since 2000.

Efficacy of PCVDr. Cynthia Whitney, an epidemiologist with the U.S.Centers for Disease Control and Prevention, reportedthat in the U.S. vaccination with PCV7 has led to a98% reduction of invasive pneumococcal disease(IPD) caused by vaccine serotypes in children underfive, a 50% reduction in disease in children tooyoung or too old to be immunized, and an 82%decline in disease in adults aged 65 or older.

“Isn’t it amazing that you can vaccinate childrenand reduce vaccine-type disease in older adults byalmost 82%? I think this is a bigger effect thananyone would have predicted,” Whitney said.

Proceedings of the Second Regional Pneumococcal Symposiumviii

“With the concrete information we have received this week,we have enough data to start an important defense

against pneumococcal disease in all countries.”—DR. CIRO DE QUADROS,

Albert B. Sabin Vaccine Institute, US

Dr. Lee Harrison of the University of Pittsburghilluminated the impact of PCVs in four clinicaltrials, from the United States to the Gambia,showing that vaccination in the Gambia decreaseddeaths from pneumococcus by 16%, and thatefficacy against IPD caused by vaccine serotypesranged from 97% to 77%. Surprisingly, long-termefficacy against all-serotype IPD was higher in HIV-positive children (45%) than in HIV-negativechildren (35%).

Meanwhile, Latin American studies show that thecurrent vaccine formulation would have an efficacyof about 60% in the region. As antigens are addedfor other dominant circulating serotypes, efficacycould rise to 84% for an upcoming 13-valent vaccine,reported Dr. Lucia Oliviera of the Pan AmericanHealth Organization.

Equity, Affordability and SustainabilityAs noted by Bolivia’s Dr. Erick Machicao, vaccinationin Latin America has been an instrument of health,equity and development. Many noted that for theconjugate pneumococcal vaccine to serve as thesame, it must be affordable over the long run.

Cost-effective analysis took different tacks: someevaluated cost-effectiveness based on the vaccine’scurrent price of US$53 per dose for a three-dosecourse; others estimated cost-effectiveness based on arange of prices as low as US$1 per dose. All found

the vaccine either cost-effective or highly cost-effective.

However, several of the speakers who presentedthe on-the-ground challenges of implementingpneumococcal vaccine stated that at its current price,the vaccine would not be sustainable as part ofuniversal childhood vaccination.

“The current price-per-dose of more than US$50prevents our country from taking a leap to introducethe vaccine in our routine program for universalvaccination,” said Dr. Expedito Luna, Director of theSurveillance and Infectious Disease Control programin Brazil.

As a result, some countries are focusing onvaccinating high-risk and vulnerable populations ofchildren, including those with underlying healthconditions.

As noted by Dr. Jon Andrus of the Pan AmericanHealth Organization, in the long-run, solutions mustcome from a combination of innovative financing,the creation of “fiscal space” by nationalgovernments, and successful negotiations betweenPAHO’s Revolving Fund and vaccine manufacturersfor the purchase of vaccines in bulk, at a uniformprice, for countries across the region.

However, as noted by Dr. Orin Levine, ExecutiveDirector of PneumoADIP, there is the “price ofinaction, as well as the price of the vaccine.”

And with the price of inaction in mind,Symposium participants endorsed a “Call to Action”on Pneumococcus in the Americas.

Proceedings of the Second Regional Pneumococcal Symposium ix

In the long-run, solutions must come from a combination of innovative financing.

—DR. JON ANDRUSof the Pan American Health Organization

In light of the burden of pneumococcal disease inthe Americas, and the existence of a safe, efficaciousvaccine, participants called for:

• The introduction of pneumococcal vaccineswherever feasible;

• The World Health Organization to expedite theprequalification of the existing vaccine forpurchase by United Nations agencies;

• Work to raise awareness among the public andpolicy makers of the burden of pneumococcaldisease and the value of vaccination;

• Increased vaccine research and expandedsurveillance;

• PAHO and its Revolving Fund for the acquisitionof vaccines to work together with nationalgovernments, bilateral and multilateral agencies,the GAVI Alliance, and the manufacturers ofvaccines to facilitate the introduction of pneumococcal vaccines.

In short, Symposium participants called for“making 2007 the year of action to combat pneumo-coccal disease in the Americas.”

Proceedings of the Second Regional Pneumococcal Symposiumx

“Isn’t it amazing that you can vaccinate children and reduce vaccine-type disease in older adults by almost 82%?

This is a bigger effect than anyone would have predicted.”

—DR. CYNTHIA WHITNEYU.S. Centers for Disease Control and Prevention

The Second Regional Pneumococcal Symposium,held 13-14 December 2006, reviewed all the majorissues associated with pneumococcal disease globally,and the possibility of its control using safe andeffective vaccines in the region of the Americas.

“I do believe that this Symposium will be thebeginning of a great job in the region of the Americasto start more efficient control of pneumococcus,which is one of the main diseases contributing tochild mortality in the region,” said Dr. Ciro deQuadros of the Albert B. Sabin Vaccine Institute.

The conference built awareness of the:

• Burden of pneumococcal disease in the region,

• Value of vaccines and,

• Processes for evaluating vaccine introduction bycountry.

Investigators reported on a comprehensiveanalysis of the regional burden of disease, whichfound that pneumococcus claims the lives of twochildren under five every hour—more than 18,000children a year.

“The deaths of children from pneumococcus in theregion of the Americas are the equivalent of fourplane crashes of children every month,” de Quadrossaid. “Why do we allow four crashes every month ofairplanes full of children? This social norm has tochange.”

The data also showed that widescaleimmunization with conjugate pneumococcal vaccinecould prevent half of the deaths and about half of the1.6 million cases of disease every year. Andeconomic analysis showed that the vaccine would behighly cost-effective, especially when taking into

account the impact of “herd immunity”—theprotection extended to members of the communitywho are not vaccinated, when vaccination of childrenstops the transmission of disease.

In opening remarks, symposium co-coordinatorDr. Orin Levine of PneumoADIP noted that theSymposium brought together key representativesrequired for successful collaborative action to reducethe huge burden of pneumococcal disease in theAmericas—people from academia, pediatrics, PAHO,the Albert B. Sabin Vaccine Institute, the CDC, theGAVI Alliance, the vaccine industry, and others.

“It has become clear in the last several years thatwe can make enormous progress against infectiousdiseases, like pneumococcal disease, but it requirescollaborative action,” Levine said.

Dr. Jon Andrus, director of PAHO’s TechnicalAdvisory Committee, noted that immunization in theAmericas is at a crossroads. “As we look back fromwhere we have come, we have created, working alltogether, an umbrella of protection,” he said. Theeradication of polio, the elimination of measles, near-elimination of rubella, were all accomplished withrelatively inexpensive vaccines, purchased in bulk onbehalf of countries for the last thirty years throughPAHO’s Revolving Fund.

“But as we look forward we still have amazingpublic health challenges to confront,” said Andrus,co-coordinator of the Symposium.

Andrus presaged the determination of Symposiumparticipants, ultimately expressed in a Call to Actionissued by the Symposium. “We are here to make adifference,” he said. “I would like to leave us with acall for action: To do whatever we can to make thatvaccine available and affordable for those who needit most. For us it is an issue of equity.”

Proceedings of the Second Regional Pneumococcal Symposium 1

Introduction

“It has become clear in the last several years that we can makeenormous progress against infectious diseases,

like pneumococcal disease, but it requires collaborative action.”—DR. ORIN LEVINE

GAVI’s PneumoADIP

Dr. Ciro de Quadros introduced the keynote speaker,Dr. David Bloom, an economist at the HarvardUniversity School of Public Health, with an analogy:“Some few weeks ago,” he said, “there was a terribleaccident here in Brazil with a collision of twoairplanes, and about 300 people fell in the Amazonregion and everybody died. Every day since then,that accident has been in the press here in Brazil.Today we will learn that every hour, two children inthis region die from pneumococcal diseases. This isthe equivalent of an airplane crash every week. Sowhy do we allow four crashes every month ofairplanes full of children? This social norm has tochange. If it does not, the inequities between thechildren that receive new vaccines and the ones thatdo not will continue to grow. To change this socialnorm, decision-makers must come to appreciate thevalue of vaccines.”

Breakthroughs in Valuing VaccinationDr. David Bloom presented new economic evidencethat shows how immunization programs can actuallyboost the wealth of nations. He reviewed new studiesthat calculate a rate of return on childhoodvaccination programs ranging from 12% to 21%,making them competitive with investments inprimary and secondary education as a stimulus toeconomic growth.

The new analyses demonstrate that public healthspending can be justified not only on moral, ethicaland human rights grounds, but can also be aninstrument of economic growth, Bloom said. Theinsights come at a time of both great advances andcolossal failures in child health.

Child Health: Great Advances and Colossal FailuresBloom noted United Nations data that shows theglobal rate of infant mortality has declined from 12%of live births in 1960 to just over 5% today—adecline of nearly 60%. In part, the decline reflectsthe expansion of basic childhood immunization asindicated by the increase in DTP vaccine coveragefrom about 5-10% of children in 1974 to about 75%by 1990. The rate has been level since 1990,however, as the great advances of the past have beenoffset by what Bloom called “colossal failures.”

Key among these is the fact that over 10 millionchildren died in 2002 before age five, and six toseven million of those deaths could have beenprevented or cured with existing medical knowledge.As a result, children account for about 20% of globaldeaths, even though they comprise only 10% of theworld’s population. Furthermore, infant mortalityrates vary across countries by a factor of more than50—and are increasing in size.

How Health Begets WealthBloom said that in the last decade, macroeconomistshave begun identifying the many ways that healthbegets wealth, and those insights are helping toanswer an age-old question: What accounts for thevast differences in wealth between nations?

“Why is per-capita income in Chile three timeswhat it is in Iran? Why is per capita income inNorway 130 times what it is in Tanzania?” he asked.

The old answer to those questions—thatdifferences among countries can be explained bydiscrepancies in physical and human capital—hasnever provided a full explanation. Only once the role

Proceedings of the Second Regional Pneumococcal Symposium2

Keynote: The Value of Vaccines

“The bottom line is that population health is an exceedingly robustand powerful predictor of economic growth.”

—DR. DAVID BLOOMHarvard School of Public Health, US

of health is considered does a more complete answerbecome possible, Bloom said.

We now know that health creates wealth in amultitude of ways:

• Healthier workforces are more productive;

• Healthier populations invest more in education, afundamental determinant of economic growth anddevelopment;

• Healthier people who expect longer retirementsare more likely to save money, an accumulation ofcapital that leads to economic growth;

• Healthy populations are a magnet for attractingdirect foreign investment;

• Health improvements trigger demographicchanges that have the potential to spur economicgrowth if the right policy environment is in place.

Additional benefits accrue from vaccinating children:

• Healthy children have better records of schoolattendance, attend school for more years, andhave better cognitive development;

• Healthy, educated children grow into moreproductive workers;

• Parents stay healthier and are more productive,with lower rates of absenteeism and presenteeism,when they have healthy children.

“The bottom line is that population health is anexceedingly robust and powerful predictor ofeconomic growth,” Bloom said. “A 10-year gain in lifeexpectancy translates into as much as one additionalpercentage point of annual growth of income percapita, which compounds over time.”

In short, improved health has the potential to takenations and individuals out of poverty. “The main assetthat the poor have is their labor. And clearly healthstatus determines the value of that labor,” Bloom said.

Competitive Return on InvestmentTo demonstrate how health, and vaccination inparticular, creates wealth, Bloom reviewed tworecent case studies. One study calculated the rate

of return if the GAVI Alliance (formerly the GlobalAlliance for Vaccines and Immunization) were toextend the use of available and anticipatedvaccines to 75 low-income countries from nowuntil 2020 at an estimated cost of US$13 billion.The investment would reduce the child mortalityrate in those countries by 1,616 per 1,000 livebirths by the year 2020.

Bloom calculated the rate of return on thisinvestment by comparing the program’s cost (US$13billion) to its benefits in economic terms, taking intoaccount worker productivity gains at the individuallevel. The results: the rate of return would be 12% in2005, rising to 18% by 2020.

A second study based on longitudinal data fromthe Philippines encompassed nearly 2,000 childrenborn between May 1983 and April 1984. The dataallowed Bloom and his colleagues to relate thechildren’s immunization experience in the first twoyears of life to their later cognitive development asmeasured by their test scores on language,mathematics, and reasoning.

“We actually find a significant positive effect ofchildhood vaccination on all three test scores,”Bloom said. He then translated those higher testscores into an impact on earnings, and compared thegains in earnings due to vaccination with theprogram costs. This yielded an estimated rate ofreturn of 21%.

“These estimated rates of return, 12 to 18% on theGAVI program and 21% in the Philippines, comparevery favorably with estimated rates of return in themost exalted instrument of development, namelyeducation,” Bloom said.

“Immunization programs make eminently goodeconomic sense because they can be expected toyield an extremely handsome return on investment.And that return is important for economic growth,for poverty reduction, and for reducing globalincome inequality,” he continued.

Bloom argued that the burden is no longer on thehealth community to provide arguments in favor ofvaccination programs. Rather, “The evidence is sostrong that the onus now is on economic leaders andpolitical leaders to say why they are not doing this,because this amounts to what in economic terms isvery much a ‘no-brainer’!”


Discussion

Following Bloom’s presentation, questions andcomments focused on the importance of communi-cating the value of vaccines to decision makers, andthe most effective ways to do so. Bloom said that tohelp ministers of finance, central bank governors,and other policymakers to understand and act uponthese arguments, the analyses need to be taken downto the level of individual vaccines and countries. Heurged economists and epidemiologists to redo all ofthe previous economic evaluations of different

vaccines, including pneumococcal and rotavirusvaccines, applying the new understandings of how tovalue vaccines.

Bloom noted the need to promote news andarticles in publications read by decision makers, suchas The Economist and the journal of theInternational Monetary Fund, as well as theimportance of face-to-face briefings for financeministers, and developing venues to bring togetherMinisters of Finance and Ministers of Health.


“Immunization programs make eminently good economic sensebecause they can be expected to yield an extremely handsome

return on investment. And that return is importantfor economic growth, for poverty reduction,and for reducing global income inequality.”

—DR. DAVID BLOOMHarvard School of Public Health, US

Pneumococcal disease is a primary cause of deathamong children in developing countries and theleading cause of death from infectious disease. Basedon current estimates, it accounts for 1.6 milliondeaths every year, including nearly one millionchildren under the age of five.

During this session, Dr. Lara Wolfson, a scientistin the Initiative for Vaccine Research of the WorldHealth Organization (WHO), reported on a majoreffort of WHO and its partners to update the data onthe global burden of disease imposed by pneumo-coccus. The project, still underway, uses state-of-the-art knowledge and methods in epidemiology andstatistics and will provide a new baseline in theunderstanding of disease and deaths caused byStreptococcus pneumoniae.

Although a pneumococcal conjugate vaccine (PCV)has recently become available, its use worldwideremains limited. Meanwhile, the public health impactand costs associated with S. pneumoniae continue togrow, fanned by the spread of antibiotic resistantstrains of the bacteria. Resistance makes the diseasemore difficult and costly to treat, and challenges theabilities of public health systems to bring pneumo-coccal disease under control.

Dr. Keith Klugman, William H. Foege Professor ofGlobal Health at the United States’ Emory University,summarized the risk factors and impact of antibioticresistant pneumococcus and described globalproblems of emerging resistant clones.

Global Pneumococcal Disease Burden Dr. Lara Wolfson described the Global Burden ofDisease project. Initiated by WHO and its partners,the project’s goal is to estimate the number of casesand deaths caused by Streptococcus pneumoniae

and Haemophilus influenzae type B worldwide,regionally, and by country. The project is analyzingthree major syndromes: 1) meningitis; 2)

pneumonia, and; 3) non-pneumonia, non-meningitisin children under five years of age, with 2000 as thebase year.

“One thing we found very consistently,” Wolfsonsaid, “is that everyone is crying out for more andbetter data, and emphasizing the importance ofimproving and strengthening surveillance togenerate that data.”

Thus far, the project has taken about two and ahalf years and involved 66 people, as a collaborationamong WHO, the PneumoADIP and the HibInitiative.

Wolfson described the project’s rigorous “four stepplus one” process. Its requirements are: a sounddatabase of evidence, peer review of estimates,inclusion of measures of uncertainty, and anindependent evaluation of both the data and themethods. WHO’s Evidence and Information forPolicy Cluster reviews the analysis and data to ensureconsistency with vital registration data, surveillancedata, and other disease burden estimates. As a finalstep, WHO consults with individual countries ontheir findings.

The literature review searched for data on diseasesyndromes, data quality, incidence age, stratificationby regions and overall child mortality levels, and theimpact of HIV. The review initially yielded almost15,000 citations, of which over 400 ultimatelyqualified for inclusion. Due to limited data sources,the researchers extrapolated hard data to countrieswith similar levels of child mortality in the samegeographic region.

Preliminary Findings in Latin AmericaWhile the project is still finalizing disease burdenestimates, Wolfson summarized preliminary findingson pneumococcus in Latin America. These included:

• Case fatality rates for Pneumococcal meningitis inLatin America range from about 15% to about76%, and are heavily driven by access to care


Global Pneumococcal Epidemiology

CO-CHAIRS Dr. Maria Teresa Valenzuela and Dr. Brendan Flannery SESSION I.

(because of the high efficacy of antibiotictreatment);

• There were between 900,000 and 1.7 million casesper year of pneumonia, causing between 8,700and 22,500 deaths per year;

• The case fatality ratio for pneumonia ranged fromjust under 0.1% to 9.1%, and the overallincidence was between 1,280 and 2,250 cases per100,000 children under five years of age;

• The majority of pneumococcal deaths are actuallyfrom pneumococcal pneumonia, a syndrome thatis often not very carefully estimated;

• Pneumococcal meningitis has the highest casefatality ratios;

• For all causes, the case-fatality ratios are closelyrelated to overall mortality rates for childrenunder five years of age.

Wolfson said that the project is nearingcompletion. An expert committee has reviewed itsresults, and the country consultation process willsoon commence, with plans to have final results inmid 2007.

Global Antibiotic Resistance of PneumococcusAntibiotic resistance in pneumococcus is a globalproblem, made worse by the emergence of multiply-resistant bacteria, and “the invasion of the clones,”said Dr. Keith Klugman. On the other hand, “There is

something that can decrease antibiotic resistance andthat is the pneumococcal conjugate vaccine,” he said.

Risks for Antibiotic ResistanceFactors that increase the risk of antibiotic resistanceinclude young age, hospitalization, and HIV positivestatus, but the greatest risk of all is antibiotic use,Klugman said. In children, the risk of carrying resistantpneumococci remains elevated for two to three monthsafter receiving antibiotics. Studies have shown,however, that a high dose, short duration course ofantibiotics is the best to way to minimize risk.

The correlation between antibiotic use andantibiotic resistance is so clear that it can be seen atthe country level. For example, in the EuropeanUnion, both antibiotic use and resistance are lowestin the Netherlands, and highest in Spain.

Invasion of the ClonesKlugman noted that the emergence of resistance hasbeen complicated by multiple resistance, in whichthe bacteria can prevail over more than one class ofantibiotic. As an example of how multiple resistancecan emerge, Klugman described a study from Canadathat shows that the most influential factor indeveloping penicillin resistance is not penicillin use,but use of the macrolide azithromycin, which is atotally different class of antibiotic. “So the macrolideis selecting strains that have multiple resistances,including penicillin resistance,” Klugman said.

High levels of resistance are often due to clones.“What happens is that resistant clones come into thepopulation and replace the susceptible strains of


“One thing we found very consistently is that everyone is crying out for more and better data,

and emphasizing the importance of improving and strengthening surveillance

to generate that data.”

—DR. LARA WOLFSONWorld Health Organization

pneumococcus,” Klugman explained. One CDC study shows that 93% of 144

resistant strains of pneumococcus from across theUnited States belong to just eight clones.Similarly, one clone was responsible for 50% ofthe cases of penicillin-resistant pneumococcalmeningitis in Salvador, Brazil, and another wasresponsible for a high level of fluoroquinoloneresistance in Hong Kong.

In the United States, however, widescaleimmunization with pneumococcal conjugate vaccinehas dramatically lowered the total number ofresistant cases of pneumococcal invasive diseasefrom about 50,000 per annum just prior to vaccineintroduction to fewer than 10,000 in 2002.

Since 2002, however, a counter-trend has emerged,Klugman said, as the number of resistant cases ofpneumonia is again on the rise, driven by the

emergence of resistant clones of pneumococcalserotypes not included in the current vaccineformulation. In particular, a multi-drug resistantserotype 19A clone is “invading the UnitedStates...and it is a very worrying trend,” Klugmansaid. Since 2002, it has increased 2.5 fold in childrenand 2.6 fold in adults.

In other words, while pneumococcal conjugatevaccines interrupt transmission of multiply resistantvaccine strains, Klugman said that resistance is nowemerging in nonvaccine types.

“It is extremely important that vaccines beintroduced, and that surveillance continues tomonitor where and how resistance is emerging sothere can be even newer vaccine formulations tocombat these emerging antibiotic resistant strains,”he concluded.


“There is something that can decrease antibiotic resistanceand that is the pneumococcal conjugate vaccine.”

— DR. KEITH KLUGMANEmory University, US

This session was sweeping in the breadth and depthof data presented on the epidemiology of S.

pneumoniae in the Americas. Drs. Maria TeresaValenzuela and Elizabeth Gómez reported the resultsof a major initiative documenting the extent ofpneumococcal disease in Latin America and theCaribbean. Dr. Maria Christina Brandileone reviewedthe prevalence of antibiotic resistant pneumococcusin the region, and Dr. Lucia Oliveira updated theextensive work of SIREVA, the pneumococcalsurveillance network in Latin America.

In addition, Dr. Brendan Flannery reported on theuse of post-vaccination surveillance in the UnitedStates for gauging vaccine impact. “I am going toshow you something that is quite exciting,” Flannerysaid. “Using terrible data like we have in the UnitedStates, we have been able to demonstrate veryimportant vaccine impact. And that is, perhaps, fordecision makers, rather convincing.”

Pneumococcus in Latin American and the Caribbean: Review of the EvidenceRepresentatives of a multinational team of publichealth experts released findings from the mostcomprehensive study ever conducted on the impactof pneumococcal disease in South America and theCaribbean.

“It is important to know that no country in thisregion has yet introduced the pneumococcalconjugate vaccine to their expanded immunizationprogram,” began Dr. Maria Teresa Valenzuela, Directorof the Public Health and Epidemiology Department atthe University of the Andes in Santiago, Chile. Animportant goal of the study, therefore, was to givepolicymakers the necessary information to decidewhether to expand their immunization programs toprotect all children against pneumococcal disease.

The Executive Summary of the report, entitled“The Burden of Pneumococcal Disease and the CostEffectiveness of a Pneumococcal Vaccine in LatinAmerica and the Caribbean: A review of theevidence and an economic analysis” was distributedat the conference. It was written by a team ofresearchers associated with the Albert B. SabinVaccine Institute, working in collaboration with: thePan American Health Organization (PAHO); GAVI’sPneumococcal Accelerated Development andIntroduction Plan (PneumoADIP) at Johns HopkinsUniversity in Baltimore, MD; and the U.S. Centersfor Disease Control and Prevention (CDC) inAtlanta, GA.

Main Findings“Pneumococcus kills approximately two childrenevery hour in the Americas, or more than 18,000children every year,” said Dr. Elizabeth Gómez,Director of Epidemiology and Statistics at theMinistry of Health of the Dominican Republic.

In addition, across Latin America and theCaribbean, the study found that S. Pneumoniae

causes an estimated 1.6 million cases of disease,including:

• 1.3 million cases of acute middle ear infectionsthat can lead to deafness;

• 327,000 cases of pneumonia;

• 3,900 cases of meningitis (inflammation of the brain);

• 1,200 cases of sepsis (blood infection);

Gómez noted that the total burden of pneumo-coccal disease in the region amounts to “a total of600,000 Disability-Adjusted Life Years (DALYs)—anextremely important element in determining cost-effectiveness that we will hear about later today.”


CO-CHAIRS Dr. Akira Homma and Dr. María Cristina Brandileone

Pneumococcal Epidemiology in the Americas

SESSION II.

Additional findings included:

• For children under two years there are 51 cases ofpneumococcal pneumonia per 100,000 children;

• For every 100,000 children under the age of three,the incidence of pneumococcal bacteremia is 87,and for sepsis the incidence is 2;

• The annual incidence of IPD in children under fiveis 32 cases per 100,000 children;

• The fatality rate of IPD in children ages zero totwo is 12%; in children under five it is 10%;

• The rate of IPD attributed to S. pneumoniae is 32%;

• The annual incidence of bacterial meningitis inchildren under age one is 138 cases per 100,000,and decreases as age increases.

In addition, Gómez said that a review of 13 studiessuggests that 43% of the cases of acute otitis media arecaused by Streptococcus pneumoniae, but she notedthat there was a paucity of available information.

MethodologyValenzuela described the “three pillars” of the study,which included a systematic review of literature; amulti-nation search for other sources of information,including interviews with physicians; and a statisticalanalysis allowing the scientists to draw conclusions andmake recommendations based on the collected data.

An initial comprehensive literature reviewidentified 6,000 publications during the period1990-2006, which were narrowed down to 143 peer-reviewed papers that were included in the analysis.The team also conducted a survey of health careproviders, contacted the ministries of health of each

target nation to obtain relevant data, andcorresponded with 36 pneumococcal researchers(out of the 46 contacted in 13 countries).

They analyzed the data to calculate incidences,fatality rates, and the ratio of syndromes due to S.

pneumoniae, which were then applied to the region’sannual newborn population of 11,500,000 livebirths, followed hypothetically through the first fiveyears of life.

Valenzuela noted that 73% of the epidemiologicalstudies had come from the eight nations in the“Southern Cone,” and that almost 60% of the studieswere carried out in just three countries—Brazil,Argentina and Chile. With some exceptions, studiesfrom countries with low under-five mortality rateswere overrepresented compared to countries wherechildren were more likely to die from the disease,such as Haiti and the Dominican Republic.

Limitations due to the small number of studies incountries with the highest mortality rates, and theongoing need for data, led researchers to suggesttheir results were conservative in estimating theburden of disease. For example, Gómez noted thatonly two studies provided information on the annualincidence of Invasive Pneumococcal Disease (IPD),but that 12 studies provided information on IPDfatality rates, and 56 contained enough data to allowthe researchers to analyze resistance to antibiotics inthe region, as well as the most prevalent serotypes.

The report “The Burden of Pneumococcal Diseaseand the Cost Effectiveness

of a Pneumococcal Vaccine in Latin America andthe Caribbean: A review of the evidence and aneconomic analysis,” was prepared by DagnaConstenla, Elizabeth Gómez, Fernando Pio de la Hoz,Rosalyn O’Loughlin, Anushua Sinha, Juan E.Valencia, Maria Teresa Valenzuela.


“It is important to know that no country in this region has yetintroduced the pneumococcal conjugate vaccine

to their expanded immunization program.”—DR. MARIA TERESA

Valenzuela, University of the Andes, Chile

Antibiotic Resistance in Latin America

Dr. Maria Cristina C. Brandileone, with the AdolfoLutz Institute in São Paulo, Brazil summarized thestatus of antibiotic resistant pneumococcus in LatinAmerica. She noted that, as in North America, LatinAmerica has witnessed an increase of resistance topenicillin over recent years, mainly in connectionwith two clones of serotype 14.

Brandileone presented data from the SIREVAlaboratory surveillance network of 21 countries inLatin America collected between 2000 and 2005.“The specific objectives were to determine theserotype, the antimicrobial resistance of the strains,identify penicillin-resistant clones, and to establishlaboratory capture” of the data, she said.

During the study period, the network analyzedapproximately 17,500 strains, 11,500 of which werefrom children younger than six years of age. Thelargest proportion of strains, 42%, corresponded to adiagnosis of meningitis, 32% to pneumonia, and 26%to others. The higher number of isolates formeningitis, however, is due to its compulsoryreporting in Latin America. In contrast, often nobiological material is collected in relation to outpatienttreatment of pneumonia, Brandileone noted.

Major Findings on ResistantPneumococcus in Latin AmericaThe preliminary analysis from the study foundparticularly high resistance associated with serotype14, which is estimated to comprise 71% of resistantstrains, due to dissemination of two serotype 14

clones. Serotype 6B accounts for another 11% ofresistant strains. “The two serotypes, 14 and 6B,together account for 82% of the total resistant strainsin the region,” Brandileone said.

Brandileone noted that the 7-valent vaccineincludes serotype 14, and would, therefore, protectagainst the resistant serotype 14 clones that havespread through the population.

Reviewing resistance data related to a number ofcountries, Brandileone pointed out that in the periodfrom 1993 to 1999, compared to 2000 to 2005,intermediate antimicrobial resistance increased from17% to 24%, while high resistance increased a non-significant 12%. However, the study did find ahigher percentage of resistance than expected inchildren younger than six years.

Resistance rates varied by country. For example, inthe Dominican Republic, 33% of the child populationhad intermediate resistance, and 25% had highresistance. In Venezuela, on the other hand, only 8%had high resistance.

To illustrate the situation on-the-ground,Brandileone reviewed data regarding penicillin-resistant pneumococcal strains in Brazil. Starting inthe year 2000, a 20% to 30% increase in resistantpneumococcus in children had occurred. Thisincrease was independent of age, but highest inchildren younger than five years.

In conclusion, Brandileone stressed the need for aclinical guide on the rational use of antimicrobials inthe region, noting that even within one country,Brazil, different regions and different hospitals usevarious antibiotic drugs. She urged that surveillancedata be monitored precisely for changes in serotypesand increases in resistance.


“Pneumococcus kills approximately two children every hour in the Americas or more than 18,000 children every year.”

—DR. ELIZABETH GÓMEZMinistry of Health, the Dominican Republic

SIREVA II: Latin America’sSurveillance NetworkDr. Lucia Helena de Oliveira, Regional Advisor forNew Vaccines with PAHO, reported on PAHO’sregional surveillance laboratory network of 21countries in the Americas that was founded in 1993,known as SIREVA. The network aims to helpepidemiologists link laboratory data with necessaryepidemiological and clinical data, to more accuratelycharacterize the human and financial burden ofpneumococcal disease in the region.

SIREVA work is guided by the recommendationsof PAHO’s Technical Advisory Committee (TAC) andits Directing Council, composed of the Ministers ofHealth of the Americas Region. The TAC hasfocused on strengthening the clinical and epidemio-logical components of pneumococcal surveillanceand the conduct of burden of disease and economicstudies. A 2006 meeting of the Directing Councilemphasized the role of immunization in reducingchild mortality in accordance with the GlobalImmunization Vision and Strategy and theMillennium Development Goals.

Serotype Surveillance and Vaccine Coverage De Oliveira summarized SIREVA’s serotypeprevalence data, comparing the periods from 1993-1999 and 2000-2004. She reported that theprevalence of individual serotypes had not changeddramatically, with the most important serotype being14, followed by 6, 5, and 1.

De Oliveira used the data to estimate the potentialimpact of different vaccine formulations on serotypecoverage in Latin America:

• Seven-valent vaccine would cover almost 59% ofserotypes;

• Nine-valent vaccine would cover 71%;

• Eleven-valent vaccine would cover 77%;

• The upcoming 10-valent vaccine would cover 74.5%;

• The upcoming 13-valent vaccine would cover 84%.

Current Work and Future PlansDe Oliveira reported that PAHO is collaborating withcountries to implement surveillance in sentinelhospitals, maintain the capacity and quality of thelaboratory network, standardize case definitions forpneumonia and meningitis cases, collect epidemio-logical data from all patients meeting thosedefinitions, and analyze and publish the data. Inaddition, PAHO is working with countries todetermine the incidence of disease using population-based studies and conducting cost-effectivenessstudies to help guide decisions regarding vaccineintroduction. Through 2007, SIREVA intends tosupport 10 countries in strengthening surveillance.

Key to the surveillance effort is use of astandardized case definition across all countries, andSIREVA defines pneumonia based on a chest X-rayshowing a pneumonia-compatible radiologicalpattern. The definition is used in a new PAHO guidefor bacterial pneumonia and meningitis surveillance


“The U.S. findings suggest that 20% of the otitis media visits in young children...

might be preventable with pneumococcal vaccine.”

—DR. BRENDAN FLANNERYU.S. Centers for Disease Control and Prevention

in children younger than five years. The guide will bereviewed on December 15-16, 2006, at a regionalmeeting of representatives from 25 countries ofEpidemiological Surveillance Systems. “During themeeting, we intend to validate this guide to publish itin March 2007,” de Oliveira said.

Measuring Vaccine Impact in the United StatesDr. Brendan Flannery, an epidemiologist with theU.S. Centers for Disease Control and Prevention(CDC), described how pneumococcal diseasesurveillance data has been used to demonstrate

vaccine impact in the United States. Hedemonstrated that, despite concerns with the qualityof surveillance, it is possible to monitor trends thatgauge vaccine impact.

Two studies—one using a sentinel surveillancesystem at eight pediatric hospitals across the country,and another using population-based surveillance—bothshowed large declines in invasive pneumococcal diseaseafter the vaccine’s introduction in 2000, with thegreatest reductions among children under two years.

Flannery noted that in children under two years,X-ray confirmed pneumonia has declined by almost50% compared to the years before vaccineintroduction.


Cobertura de VacunasConjugadas para Neumococos

Venezuela70%76%81%

Brasil63%80%82%

Paraguay60%80%84%

Columbia70%84%87%

El Caribe65%79%83%

Mexico62%66%69%

Chile41%66%73%

Argentina53%76%81%

Uruguay51%76%86%

América Latina58,9%71,0%77,0%

4 6B 9V 14 18C 19F 23F + 1 5 + 3 7F 7-val 9-val 11-val

Fuente SIREVA-

In addition, a study of outpatient visits in the UnitedStates found a significant reduction in all visits for otitismedia, albeit with wide confidence intervals. “The U.S.findings suggest that 20% of the otitis media episodesamong children younger than two years old...wereprevented with pneumococcal vaccine,” Flannery said.This would mean two million fewer visits per year forear infections in this age group alone.

Meanwhile, hospital discharge data show thatinvasive pneumococcal disease has also decreasedamong persons 65 years and older.

Flannery emphasized the value of including X-raydata on pneumonia. For example, studies in Uruguayand Chile that did so showed rates of disease thatwere approximately 100 times higher than themeasured incidence of invasive pneumococcaldisease. Further, in Chile the measured rate wastripled by adding ambulatory patients.

He noted that comparisons of disease surveillanceresults before and after the introduction of pneumo-coccal vaccine can provide a clearer idea of theproportion of disease due specifically to S. pneumoniae,which will ultimately allow far more accurate estimatesof the burden and cost of pneumococcal vaccine.

DiscussionDuring a wide-ranging discussion led by Dr. Ciro deQuadros, members of the audience asked theresearchers to elaborate on a number of topics.

Rates of Morbidity and Mortality in Latin America and the Caribbean

QUESTION: Xavier Sáez-Llorens from Panamaquestioned the data regarding the death toll attributedto pneumococcal pneumonia, arguing, “Obviously, atleast in Central America or in some other countries,the rate is well below this mortality.” Conversely, headded that the incidence of acute otitis media seemedmuch too low, which he blamed on “significantunderreporting,” particularly for children under 12months. He suggested breaking down the data byregion in order to “capture more information.”

QUESTION: Antonio Arbo from Paraguayquestioned the incidence for meningitis, suggesting

there may be underreporting reflected in the data. Herecommended the researchers indicate whether caseshave been confirmed with cultures. Commenting onthe death rate for pneumococcal pneumonia (for sickchildren under the age of two), he noted the scarcityof studies might have led to conclusions that, “do notreflect the situation in the countries.” “If we considerthat eight out of 100 die, we are overestimating...it isimportant to clarify these limitations,” he added.

RESPONSE: Gómez said that the fatality rate foringitis represented one of the most solid pieces ofdata in the report. “This information summarizes 18papers representing the three sub-regions,” she said.Among the countries contributing data were Chile,Brazil, Colombia, Venezuela, Guatemala, Mexico, theDominican Republic, and Cuba. Additionally, thedata on pneumococcal meningitis included onlyevents that had been confirmed by “isolation of theetiological agent.”

Gómez conceded the number of studies wasindeed small, but noted that her team had beenconservative in estimating burden of disease. “Thesame methodological limitations that we brieflypresented allowed us to see very clearly that there isimportant underestimation of the magnitude of theproblem,” Gómez said.

Valenzuela noted that cases of otitis media areunder-reported. Many of the conclusions regardingthe role of S. pneumoniae in causing acute otitismedia were extrapolated from the work of Dr.Adriano Arguedas of Costa Rica, Valenzuela said. Sheadded that Dr. Arguedas’ work clearly supports thefinding that S. pneumoniae is the causal agent in43% of all cases of acute otitis media in the region.Valenzuela also noted that the research team had aparticularly hard time identifying population-baseddata on acute otitis media.

Antibiotic Resistance and Serotype 14in Latin America

QUESTION: Antonio Arbo asked for the totalnumber of serotype 14 strains examined for thestudy. He noted that if it is the most widelyrepresented serotype, it would be logical that thefrequency of resistance would be higher as well.


RESPONSE: Brandileone noted that her dataincluded about 9,000 samples of all strains fromeight countries, but she did not have the specificnumber of serotype 14. “What you suggest is logical,but it is interesting to see that the proportion ofresistant serotype 14 strains has increased with time,”she said.

QUESTION: Raúl Ruvinsky commented that, inArgentina, serotype 14 accounts for 34% out of 2,100isolates—a percentage similar to those found in theother countries. It is the one with the highestresistance, as compared to all other serotypes.

RESPONSE: Brandileone said that unpublisheddata show that clone Spain of serotype 14 beganincreasing regionally starting in 1997, when it hadalmost no presence. For example, in Brazil, the cloneinitially was only located in the state of São Paulo.Today, it has spread to all the regions in the country.

COMMENT: Dagan noted that if the vaccineintroduced seven years ago had not alreadycontained type 14, its recent meteoric rise would nowbe considered a replacement strain.

The Definition of PneumoniaUsed by SIREVA

QUESTION: Gustavo Aristizabal from Bogota,Colombia, Greta Miño from Ecuador, and othersquestioned the definition of pneumonia used bySIREVA. Some felt X-ray-compatible pneumonia wastoo restrictive. Another person suggested that bloodcounts and quantitative PCR be used.

Others supported an X-ray based definition. “AnX-ray definition is probably the best clinicaldefinition that we now have. The only otherdefinition would rely on measuring seroreactiveprotein, but these tests may not be available,” saidone participant.

Ruvinsky noted that “Perfection is the enemy of thegood,” and that more accurate methods are generallynot available in the countries. As it is, most hospitalsfail to isolate 10% of cases. In addition, he noted that athree-year study of the burden of disease in Argentinafound that X-ray diagnosis has worked well.

RESPONSE: De Oliveira replied, “I am an epidemi-ologist, as were most of the individuals who workedon this guide. When we think in terms of publichealth, we have to balance sensitivity and specificityin case definition. It is completely different when adoctor looks at the patient from the clinical point ofview. We are going to have false negative cases andfalse positive cases, but we need to strike thatbalance. We know that it is not a perfect casedefinition but it is a definition to work with in publichealth.” She emphasized that there would be anopportunity to validate the guide with a largenumber of individuals from the Ministries of Healthat a meeting that directly followed this one.

COMMENT: There is a tool available on the WHOwebsite for standardization of the interpretation ofX-ray confirmed pneumonia. There is a paper by Dr.Thomas Cherian in the WHO Bulletin, and a paperin Spanish by Dr. Rosanna Lagos that explains thesurveillance in Latin America.


Three presentations captured the stunning array of“direct and indirect effects” of the pneumococcalconjugate vaccine (PCV). The direct effects areexperienced by the children vaccinated: lives saved,illnesses averted and nights at home in bed ratherthan in emergency rooms or local clinics. Indirecteffects are health benefits experienced by thevaccinated child’s younger and older siblings,parents, friends, grandparents, teachers as well aschildren not yet vaccinated—in short, thecommunity at large.

The reason for these indirect effects is “herdimmunity,” which occurs when vaccination in thetarget population stops transmission of pneumo-coccus in the larger “herd.” In the United States, theimpact of herd immunity since vaccine introductionin 2000 has proven to be greater than anyoneanticipated, according to Dr. Cynthia Whitney of theU.S. Centers for Disease Control and Prevention(CDC).

A presentation by Dr. Lee Harrison illuminated theimpact of PCVs in four clinical trials, from theUnited States to the Gambia, showing that theintroduction of PCV will bring large public healthbenefits to developing as well as developed nations.

A third presentation by Dr. Ron Dagan addressedthe vaccine’s impact on otitis media (OM), or middleear infection, of which there are 24 million cases ayear in the U.S. alone.

Real-Time Impact in the U.S.Dr. Cynthia Whitney of the U.S. CDC shared the U.S.experience with PCV7, which was licensed in 2000.The government recommended that the vaccine begiven to all children under 2 years and to certainhigh-risk children aged 2 to 4 years. By 2005, about83% of children aged 19-35 months had receivedthree or four doses.

“Disease caused by the vaccine types has dropped

dramatically in young children following conjugateintroduction, and herd immunity appears to beprotecting unvaccinated kids,” Whitney said.

The U.S. experience with PCV7 includes a 98%reduction in IPD caused by strains covered by thevaccine in children under 5 years, a 50% reduction indisease in children either too young or too old to beimmunized, and an 82% decline in disease in adultsaged 65 or older.

Whitney reviewed highlights of post-introductiondata based on the CDC’s Active Bacterial Core (ABC)surveillance system, which operates in 10 states andtracks invasive pneumococcal disease in a populationof about 20 million people.

Summarizing the major effects of pneumococcalvaccination, Whitney reported that the rate ofvaccine type invasive pneumococcal disease (IPD) inchildren under five dropped from about 80 cases per100,000 children at baseline in 1999 to 1.5 cases per100,000 children in 2005—a 98% reduction in IPD.

A case control study conducted in thesurveillance areas demonstrated that efficacyagainst individual vaccine serotypes ranged from alow of 87% against 19F to a high of 100% against9V. The vaccine extended some cross-protectionagainst vaccine-related strain 6A, but it did notafford similar protection against vaccine-relatedstrain 19A.

Whitney also reviewed the effect of variousvaccine schedules, and reported that even a singledose given to infants before the age of seven monthsexhibited 73% effectiveness, although protection didnot persist more than 6 months after a single dose.Schedules of two, three, or four doses all had 95%-100% effectiveness and protection lasted. “This isgood news in that there is some flexibility forvaccine schedules for countries that introducepneumococcal conjugate vaccine. I think a variety ofdifferent three-dose schedules would probably alwaysbe effective,” she said.


Impact of Conjugate Pneumococcal Vaccines: Direct and Indirect Effects

CO-CHAIRS Dr. Ron Dagan and Dr. José Ignacio SantosSESSION III.

Herd Effects in Children and AdultsWhen enough of the susceptible population isvaccinated, transmission of disease can be reduced,thus protecting other members of the population, or“herd.” Epidemiologists have found strong evidenceof such “herd immunity” from pneumococcalconjugate vaccine in the U.S., Whitney said.

In children, this evidence includes a drop invaccine-type disease in children who are either tooyoung or too old to have received pneumococcalconjugate vaccine: a 50% disease reduction in infantsunder two months of age (when the first dose isgiven) and a similar drop in children aged 5-17 years.

In adults ages 65 and older, disease rates havefallen from about 60 per 100,000 to about 45—a 34%decline—since vaccine introduction. For vaccineserotypes only, disease rates have fallen “a whopping82%,” Whitney said. At the same time, nonvaccinetype disease has gone up a relatively small amount,compared to the magnitude of the decline.

“Now isn’t that amazing that you can vaccinatechildren and reduce disease in older adults by almost82%? I think this is a bigger effect than anyonewould have predicted,” Whitney said.

Other Findings in the U.S.Whitney reported on a number of other importantfindings based on the nearly 6 years of PCV7 use inthe United States. Among them:

• Impact on Adults Living with HIV: A study by Dr.Brendan Flannery demonstrated that thechildhood pneumococcal vaccine is extendingprotection to adults with HIV/AIDS. From 1999and 2004, overall (all serotypes) invasive disease

rates dropped by 37% in adults between 18 and64 years of age who are living with HIV, includinga 62% drop in disease caused by vaccine types.The drop in disease caused by vaccine serotypeswas similar to the drop experienced by adults notinfected with HIV. Unlike healthy adults, however,adults with HIV/AIDS had a 43% increase indisease caused by nonvaccine serotypes.

• Replacement: “There are 90 pneumococcal vaccineserotypes and this vaccine is taking away seven ofthem. Will some of the other ones take over?”Whitney asked. Post-licensure data show a largedrop in vaccine-type disease in children under 2years, from 160 cases per 100,000 children to 2cases per 100,000. However, one nonvaccineserotype has countered this trend. Serotype 19Aincreased from five cases per 100,000 children atbaseline, to 15 per 100,000 in 2005. “Themagnitude of this replacement disease has beenvery small compared to the vaccine benefit,”Whitney emphasized.

• Penicillin resistance: The vaccine has greatlyreduced the amount of penicillin-resistant S.pneumoniae. After having increased dramaticallyin the decade before the vaccine was introduced,the number of infections caused by penicillin-resistant strains has since plummeted. This isbecause serotypes that were most resistant werealso included in the vaccine. “As predicted, youtake those strains out of circulation with thevaccine, and we see this nice drop in resistantdisease,” Whitney said.

In summary, Whitney said the widespread use of


“Disease caused by the vaccine types has dropped dramatically in young kids following conjugate introduction,

and herd immunity appears to be protecting unvaccinated kids.”

—DR. CYNTHIA WHITNEYU.S. Centers for Disease Control and Prevention

pneumococcal conjugate vaccine has led to largedeclines in invasive disease rates in young children, aherd benefit in unvaccinated children and adults, anindirect benefit to highly susceptible adults (partic-ularly those living with HIV/AIDS), and fewerresistant infections. At the same time, but to a

limited extent, replacement disease reduces benefitin some highly susceptible groups, such as thoseliving with HIV/AIDS.

“The main question now is: How can weencourage introduction of conjugate vaccines inmore places?” said Whitney.


Vaccine-Type Invasive Disease in Children <5 YearsABCs 1998–2005

81

63

27

9.4 4.8 2.4 1.5

100

80

60

40

20

01998/99 2000 2001 2002 2003 2004 2005

98% reduction

CDC unpublished data and MMWR Sep 16, 2005

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es/1

00,0

00 p

op

ula

tio

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70

60

50

40

30

20

10

01998 1999 2000 2001 2002 2003 2004 2005

Lexau et al. JAMA 2004 and unpublished data

Herd Effect in AdultsInvasive Pneumococcal Disease Rates Over Time

ABCs, 1998-2005

-34%

-16%

-48%

2005 vs. baseline

PCV765+ years

40-64 years

18-39 years

The take home message today is that use of conjugate vaccine in children has been very effective for disease prevention in adults. And here are the data to show it.

PCV Efficacy Against InvasiveDisease and Pneumonia Dr. Lee Harrison, of the University of Pittsburgh,reported efficacy data from four clinical trialsconducted in different settings. All data suggestedthat the introduction of pneumococcal conjugatevaccines will have a huge positive public healthimpact in both developed and developing countries.

The four trials took place in 1) Northern Californiain the United States; 2) among American Navajo andApache Indians in the United States; 3) Soweto,South Africa; and 4) the Gambia. They evaluated theefficacy of PCV against IPD and pneumonia. Efficacyagainst IPD caused by vaccine serotypes ranged from97% in the California trial, to 77% in both theAmerican Indian and Gambian trials.

Among the most impressive findings was a 16%reduction in deaths caused by pneumococcus in theGambia, as well as higher long-term efficacy againstpneumococcal disease in HIV-infected children thanin uninfected children in South Africa.

The U.S. trials used the 7-serotype vaccine, laterknown as Prevnar, while the South African andGambian trials used CPV9 (Prevnar plus serotypes 1and 5). The Northern California Kaiser Permanentetrial ultimately served as the basis for licensure ofPCV7 in the United States in 2000, “and it now is anintegral part of our immunization schedule given attwo, four and six months, with a booster at 12 to 15months,” Harrison said.

The Northern California Kaiser Permanente trialvaccinated 38,000 infants with a three-dose schedule

plus a booster. There were 39 vaccine-serotype casesin the control group, and one in the vaccinatedgroup. The efficacy for IPD against vaccine serotypeswas 97%, and against all serotypes was close to 90%.Efficacy for first radiographic pneumonia was a moremodest 30%.

A breakdown by serotype showed that efficacyranged from about 85% for 19F and 6B to 100% forfour others (there were no serotype 4 cases, soefficacy could not be determined).

The American Indian trial was a group-randomized double-blind trial of PCV7 versusmeningicoccal C conjugate. It enrolled about 8,000Navajo and White Mountain Apache children whowere randomized into 38 different units, either incommunities or combinations of communities. “Thepotential advantage of this design is that it measuresthe direct effects plus the indirect effect of herdimmunity,” Harrison said.

The trial was stopped early, however, because ofthe U.S. licensure of Prevnar. Results, therefore, werebased on a small sample size. They showed efficacyfor IPD against vaccine serotypes of 77%, with a verywide confidence interval, Harrison said. Efficacy forall serotypes was about 54%.

The South-African trial, conducted by Dr. KeithKlugman, immunized nearly 20,000 infants withthree doses, and no booster dose.

The study included both HIV-negative and HIV-positive children. The results: for HIV-negative children,the efficacy against IPD with vaccine serotypes was85%, and against first radiographic pneumonia was25%. In HIV-positive children, the efficacy against IPD


“Unexpectedly, long-term efficacy against all serotype diseasewas higher in the HIV-infected than the HIV-uninfected.”

—DR. LEE HARRISONUniversity of Pittsburgh, US

with vaccine serotypes was 65%, and against firstradiographic pneumonia was 13%. In neither case wasthere a significant reduction in mortality.

A follow-up study looked at efficacy beyond the2.3 years of the initial trial. Following children for 6.2years, the study showed long-term efficacy againstall-serotype IPD was 35% in HIV-negative children,and 46% in HIV-positive children, with efficacywaning much more quickly among the latter group.

“For me, unexpectedly, long-term efficacy againstall serotype disease was higher in the HIV-infectedthan in the HIV-uninfected,” Harrison said. And,because of the huge increased risk of IPD in HIVpositive children, the vaccine prevented a burden ofinvasive disease that was 59 times higher than thatprevented in HIV-negative children. “This gives you asense of the public health impact of the vaccine inHIV-positives,” he added.

The Gambian trial vaccinated more than 17,000infants with three doses of vaccine, without a booster.

It found that immunization reduced mortality by16%, with an absolute mortality reduction close tofive deaths per 1,000 child years. “This suggests thatfuture trials should look at mortality as an endpoint,”Harrison said.

The study found 37% efficacy against firstradiographic pneumonia, 7% against clinicalpneumonia, 77% against vaccine-serotype IPD, 50%against all-serotype IPD, and 15% against admissionsto the hospital.

In conclusion, Harrison said, “Given the burden ofpneumococcal disease in developing countries, theintroduction of pneumococcal conjugate vaccines willhave a huge positive public health impact.”

PCV Impact on Otitis MediaDr. Ron Dagan, Professor of Pediatrics and InfectiousDiseases at the Ben-Gurion University of the Negev inBeer-Sheva, Israel, summarized the impact ofvaccination on otitis media (OM), an infection of themiddle ear. OM is the most common bacterial infectionin children under five for which antibiotic treatment isprescribed worldwide. In the United States alone, thereare 24 million cases of otitis media every year.

Dagan addressed four questions about the vaccine:whether it would reduce the incidence of OM;

whether it would reduce associated sequelae; whetherit could be used therapeutically; and what impact itwould have on antibiotic resistant cases of OM.

Does PCV Reduce Otitis Media or Just Alter its Bacteriology?The answer is “both.” Some studies show thatvaccination somewhat reduces the incidence of OM,according to Dagan. For example, a study in a daycarecenter showed that administering a 9-valent vaccine ledto a 26% reduction in prescription for antibiotics to treatOM. United States data collected after the introductionof PCV7 showed that OM visits declined by 20% inchildren less than two years. He noted, however, thatthe downward trend in visits had begun before vaccineintroduction, leaving open the question of causality. Thequestion is whether the trend will persist.

But vaccination also modifies the bacteriology ofOM. It not only changes the serotypes involved in OM,but also leads to an increasing proportion of OM casescaused by other pathogens, especially nontypableHaemophilus influenzae and Moraxella catarrhalis.

For example, four studies conducted in the U.S.,Finland, and the Czech Republic showed an efficacyagainst vaccine-type strains of S. pneumoniae of between56% and 67%. At the same time, in one of those studies,OM caused by nonvaccine serotypes, as well as by H.

influenzae and M. catarrhalis increased, yielding a non-significant vaccine efficacy of just 6% against OM.

This phenomenon raises a new question: whetherthe planned 10-valent vaccine that will be conjugatedwith an outer protein of H. influenzae may evenmore effectively reduce OM. Indeed, initial testsshow this may be the case, Dagan said.

Does Vaccination Reduce AntibioticResistance in OM?Yes, said Dagan, but this reduction can becomplicated by replacement with other nonvaccineserotypes, especially when antibiotics are used.

He noted that the current PCV7 vaccine includesthe most resistant serotypes found in the U.S. and inmany parts of the world. Preventing disease by thoseserotypes, therefore, also prevents drug-resistantdisease. But continuing exposure to antibiotics maywork against the effects of the vaccine, as seen in one


French study. It found that children who werevaccinated and did not receive antibiotics had lessrisk of carrying resistant pneumococci while experi-encing OM than did children who were vaccinatedand who did receive antibiotics.

The use of antibiotics, “in the presence of a littlebit of replacement, may attenuate the whole effect ofthe vaccine,” Dagan said.

Does the Vaccine Reduce SequelaeAssociated with OM?Somewhat, according to Dagan. For instance, inCalifornia, vaccination was associated with a greaterthan 50% drop in the cases of children who soughttreatment for OM in six or more clinic visits. “So itmight be that early vaccination reduces complex otitismedia,” Dagan said, and this could reduce the needfor ear tubes. In both Finland and the United States,vaccination did, indeed, reduce the need to ventilatethe ears by an impressive 40% and 20%, respectively.

Does PCV Work as a Therapeutic Vaccine?No, said Dagan. Studies among children in Belgium andthe Netherlands tested whether vaccinating childrenwho already have recurrent OM would prevent its

further recurrence. The result: “Children who receivedthe vaccine have a little bit more, not a little bit lessotitis media. So it is not a good idea to take a conjugatepneumococcal vaccine and give it to reduce cases inalready established, recurrent otitis media.” Dagancautioned that when people try to give the vaccinetherapeutically, it may do more harm than good.

Dagan concluded by noting that PCV exhibits someefficacy against otitis media, but it is “definitely lessimpressive than what you get with invasive infection,pneumonia, and meningitis.” He said the evaluation,however, is complex and far from conclusive. Futurestudies are needed on the reduction of diseaseburden, the modification of pathogens causing OM,vaccine effects on antibiotic use and antibioticresistance, and on the potential additional benefits ofother pneumococcal vaccines such as the 10-valent.

DiscussionQuestions were directed to Drs. Lee Harrison, RonDagan and Cynthia Whitney.

Two or Three Doses

COMMENT: Adriano Arguedas noted that the U.S.data regarding the two doses plus a booster methodis similar to data collected from Hib vaccine trials in


Community-Wide Vaccination with the PCV7 Significantly Alters the Microbiology of AOM

Proportion of the Various Pathogens Causing AOM

Block et al, Pediatr Infect Dis J 23:829-33, 2004

GASMC

HI

PNC

GASMC

HI

PNC

1992 - 8n = 336

9%2%

48%

41%

11%2%

31%

56%

2000 - 3n = 83

Finland. He said it is very important data for LatinAmerican countries where the main reason thevaccine is not used is the cost.

RESPONSE: Whitney said that there are alsoimmunogenicity studies with pneumococcus suggestingthat two doses in the first six months of life provideantibody levels that are nearly as good as three doses.“We now have the case control studies showing that the2-plus-1 schedule is highly effective,” she said. Thatschedule was just introduced in the United Kingdomand is now being used in Quebec, Canada. Preliminarydata show that their disease rates are plummeting.

COMMENT: Dagan voiced “a bit of a less super-optimistic view on this.” He explained that the dosagestudies have measured impact on IPD, but the biggerburden of death in the world is from pneumococcalpneumonia, and the biggest associated burden ofdisease is OM. “And so a lower number of doses maygive very good protection from invasive disease, butmay also significantly lower protection for pneumo-coccal pneumonia,” he said. It may also alter the post-vaccination carriage rate and lower the impact of herdimmunity. He suggested further investigation andcaution regarding the 2-plus-1 vaccine schedule.

Revaccination

QUESTION: Telma Carvalhanas, Brazil, inquiredabout the panelists views of revaccination, especiallyamong those older than 60.

RESPONSE: Whitney replied that there are not gooddata on how long the pneumococcal polysaccharidevaccine, the 23-valent vaccine, lasts. Some studiessuggest that antibodies decline after approximately fiveto eight years, and if you revaccinate after about fiveyears, antibodies go up again, but not as high as thefirst time. As a result, there is concern that immunetolerance may be developing. Revaccination in olderadults, however, is being considered in the U.S.

Serotype 1 in the U.S.

QUESTION: De Oliveira asked about a reportpublished on the increase of emphysema due toserotype 1 in the United States.

RESPONSE: Whitney responded that a study in Utahreported on an unusual serotype distribution—onewith far more of serotype 1 and 3 than commonly seenin U.S. populations. She noted that the increase inserotypes 1 and 3 had begun even before the vaccinewas licensed. “So I am not so sure that any of what wesee in Utah is a vaccine effect,” she said, adding that itis the change that needs to be better understood.

Vaccine Efficacy in People Living with HIV/AIDS

COMMENT: Klugman noted that a paper he justpublished documented an epidemic of serotype 6Aamongst the HIV-infected children. Therefore, if thevaccine can offer cross-protection against 6A in HIV-infected children, “it will really protect kids throughthe first five or six years of life,” he said.

QUESTION: Santiones asked if anybody hadanalyzed the long-term efficacy of CVP in HIV-infectedchildren related to optimal antiretroviral therapy in theSouth African study. “Because we run a clinic inPanama, an HIV clinic with more than 200 kids ontriple therapy and very well controlled. We have seen afew pneumococcal infections in this population. Whatdoes the South African data show?” he asked.

RESPONSE: Klugman replied that there is not a lotof evidence, although studies in HIV-infected kids arenow looking at the impact of early retroviral therapyversus later therapy, and how this changes theresponse to the vaccine. In adults, evidence shows thatthe burden of pneumococcal disease has greatlydecreased in the antiretroviral era, but still remainsseveral-fold higher than in HIV-free comparable adults.

Antibiotic Use, Vaccination, and Otitis Media

COMMENT: Xavier Sáez-Llorens questionedwhether the recent reduction in antibiotic use for OMis the result of reduced disease due to vaccination orto other factors, such as new clinical guidelines onantibiotic use, and the fact that OM caused byHaemophilus and Moraxella probably resolve sponta-neously more frequently than does pneumococcus.


The development and licensing of the world’s firstpneumococcal vaccine for children was a watershedmoment for public health. But, according topresenters in this session, it was the beginning, notthe end, of the fight against pneumococcus.

Industry is gearing up to fill the large and growingdemand for a childhood pneumococcal vaccine.Multinational companies have some 25 vaccines indevelopment, and emerging suppliers have aboutseven, according to Dr. Akira Homma.

Representatives of both multinational companiesand emerging suppliers updated the Symposium ontheir vaccine development plans.

Even as new vaccines move through development,the scientific community is tracking anotherphenomenon, known as serotype replacement: thepost-vaccination phenomenon of nonvaccineserotypes replacing vaccine serotypes in carriage andin disease. Dr. Ron Dagan summarized what isknown about replacement related to pneumococcalvaccines, concluding that, “The overall benefit fromvaccination exceeds by far any increase byreplacement disease.”

Serotype Replacement in PerspectiveDr. Ron Dagan, of Ben-Gurion University, Beer-Sheva,Israel, began by acknowledging that “Serotypereplacement is probably one of the most complexand problematic issues because we do not yet knoweverything, but we know a lot is going on.”

Dagan discussed serotype replacement inrelationship to the overall effect of the vaccine inreducing disease, the possible effect of antibioticuse, and the natural changes occurring in serotypedistribution.

He pointed to one study by the U.S. Centers forDisease Control and Prevention that showed aprojected annual reduction of IPD in children under

age 5 of more than 12,500 cases, compared to anincrease of fewer than 1,000 cases due to nonvaccineserotypes.

Dagan said that while we know the net effect ofthe vaccine, we do not always know to what extentserotype replacement might be mitigating its impact.This is especially true for disease syndromes, such aspneumonia, in which the starting bacteriology isunknown. However, Dagan emphasized that we doknow the vaccine’s overall impact is to reducepneumonia. “We don’t know whether a reduction of20% is actually reduction of 40%, with 20%replacement, or if it is no replacement at all,” he said.

Dagan reported that replacement definitely occursin the carriage of pneumococcal serotypes, as well asin otitis media, in which there is significantreplacement disease.

Replacement is possibly more of a problem inadults than in children, according to Dagan. Becausechildren transmit replacement serotypes to adults,who may be more susceptible to them. In fact,replacement serotypes have been a problem forpeople living with HIV, particularly for women andAfrican Americans with HIV, Dagan said.

Replacement with Antibiotic-ResistantSerotypesOther studies have shown the rise in some antibiotic-resistant nonvaccine serotypes. However, “They tendto go up even before vaccination because they mayhave more virulence factors and they tend to beclonal,” Dagan said. He noted that this makes it moredifficult to tease out the actual effects of vaccination.In addition, “vaccination does not mean that wereduce antibiotic use,” meaning that the predominantfactor driving antibiotic resistance—use ofantibiotics—is still in place.

In the case of serotype 19A, an antibiotic-resistantclone that rose threefold in the United States in thefour years following vaccine introduction, Dagan


CO-CHAIRS Dr. Rosanna Lagos and Dr. Keith KlugmanSESSION IV.

Pneumococcal Vaccine Development:Update & Issues

argued that “the vaccine may have played a role butantibiotics played another role.” In addition,multidrug resistant nonvaccine serotypes areincreasing in regions in which the vaccine is notused. This includes a multidrug resistant 19A inKorea and a multidrug resistant 14 in Brazil andother parts of Latin America.

In conclusion, Dagan noted: “We have tounderstand that things occur with vaccination, andwithout vaccination...but don’t blame anything onthe vaccine.” Saying that replacement is a realphenomenon, Dagan called on the need for moresurveillance. “And so far, in my opinion, the overallbenefit from vaccination exceeds by far any increaseof disease replacement,” he said.

Wyeth: Existing and Upcoming Vaccines“There is now a vaccine available, the 7-valentvaccine, which is effective against the most seriousdisease,” said Dr. Peter Paradiso, Vice President ofWyeth Vaccines. In addition, “The unanticipated,indirect effects of this vaccine add a dimension ofvalue that we could not have anticipated.”

Wyeth’s vaccine is known as Prevnar in theUnited States, where it is now part of the universalchildhood vaccination schedule. Known as Prevenarelsewhere, the vaccine has been launched in 73different countries, with more than 125 million dosesdistributed.

Prevnar was designed to cover the most prevalentserotypes globally, and includes serotypes 4, 6B, 9V,14, 19F, 18C and 23F. But the vaccine isn’t perfect,according to Paradiso. At the time of licensure,Paradiso said Wyeth had hoped the vaccine wouldprovide cross-protection to other serogroups, partic-ularly 6A and 19A. And, while researchers found thatthe vaccine afforded some cross-protection against6A, it was not enough to generate herd immunity—and there was no cross-protection against 19A.

Future VaccinesWyeth is now focusing its pneumococcal vaccinedevelopment on a 13-valent candidate that buildsPrevnar. Paradiso explained that one key tosuccessfully expanding serotype coverage is to notnegatively affect the serotypes that are already there.The 13-valent conjugate pneumococcal vaccine (13vPnC) contains the original seven serotypes, plus 6A,7F, 3, 1, 5, and 19A. Serotypes 1 and 5 are importantin many parts of the word, and 19A is responsiblefor an increased burden of disease in the UnitedStates since Prevnar’s introduction, Paradiso said.

Development and testing of 13v PnC faces anotherchallenge: placebo-controlled trials cannot beconducted in most populations, especially forinvasive disease, because an effective vaccine isalready available. Therefore, Paradiso said that theywill gauge efficacy through using a correlate ofimmunity specified by WHO guidelines, namely theproportion of infants achieving a concentration of


“Serotype replacement is probably one of the most complexand problematic issues because we do not yet know

everything, but we know a lot is going on.”

—DR. RON DAGANBen-Gurion University, Israel

anticapsular antibody of 0.35 _g/mL within onemonth of immunization.

Wyeth recently concluded a Phase II proof-of-concept trial for 13v PnC. “We demonstrated withmore power than we had expected that this vaccineis going to be able to induce a good protectiveresponse to all 13 serotypes,” Paradiso said.

Wyeth is now conducting Phase III trials, workingtoward licensure, and building manufacturingfacilities to accommodate the new serotypes.

GlaxoSmithKline: Two-at-a-BlowWilliam Hausdorff with GlaxoSmithKline (GSK)described the development of a vaccine that targets twomajor bacterial respiratory pathogens, S. pneumoniae

and H. influenzae. He showed data indicating that H.

influenzae represents 22-56% of bacterial AOM inseveral studies, including 34% in a Chilean study.

The vaccine, known as PHiD-CV (forPneumococcal Haemophilus influenzae Protein D-Conjugate Vaccine) contains a conserved H.

influenzae protein, which is a pathogenicity factor inotitis media and is immunogenic in humans. PHiD-CV contains the same seven pneumococcal serotypesfound in Prevnar, as well as serotypes 1, 5, and 7F.

“In addition to accounting for quite a largenumber of cases of invasive disease, these serotypeshave other very interesting properties, such as theability to cause outbreaks of meningitis in Africa,”said Hausdorff. Serotypes 1, 5, and 7F are alsoprevalent in Latin America, representing from 17-32% of all IPD in children under six in Argentina,Brazil, Chile, Colombia, and Uruguay. Taken together,the 10 serogroups in the vaccine are responsible forapproximately 85% of invasive pneumococcal diseasein children worldwide.

The precursor to PHiD-CV was an 11-valentconjugate that also included serotype 3, and GSKtested this vaccine in a clinical trial dubbed POET—the Pneumococcal Otitis Media Efficacy Trial-conducted in the Czech Republic as a double-blind,randomized controlled study comparing the 11-valentconjugate vaccine with the control vaccine, Havrix (avaccine for hepatitis A). Two years of surveillancetracked the occurrence of otitis media.

The results, published in The Lancet, showedefficacy of 58% against pneumococcal otitis mediacaused by the vaccine serotypes. All serotypesappeared efficacious, with the sole exception ofserotype 3, which “was good for nothing,” and wastherefore removed from the subsequent vaccineformulation. Efficacy against Haemophilus-causedotitis media was 35%. “At the end, the effect was42% regarding all bacterial AOM cases,” Hausdorffsaid. However, he noted that the magnitude of theeffect on all bacterial AOM would likely varydepending on the starting epidemiology. InFinland, for example, where Moraxella causes agood proportion of otitis media, the vaccineimpact would be predicted to be lower, but stillpotentially prevent 28% of all bacterial AOMcases.

Thus far, more than 10,000 children have receivedthe PHiD-CV vaccine or its precursor, the 11- valentvaccine. GSK anticipates licensure of this vaccine bythe end of 2008 and plans to submit the vaccine forprequalification to WHO in 2008. In addition, GSKwill carry out a double-blind, randomized efficacytrial for otitis media and pneumonia in 24,000children in Argentina and Panama.

“We are currently in negotiations with interna-tional public health groups to ensure availability ofthe vaccine for all children in need,” he concluded.


“The unanticipated, indirect effects of this vaccine add a dimension of value that we could not have anticipated.”

—DR. PETER PARADISOWyeth Vacines

sanofi pasteur: Protein Vaccine in HandRobert Hopfer, of sanofi pasteur, dedicated his talk tothe memory of his friend and colleague, JimMaleckar, who passed away suddenly in July 2006.Hopfer said that Jim had worked in the vaccineindustry for more than 15 years, the last seven withsanofi pasteur at Swiftwater, where he was the leaderof research and development for the pneumococcaland meningococcal product franchise. “We miss himvery much, as does the entire pneumococcal vaccinecommunity,” Hopfer said.

Sanofi pasteur currently produces a 23-valentpneumococcal polysaccharide vaccine for adults thatis licensed in more than 70 countries, and is workingon developing both conjugate vaccines and proteinantigen vaccines, Hopfer said.

“The global demand for pneumococcal vaccine isunmet,” Hopfer said. “The huge overall demand for apediatric vaccine will only be met by multiple suppliers.”

In the past, sanofi pasteur worked on an 11-valentglycoconjugate vaccine, but its complex formulationcoupled with low yields made industrializationunfeasible. . “Therefore, we are not pursuing furtherdevelopment of this vaccine,” Hopfer said.

Protein Antigen VaccinesHopfer emphasized the potential of protein antigenvaccines, and noted that the company is “at thethreshold of starting a Phase I study” of one suchvaccine. Such vaccines are based on highlyconserved proteins that are common to most, if notall, pneumococcal serotypes. Hopfer said that sanofi

pasteur is in the process of conducting a compre-hensive evaluation of potential protein antigencandidates—of which there are more than 2,400.

A number of challenges exist for protein antigenvaccines, including the need to establish proof-of-concept for the approach, and to develop alternativesto efficacy trials, given that the current correlates ofprotection are based on glycoconjugate vaccines.

The company previously worked on aPneumococcal Surface Protein A (PspA) candidatethat went through Phase I clinical trials. PspA, aconserved surface protein, is a virulence factor thatinterferes with activation of complement within theimmune system. While the trial showed that PspAwas safe and immunogenic in adults, mostindividuals in the Phase 1 study demonstrated pre-existing anti-cardiac myosin antibody levels prior tovaccination, and some individuals who received theantigen developed an increase within 30-days post-vaccination. These responses were transient andthere was no indication of clinical significance evenafter intense clinical and laboratory investigations.However, this experience prompted the company topursue development of alternative pneumococcalprotein antigens, Hopfer explained.

Sanofi pasteur aims to develop a multivalent proteinvaccine that would protect against different stages ofdisease, provide greater serotype coverage thanconjugate vaccines, require a less complex manufac-turing process, and offer opportunities to exploresynergy between polysaccharide antigens andadditional pneumococcal protein antigens “andultimately provide a long-term contribution to globalreduction of pneumococcal disease,” Hopfer concluded.


“We are currently in negotiations with international public health groups to ensure availability of the vaccine

for all children in need.”

—DR. WILLIAM HAUSDORFFGlaxoSmithKline

Instituto Butantan: Zeroing in on Whole Cell VaccineDr. Luciana Cerqueira, Director for Investigation andDevelopment at Brazil’s Instituto Butantan,summarized the institute’s work on pneumococcalvaccine development. She noted that the studies atInstituto Butantan were catalyzed by PAHO andSIREVA, which began conducting surveillance ofserotype prevalence in Latin America in 1993. Thefinding that serotype prevalence in Latin Americadiffered from that in Europe and the United Statescatalyzed additional research into alternatives to the7-valent vaccine, which covered only about 60% ofthe serotypes in Brazil, Cerqueira said.

Butantan initially worked on production of polysac-charide 23F in fermenters as part of a coordinatedeffort with other centers to develop a multivalentpolysaccharide conjugate vaccine, but later concludedthat such a vaccine process would be too complex.

They soon began examining protein alternatives,especially two well-characterized surface-exposedproteins, and pneumolysin proteins. Butantan hassince worked on development of recombinantprotein vaccines, recombinant Lactobacillus vaccines,DNA vaccines, and conjugation of polysaccharidewith PspA recombinant protein.

More recently, Dr. Richard Malley of Children’sHospital Boston proposed that the Institute producea whole cell pneumococcal vaccine under goodmanufacturing practices (GMP) conditions forclinical trials. Malley and Dr. Porter Anderson at theUniversity of Rochester, New York, had found that awhole cell pneumococcal vaccine reduced carriage ofpneumococcus and provided cell-mediatedprotection.

Butantan began work on the project, changing theculture medium and improving yield, Cerqueira said.They also developed an alternative adjuvant thatsucceeded in getting protection against intranasalchallenge. Butantan has set up a fermentationlaboratory and a GMP pilot plant for the project, withplans to start GMP production in 2007, Cerqueirareported. A Phase I clinical trial is planned forSweden, followed by trials in Brazil and South Africa.

The project is now supported by the nongovern-mental organization PATH, “so we should have theresources to take this project to completion,” she said.The intranasally administered whole cell vaccine isButantan’s first priority. “If the whole cell vaccineworks as well in humans as in mice...it wouldprovide very cheap and broad ranging nonserotypespecific protection,” she said.


“The huge overall demand for a pediatric vaccine will only be met by multiple suppliers.”

— DR. ROBERT HOPFERsanofi pasteur

“If the whole cell vaccine works as well in humans as in mice...it would provide very cheap and broad ranging

nonserotype specific protection.”

—DR. LUCIANA CERQUEIRAInstituto Butantan, Brazil

Emerging Market Manufacturers:Their Rising Role

“The rich countries have already spoken, and nowthe developing countries will say something,” beganDr. Akira Homma, President of the DevelopingCountry Vaccine Manufacturers Network (DCVMN).

Formally organized in July 2005, the DCVMN wasformed to provide quality vaccines at affordableprices to the developing world, and to obtainrecognition of the essential role of developingcountry vaccine producers in assuring the availabilityof vaccines to immunize every child, said Homma.

Homma highlighted the size of the potentialpneumococcal vaccine market: an annual 43 milliondoses in high-income countries; 131 million doses inmiddle-income countries; and 178 million doses inlow-income countries, for a total global market of 352million doses worth US$5.3 billion annually. Thisleaves a current production capacity deficit of some250 million doses, Homma said. But whereas

multinational companies have some 25 vaccines indevelopment, emerging suppliers have only about 7in development and are 6 to 10 years from reachingthe market, he said.

Full membership in DCVMN requires WHOprequalification. The DCVMN member list nowincludes seven laboratories, with another fiveassociate members who are in the process of prequal-ification. (See box of DCVM members.)

DCVMN members are approaching pneumococcalvaccine development from a variety of perspectivesand technologies, Homma said. These includedevelopment of a polysaccharide vaccine by Bio-Manguinhos/Fiocruz, a nonencapsulated vaccine byIndian Immunobiologicals, a regional approach tovaccine serotypes by BioVac Institute, and a possibleprotein technology by Shanta Biotechnics Ltd.

Insufficient funding remains a major issue forvaccine development by DCVMN members. And,Homma pointed out that while DCVMN membersnow provide 80% of the vaccines needed to supply


* WHO Pre-qualified full members.

1. Bharat Biotech

2. Biological E

3. Bio Farma*

4. Bio-Manguinhos/Fiocruz*

5. Birmex

6. Butantan

7. Chengdu Institute of Biological Products

8. CIGB*

9. Finlay Institute

10. Institut Pasteur, Senegal*

11. Kangtai

12. Lanzhou Institute

13. Panacea

14. Razi Institute

15. Serum Institute of India*

16. Shantha Biotech*

17. VACSERA

18. Cheil Jedang

19. LG Lifescienses*

DCVMN Members

UNICEF and PAHO’s Revolving Fund, “We don’thave 80% of the money, because all of these vaccineshave a low price, very few pennies...and are not newvaccines with high-aggregate values.”

Finally, Homma challenged the idea that themain reason for delay in getting new vaccines todeveloping countries (23 years in the case of HepB)is that the price of a vaccine must remain high inits early stages of marketing for the manufacturerto earn its cost of research and development.Rather, Homma said, “The price will only comedown when new manufacturers enter into themarket and equilibrate demand and supply. Thenthe price will come down and we will make itpossible for all the countries to benefit frompneumococcal vaccines.”

DiscussionThe Ethics of Trials for New Pneumococcal Vaccines

QUESTION: A participant asked GSK’s Hausdorffabout the ethics of conducting a placebo-controlledtrial in Panama and Argentina when a vaccine isalready available.

RESPONSE: Hausdorff said that the study,designed in collaboration with public health officialsin the region, will aim to understand the magnitudeof the impact on pneumonia of a conjugate pneumo-coccal vaccine with a global formulation in LatinAmerica. “We have data from sub-Saharan Africa andfrom the United States, but the lack of data fromLatin America is helping to slow down introduction

of conjugate pneumococcal vaccines. That is thequestion that we were asked by Latin Americanpublic health officials and that we want to be able toanswer.”

Co-investigator Dr. Xavier Sáez-Llorens added thatthe inclusion of a placebo group is “not only ethical,but is also key for several reasons.” He pointed outthat the vaccine differs from others now on themarket because, in addition to pneumococcus, itintroduces potential protection against nontypeableHaemophilus. Additionally, he said that theGovernment of Panama is not considering the public-sector introduction of Prevnar in the upcoming yearsbecause it considers rotavirus and hepatitis to behigher vaccine priorities. Finally, he said that thestudy is designed only to evaluate prevention of otitismedia and pneumonia, not invasive disease, which isthe principal target of Prevnar.

Which Proteins?

QUESTION: Another participant asked sanofipasteur’s Hopfer which proteins are being used inthe vaccine about to enter Phase I clinical trial.Hopfer declined to answer.

Why Not a 23-Valent PCV?

QUESTION: Klugman noted that there is accumu-lating evidence that conjugate vaccines in the elderlymay offer some advantage over the polysaccharidevaccine. He asked, therefore, why Wyeth wasn’tthinking in terms of a 23-valent conjugate or a 20-valent conjugate.


“The price will only come down when new manufacturers enter into the market

and equilibrate demand and supply.”

—DR. AKIRA HOMMADeveloping Country Vaccine Manufacturers Network

RESPONSE: Rather than develop a 23-valentconjugate, Paradiso said Wyeth might think in termsof formulating vaccines targeted regionally or for anadult population, including a possible 13-valentvaccine for adults. He noted that studies withPrevnar in adults over 70 have already shown goodresults. Regarding infant vaccines, “We cannot takeevery vaccine through the kind of clinical trials weare going through with 13-valent,” he said. Therefore,they would need to develop a consensus withregulatory authorities on how to streamline theregulatory process.

What Do Suppliers Want from the Public Sector?

QUESTION: Orin Levine asked, “If the publicsector were Santa Claus and the private sector had a

wish list of what it wants from us in order to helpspur that collaborative action to get pneumococcalvaccines out, what would that short wish list be?”

RESPONSE: Paradiso said that he would want toknow how much vaccines the public sector needsand when. “We are interested in supplying thevaccine. We need to understand what the demandwill be beyond 2010 so that we can build for thatdemand. We have the knowledge and the capacity,but if we are going to build it we have to knowsomebody is going to be there to use it in the end.”

RESPONSE: Hopfer said they would like to knowthe epidemiological data and surveillance data fromcountries where the number of isolates has been low,to help define a formulation that will truly be globalfor a very long term.


It is widely acknowledged that the new conjugatevaccines, including those for pneumococcus, will bemore expensive than the older vaccines that weresimpler to develop and manufacture. Decisionsabout introducing the new vaccines thereforedepend, in part, on an assessment of their “cost-effectiveness” compared to other healthinterventions. “Cost-effective” interventions providea health benefit but cost, rather than save, money.

Economists and epidemiologists around the worldare therefore conducting cost-effectiveness studies onPCVs. This session reported on such studies in someof the worlds’ wealthiest and poorest nations, as wellas in the transitional economies of Latin America. Inmost cases, the results pointed toward a vaccine thatwas cost-effective to highly cost-effective.

Significantly, when the vaccine’s herd effect wasconsidered in the wealthiest nations, the conjugatepneumococcal vaccines were catapulted into the

highly cost-effective category. In the United States,for example, incorporating herd effects drops thecost-per-life-year-saved from US$80,000 to US$7,500,according to Mr. Tom Ray, a health services analystwith Kaiser Permanente.

The studies used similar approaches to determinecost-effectiveness. They estimated the costs andbenefits of the vaccine, and translated this into acommon measure: the number of disability-adjustedlife years or DALYs averted, and the cost per DALYaverted.

According to WHO thresholds, highly cost-effective interventions have a per DALY cost of nomore than one times the per capita GNI; cost-effective interventions have a per DALY cost ofbetween one to three times the GNI; and more costlyinterventions are not cost-effective.

Elements comprising vaccine cost typicallyincluded the price of the vaccine itself, the number of


Cost Effectiveness of PCV7 Before and After Incorporating Herd Effects

$33,000

$5,700

$112,000

7,800

G. Thomas Ray PIDJ 2006

0

20,000

40,000

60,000

80,000

100,000

120,000

After

Before

Cost Per Life-Year Saved

Cost per IPD Episode Prevented

SESSION V.

Opportunities and Challenges for PCV Introductions

doses, and the administration costs. Offsetting thesewere medical savings derived from the cases ofpneumococcal disease prevented and nonmedicalsavings, mainly based on the prevention of lost worktime by parents. As seen in Dr. David Bloom’s earlierpresentation, this was a very conservative measure ofnonmedical savings.

Following the cost-effectiveness presentations,speakers gave three perspectives on vaccinefinancing, those of the World Bank, thePneumoADIP, and PAHO.

Cost-Effectiveness in High-Income Countries“Conjugate pneumococcal vaccine is a very expensivevaccine compared to other routinely used infantvaccines, and the question is, ‘Is it worth it?’,” beganTom Ray, a health services analyst with KaiserPermanente.

To answer the question, Ray reviewed fourteencost-effectiveness studies conducted in high-incomecountries in Australia, Europe, and the United States.

ResultsThe studies estimated the number of cases of diseaseand hospitalizations that would be prevented per1,000 children vaccinated. A study conducted inGermany estimated that 600 cases of otitis media and60 cases of pneumonia would be prevented, whereasanother study conducted in Norway estimated thatfewer than 50 cases of otitis media and fewer than 5cases of pneumonia would be prevented through thevaccine. Based on all 14 studies, 4.5 deaths could beprevented for every 100,000 children vaccinated.

An estimate of the savings associated withvaccination showed that about 53% were related tosavings in medical costs, and about 47% were innonmedical costs. “So in these high-incomecountries, non-medical costs have a significantimpact on cost-effectiveness,” Ray said.

In most of the studies, the cost-per-life-year-savedranged from US$30,000 to US$160,000. In general,Ray noted that in high income countries, healthinterventions that cost less than US$50.00 per-life-year-saved are considered cost-effective; betweenUS$50,000-US$100,000 are borderline; and overUS$100,000 are not very cost-effective.

The Herd EffectIn the U.S. study, the incorporation of herd effectsdropped the cost-per-life-year-saved fromUS$80,000 to US$7,500. Another U.S. studyshowed that in persons older than 65, the rates ofinvasive pneumococcal disease dropped 30-35%after PCV introduction in children. In fact, “Mostof the cases of invasive disease that wereprevented by the vaccine were actually in non-vaccinated people,” he said.

“If the experience in the United States is anyindication, then the herd effect could have asignificant impact on the cost-effectiveness of PCV inother countries,” Ray said. He cautioned, however,that a number of factors could affect the impact ofthe herd effect. For example, an altered vaccineschedule or the vaccine’s coverage rate could make adifference. The U.S. results reflected a 70% coveragerate in children. “If only 30% of the children arevaccinated, there will be less of a herd effect,” hepointed out.


“If the experience in the United States is any indication,then the herd effect could have a significant impacton the cost-effectiveness of PCV in other countries.”

—MR. TOM RAYKaiser Permanente, US

Cost-Effectiveness in the World’s Poorest CountriesDr. Anushua Sinha, Assistant Professor of PreventiveMedicine and Community Health, UMDNJ — NewJersey Medical School, USA reviewed a study of thecost-effectiveness of PCV in 72 GAVI-eligiblecountries, in which per capita income is under $1,000.

“We pooled results in terms of cost of vaccination,disease costs and health benefits gained across 72countries,” Sinha explained. The study consideredcosts to the health system, to families, and tomembers of society.

In terms of costs, Sinha said that the modelassumed a vaccine cost of US$5 per dose, based bothon price projection, but also on the assumption thatpublic market funding in GAVI-eligible countrieswould be very different from the current privatemarket price US$53 per dose, Sinha said. The studybased its assumption of vaccine efficacy on the resultsof a clinical trial in The Gambia of the 9-valent vaccine.

ResultsThe study found that vaccination in the 72 countrieswould save from 262,000 to 470,000 lives per year,with the larger number factoring in a strong herdeffect. Vaccination would avert from 8.3 million to15 million disability-adjusted life years; and the costper DALY averted would range from $22 to $100 (ininternational dollars). This is less than one timesthe countries’ average GNI of $450, making thevaccine highly cost-effective based on WHOstandards, Sinha said.

The model considered vaccine prices from $1 to$10 per dose. “As we vary vaccine dose costs andvaccine efficacy in this analysis, it is hard to makethis vaccine not look highly cost-effective,” Sinha said.

Economic Burden ofPneumococcal Disease in Latin America and the Caribbean Dr. Dagna Constenla, independent consultant,summarized the findings of the cost-of-burdenanalysis from the new report on PCV in LatinAmerica and the Caribbean. (See Session II forrelated findings regarding the burden of pneumo-coccal disease in Latin America).

Findings on the economic burden of pneumo-coccal disease were based primarily on data from 10countries: Argentina, Brazil, Chile, Colombia, theDominican Republic, Honduras, Mexico, Panama,Uruguay, and Venezuela.

In conducting the study, the researchers estimatedthe costs incurred for a variety of medical services.For instance, the cost of pneumococcal diseaseranged from $82 per patient for a case of acute otitismedia to $1,792 to provide inpatient care to a childwith pneumococcal meningitis. The study estimatedthe total economic burden of pneumococcus bymultiplying the number of expected disease eventsby the mean cost per event.

The study found that pneumococcal disease incursa cost of $333.4 million in the 10 countries, or theequivalent to US$28 per child born in the region byage five. It includes US$293 in direct medical costs.


“As we vary vaccine dose costs and vaccine efficacy in this analysis,it is hard to make this vaccine not look highly cost-effective,”

—DR. ANUSHUA SINHANew Jersey Medical School, US

Out-of-pocket expenses for families add anotherUS$40 million in costs. When translated intodisability-adjusted life years lost, the annual cost ofpneumococcal disease in the region is more than600,000 DALYs.

Cost-Effectiveness of CPV in Latin America and the CaribbeanDr. Juan Esteban Valencia, Health Economist andProfessor, CES University in Medellín, Colombia,summarized the findings of the cost-effectivenessanalysis. The study weighed the costs of the diseaseagainst the potential benefits of vaccination,determined on the basis of vaccine efficacy. It foundthat region-wide vaccination with PCV7 would prevent:

• 9,478 child deaths, or 53% of deaths due to S.

pneumoniae;

• 680,000 cases of acute otitis media;

• 176,000 cases of clinical and chest X-ray positivepneumonia;

• 2,768 cases of invasive pneumococcal disease.

From an economic standpoint, this would saveUS$180 million, and avert 321,876 DALYs annually,Valencia said.

They next factored in the cost of the vaccine,assuming three-doses per child. At US$53 per dose(the price paid by the Revolving Fund), the totalregional direct cost of the vaccine was $1.83 billion.They calculated the vaccine cost at various prices, thelowest being $5 per dose. At this price, the regionaldirect cost of vaccine came to US$200 million.

The cost per DALY averted ranged from US$5,106with a vaccine price of US$53 per dose, to US$62 perDALY with a vaccine price of US$5 per dose, Valenciareported. The cost per life saved would range from ahigh of US$171,130 to a low of US$2,110.

Based on a standard formula for cost-effectiveness,Valencia concluded that the vaccine would beconsidered cost-effective. And, as the price of thevaccine drops, its cost-effectiveness increases,because the value of the DALY drops in kind.

Valencia noted that neither the herd effect nor aloss in quality of life resulting from disease wereincluded in the analysis, making it a conservativeestimate of cost-effectiveness.


Number of Events Cases of Annually/

Pneumococcal Disease Total Events Annually 1,000 Children

Hospitalized 181,880 16

Treated as outpatients 1,411,840 121

Total 1,593,720 136

Costs Direct medical costs(health care system, 2005 US$) Cost US$ per child

Hospitalizations 174,771,120 15

Treated as outpatients 118,642,469 10

Total 293,413,589 25

Direct medical/non-medical costs (borne by families, 2005 US$) Cost US$ per child

Total 39,993,931 3

All medical and non-medical costs

Overall total costs 333,407,520 28

Vaccine Financing PerspectivesRepresentatives of the World Bank, the PneumoADIPand PAHO each presented their organization’s viewsregarding financing of conjugate pneumococcalvaccines. Major themes revolved around the need forcountries to create “fiscal space” for vaccinepurchases, as well as the importance of developingsustainable financing mechanisms that enhanceequity within countries.

World Bank Perspective on Vaccine FinancingSantiago Cornejo of the World Bank outlined threethings needed to help mobilize resources for the new,more expensive vaccines coming available:

• Countries need to create “fiscal space”;

• The public health community needs to show theevidence that will lay the basis to prioritizespending on vaccines, and;

• Communications must be tailored to reach thenational decision makers.

While the World Bank is a decentralizedinstitution, with no single policy, Cornejo said that itis a strong supporter of immunization. “We believeimmunization is a cornerstone of health systems andwe often use the immunization coverage rate as anindicator of performance on our disbursements. Sothat shows how relevant we think it,” he said.

The World Bank lends support to vaccines insituations of crisis management and provides time-limited support, such as loans for polio vaccines fordisease eradication, Cornejo said. However, it tendsnot to extend many loans for ongoing vaccinationprograms, as that is not a sustainable way tofinance the recurring costs of such programs. “Ifyou are going to take a loan with high interest inorder to finance your vaccine you should be verycareful,” he said.

The Bank has helped design innovativemechanisms to finance new vaccines on a globallevel. These include Advance Market Commitments(or AMCs) and IDA “buy-downs.” As an example ofthe latter, an initial loan with high interest ratesgiven for polio immunization could be converted toan IDA—a loan with better interest and repayment


Conclusions of Cost-Effectiveness of a Pneumococcal Vaccine

Cost – Effectiveness ratio (US$/DALY) less 1 per capita GDP is Highly Cost effective (WHO Report 2002).

US$/DALY581

US$10

US$/DALY2,653

Cost-Effective Highly Cost-Effective

US$/DALY1,619

US$/20

US$/DALY3,691

GDP L. A.US$4,404

US$/40

US$/DALY62

US$/5

< per capita GDP 1 - 3x per capita GDP

terms—if the country reaches certain performancelevels, Cornejo said. Donors can also help pay offthe debt.

Affordability and Sustainability. Cornejostressed the importance of affordability and sustain-ability. “In order to be affordable, the price will needto be decreased. But, we need to realize that most ofthese new vaccines are going to be more expensivethan the traditional vaccines,” he said.

Two other issues affect affordability and sustain-ability, according to Cornejo. First is the fact that manycountries will be considering the introduction of morethan one higher-priced new vaccine. These includevaccines for pneumococcus, rotavirus and HPV.

Secondly, vaccine price is just one aspect of thetotal cost of vaccine introduction. “Nonvaccine costscan be extremely high, for example the impact ofrotavirus on cold chain,” he said.

Create Fiscal Space. Cornejo said that newresources for vaccine introduction could be mobilizedby either obtaining new donor financing or creating“fiscal space” in national budgets. Cornejo noted anumber of options that create fiscal space: 1)redirecting resources, for instance by reducingdefense spending or freeing up funds from otherhealth interventions; 2) reducing wastage in existingprograms; and 3) enacting new earmarked taxes.

“But whatever mechanism we use to financeimmunization, for the Bank it is an issue of equity,”Cornejo said. “We must make sure that those withlower resources within the country have the ability toaccess these new vaccines.”

Provide Evidence and Communicate withDecision makers. Cornejo noted that advocacy forpneumococcal vaccines at the global level is wellahead of advocacy at the country level, especially incomparison to HIV/AIDS and malaria. Cornejo saidthat the difficulty is due, in part, “to our success”with immunization, especially in Latin Americawhere coverage rates are high; the disease burden islow, and cheap vaccines are available.

“So we have been on a kind of cruise-controlmode,” he said. “But now we are living in abrand-new era that will require mobilization ofmore and new resources for vaccines. Therefore, itis very important that we improve our advocacymessage in order to mobilize these resources forvaccines.”

To do this, he urged the development of tailored,country-specific advocacy plans, with messagestailored for people that do not have a background inimmunization. He also stressed the importance offinding champions outside the immunization arenawho could effectively communicate the issue.

The GAVI Investment Case for Pneumococcal VaccineDr. Orin Levine, Executive Director of GAVI’sPneumoADIP, described the ADIP, the work of theGAVI Alliance, and the recently approved global“Investment Case” for pneumococcal vaccinepresented to GAVI. “About one in 10 child deaths isdue to pneumococcal disease,” Levine said. “But achallenge we have faced is that many people did notrecognize pneumococcal disease, in part because ofthe difficulty of diagnosis.”


“It is very important that we improve our advocacy message in order to mobilize these resources for vaccines.”

—MR. SANTIAGO CORNEJOthe World Bank

PneumoADIP: Finding Pneumo. The mission ofGAVI’s PneumoADIP is to improve child health andsurvival by accelerating the evaluation of and accessto new life-saving pneumococcal vaccines for theworld’s children. Created in 2003 with an award toJohns Hopkins University of US$30 million, thePneumoADIP is organized around three main areas:establishing the value of the vaccine; communicatingits value; and delivering that value. It supportsactivities in more than 56 countries, and is helping tore-energize the SIREVA network in Latin America,Levine said.

“The whole idea is to use evidence to generate thepolitical will to appropriately prioritize diseaseprevention and vaccine introduction,” Levine said.“All of our work is designed to try to ensure a reliablesupply of affordable vaccine and ensure financing.”

He stressed that reaching the MillenniumDevelopment Goal #4 of improving child survivalrequires pneumonia prevention, and pneumococcaldisease is an especially important target.

The GAVI Alliance. PneumoADIP is a program

supported by the GAVI Alliance, which includes the

major international institutions involved in global

health such as the World Bank, WHO and UNICEF. It

also includes public and private sector donors, bilat-

eral donors from industrialized country govern-

ments, the Bill and Melinda Gates Foundation, and

manufacturers based in both industrialized and

developing countries. “The GAVI Alliance comes together to agree on a

common set of objectives and they have collectivelybeen able to mobilize financial resources,” Levine

said. “Between 2006 and 2015, they have 10 yearcommitments for the 72 GAVI countries on the orderof US$6 billion...and that is definitely a majorimprovement over what we have had in the past.”

Global Investment Case for PCV. To maximizethe impact of these resources, the GAVI Allianceutilizes “investment cases” that argue for thefinancing of different new vaccines. ThePneumoADIP recently presented an investment casefor PCV to the GAVI Board.

“Its objective is, quite simply, to acceleratepneumococcal vaccine use in the world’s 72 poorestcountries by 15 years over historical precedence. Inthe process, we estimate that we will prevent 3.9million child deaths by 2025,” Levine said.

The investment case emphasized that widescaleprevention of pneumococcal disease in GAVIcountries would translate into almost a 10%reduction in all mortality in children under five.

In addition, “Pneumococcal disease is a problemthat is getting worse, not better,” Levine said. “HIVincreases the risk of pneumococcal disease by 20-40fold. Antibiotic resistance complicates treatment andpneumococcal pneumonia is a common partner ofpandemic influenza—it would add on the order ofalmost half a million deaths in children should apandemic hit GAVI countries.”

The investment case also stressed that the timewas right for financing PCV: its safety, efficacy andcost-effectiveness has been established, and currentand upcoming vaccine formulations would providean adequate supply to GAVI countries through 2011.In addition, investment now would contribute over


“The whole idea is to use evidence to generate the political will to appropriately prioritize disease prevention

and vaccine introduction.”

—DR. ORIN LEVINEGAVI’s PneumoADIP

time to the development of sustainable andaffordable pricing.

Costs to GAVI for both the vaccine and strategicand technical costs were forecast to be betweenUS$127-189 million between 2007 and 2010, and anadditional US$440-951 million between 2011 and2015. Country co-financing would contributeadditional funds, totaling perhaps US$21-31 milliondollars from 2007-2015.

The pneumococcal vaccine investment case wasmade in tandem with a similar case for acceleratingrotavirus vaccination, and a requested grant ofUS$200 million to support price negotiations and thestrategic and technical activities needed for rollout.

The GAVI Board approved all three. “We havetaken an historic step to shorten the time lag that wehave always had with new vaccines,” Dr. Levine said.

PAHO Perspective“This is a new era of immunization,” said Dr. JonAndrus of the Pan American Health Organization(PAHO). “There are new vaccines, new targets, newsupply paradigms, new challenges... We can use thesuccess of the Revolving Fund ...to make a differencein the Americas with pneumococcal disease.”

Optimizing Use of the Revolving Fund.Underpinning past advances in disease reductionthroughout much of the Americas has been PAHO’sRevolving Fund, which bulk purchases vaccines onbehalf of countries. PAHO has tallied up successes infighting disease: the eradication of polio, reduction ofHaemophilus influenzae b, measles elimination, andnear-elimination of rubella.

Both capitalization of the Fund and expenditureshave increased over time, and dramatically so sincethe introduction of MMR vaccine in 1997. Today, the

Revolving Fund delivers 14 antigens on a routinebasis, and 37 countries in the Americas use the Fund,with only a handful of exceptions, including Canada,the U.S., Chile, and Mexico.

Key to these successes has been:

• Country-based interagency coordinatingcommittees,

• A policy of rapid deployment of vaccine tosusceptible populations,

• Assured supply and work with a diversity ofsuppliers,

• National immunization managers overlookingtheir country’s plan of action, and,

• Budget line items for vaccination.

In the Americas, 26 countries have laws regardingvaccination, with proposed legislation in anotherthree. Andrus noted that a line item in the nationalbudget for vaccine purchase has been essential. But,counterintuitively, laws that prohibit import taxes onvaccines can indirectly increase the vaccine cost byup to one-third by cutting off the revenue streamprovided by import taxes.

The Revolving Fund’s ability to negotiate auniform price has also been critical to past successes.Andrus said that uniform pricing of a vaccine hasallowed the development of health equity, lowtransaction costs, and rapid deployment.

Today, however, many countries have recognizedthat continued improvement in public health andachievement of the Millennium Development Goals(MDGs) will require introduction of pneumococcaland rotavirus vaccines.

Andrus identified two challenges in making thenew vaccines affordable: the Revolving Fund’s ability


PAHO has tallied up successes in fighting disease:the eradication of polio, reduction of Haemophilus influenzae b,

measles elimination, and near-elimination of rubella.

to negotiate an affordable price and the ability ofcountries to create the necessary fiscal space andimproved vaccine laws that will ensure sustainability.

Creating Fiscal Space. PAHO is working on thesupply side to create fiscal space, Andrus said. Theorganization is critically reviewing its managementof the Revolving Fund. “We think we can reducecosts, make more efficient use of resources, andimprove the service to countries,” Andrus said. It isworking to assure supply chain efficiency from thecosts of vaccine acquisition to the costs of supplyprocessing, inventory, and distribution. “At each link,we can analyze where we at PAHO can improveservices to the countries,” Andrus said.

At the same time, an independent assessment ofthe Fund’s work determined that 60% of theproblems in efficiency are at the country level. “Forexample, if a vaccine stays at a central supply and isnot picked up, costs are incurred. We need to workmore closely with the countries in tackling thechallenges that would reduce costs,” he said.

Defining the Vision. In September 2006, PAHO’sDirecting Council, composed of all the ministers ofhealth from the Latin American and Caribbeancountries, issued a resolution that articulated threeprinciples for immunization:

• Sustaining the development of nationalimmunization programs in the context of the

overall health objectives, and accelerating theuptake of priority new vaccines;

• Closing equity gaps and contributing to theachievement of the MDGs and the goals of theWHO’s Global Immunization Vision and Strategy;

• Continuing to build health systems andinfrastructure within the Americas.

To realize the vision, PAHO is strengtheningoperational preparedness and national capacities fordecision making. It is working with countries torevitalize national plans of action for immunization,which are especially important now that multiplenew vaccines are becoming available. One planningtool is Pro-Vac, a PAHO initiative that combineseconomic analysis, disease surveillance, and epidemi-ological studies. Strongly evidence-based, it providesprograms, expertise and training to guide decision-making.

To enhance sustainability of its immunizationprograms, PAHO is also transitioning from achildhood immunization program to a familyimmunization program in order to enable thedelivery of vaccines for influenza, HPV and HIVwhen they become available. “We are moving fromsustainability of just vaccines to the sustainability ofthe overall immunization program that can reach outand deliver more services to more people,” Andrusemphasized.


“This is a new era of immunization. There are new vaccines,new targets, new supply paradigms, new challenges...

We can use the success of the Revolving Fund ...to make a difference in the Americas with pneumococcal disease.”

— DR. JON ANDRUSPan American Health Organization

Public health officials described the pneumococcalburden of disease and vaccination programs in threeLatin American countries: Brazil, Mexico and Chile.Although none of the three has universal vaccinationwith PCV, Mexico initiated a vaccination campaign innine Mexican states in 2006, with plans to continue toexpand that program; Brazil has a program to vaccinatehigh-risk children; and Chilean researchers aredocumenting the epidemiologic evidence needed bydecision makers. Chile’s Dr. Rosanna Lagos said the datawill lead to the inevitable conclusion that the “7-valentvaccine currently available should be implementedimmediately in children with higher-risk conditions.”

All three country representatives noted both theopportunities represented by conjugate pneumo-coccal vaccine to control disease and the economicchallenges of expanding the universal vaccinationschedule.

Lagos noted the ethical urgency of addressing thesituation in which wealthier citizens can buy vaccinesthat are not yet available to the majority of thepopulation. She noted that countries in transitionface particular challenges in resolving this dilemma.

“In the developed world, we know that thesediseases impose an important economic burden andthat mobilizes decisions for the use of vaccines,” shesaid. And in the poorest countries, immediateintroduction is motivated by the urgent need to savemany lives. However, Lagos said that although thechildhood mortality rate in countries like Chile iscomparable to the United States, “We don’t have theresources that would allow us to easily disbursefunds in long-term immunization programs.” Forinstance, immunizing all Chilean infants againstpneumococcus would cost the same as current Statespending per capita on health.

BrazilDr. Expedito Luna, Director of the Surveillance andInfectious Disease Control program at the Ministry ofHealth in Brazil, noted that the country’s public

health system serves 80% of the population, whilethe remaining 20% use private providers. Thissystem has had marked success in vaccination. Asnoted later by Dr. Luna, Brazil has wideimmunization coverage delivered through over 100vaccination facilities countrywide. The coverage forpolio and measles immunization is close to 100%.Most recently, the oral rotavirus vaccine wasintroduced in the universal vaccination program.Brazil works not only on childhood vaccination, butalso on vaccine schedules for adolescents, adults, andthe indigenous population. Overall, there is highvaccine coverage and historically low levels ofvaccine-preventable disease.

This success has enabled the strong promotion ofvaccination in Brazil’s health funding: the vaccinebudget has increased nine times in the past decade,to a 2006 level of $350 million U.S. dollars, Lunasaid.

Burden of DiseaseBrazil does not currently have a national system fortracking pneumococcal disease. However, there areseveral other forms of surveillance that “give us someclues on the behavior of these diseases here in ourcountry,” said Luna. These include: epidemiologicalsurveillance on meningitis conducted in Brazil since1975; a good record of hospitalizations in the publichealth system; a national mortality informationsystem; and Brazil’s participation in SIREVA.

Data from 2005 shows that all-cause pneumoniawas the second leading reason for hospitalizations(behind childbirth). It accounted for almost 10% ofhospitalizations, and constituted the primary causeof hospitalizations in the elderly and those ages oneto four.

Meningitis surveillance shows that pneumococcalmeningitis infections have remained relativelyconstant in Brazil since 1998, while “meningitis dueto Haemophilus influenzae practically disappearedupon the introduction of the vaccine in 1999,” notesLuna.


SESSION V-A.

Country Spotlights

SurveillanceOne of Brazil’s goals is to enhance the detection of S.

pneumoniae isolates; at present, the public healthlaboratories only detect between 300 and 350 isolatesper year. Therefore,

Brazil plans to implement a surveillance system,as part of a PAHO network, for X-ray confirmedbacterial pneumonia in children under age five andadults over age 60.

The new surveillance system, which may beginoperating in 2007, will be implemented in five of the27 Brazilian states, with each state representing oneof the five geographic regions of Brazil, stretchingfrom the Amazon to the south. In Parana, a statewith 10 million inhabitants and a highly organizedhealth network, there will be an additionalpopulation study as part of SIREVA II.

Status of Vaccination for PneumococcusAt present, there is no universal pneumococcalvaccination in Brazil. However, since 1999, there hasbeen an annual campaign to vaccinate the institu-tionalized elderly with the 23-valent vaccine. Andsince 2002, the national network of ReferenceCenters for Special Immunobiologicals has offeredPCV7 only to at-risk children.

In 2005, Brazil purchased 291,000 doses of bothvaccines at a cost of approximately $5 million USdollars. But less than 10% of the elderly have beenvaccinated, and, regarding high-risk children, thecoverage remains low as well.

“The current price per dose of more than $50 USdollars,” says Luna, “prevents our country from

taking a leap to introduce the vaccine in our routineprogram for universal vaccination.” Universalpneumococcal vaccination of the 3,200,000 childrenborn each year in Brazil would require more thandoubling the national budget for vaccines.

Brazil’s strategy, therefore, is to develop nationalproduction of the vaccine, with production initiativescurrently ongoing at the Instituto Butantan and atFiocruz in Rio de Janeiro. Luna concludes, “We hopethat these initiatives have good sustainability andthat this also leads all international producers toreduce prices.”

Mexico Dr. Norma Matias, of the National Center for theHealth of Infants and Adolescents, discussed theintroduction of the conjugated 7-valent pneumo-coccal vaccine in Mexico.

Burden of Disease and SurveillanceHow heavy is the pneumococcal disease burden inMexico? One study in 32 daycare centers in twoMexican states showed that 30% of 2,777 childrenunder the age of seven were colonized by pneumo-coccus. The most frequent serotypes were 19F, 6B,6A, 23F and 11A. Some 56% of the isolated serotypesare included in the 7-valent vaccine. Another study atChildren’s Hospital showed that of hospitalizationsfor invasive pneumococcal disease, 62.5% of theserotypes were penicillin-resistant, with 23F, 19F and14 being the most frequently-resistant serotypes.

Now, one of Mexico’s most important objectives isto improve current epidemiological surveillance inorder to better assess the vaccine’s impact, Matias


“The current price per dose of more than $50 US dollars prevents our country from taking a leap to introduce the vaccine

in our routine program for universal vaccination.”

—DR. EXPEDITO LUNAMinistry of Health, Brazil

says. The National Center for the Health of Infantsand Adolescents is working with Boston Universityon this objective. The researchers plan to measurethe immunobiological response to three doses of thevaccine in Mexican children, and they will track anychanges in serotypes and antimicrobial resistance.

Status of Vaccination for Pneumococcus“Given the vaccine cost, it was not going to bepossible to vaccinate every child universally,” saidMatias. “As part of the strategy to introduce thevaccine to susceptible children, we had to define thepopulation that was going to benefit most.” Indetermining which children should get the vaccine,researchers looked at which Mexican states had thehighest incidence of death from lower respiratoryinfections, the greatest poverty, the highestpercentage of indigenous population, and the lowestrate of economic growth.

The first vaccination campaign took place duringthe first National Health Week in February of 2006,in a total of 41,143 children under the age of twoyears, in nine Mexican states. In August of that year,the campaign broadened to 228,777 children in 14states. In 2007, Mexico expects to vaccinate 326,506children against pneumococcal disease. Childrenreceive three doses: at two months, four months and12 months. Children over the age of one year receivetwo doses spaced six months apart.

Meanwhile, the national vaccine schedule inMexico, as elsewhere, has been expanding andbecoming more costly. In 2007, the government will

introduce the acellular pertussis and inactivated poliovaccine, as well as the hepatitis B vaccine at birth.“This, plus the introduction of the last two vaccines,conjugated pneumococcal vaccine and rotavirusvaccine, will take the vaccination schedule for a childto over $193,” said Matias.

Nevertheless, Mexico is determined to reduce theirinfant mortality, which declined greatly in the 1980sand 1990s, but has since plateaued. “We hope thatthis plateau decreases with the new interventionmeasures underway in public health,” Matias said.

ChileDr. Rosanna Lagos, Coordinator for the Center ofExperimental Vaccines, a research arm of Chile’sMinistry of Health, reported that Chile does not yethave a national vaccination program for pneumo-coccal disease. However, researchers have beenworking to “generate evidence for public healthdecisions that are impossible to avoid regarding theuse of conjugated vaccines.”

SurveillanceStarting in 1994, Chilean public health officialsbegan recording the isolates of invasive S.

pneumoniae and other clinical information onchildren hospitalized with pneumococcal disease.Since then, improvements in the standardization ofdata and laboratory procedures have strengthenedthe ability to identify pneumococcal disease in febrilechildren in emergency rooms. Some 40% to 50% ofthe invasive pneumococcal disease is now detected in


“Given the vaccine cost, it was not going to be possible to vaccinate every child universally. As part of the strategy

to introduce the vaccine to susceptible children, we had to definethe population that was going to benefit most.”

—DR. NORMA MATIASNational Center for the Health of Infants and Adolescents, Mexico

this setting, leading to a near-tripling of the reportedincidence of the disease in children under age five inthe metropolitan regions of Chile.

The most frequent serotypes in this populationare 14, 5, 1 and 6B. Certain serotypes were closelyassociated with variations in disease incidence inparticular age groups. Notes Lagos, “A serotypestudy of one-to-two years may be insufficient toknow the real coverage to be offered by thesevaccines.”

The fatality rate in children without high-riskconditions was about 4%, and about 8.2% in thosewith risk factors. Notes Lagos, “the incidence of

invasive disease exceeds 200 cases per 100,000 forchildren with chronic illness, which results in arelative risk seven times higher than children notcarrying these conditions.”

Call to ActionLagos asserted that the conjugate vaccine couldprevent a great proportion of invasive infections andpneumonia in all children. “From my modest point ofview,” concludes Lagos, “pneumonia prevention...is ahighly powerful public health reason to implementthe routine use of conjugated pneumococcal vaccineswith enhanced antigenic spectrum.”


“From my modest point of view, pneumonia prevention...is a highly powerful public health reason to implementthe routine use of conjugated pneumococcal vaccines

with enhanced antigenic spectrum.”

—DR. ROSANNA LAGOSCenter of Experimental Vaccines, Chile

Noting that pneumococcal vaccine can be aninstrument of health, equity and development,presenters infused this session with a sense of urgency:the objective being to accelerate the introduction ofconjugate pneumococcal vaccines, rather than simplyproceed with business as usual. A series of presen-tations in two Round Table Discussions illuminated on-the-ground realities as countries evaluate their needsand begin the process of vaccine introductions. Thesession concluded with a resounding Call to Action onpneumococcal disease and vaccine introduction inLatin America and the Caribbean.

Round Table: Immunizations in High Risk and VulnerablePopulationsCountries with limited resources are evaluating thepotential use of conjugate pneumococcal vaccine fortheir most at-risk populations. In Brazil, governmentprograms extend the safety net of vaccines to highrisk-populations including children with numeroushealth conditions, the elderly, and indigenous andremote populations.

In Bolivia, one of the poorest countries in SouthAmerica, where six out of 10 Bolivians live below thepoverty line, the immunization program has been an“instrument of equality,” said Erick Machicao.Presentations enumerated the success and challengesas these efforts move forward.

BrazilDr. Expedito Luna, Director of the Surveillance andInfectious Disease Control program, presented Brazil’sprogress in immunizing vulnerable and high riskpopulations. Robust funding of vaccination has allowedBrazil to “create strategies for population groups thatwould not be contemplated in the universal childhoodvaccination,” said Luna. Programs were created to reach

those over age 60; indigenous communities and thosewho live in remote areas; those at high-risk because ofhealth condition; and pilot initiatives for quilombos

(isolated communities formed by fugitive slaves), sexworkers, inmates, and adolescents.

As a result, for example, some 33.5 million peopleover the age of 60 are vaccinated with a variety ofbiologicals, covering influenza, tetanus, diphtheria,and pneumococcus. However, Luna said that seriouschallenges remain to increasing vaccine access andcoverage for high-risk populations.

The indigenous population is composed of 300ethnic groups and 400,000 individuals spreadthroughout Brazil, often in small, remote communities.To reach remote populations, Brazil developedOperation Gota (“Operation Drops”—named after theoral polio vaccine), an alliance between the Ministry ofHealth and the Brazilian Air Force and Army. It serves80,000 inhabitants in more than 1,500 smallcommunities in eight Brazilian states, located either inthe Amazon jungle or in the pantanal—a remoteswamp area on the border with Paraguay and Bolivia.The sites are served by helicopter and sometimes byboat, at a cost of $1.5 million per year.

Thus far, indigenous populations receive the 23-valent pneumococcal vaccine, but not the conjugatedvaccine, notes Luna, and retention of doctors andnurses remains a challenge.

Those at high risk because of health issues arevaccinated through 38 Reference Centers for SpecialImmunobiologicals around the country. These arecenters within hospitals that offer vaccines that arenot part of the universal vaccination program. Theyinclude the 23-valent pneumococcal vaccine foradults and PCV7 for children. These are offered topeople with health indications such as chronicpulmonary disease, childhood cancer, insulin-dependant diabetes, and HIV/AIDS.

However, Luna noted that the number ofReference Centers for Special Immunobiologicals


SESSION VI.

Next Steps in the Global Prevention of Pneumococcal Disease

CO-CHAIRS Dr. Ciro de Quadros and Dr. Jesus Feris

needs to be increased, as many people with chronicconditions live far from any center. In addition,outreach for the vaccine programs needs to extendbeyond the Centers’ regular patient base. Forinstance, Luna said that the number of peoplevaccinated with the 23-valent pneumococcal vaccineis much lower than the number of new patients whoregister with the HIV/AIDS program, suggestingthat referrals for vaccination are inconsistent.

Economic CostsBetter coverage, of course, entails greater cost. Atpresent, the Reference Centers’ vaccine programaccounts for almost 7% of the value of the nationalvaccine purchasing program, while serving relativelyfew people. Luna noted that further enhancement ofthese strategies “will bring a sustainability problemin connection with costs.”

Finally, for Brazil, there is concern about theimpact of new vaccines on the national vaccineproduction program, and whether the large numberof products entering the market may overwhelm thenational public sector of vaccine producers. “We wantto guarantee scientific and technological developmentin our country and the sustainability of ourimmunization program in the long term,” said Luna.

BoliviaDr. Erick Machicao, National Expanded Program onImmunization Manager of Bolivia, described thevaccination strategies for high risk and vulnerablepopulations in Bolivia, which is one of the poorestcountries in South America. Vulnerable populationsinclude those in the remote Amazon jungle, those in

the remote highlands, and internal migrants in andaround the cities. Access to healthcare is extremelyvariable, depending on income, education, andgeographic location.

Components of Success. In the face of greatdisparities in wealth and access to healthcare,Bolivia’s Expanded Program on Immunization is an“instrument of equality,” says Machicao. Bolivia hasbeen able to achieve universal coverage for severalvaccines. Machicao credits Bolivia’s experience in theeradication of polio and smallpox with building thecapacity to achieve wide vaccine coverage. Recently,Bolivia attained 95% coverage of the adultpopulation in a rubella vaccination campaign, andbrought yellow fever under control.

Machicao described some of the components ofBolivia’s successful vaccine strategy:

• Advance planning and adequate resources;

• A strong and well-monitored cold chain;

• Committed staff that follows children throughtheir complete vaccine schedules;

• Commitment on national, department and locallevels, and strategic interagency alliances;

• Local resources contributed through municipalhydrocarbon taxes;

• Effective communications; and

• Participation by farmers, neighborhood associ-ations, the armed forces, the police forces, andbusinessmen and businesswomen.


“We want to guarantee scientific and technological developmentin our country and the sustainability

of our immunization program in the long term.”

—DR. EXPEDITO LUNAMinistry of Health, Brazil

“We have a national development plan and asectoral health plan to allow us to have much moreequity in these vaccination and epidemiologicalsurveillance activities,” says Machicao. The plansunderscore the importance of community organi-zation, cross-cultural communication, socialinclusion, and the right to health for all. In additionto promoting disease prevention, work on thecommunity level allows for “timely detection in thecommunity for patients suspected of having diseases

which are immune-preventable.” At a recent yellow fever vaccination conference in

Bolivia, urban neighborhood organizations and ruralfarmers were both represented. Their message, saysMachicao, was: “we want to be an active part inplanning, monitoring and evaluating vaccinationactivities.” Machicao concludes, “Bolivia is a countrywith incredible challenges, but vaccination ofpopulations at risk is feasible.”


“Bolivia is a country with incredible challenges,but vaccination of populations at risk is feasible.”

—DR. ERICK MACHICAOMinistry of Health, Bolivia

Dr. José Ignacio Santos, Director of Hospital Infantilde Mexico Federico Gómez, presented an overview ofconsiderations that middle-income countries mustinevitably weigh as they consider implementing newconjugate vaccines. He noted that public healthauthorities must balance questions regarding thevalue of the vaccines, the burden of disease, afford-ability and cost-effectiveness, and the necessity ofcovering the basic health needs of large populations.

With similar concerns in mind, Dr. Ida B. Molina,National Expanded Program on ImmunizationManager of Honduras, presented a blueprint forvaccine introduction and implementation, outliningbasic processes that are typically necessary toaccomplish such changes.

Dr. Maria Belén Jaimes Sanabria, with theColombian Ministry of Health, detailed the consider-ations of one country as it assesses the possibility ofadopting a conjugate vaccine against S. pneumoniae.

Dr. Santos dedicated his talk to Dr. Jean LaMontagne, “one of the pioneers and founders of thechildhood vaccination programs in the UnitedStates.” He noted that Montagne was born in Mexico,and died there suddenly while attending a globalforum on health. “I believe that, two years after hisdeath, it is important to remember those who havemade the application of vaccines feasible for manychildren in the world,” Santos said.

Recent History with Conjugate Vaccines Conjugated vaccines have been in existence for thelast 20 years, Santos said, noting, for example, thatchildren in the industrialized world and in nationsthroughout the Americas have benefited from avaccine against Haemophilus influenza (Hib). “Thishas been feasible due to the development and distri-bution of safe, effective and affordable, but notinexpensive, vaccines,” Santos said.

In the last ten years, Santos said, many nations in theAmericas have rapidly introduced new vaccines,

including the Hib vaccine, the hepatitis B vaccine andthe viral MMR, which has replaced the old measlesvaccine. Success with introducing the Hib vaccine in theregion was built on the experiences of a few countriesthat went first, including the United States, Canada,Uruguay and Chile. “Remember that Hib was sold as avaccine against meningitis, but the true value added wasagainst pneumonia,” Santos said. He emphasized thepositive role of PAHO’s Technical Advisory Group inaiding vaccine introductions, as well as that of itsRevolving Fund, which buys in bulk to reduce costs.

Now, the introduction in the United States of anew conjugated vaccine containing seven serotypesof Streptococcus pneumoniae has led to a significantdecrease in illness and death, Santos said, includingthrough an unforeseen outcome—herd immunityamong individuals who were not vaccinated.

This raises a critical question: “How can we ensurethat the poorest have access to this new biological?”he asked.

Implementation Issues for S. pneumoniae in Latin AmericaSantos noted the importance of having solidinformation on the burden of the disease, a goal madedifficult by the fact that S. pneumoniae is only one ofthe causes of pneumonia, meningitis, sepsis and acutemedia otitis. Nonetheless, “I am very positivelysurprised by all the information presented here, withthe support of the Sabin Institute, so as to get at leastan approximate burden of disease,” he said.

Most significant is the finding that two children dieper hour in Latin America and the Caribbean due to S.

pneumoniae. Therefore, “Being able to include thisbiological in our schedules, as well as other biologicalsnow in the pipeline, would allow us to reduce thenumber of deaths due to this microorganism and also,undoubtedly, help many countries fulfill theMillennium Development Goals, in particular goalnumber 4 to reduce childhood mortality by two-thirds,between 1990 and 2015,” he said.


SESSION VI-A

Implementation Issues

Santos stressed the importance of cost-effectiveness studies, and a determination of thevaccine’s affordability in relation to the grossdomestic product of a country. “The most importantaspect is economic commitment within the countriesto ensure program sustainability,” he said.

He noted the major dilemma facing “sandwichcountries,” transitional economies that are neitherrich nor poor enough to be considered “GAVIcountries.” Only seven nations in the Americas areeligible for support from the GAVI Alliance, and“seven countries represent less than 16% of the 11.7million children born every year in this region,”Santos said. “The other countries are left with avaccine that costs US$53 a dose.”

In addition to illustrating the issues of cost-effectiveness and affordability, Santos noted thatsuccessful implementation requires sufficientinfrastructure and a robust epidemiologicalsurveillance program that can evaluate vaccine impact.

Unresolved IssuesSantos pointed to conflicts that are inherent inefforts to introduce new vaccines, including betweenthe private and public sectors and potentialopposition on the part of parents to multipleadditional injections, with the possibility that anti-vaccine constituencies would grow in influence.

Efficacy may also be a concern, Santos said, as it isonly about 60% in the region. However, “given theseverity of the disease and the mortality risk, thevaccine clearly would be justified with a 40%efficacy,” he argued. Meanwhile, data for a 10-valentvaccine, expected to be licensed in 2008, indicates itwould provide greater coverage of the specific

serotypes identified in the region, Santos said. He alsonoted concerns about serotype replacement, urgingthat they not be used as a basis to reject the vaccine.

In the final analysis, history has taught us thatsuccess in vaccination programs depends on“decisions that are made with unquestionablescientific rigor,” said Santos.

Blueprint for Implementation Dr. Ida B. Molina outlined three main stages ofvaccine introduction and implementation: the pre-introduction stage that ends with a decisionregarding introduction; the operational stage, guidedby an introduction plan; and impact measurement.

Pre-introduction and Criteria. Although bothpolitical and technical considerations enter into thepre-introduction stage and decision-making, thedecision should be clearly driven by public healthpriorities, Molina said.

To reach a decision, several main criteria need tobe evaluated:

• The burden of disease based on surveillance;

• Technical feasibility, such as cold chain requirements;

• The efficacy, immunogenicity, and safety of thevaccine, based on clinical trial data;

• Comparison of the vaccine to other possible publichealth interventions to determine the bestintervention;

• Assessment of the security of the vaccine supply;

• Analysis of the vaccine’s cost-effectiveness andcost-benefit.


“The most important aspect [of vaccine implementation] is economic commitment within the countries

to ensure program sustainability.”

—DR. JOSÉ IGNACIO SANTOSHospital Infantil de Mexico Federico Gómez, Mexico

Like Santos, Molina emphasized the key role cost-effectiveness analysis plays in decision-making, andhighlighted equity concerns. She said two thingsmust be evaluated: the impact of vaccineintroduction on the national budget and its ongoingfinancial sustainability.

“In my country, Honduras, we are facing vaccineswhose cost is five times higher than the total cost ofall the current vaccines in the program,” she pointedout. “If the costs of vaccines are not affordable,greater inequalities among the populations and theirvaccination schedules will be generated.”

At the end of this pre-introduction stage, however,“we need to make a decision and this is an individualdecision in each country,” Molina said.

An Introduction Plan. Once a vaccine is approvedfor introduction, health authorities must developnational plans of action that can be integrated intoeach country’s National Immunization Program andNational Health Plan.

Plans should be “viewed as instruments forresource mobilization,” that take into accountfinancing of existing immunizations, laws thatfavor financing and sustainability, and resourceoptions. These include national funds, funds of theStrategy for the Reduction of Poverty and theMillennium Account, and private sector anddonors’ support.

Plans should specify objectives and goals, targetpopulations and areas, target dates, harmonizationactivities, vaccine supply, training, communicationsand information systems upgrades, strengthening of

epidemiological surveillance, and costs. And, afterimplementation, Molina noted the importance ofmeasuring impact.

In conclusion, “It is fundamental to develop a planfor the introduction and implementation thatguarantees sustainability,” said Molina. She notedthat the Revolving Fund continues to be amechanism to ensure a regular flow of qualityvaccines at affordable prices, offering security andconfidence to the countries.

Colombia: One Country’s ExperienceColombia has a national commitment to achievingMillennium Development Goal #4 and reducingchild mortality by 60% by the year 2015, said JaimesSanabri of the Ministry of Health in Colombia. “Tothat end, Colombia has proposed to reduce deaths inchildren younger than 5 years of age to 17 deaths per1,000 live births, taking into account that thebaseline for 1990 was 37 deaths per 1,000,” she said.Progress is being made: in 2002 the child mortalityrate was 28 deaths per 1,000.

To continue that progress, Colombia is updatingits Expanded Programme on Immunization (EPI) andadding new vaccines, she said. And, it is in thiscontext that public health authorities are assessingthe possible introduction of a conjugate pneumo-coccal vaccine.

Though the burden of pneumococcal disease hasnot been fully confirmed, data from the Ministry ofSocial Protection, the National University and the


“If the costs of vaccines are not affordable,greater inequalities among the populations

and their vaccine schedules will be generated.”

—DR. IDA B. MOLINAMinistry of Health, Honduras

National Department of Statistics in Colombia hasfound that:

• Pneumonia is the third leading cause of death inchildren younger than 1 year of age, and thesecond in children between the ages of 1 and 4,

• An estimated 1,200 children under five die ofpneumonia every year,

• Pneumococcal pneumonia is estimated to killbetween 250 and 900 children every year,

• There are 470,000 to 1.4 million cases ofpneumonia in children under five every year,

• The total incidence of pneumococcal meningitishas been estimated in 850 to 1,600 cases a year inchildren under five.

The existing vaccine could therefore save the livesof a significant number of children. Jaimes Sanabriasupported her conclusions with an initial analysis ofthe serotypes present among children hospitalizedwith pneumococcal diseases.

An analysis of 2,022 serotypes isolated from 137hospitals in Colombia in 1994 revealed that 64% ofthe serotypes correspond to those in CVP7, and thatthe vaccine would have a “potential effectiveness inColombia of 62%,” she said.

However, a determination of cost-effectiveness ofthe new vaccine is still needed. As Dr. MarthaPatricia Velandia, National EPI Coordinator ofColombia, later noted, “The cost of the pneumococcalvaccination schedule accounts for what theColombian state gives to each person in healthduring a month. Therefore, data is needed formaking a decision,” she said.

For now, Colombia has decided to introducePCV7 for the youngest of its most vulnerablechildren: those with HIV, congenital heart disease,bronchial asthma, cancer, and other life-threateningconditions. The nation’s Public Health SurveillanceSystem is studying the cost-effectiveness of apneumococcal vaccine for children in thatpopulation under the age of two.

Two other cost-effectiveness studies—of vaccinesfor rotavirus and hepatitis A—are also in the works.

Jaimes Sanabria noted that the cost of implementingthe rotavirus vaccine alone would cost the countryalmost US$14 million, and that the country’s currentbudget for EPI is US$50 million.

Meanwhile, one other relatively new vaccine hasalready had an impact on child mortality: the Hibvaccine has greatly reduced the cases of Hib-associated meningitis.

As the country strives to implement newprograms and raise its overall coverage of basic EPIvaccines from 92% to 95%, Jaimes Sanabria notedthat there are many challenges. Among them arethe need to strengthen management andinfrastructure, as well as the information system,the cold chain, and the surveillance of vaccine-preventable diseases.

DiscussionDiscussion revolved around questions of vaccineefficacy in Latin America, the role of variousleadership bodies, and political and technical consid-erations in decisions about vaccine introductions.

Surveillance and Vaccine Efficacy

COMMENT: Miguel Tregnaghi of Argentina notedthat while it is extremely important to have a solidassessment of both vaccine efficacy and burden ofdisease, those findings vary greatly depending on thestudy and the type of surveillance conducted. Heemphasized that ongoing surveillance will yieldfuture data that will help us make decisions.

Efficacy in High-Risk Populations

COMMENT: Lucia Bricks of Brazil noted that PCVis a very important vaccine, but that efficacy in high-risk groups where the vaccine is becoming availableis expected to be much lower than 60%. Thisincludes populations with unconventional riskfactors, such as premature babies which account for10% of the population at high risk of pneumococcaldisease. In addition, she said, serotype replacementproblems could be larger in high-risk groups that areimmunosuppressed, she said.


How Much Information Is Enough?

COMMENT: Xavier Sáez-Llorens of Panamaquestioned “whether we need in fact more data forthe introduction of the vaccine.” He suggested thatMexico’s plan to “spectacularly update” itsvaccination program is driven more by political thantechnical considerations. He also urged thatcountries not “reinvent the wheel.” “If Costa Ricaand Colombia, which neighbor Panama, have a lot ofrotavirus, why is our country going to be completelydifferent?” he asked, noting that sometimes askingfor more data delays the introduction of effectivevaccines.

Sáez-Llorens also disagreed with Santos’ character-ization of Hib and HepB vaccine introductions in theAmericas as rapid. “I would say it is the opposite.Their introductions were extremely slow—10 to 12years. I wonder: who takes responsibility for thosedeaths and sequelae in the 10 to 12 years that theintroduction of the Haemophilus vaccine was delayedin the Americas?”

RESPONSE: Santos replied that in his experience,after Hib was first introduced in Latin America in1999, by 2002 it was in almost all Latin Americancountries. “The following year the hepatitis B vaccinewas ready and the following year we were alreadyworking on a campaign to eradicate congenitalrubella syndrome,” he said. Regarding the value ofthe vaccine, he noted that worldwide, almost 90% of

the deaths due to pneumococci occur in other partsof the world, specifically in Africa and South EastAsia. “How many deaths are too many? I believe thatone death is too much,” he said. Definitely, there arelocal, regional and national differences. That is whyinformation is important even though it might belimited information, he added.

PAHO’s Role

COMMENT: Xavier Sáez-Llorens argued thatPAHO has received unjustified credit for theintroduction of vaccines in the Americas—eventhough the Revolving Fund has been an excellentinitiative because it helps to reduce prices. “Theintroduction of vaccines in many of our countries hasbeen related more to persons than to power groups,”he said.

RESPONSE: Santos emphasized PAHO’s positiverole. “The Americas were the first to eradicatesmallpox, the first in eliminating polio, and the firstin controlling measles. I think this speaks tosomething more than personal or political decisionsby the countries,” he said, noting that those advanceswere made by the member countries of PAHO.

Dr. Molina added, “There is no doubt that theRevolving Fund has been an extraordinary supportmechanism for maintaining immunization programsin our countries.”



“With the concrete information we have received thisweek, we have enough data to start an importantdefense against pneumococcal disease in allcountries,” said Dr. Ciro de Quadros.

Conference organizers presented a Call to Actionthat was discussed and approved by Symposium partic-ipants. (See addendum.) Given that, in Latin America,pneumococcal disease kills two children per hour, andcauses at least 1.6 million cases of disease every year,and that there is a safe and effective vaccine forchildren, the Call to Action agreed to “promoteadaptation of pneumococcal vaccines whereverfeasible,” and to “make 2007 the year of action.”

Presentations by Dr. Jon Andrus from PAHO, Dr.Orin Levine from PneumoADIP, Ms. Lisa Jacob fromGAVI, and Dr. Ciro de Quadros from the Albert B. SabinVaccine Institute all highlighted the need for concertedaction. The following are highlights from their talks.

Dr. Jon Andrus, PAHOSince the first regional meeting on pneumococcus inMexico City, in November 2004, much has beendone, but we still have much to do. We have the data,we have the vaccine, but it is the same situation: Wedon’t have a vaccine at a price that all the countriescan afford to introduce to reduce mortality.

Therefore, PAHO will continue to push the agenda atthe highest political levels, and, most importantly, willcontinue to use the Revolving Fund and to improve itseffectiveness. We will maintain our team of interna-tional field consultants working with the countries andcommunicating with the Revolving Fund as countriescontinue to develop the fiscal space for new vaccines.

Dr. Orin Levine, GAVI’s PneumoADIPWe are going to need collaborative action to besuccessful, and this Call to Action is an example ofthat. We have heard today about country experiencesand ways in which countries have been very

successful in taking evidence, and using it to generatepolitical will, support for introduction of new vaccines.

We have discussed today the price of the vaccine andthe substantial challenges ahead in implementation.But, as a community of people who take care ofchildren with pneumococcal disease and whointimately know the value of the vaccine, it is importantfor us to also make apparent the price of inaction, aswell as the price of the vaccine. The challenge ahead isto find that balance and to urge the forces of inaction tothe side on the basis of evidence, so that we can havethe kind of impact that has been projected.

We have been very successful in generating fundingand focusing a new level of attention on health andimmunizations. Our success has been based on thepromise that these vaccines will deliver the kinds ofreturns that David Bloom and others have shown arepossible. We need to deliver on those promises.

Ms. Lisa Jacobs, the GAVI Alliance SecretariatWe very much support this Call to Action onpneumococcal vaccines. GAVI already has acted, andwe will continue to act. Pneumococcal vaccine hasbeen one of our priority new vaccines since 2000.Many factors influenced the recent decision by theGAVI Board to support the purchase andintroduction of the vaccine: the PneumoADIP’sinvestment case, the evidence of disease burden, theintroduction of the vaccine in the U.S. with itsdemonstrated herd immunity, and the very positivedialog that has emerged with manufacturers.

GAVI has been blessed with some very publiccommitments. Most recently the International FinanceFacility for Immunization sold its first bond issue forUS$1 billion dollars. Another US$2.2 billion have beenfully committed. And, Brazil and South Africa havecommitted to join the next bond issue. The other veryexciting new innovation is the Advance MarketCommitment (AMC) mechanism, with its profoundimplications for speeding access to that vaccine.

SESSION VI-?

Call to Action

CO-CHAIR Dr. Ciro de Quadros


GAVI has also enacted a country co-financingpolicy that will apply to the new pneumococcal androtavirus vaccines. It asks countries to put up a littlefunding and is meant to open a budget line thatwould gradually increase. That way, by the timeGAVI support stops, countries will have the resourcesto continue paying for the vaccine.

Six countries in the Latin American region areeligible for GAVI support: Nicaragua, Cuba,Honduras, Haiti, Guyana and Bolivia. Our plan is tofinalize the guidelines for applications for these newvaccines in May of 2007, make those available tocountries, and solicit applications for review byautumn. We hope for pre-qualification of bothPrevnar and the rotavirus vaccine by the end of 2007.

Dr. Ciro de Quadros, The Albert B. Sabin Vaccine InstituteAfter all the information and enthusiasm generated bythis meeting, there is momentum that facilitates the

introduction of the vaccine by governments. Therehave been more than 34 articles in the newspapersand news agencies from yesterday to today. There isunprecedented communication in Latin Americaabout pneumococcus, the burden of disease, andprevention. Through social communication, theseissues are all over the region of the Americas. We havesomething very important ahead of us.

There are no doubts that the birth of GAVI wasvery important for vaccination programs all overthe world. Progress in the poorest countries hasbeen extraordinary. But, it is clear that for LatinAmerica, in particular, the target population ofGAVI is relatively small. However, GAVI couldactively participate in the region of the Americasthrough other mechanisms; they could make adonation to the Revolving Fund. The Fund willhave a US$70 million deficit by 2015. If GAVIcontributed US$20-30 million to the RevolvingFund, it would greatly facilitate the purchase ofnew vaccines.

Therefore, We Agree to:

Support immunization as a common public good,an economic necessity and a vital political priority...

Request that the World Health Organization expedite the prequalification of the existing vaccine...

Promote adaptation of pneumococcal vaccines wherever feasible...

Work to raise awareness...

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Considering that:

• Pneumococcal disease kills up to one millionchildren worldwide every year, with 90% ofdeaths in developing countries;

• In Latin America, pneumococcal disease kills18,000 children every year — two every hour —and causes at least 1.6 million cases of disease;

• These include such deadly conditions aspneumonia, bloodstream infections andmeningitis, as well as ear infections that can leadto hearing loss;

• While appropriate treatment, including wise use ofantibiotics and good nutrition, lowers theincidence of pneumococcal disease, vaccines arethe most efficacious way of preventing it;

• Latin America suffers a high economic burdenfrom pneumococcal disease, with direct medicalcosts estimated to surpass US$293 million peryear, and families bearing more than US$40million in additional costs;

• There is a solution. An existing pneumococcalconjugate vaccine dramatically reduces disease,disability and deaths from pneumococcal disease;

• Adding the current pneumococcal conjugatevaccine to childhood immunization schedules canbegin saving lives and preventing disease now;

• New vaccines that promise even greater impact inLatin America are expected to become availableover the next two to four years;

• Prevention and control of pneumococcal diseaserequires collaborative action by governments,industry, health organizations and internationalagencies.

Therefore, We Agree to:

• Continue to support immunization as a commonpublic good in the region, an economic necessityand a vital political priority;

• Request that the World Health Organizationexpedite the prequalification of the existingvaccine for purchase by United Nations agenciesas soon as possible;

• Promote adaptation of pneumococcal vaccineswherever feasible;

• Work to raise awareness among the public andpolicy makers of the burden of pneumococcaldisease and the value of vaccination;

• Encourage increased vaccine research andexpanded surveillance;

• Call upon PAHO and its Revolving Fund for theacquisition of vaccines to work together withnational governments, bilateral and multilateralagencies, the GAVI Alliance, and the manufac-turers of vaccines to facilitate the introduction ofpneumococcal vaccines;

• Make 2007 the year of action to combat pneumo-coccal disease in the Americas.

Call to ActionBy Participants of the Second Regional Pneumococcal SymposiumSão Paulo, Brazil14 December 2006


Dr. Ciro de Quadros introduced Dr. María LuisaÁvila, the Minister of Health of Costa Rica and Dr.Roberto Tapia, Vice-Minister of Prevention &Protection of Health

Ministry of Health, Mexico, to deliver the closingremarks.

“In Costa Rica, we consider vaccines part of thehuman development necessary for each nation,” saidDr. María Luisa Ávila, “It is completely unfair that, ina country such as ours, some children are vaccinatedwith all the possible immunobiologicals whileanother group of the population receives only thebasic schedule.”

Thanking the Pan American Health Organizationfor its help in the development of Costa Rica’svaccination programs, Ávila emphasized hercountry’s commitment to updating its vaccinationschedule.

However, she noted a challenge beyond technicalfeasibility or cost. “Unfortunately, there are otherobstacles... people who believe that pneumococcus isnot an important disease in the country... So, inaddition to having to fight against economicconstraints, we have to fight against the mentalconstraints, which may be worse,” she said.

“I hope that our countries move forward toward ashared goal and that the introduction of newbiologicals becomes a prompt and effectivesituation,” Ávila concluded.

Dr. Roberto Tapia, asked, “Taking this plan ofaction, what else needs to be done? For it to work, he

said, “The most critical task is to build politicalsupport. And this can be done by promoting theunderstanding of vaccines as a key pillar to achievinghealth, equity and economic development.”

He urged promoting this message not only topoliticians, but also to the community. He urged thatactions be taken to:

• Update countries’ legal mandates to vaccinate, anddo so in a way that helps develop new means offinancing. He noted that many nationalvaccination laws address the old framework ofvaccine schedules;

• “Give a thrust to justice” and consider vulnerablegroups a priority. Vaccination for those in ruralareas, prisons, and many marginalized circum-stances would assure that people receive apreventive intervention;

• Design a financing scheme for countries withintermediate economies;

• Increase advocacy. Tapia noted that at the countrylevel, HIV/AIDS and malaria have made significantprogress because of the advocacy of civil organi-zation. “With pneumococcus we have no civilorganizations that are similarly striving,” he said;

• Build a national consensus. When all contribute todecision making, “The barrier of fear and individ-ualized criticism is interrupted, and the decision-making process is accelerated.”

Closing Remarks

“The most critical task is to build political support.And this can be done by promoting the understanding of vaccines asa key pillar to achieving health, equity and economic development.”

— DR. ROBERTO TAPIAMinistry of Health, Mexico


Tapia stressed the importance of a communicationstrategy built by all the stakeholders, and which,“above all, empowers individuals to be informed andto make the decision to request the vaccine.”

For vaccine introduction, Tapia emphasized the

“element of mysticism—meaning passion and pride.”“This must not get lost, because it is the engine thatkeeps the machinery working,” Tapia concluded. “Wehave to convey this ‘mysticism’ to the population. Theunderstanding of society is the best sustainability.”

“The understanding of society is the best sustainability.”

— DR. ROBERTO TAPIAMinistry of Health, Mexico

Millennium Development Goal #4

Reduce the under-five child mortality rate by two-thirds, between 1990 and 2015.

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