98 7 YEARS 6 AND 5 COUNTINGlobby.la.psu.edu/020_Compulsory_Licensing/...• Modest research programs...

987654321

How Can We Overcome Obstacles

to an AIDS Vaccine?

AIDS VACCINE ADVOCACY COALITION

MAY 2000

YEARS ANDCOUNTING...

Copyright © AIDS Vaccine Advocacy Coalition. All rights reserved.

This report is dedicated to Neal Nathanson, Director, Office of AIDS Research, in appreciation for his masterfulattention to all AIDS issues and his commitment to developing an HIV/AIDS vaccine.

AVAC gratefully acknowledges many friends and colleagues in government, industry, and community advocacy fortheir expertise and advice as we researched and prepared this report. We especially thank Deborah Birx, AnnCacho, Jose Esparza, Pat Fast, Gregg Gonsalves, Peggy Johnston, Wayne Koff, Bonnie Mathieson, and Gary Nabelfor their helpful comments.

AVAC does not accept funding from government or industry. This publication and AVAC’s other policy andadvocacy work is made possible by the dedicated work of AVAC advocates and contributions from the Royal S.Marks Foundation Fund, Until There’s a Cure Foundation, Broadway Cares/Equity Fights AIDS, the John M.Lloyd Foundation, the Gill Foundation, amfAR, and many individual donors’ contributions and in-kind support.

7 YEARS AND COUNTING...HOW CAN WE OVERCOME OBSTACLES TO AN AIDS VACCINE?

1

E X E C U T I V E S U M M A RY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

INTRODUCTION: WHERE WE STAND TODAY . . . . . . . . . . . . . . . . . . . .4

RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

U.S. GOVERNMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

THE GLOBAL RESPONSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22

INDUSTRY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

THE PUBLIC: BLUEPRINT FOR ACTION . . . . . . . . . . . . . . . . . . . . . . . .40

ABOUT AVAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45

TABLE OF CONTENTS

P R O F I L E S

The Dollar Value of Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7

Announcement of Interim Goals and Milestones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18

Moving Toward US Government-Sponsored Efficacy Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

The Long March of Science, What’s New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26

The Push to “Pull” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29

Vaxgen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Tax Incentives for Vaccine Research and Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37


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The idea of finding a vaccine to prevent HIV hasfinally captured the attention of government leadersand affected communities. Increasing sums of public money are available for the effort. Researchis percolating in industry. Willing trial volunteershave signed up for injections. Politicians and thepublic have opened their eyes to the devastation of AIDS in Africa, and decided they should dosomething.

So why are we still writing reports?

Because scientists do not yet understand the basics,including how to build protective immunity to HIVin humans, or how to use animal models most effec-tively in research. Because, for all the hype, gov-ernments have not passed legislation to help theprivate sector work on HIV vaccines. Because noone knows how we would get a vaccine to the peo-ple of Africa, India and other countries in Asia ifwe had one. Because Merck recently announcedthat their current HIV candidate is likely only afirst step. Because we have not come close todemonstrating an efficacious vaccine.

The last year was one of great activity across USagencies and throughout the world. We should allbe proud. But neither the rhetoric nor more dollarsgot us a major breakthrough. HIV remains one ofthe most puzzling and challenging foes to facehumanity.

And behind all the activity, we see real signs oftrouble: private industry driven increasingly by the

thirst for huge profits and blockbuster products,government programs resisting coordination andlosing leadership, mounting controversy over a pro-posed government vaccine trial, and a tendency inCongress to spend money without making structuralpolicy changes.

This year’s AVAC report documents the steadilyincreasing activity in the quest for a vaccine against HIV:

• Leadership by President Clinton to find vaccinesfor the major infectious-disease killers, includingHIV/AIDS.

• Needed increases in funding at the NationalInstitutes of Health.

• Modest research programs at the major pharma-ceutical companies and among some biotechmavericks.

• Five thousand individuals, predominantly in theUS, volunteering to participate in the first HIVvaccine efficacy trial.

• Progress toward a government-sponsored, large-scale human trial.

• Establishment of milestones for public sectorresearch.

• Growing public awareness of the internationalAIDS crisis.

• Activity by governments, researchers, and advo-cates in scores of countries.

EXECUTIVE SUMMARY


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• Funding of product-oriented research outside ofgovernment institutions.

• New guidelines on the ethics of vaccine trialsand expectations of improved internationalcoordination.

We also voice our impatience:

• The US Department of Defense has a directedHIV vaccine research program. So why is itconsistently underfunded?

• The President and Congress proposed importantincentives. So why are these bills facing opposi-tion or disinterest?

• Industry says it faces difficulties in dedicatingresources to HIV vaccine research. So why dothey seem tongue-tied when asked what incen-tives they need?

• NIH funding has skyrocketed. So why are therestill not enough non-human primates availablefor needed research?

• We are almost 20 years into the epidemic and30 million people live with HIV. So why hasthere been only one Phase 3 trial of a vaccinethat might prevent this disease?

Several actions are necessary to accelerate develop-ment of HIV vaccines, including 1) expanding gov-ernment programs and providing additional targetedfunding for specific research priorities, 2) passinglegislation that provides incentives for private sec-tor involvement in HIV vaccine research, and, 3)funding public outreach, education and communica-tion programs.

Business as usual and territorial mentalities are theenemy of rapid progress towards an HIV vaccine.No one agency or company can find a vaccine andmake it readily available. Public and private sectorsmust find new ways to partner. The Centers forDisease Control has been criticized for the way inwhich it funded ancillary studies in the VaxGentrial, but it is just these kinds of partnerships thatare critical to moving research forward and securingthe benefits of science for everyone.

In 1997, the President said he wanted a vaccinewithin a decade. We have seven years to go.There’s funding, public support, and renewed hopein the scientific community. With new partner-ships, a new sense of urgency, and broad based coop-eration, the dream of a vaccine that saves tens ofmillions of lives is within reach.


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In less than four months, the 10-year challenge tocreate an AIDS vaccine will be one-third over, andthe daring challenger, President Bill Clinton, willleave office. This year, dramatic changes in therhetoric and actions surrounding development of anHIV vaccine appear everywhere we look.

You will see a difference in this year’s AVAC report.We believe the world has turned an important cor-ner. The political will to make an AIDS vaccinefinally shows signs of life. The National Institutesof Health are not our primary focus this year. Theforesight and continuing effort of NIH is beginningto be repaid and replicated around the world.

On the other hand, in some ways, Clinton’s chal-lenge seems like wishful thinking. Not only havewe been unable to agree on what a promising AIDSvaccine candidate would look like, objections areraised when a publicly-funded large scale trial of amodestly promising vaccine is proposed.

The vaccine issue belongs not to Clinton or theDemocrats—rather it touches on the security of ourcountry and stability in the world, particularly inAfrica, Asia, and Eastern Europe. A change in thepolitical landscape with Presidential andCongressional elections this fall may very well

change the balance of power in both branches,which raises concerns for continuing and expandingthe effort. Each candidate for President andCongress must realize that the ultimate goal—preventing AIDS—has staggering, far-reaching consequences. We do and will call on each activepolitician, regardless of the rest of his or her politi-cal agenda, to endorse accelerated development ofHIV vaccines. If there ever were a bipartisan issue,this is it.

Six years have passed since the decision not to goahead with monomeric gp120 in the US in 1994.Something like $781 million has been spent duringthose years, and there’s so much we still don’t know.As Mark Schoofs points out in, “The Agony ofAfrica” in The Village Voice, (November, 1999)“Even when pushed, science crawls.”

The moment has come to step up the effort, put onsome pressure and prepare to run a series of efficacytrials around the world. All the old, AIDS-activistslogans could be dusted off and still apply: PeopleAre Dying and people need experimental vaccines.It is 1982–83 again in other parts of the world andin communities across America. Nobody’s stormingthe NIH, disrupting the stock market, or stagingdie-ins in the streets. It might help if we did.

INTRODUCTION: WHERE WE STAND TODAY


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AVAC started criticizing NIH and industry for theinadequacy of their HIV vaccine programs in 1995and telling everyone else to get on the ball. Therewas too little going on anywhere else to criticize.Today, we are happy to report interest and activityhave grown to a point where advocates can compli-ment and critique multiple efforts on many fronts.Today it is possible to see how to actually get to anAIDS vaccine.

Not that the way will be quick or easy. It has taken18 years to get here. We only have managed that—and with limited resources—because a small band ofdedicated people recognize the importance of theirwork and are working as hard as they can.

We must prepare for the difficult road ahead by put-ting sufficient resources into what are known to bethe key contributing components of a comprehen-sive vaccine research effort. This year, we havethree overarching recommendations, with a few spe-cific recommendations for each.

1. Expand government programs as rapidly asthey can effectively handle expansion.

• Expand translational work at NIH: the researchthat facilitates moving products from the lab todevelopment.

• Permanently and adequately fund Department ofDefense vaccine research.

• As industry becomes more involved, negotiatefor trade-offs, such as reasonable pricing, beforepublic funds are handed out.

• Conduct clinical trials more smoothly and expe-ditiously.

• Supplement funding beyond current and proposedincreases for NIH in seven specific areas identi-fied by AVAC. AVAC estimates that an addi-tional $70 million could be effectively used to:

• Prepare research sites in the US and othercountries (including epidemiological studies,immunologic studies, training investigators,preparing countries, building infrastructure,and other site preparation work).

• Provide more and higher quality non-human primates. (Implement plans toincrease the stock of primates, includingpathogen-free and immunologically charac-terized and related animals.)

• Develop new assays rapidly and placeadvance orders for new cell-sorting andother technology that would be used to analyze results from efficacy trials.

• Target additional resources to biotech companies through the Vaccine Design andDevelopment Teams initiative.

RECOMMENDATIONS


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• Prepare key communities and the public forthe ongoing vaccine effort.

• Provide adequate funds to expeditiouslyconduct efficacy trials in the US and abroadas soon as candidates become available.

• Create private-public partnerships to champion and develop orphan-vaccine concepts and support vaccine trials.

2. Pass legislation that provides incentives forprivate sector involvement in HIV vaccine re-search—both “pushes” and “pulls” are needed,because purposeful company activity is crucial.

• Pass the Vaccines for the New Millennium Actintroduced by US Senator John Kerry andRepresentative Nancy Pelosi.

• Establish purchase funds and other access assur-ances now.

3. Fund public outreach, education and commu-nication programs.

• Focus education and communication efforts in key communities.

• Develop and implement a strategic communications plan.

In two more years, we come to the halfway mark of10 years to develop a vaccine. By then we couldhave a real, substantial and significant internationaldrive underway. This is a fantastic, almost incredi-ble challenge, but mankind has done monumentalthings before. Let’s get together, stop quibbling,cheer the workers on, and go!

To get involved or to read past AVAC reports, visit ourWeb site: http://www.avac.org

http://www.avac.org


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This chart shows that a new treat-ment or vaccine can slash the inci-dence of a deadly infectious disease.Because infectious diseases aretransmissible, the health of others isyour health. Yet, private and publichealth-care plans often don’t payfor check-ups or immunization.

Vaccines, even administered to millions, are worth hundreds orthousands of times more per personand per dose than the pennies weexpect them to cost. For peoplewho have not caught and do notexpect to catch an infectious dis-ease, this is a difficult argument tosell, particularly when vaccinationand hygiene has made occurrenceof a disease rare.

A vaccine is insurance against rarecatastrophic events and the insur-ance itself is a form of protection.That’s why vaccine advocacy ishard to generate especially whenthe disease burden has beenreduced as dramatically as it has inthe developed world. In the US,we live in a relatively healthy bub-ble of a relatively unhealthy globe.Given emerging infections, clearly,the best way to keep the diseasesout—is not to build barriers—butto improve health “out there.”

Like clean air and water, an infec-tion-free environment is a commongood. Sanitation and vaccinationare the only two proven routes tothat end. If we, as individuals, canhappily spend a hundred billiondollars a year treating sometimesminor ailments, why can’t we findadequate resources for full-scaleefforts on the vaccines needed mostdesperately in the world?

According to the US Departmentof Health we will spend an estimat-ed $110–120 billion on prescriptiondrugs this year, which has almostdoubled since 1995 and quadrupledsince 1990. The entire budget forvaccines around the world is esti-mated to be no more than $3 bil-lion. Where’s the sense in that?

T H E D O L L A R VA LU E O F P R E V E N T I O N

Annual Disease Rates for Selected Infectious and Noninfectious Diseases

United States, 1900–1996

Source: Armstrong et al, JAMA, 1999, 281: 61; and CDC

100

75

50

25

0

1900 1920 1940 1960 1980 ( Year)

T U B E R C U L O S I S

P O L I O M Y E L I T I S

N O N I N F E C T I O U SD I S E A S E S

“Today marks the first time, after more than

4,000 meetings stretching back more than half

a century, that the Security Council will dis-

cuss a health issue as a security threat. We

tend to think of a threat to security in terms of

war and peace. Yet no one can doubt that the

havoc wreaked and the toll exacted by HIV/

AIDS do threaten our security. The heart of

the security agenda is protecting lives–and we

now know that the number of people who will

die of AIDS in the first decade of the 21st

Century will rival the number that died in all

the wars in all the decades of the 20th Century.”

Vice President Al Gore

United Nations Security Council Opening SessionJanuary 10, 2000


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NATIONAL POLICY

President Clinton Calls for a Vaccine

President Clinton advocated development of anAIDS vaccine at least six times during his twoterms in office. He promised to make NIH the“engine of discovery” for HIV vaccines in his 1997State of the Union address to Congress. He pro-posed that our country develop an AIDS vaccine inthe next decade in May that year. He pledged atthe UN’s General Assembly to work with industryon vaccines for AIDS, tuberculosis and malaria infall 1999, perhaps in response to the LifesavingVaccine Technology Act that Congress introducedin the 105th session.

This year we got more: State of the Union promisesabout vaccines, announcement of existing programsand a purchase-tax-credit proposal, which costs thegovernment nothing until a vaccine is licensed andsold. The proposal will take years to implement.

The words are good. The danger is that they willnot be enacted with new incentives and funding.The President’s advisors in the Office ofManagement and Budget, Treasury, and NationalSecurity support action. The President’s AdvisoryCouncil on HIV/AIDS urged concrete steps andpassed seven resolutions relevant to AIDS vaccinedevelopment—dormant proposals still on the table.

Congress Keeps Pace with Funds,Proposed Legislation

Congress continues to increase funding to recordlevels for medical research at the National Institutesof Health. NIH has, in turn, continued to increasethe share for AIDS vaccine research, which rosefrom $111 million in 1996, when we published ourfirst report, to $239 million in fiscal year 2000—not a pace comparable to a hot stock market butenough to allow broader basic research grants andapplied research programs.

0STATUS Presidential and Congressional proposals • Growing budgets 0RECOMMENDATIONS Sustain in-

creased NIH funding • Ensure leadership at all agencies involved • Increase funding for Department of Defense research •

Identify possibilities for acceleration of FDA review • Provide enough non-human primates for research• Coordinate work of

agencies •Set milestones for cooperative agreements and contractors • Move forward with planning a Phase 3 trial of Canarypox

U.S. GOVERNMENT

“...today I commit the United States to a concerted effort to accelerate the developmentand delivery of vaccines for malaria,TB,AIDS, and other diseases disproportionatelyaffecting the developing world.”

President Bill ClintonThe United Nations, September 1999


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On the legislative front, the Lifesaving VaccineTechnology Act, introduced a year ago in Marchwould create incentives for industry to invest moreheavily in areas with the greatest global public-health need.

This year, Senator John Kerry and RepresentativeNancy Pelosi added a vaccine-purchase fund to thelegislation proposed last year in order to make theproposed incentives both “push” on research and“pull” to create a market for these vaccines. TheVaccines for the New Millennium bill is this year’sgold standard for legislation to spur HIV vaccineresearch and development. (see page 37).

Show Political Will

The executive and legislative branches of our gov-ernment seem to lack the political will to make themore difficult policy changes that must follow thefunding. Money for research is the easiest elementin the equation. The other elements are partner-ships with industry, incentives for private sectorinvestment, shared objectives, and consistent, con-certed action. We must raise this issue to the levelof an intensive program with ambitious goals.Everyone involved should be encouraged to be on afaster track.

Only the US government is in a position to“Marshall” that plan and “Manhattan” this projectwith commitment and leadership. As PresidentClinton said: “...a new national goal for science inthe age of biology. If America commits to find anAIDS vaccine and we enlist others in our cause, wewill do it. I am prepared to make it happen.”

US AGENCIES

Congress Narrowly Tops Past Funding

Congress appropriated $5,962.7 million for AIDS

programs this year, which the Clinton administra-tion touts as the most ever. This appropriationbarely tops past figures and getting those fundsbecomes more and more difficult. Two of the great-est supporters of aggressive funding for NIH will orhave moved on: Representative John Porter (R-IL)who chairs the House Appropriations Subcommitteeon Labor-Health and Human Services-Educationand NIH Director Harold Varmus, who charmed thatSubcommittee for years. That leaves the questionof maintaining the funding for AIDS to us. Wemust redouble our efforts on the legislative front.

NATIONAL INSTITUTES

OF HEALTH

This year NIH got a healthy 15% increase. Theannual increase has traditionally been the discre-tionary part of NIH’s budget, since NIH is reluctantto cut from previous institute budgets. A smallershare than in previous years will go to AIDS re-search. The Office of AIDS Research (OAR) man-ages that share, which allots a larger portion of itsincrease to vaccine programs.

Vaccines have gone from 9% of the NIH AIDSbudget when Neal Nathanson took over the Officeof AIDS Research to 12% proposed for this year.This adds up to $239 million, enough to support theproposed new programs minimally. Nathanson an-nounced recently that he will be leaving his posi-tion in September 2000. The NIH operating budget(for staff, supplies, travel, etc.) has not increasednearly as much as the budget for grants and contracts.For vaccines, which have expanded disproportion-ately to the total NIH budget, this means morework per staff person and insufficient travel funds.

OAR may use a discretionary fund for peer-reviewedprojects, in addition to the budgets of individual in-stitutes. In past years, this fund has often supportedvaccine or other prevention projects. OAR is


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required by law to update its Plan for HIV-RelatedResearch each year before submission of budgetrequests for the coming year. To identify prioritiesin the plan in the past has been difficult becausethe plan must include all current and probable areasof research. OAR identifies priorities for futureresearch up front for each topic, which helps withan analysis of the plan.

The 2001 plan proposes to:

• Conduct domestic and international vaccine trials.

• Develop and test new vaccine strategies.

• Improve animal models and trials.

• Identify and develop functional antibodies to useagainst maternal-infant transmission in order toinform vaccine design.

• Move vaccine concepts rapidly to clinical tests.

These priorities are very close to the TreatmentAction Group’s recommendations made in itsrecent report on NIH-funded research. OAR hastracked NIH vaccine spending in five categories.Trends for the last three years are shown below.

DO

LL

AR

S

(Mil

lio

ns)

0

20

40

1997 (130 M i l l i on )

Prepare for efficacy trials Phase 1 & 2 trials Pediatric vaccines

Vaccine design and animal testing Host defense mechanisms

13 (10%)

18 (14%)

8 (6%)

38 (29%)

53 (41%)

14 (10%)

11 (7%)

22 (15%)

45 (31%)

56 (37%)

14 (8%)

25 (14%)

13 (7%)

74 (40%)

56 (31%)

1998 (147 M i l l i on ) 1999 (181 M i l l i on )

60

80

100

120

140

160

180

200

1997–1999 NIH VACCINE SPENDING BY CATEGORY

Source: NIH Office of AIDS Research


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CENTERS FOR DISEASE CONTROL

AND PREVENTION

The CDC created an AIDS vaccine unit, headed byDr. Bill Heyward, last year, after years without one.That program primarily supports VaxGen in its effi-cacy trials by providing domestic and internationallogistical support and funds to perform additionalepidemiological, social, and behavioral research—a total of $8 million over a period of four years. Dr.Heyward’s move to VaxGen was followed by nega-tive articles in the media, which increased scrutinyfrom Congressional appropriators.

Dr. Timothy Mastro recently accepted the positionof chief of the HIV Vaccine Unit in the Epidemio-logy Branch of CDC’s Division of HIV/AIDSPrevention. Dr. Mastro served as Director of TheHIV/AIDS Collaboration-Thailand, a joint researchproject between CDC and the Thai Ministry ofPublic Health, for the past seven years. The vac-cine unit currently has a staff of four, a small staff byCDC standards. One or two people may be hired inthe near future.

Another CDC activity was an NIH-funded, qualita-tive study of community attitudes toward vaccinetesting. This study is out of money and in the dol-drums, with large amounts of potentially importantdata unanalyzed and unpublished.

DEPARTMENT OF DEFENSE:

WALTER REED ARMY INSTITUTE

OF RESEARCH

Since the beginning of this epidemic, the US Armyhas played an important research role, extraordinaryfor its funding level. The Army must protect ourtroops and has a long history of vaccine researchand development of vaccines not developed aggres-sively by industry.

WRAIR complements NIH research programs, andis an essential component of the HIV vaccineresearch enterprise. Aside from the fact that it con-sistently produces important scientific work, the military, by design, runs highly structured, directedprograms unlike NIH’s broader, peer-reviewed grantprograms. Each approach has its strengths, and webelieve government should pursue both.

Annual Dance for Dollars Must Stop

WRAIR has five sets of products in clinical trialsand four new products in production or develop-ment. Their clinical testing sites are in the US andThailand. They are building infrastructure inUganda, with cohorts for Phase 2 trials in develop-ment in Uganda, Kenya, and Thailand. They havesurveillance activities throughout South America,Africa (East, West, and North) and Southeast Asia.

Funding for this program is an annual skirmish.Pentagon officials have consistently cut the pro-gram’s budget requests, which Congress thenrestores because of public support. In past years, theNational Organization Responding to AIDS(NORA) and AVAC have succeeded in restoringthe budget, but DoD uses this dance to get budgetincreases for areas other than vaccines.

President Clinton’s proposed annual AIDS-vaccinebudget for WRAIR is $24 million, with $17 millionavailable for scientific work. With annual expendi-tures for scientific projects of approximately $32million, WRAIR has relied on Congress for supple-mental funding each year. WRAIR needs an annu-al appropriation of close to $50 million to have $32million available for vital vaccine research anddevelopment projects.

We strongly believe that DoD should recognize the important public contribution that is being madeand will be made by its HIV vaccine program.


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The defense department should give WRAIR rea-sonable funding in its budget requests, in light ofthe fact that the UN Security Council and othersclearly identify AIDS as a serious security risk. Anannual DoD appropriation of approximately $280billion, with a pittance of $50 million for vaccineresearch, will allow meaningful progress against thisdisease, which our troops could now contract any-where in the world.

WRAIR plans to conduct a Phase 3 trial in Thai-land in 2002 that will compare several prime booststrategies, which will probably include combinationsof DNA or Canarypox and gp120 or gp140.

FOOD AND DRUG

ADMINISTRATION

Because HIV vaccines have progressed so slowly,the ultimate role of the FDA has been under-appre-ciated. This agency must approve the initiation ofhuman trials of any candidate vaccine, any efficacytrials, and license any product. FDA must securepublic safety for drugs, foods, and biological prod-ucts—an increasingly overwhelming responsibility.

We have heard few complaints to date about FDA’swillingness to work with vaccine developers andmove their products forward. FDA encourages com-panies and others to work with them before applica-tion to accelerate the process.

Last year, FDA gave two candidate vaccinesInvestigational New Drug status, allowing them tomove forward with clinical trials. The average forthe last five years has been three per year. Theseapplications must come from researchers, develop-ers, or government sponsors, but the FDA reviewprocess, coupled with rapidly escalating agencyrequirements for data needed to complete an application, can add many years of research after

completion of the first successful efficacy trial.

FDA must be encouraged to expedite the vaccinedevelopment process as much as possible. Inresponse to activists’ demands for expeditedapprovals, the agency developed streamlinedprocesses and special programs to get drugs forAIDS and other life-threatening illnesses to thepeople who need them. Drug companies welcomedthis change. The Biologics group at FDA, whichoversees vaccines, could take a lesson from theTherapeutics division.

AVAC knows that trial participants’ safety must beforemost, but we commit to work with FDA andinvestigators to improve existing regulations andprocesses.

COORDINATION

AVAC and the President’s Advisory Council havecriticized the mechanisms by which federal agencieswork together. Dr. Nathanson was charged withcoordinating the work of these agencies at aPresident’s meeting on AIDS in 1998. He convenesa biennial meeting of NIH, Walter Reed, CDC, andFDA to share information. Dr. Margaret “Peggy”Johnston, Assistant Director for HIV/AIDSVaccines at the Institute of Allergy and InfectiousDiseases, reports directly to Dr. Fauci for thisresponsibility. Individual managers in the agenciesmaintain close relationships with counterparts inother agencies.

Still, as in years past, we see little evidence thatthese agencies coordinate efforts effectively. Withincreased awareness of the economic and securityimpact of AIDS and the need for internationalresearch and trials, the State Department, USAID,and others should be brought into the process.


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AIDS VACCINE PROGRAMSAT NIH

NIAID DIVISION OF AIDS

The NIAID Division of AIDS funds and managesthe lion’s share of AIDS research at NIH and theworld. Its Director, Dr. Jack Killen, has announcedthat he will leave this year. The Division statesthat “basic science and applied research, fueled byNIAID investments, are creating unprecedentedopportunities to expand vaccine discovery anddevelopment within the next five years.” A goodfaith effort is being made to do so for basic research,translational and applied research, and clinicalresearch.

But the Office of AIDS Research (OAR) has iden-tified 85 separate strategies to pursue in fiscal year2000, so it is a juggling act to apportion ever risingresources between investigator-initiated and direct-ed research. By plan, the bulk of the research isinvestigator-initiated, that is, investigators competefor grants through a peer-review process. A separatestudy section for evaluating vaccine grant proposalswas piloted in 1998. In fiscal year 1998, 38% wentfor basic research, 34% was used for targeted researchinvolving preclinical product development, and28% funded adult and perinatal research and devel-opment of clinical trial infrastructure. (Based onresearch by TAG and AVAC.)

Dr. Peggy Johnston came to her position as AssistantDirector for HIV/AIDS Vaccines in 1997 after program management had planned several newlyconceptualized initiatives which were not yet in place.With a number of vacancies in her group, she isvaliantly dealing with the fallout, but is a long wayfrom a fully-staffed, smooth-running program.

The challenge—to take the peer-review system andput in place a well-coordinated, overall program—will be achieved by managing grant portfolios anddeveloping targeted programs such as those outlined

below to fill the gaps. The schema for these pro-grams, conceived in 1996–98, and developed overthe last few years, has taken many years to put inplace (See page 16). Unfortunately, more years willpass before we can evaluate whether they workedand fit together well.

A description and status report for each programand other useful information can be found at theNIAID Division of AIDS (DAIDS) Web site:http://www.niaid.nih.gov/aidsvaccine

DAIDS PROGRAMMATIC GOALS

AND MILESTONES FOR

FISCAL YEARS 2000 AND 2001

FY 2000 Funding

• Continue active oversight of unsolicited awards.

• Fund Innovation Grants (ongoing).

• Fund new HIVRAD and IPCAVD applications.

• Fund Vaccine Design and Development Teams.

• Establish Vaccine Trials Network.

FY 2001 New and Continuing Initiatives

• Innovation Grant program announcements(ongoing).

• Second IPCAVD program announcement.• SIV Evaluation Units Requests for Proposals.

• HIV Database Request for Proposals.

• HIV Production Contracts, a 3-part Request for Proposals.

“Every NIAID research program aims toimprove health. Even the most esoteric investigation is undertaken with the hopethat it, in combination with many other studies, will provide insight to improve diagnostics, treatment, and/or prevention.”

NIAID Strategic Plan, October 1999


15

Planning is underway for fiscal year 2002.

Soon it will be possible to examine the ability ofthis system to generate a pipeline of productresearch and development. We encourage DAIDSto do so carefully in order to make sure its initia-tives are performing as planned.

DALE AND BETTY BUMPERS

VACCINE RESEARCH CENTER

Last spring, near the second anniversary ofPresident Clinton’s ten year challenge, he attendedthe ground-breaking ceremony for the Dale andBetty Bumpers Vaccine Research Center. TheCenter will be a beautiful new laboratory dedicatedto vaccine research and development, with an ini-tial focus on an HIV vaccine. Since the groundbreaking, the Center’s new director, Dr. Gary Nabel,has been putting together an organization and wait-ing to move in.

Meanwhile, Nabel’s former laboratory at Universityof Michigan has been making a wide range of con-struct antigens to test in animals and humans. Theirfirst protocol will be a small Phase 1 safety trial ofone DNA construct at the NIH clinical center.Nabel has conducted a number of planning meet-ings and recruited at least two top scientists to leadtwo of the four areas of the lab: Dr. GordonDouglas, formerly of Merck, to manage productdevelopment efforts, and Dr. Norm Letvin to leadits animal testing program. Douglas and Letvin arenot full time employees, so the program may havethe best people but not their full effort. Remainingto be filled are leaders for the human immunologylabs and human testing groups.

This team will be under tall orders. At last year’sceremony, President Clinton said, “I am confidentthat this is a place where miracles will happen.

AIDS VACCINE RESEARCHCOMMITTEE

One of the major recommendations of the 1996Levine panel was to “restructure the entire NIH/AIDS vaccine research effort and that a trans-NIHvaccine program should be established with leader-ship and oversight provided by distinguished, non-government scientists.” The restructuring, such asit is, is described above. The distinguished panel isthe AIDS Vaccine Research Committee (AVRC), chosen and led by Dr. David Baltimore. This high-profile group of ten scientists and one AVAC mem-ber has been meeting three times a year since 1997.

What it has done and how well it has worked isopen to discussion. IAVI Report quoted oneunnamed researcher as referring to the Committeeas “a science club.” The group has reviewed a largenumber of scientific issues and made recommenda-tions about them. It gave its imprimatur to theinnovation grant program and organized withNIAID the only national AIDS vaccine meetinglast year. The Committee has relied on manage-ment at NIH to help guide its efforts, and focusedon particular issues that have been brought to orcome to its attention. To date, it has not attemptedto provide leadership and oversight for the entireNIH/AIDS vaccine research program. In its tenure,AVRC has focused on a number of critical scientificissues, including animal models and primate re-sources, neutralizing antibody, CTL measurement,mechanisms of live attenuated vaccines, the role ofclades, vectors, and, of course, innovation.

We agree with the original Levine Committee rec-ommendation that the Committee should provideadvice and consent for the program overall, not justthe scientific agenda. This will require moreresources, direction from the Committee, and coop-eration from NIH.


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I N I T I A T I V E S P U R P O S E DATE OF 1ST FREQUENCY OF # OF AWARDS

APPLICATIONS APPLICATIONS TO DATE (4/00)

Extramural R01 Grants;Intramural Contracts

Unsolicited investigator-initiated research. — On-going 80 new R01 grants, 55full and partial intramu-ral awards in FY1999

Reagent Support; HIVMolecular ImmunologyDatabase

Researcher support. — On-going 2 contracts (1 each)

Innovation Grants To draw researchers into the HIV vaccinefield and increase the number of promisingconcepts entering the research pipeline.

1997 3x/year 191 grants

HIV Vaccine Research andDesign (HIVRAD)

To support development of HIV vaccineconcepts into products.

1998 1x/year 3 complete awards, 1 partial award

HIV Vaccine Design andDevelopment Teams

To promote a development-oriented approachto vaccines by funding teams of researchersfor long-term coordinated projects.

1999 5 yearawards

Pending

Integrated Preclinical /Clinical AIDS VaccineDevelopment (IPCAVD)

To encourage academic-industry collabora-tions that will move vaccines through the final preclinical stages and into earlyclinical trials.

1997 1x/year 8 active awards, 12 total awards

Primate Testing Contracts To create a standardized challenge systemthat would allow investigators around theworld to generate comparable results withvaccines in primates.

— On-going Supplements to 2 existing contracts

Simian Evaluation Units To evaluate promising SIV and HIV vaccinesin non-human primates.

1998 5 yearawards

Renewal competition pending

HIV Vaccine DevelopmentResources Contracts

Resources to facilitate development ofpromising vaccine candidates into testableproducts.

1998 7 yearawards

14 contracts

Vaccine Trials Network(VTN)

Domestic and international human testingof HIV vaccine candidates, all phases.

1998 5 yearawards

3 core functions award-ed, site awards pending

NIH VACCINE FUNDING PROGRAMS:WILL THEY DELIVER A PREVENTIVE HIV VACCINE?

Source: NIAID Division of AIDS and Office of AIDS Research


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SCIENTIFIC REVIEW

In the second half of 1999 there was a spirited debate in the scientific community about proposedchanges in the NIH system for scientific review.OAR Director Neal Nathanson, with support frommany AIDS scientists and activists, led successfulopposition to a proposed reorganization that wouldhave redefined the system of Integrated ReviewGroups and eliminated the dedicated AIDS reviewgroup. AIDS study sections will continue to be organ-ized together into an AIDS specific review group.

Another Levine panel recommendation was to cre-ate a separate vaccine study section dedicated toapplications that focus on vaccine development forAIDS and non-AIDS vaccine research. The goalwas to have a panel of vaccinologists and appliedscientists review vaccine grant applications that areperceived to be less appealing to basic sciencereview groups. After studying this proposal, theCenter for Scientific Review, which manages themajority of peer review at NIH, created a SpecialEmphasis Panel, which should eventually become aChartered Review Committee. This pilot study sec-tion has met five times since November 1998. To date, it has considered more than 450 grantapplications, including the AIDS vaccine innova-tion grant applications. One-third to one-half of the applications have been AIDS vaccine

applications. We consider this a success and recom-mend that the study section be allowed to matureand be made permanent.

The Fogarty Center has a thriving program in theUS to train researchers and clinicians from thedeveloping world in the US, and also providesdirect funding of developing country research insti-tutes. Fogarty, with the Institutes, should considerbroadening its focus to increase the capacity ofaffected countries to establish their own researchand development efforts, which several countrieshave expressed interest in doing.

In addition to NIAID, other NIH institutes doimportant AIDS vaccine research. The NationalCancer Institute (NCI) received $21.4 million infiscal year 1999 that goes almost exclusively for pre-clinical work. About half of this funding stayed within NCI for intramural researchers. TheNational Center for Research Resources (NCRR)received $8.9 million in fiscal year 1999, mostly forprimate centers and General Clinical ResearchCenters at universities and hospitals. NCRR pro-vides important core support for primate researchers.Neither of these efforts, NCI intramural researchnor NCRR AIDS programs, has received properscrutiny. We call for careful evaluation of theireffectiveness and relation to the larger programs bythe AVRC in the near future.


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In last year’s report, we printed anopen letter to NIAID DirectorFauci and OAR DirectorNathanson asking that NIH estab-lish clear, publicly identified inter-im milestones, and a system tomonitor NIH programs to deter-mine how well they work at broad-ening the product pipeline. Wewant the program leaders to haveambitious, realistic targets to meas-ure themselves against, because webelieve that without interim goalsthat can be tracked, the ultimategoal of an HIV vaccine is less likelyto be realized in a timely way.

In their two-page reply, which citedrecent leadership positions filled,scientific advances, and efforts theyhave made to move things forward,Fauci and Nathanson made thisresponse, “progress cannot be meas-ured simply by the number of productspassing specific milestones, because thequality of the product is much moreimportant than the number tested, asdocumented by the failure to identi-fy many highly promising vaccinecandidates in spite of the largenumber of NIH-funded Phase 1 and2 trials conducted over the last 10years.” They close by suggestingthat the question of vaccine moni-toring be discussed by the AVRC.

When this answer was quoted in

IAVI Report, Bill Snow of AVACmade the following reply, “of coursethe quality of products is most im-portant, but key questions can beanswered by testing and improvingon every reasonable approach. Westill hope that NIH can identifyappropriate annual objectives thatkeep things moving as quickly aspossible.”

So, Dr. Nathanson put this on theAVRC agenda and it was discussedat two of the last three meetings.In January, Dr. Peggy Johnston, whoheads the NIAID Division of AIDSvaccine program, presented the pro-grammatic goals on page 14. Shealso presented the following currentscientific milestones for her pro-grams and team:

• Pseudovirion into Phase 1 trial:Q2–2000

• P55 particle into Phase 1 trial:Q3–2000

• Viral vector into newborns:Q2/3–2000

• MVA into Phase 1 trial:Q1–2001

• VEE replicon into Phase 1 trial:Q1–2001

• Vaccine Design & DevelopmentTeams milestones: TBD Q2–2000

• Canarypox Phase 2 US/Caribbean, Q1–2000 (will not occur until the secondquarter)

• Canarypox into Phase 2b trial:Q1–2001 (already an unrealistic goal)

Making these objectives public is abig step forward in helping theAVRC, AVAC, the interested pub-lic, and the DAIDS team itself allbecome aware of the reasonableexpectations for progress.Circumstances may change, but ifwe all know precisely what we’reworking toward in the short term,we stand a much better chance ofmeeting those interim objectivesand reducing delays between activi-ties. We encourage Dr. Johnston’sgroup to set goals for all of theircooperative agreements and con-tractors, particularly for the big,high-priority projects like the com-parative animal studies and VaccineTrials Network.

We also think it still would makesense to set some goals for the lesstangible but equally importantneeds, such as the number of indus-try partners involved in developingHIV vaccines and the number ofcountries ready to participate invaccine research.

A N N O U N C E M E N T O F I N T E R I M G OA LS A N D M I L E S TO N E S


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Agonizingly slow progress is beingmade toward a US government-sponsored efficacy trial of theCanarypox vector with some HIVantigens inserted and an envelopeboost. Aventis Pasteur (formerlyPasteur Merieux Connaught) hasimproved its antigen and vectors atleast four times since 1994, requir-ing new Phase 1 trials to be con-ducted by AVEG. In the sameperiod, confidence that the enve-lope boost would provide function-al antibody has eroded to the pointwhere only VaxGen is pursuingthat approach, while others searchfrantically for an envelope con-struct that will elicit broadly neu-tralizing antibodies. As time hasticked away, several other viral vec-tors, designed to induce cell-medi-ated immunity have been advanced.Only two of those have even begunin human trials despite the involve-ment of IAVI and many others.

The HIVNET network was set upto run vaccine efficacy trials thatnever materialized, but did runbehavioral and microbicide efficacytrials. This network is now beingdismantled, and the newer VaccineTrials Network (VTN) is only nowabout to fund a limited number ofcore sites. Site expansion will fol-low only when a particular largetrial moves forward.

The VTN proposes that its firstventure into efficacy studies withthe Canarypox-gp120 approach benot a full-scale definitive licensingtrial, but what is variously called a“Phase 2b,” “intermediate,” or“proof-of-concept trial.” Such atrial could give a rough estimationof any efficacy (<30% vs. 30–70%vs. >70%) and provide the oppor-tunity to do some informative sub-analyses.

Two techniques are being devel-oped that would allow a reasonableanalysis for cellular correlates ofimmunity in larger numbers thanany human or animal trials to date:1) ELISPOT assays that identifyindividual cells by the antibody orcytokine they secrete, and 2) flowcytometry that would sort cells bythe surface markers and cytokinesthey contain. The ability to dosuch assays in bulk on frozen sam-ples has not yet been achieved, but will almost surely be availablein time.

Any decision about whether or notto move into an efficacy trial ofthe Canarypox vector must takeinto account how long it will bebefore other products will realisti-cally be ready for efficacy trials.Waiting for other antigens may notbe the optimal way to move

quickly, since experience has taughtus that no approach has ever gonedirectly from the lab throughhuman trials without iteration andimprovement. As we have learnedwith this approach and others,those processes take years.

Acknowledging that reality, thereis every reason to move ahead asquickly as possible with the Phase2b Canarypox trial. To delay test-ing of one product simply becausesomething better is believed to liedown the road, could be a scientif-ic and human tragedy. We callyour attention to the Salk andSabin polio vaccine story in whichthe less scientifically appealing andsophisticated approach carried theday and ended an epidemic.Whether Canarypox is a usefulvector for HIV vaccines is anempirical question that can only beanswered with experimentation.

When Neal Nathanson took officeat the Office of AIDS research in1998, he said, “The crucial thing isto explore all promising ideas asquickly as possible. The way thisepidemic is going, any otherapproach would be intellectuallyabsurd and ethically uncon-scionable.” We agree, and supportNIH in moving forward withpreparations for a Phase 3 trial.

M OV I N G TOWA R D U. S . G OV E R N M E N T- S P O N S O R E DE F F I C AC Y T R I A LS


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MOVING TOWARD U.S. GOVERNMENT-SPONSORED EFFICACY TRIALS CONTINUED

Maybe all we’ll find out is that thisapproach to an HIV vaccine is notefficacious, but even that would beprogress. Certainly we’ll have a betteridea of how the animal experimentsrelate to the human. And govern-ment will have done a Phase 3 HIVvaccine trial for the first time, whichwill make the subsequent trials ofrelated or different vaccines smootherand faster.

Two years ago in our Agenda forAction, AVAC stated that a far greaternumber of clinical trials must be initi-ated if there is to be any chance ofreaching a ten-year goal for an HIVvaccine. Then and now, we supportthe evaluation of vaccine products inclinical trials when the products andtrial designs are likely to helpresearchers learn more about vaccinesand protection from HIV.

If candidate HIV vaccines were drugsthat could totally eradicate an infec-tion, they would be tested on eventhe slimmest evidence of potential.For both drugs and vaccines, uncer-tainty is involved and lives potentiallysaved. Where there is real potentialfor progress on HIV vaccine research,it is incumbent upon us to act.

“Last year, AIDS killed about ten times more

people in Africa than did armed conflict…

The breakdown of health and education servic-

es, the obstruction of humanitarian assistance,

the displacement of whole populations and a

high infection rate among soldiers—as in other

groups which move back and forth across the

continent—all these ensure that the epidemic

spreads ever further and faster.”

Secretary-General Kofi Annan

United Nations Security Council Opening SessionJanuary 10, 2000


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Governments and citizenry in countries rich andpoor have finally woken up to the magnitude of theinternational epidemic and its catastrophic impacton Africa, Asia, and other regions. Hopefully, wewill not return to pleasant slumber.

Leaders in the West have recognized the impor-tance of making vaccines primarily for use in devel-oping world populations. Yet development of thesetargeted products has a long lead-time and some-what uncertain outcomes. Deciding to make aproduct, or multiple products, to test in a certainpopulation allows infecting viruses from that loca-tion to be used in the vaccine design. But the timebetween that decision and large scale testing couldeasily be five or more years.

In the mean time, these approaches may look lessappealing, and new approaches may be conceptual-ized and developed. Simultaneously, almost everydesirable population for testing is changing—itsvirus, its seroincidence (especially with quality pre-vention efforts) and its politics. The countries withdemonstrated interest in vaccine trials, Thailand,Uganda, South Africa, and China are working withresearch partners. Other countries may not be

politically stable enough to live up to commitmentsto launch trials.

Partnerships for clinical trials

Other players have adopted the Department ofDefense and IAVI mode of developing vaccines bybrokering between developers and affected coun-tries. Each research group wants a trial site to have:

• Cooperative, enthusiastic government and agencies.

• Scientific experience.

• Some health infrastructure.

• A sizable cohort of at-risk individuals.

• A high seroincidence.

Every site wants:

• Whatever vaccine approach currently looksmost promising.

• An antigen developed from local virus strains.

• Access to a successful vaccine.

• Improvement of their infrastructure.

0 S TAT U S UNAIDS Ethics Guidelines issued • IAVI receives funding and signs contracts • Public awareness of

global nature of epidemic • Multiple human trials beginning • Increasing government interest • Increasing number

of partnerships • Growing advocacy 0R E C O M M E N DAT I O N S Ensure ethical trials through advocacy • Fund

IAVI and other efforts to advance international research • Support new mechanisms to deliver existing vaccines • US

government agencies should facilitate partnerships

THE GLOBAL RESPONSE


23

The prime, targeted countries have an embarrass-ment of suitors. Most also have a serious enoughepidemic to work with many researchers. Theserelationships require a long-term commitment fromdeveloped countries to work with developing-coun-try scientists and provide training and infrastructureover many years. These important negotiationsshould probably not be left entirely to the agenciesand scientists involved. Other US governmentagencies, including the State Department andUSAID, and European Union agencies should helpfacilitate these matches. Since 1992, WHO andUNAIDS have been assisting developing countriesin the development and implementation of nationalAIDS vaccine plans.

Several developing countries have made the long-term commitment of educating their populationsand are already conducting preventive vaccine tri-als: Thailand, China, Cuba, Brazil, and Uganda. AVTN trial is set to begin in Haiti, Trinidad/Tobago,and Brazil. Planning for trials is in various stages ofdiscussion or development in several more coun-tries, including Russia, India, and a number ofAfrican countries, including Kenya, Zambia,Zimbabwe, Botswana, Malawi, and Ethiopia.

Several countries in the developed world are alsobeginning to create programs and invest in vaccineresearch and development. These include the UK,European Union, Japan, Australia, and Canada.Canada and the Netherlands are also participatingin the Vaxgen efficacy trial.

Most encouraging to us has been the awakening ofdeveloping countries to the possibility of developingor contributing to the pre-clinical development ofvaccine candidates themselves. Their resources aredwarfed by the companies, governments, and foun-dations of the Northern hemisphere, but thesemoves toward empowerment in the face of an over-whelming disaster bode well for cooperative activityand concerted action. Nothing, perhaps, would

move the vaccine development effort forward morequickly than invigorated governmental and scien-tific partnerships, and a sense of ownership by popu-lations where vaccines must be tested and wherethey are most needed.

INTERNATIONAL

ORGANIZATIONS AND

AGENCIES

The important international agencies, WHO-UNAIDS and World Bank are each making differ-ent contributions to globalize the AIDS vaccinedevelopment effort. A few charities and founda-tions, notably amfAR and Elizabeth Glaser PediatricAIDS Foundation, are funding pre-clinical research.The International AIDS Vaccine Initiative, however, stands out for its activities and accom-plishments. These include assembling a staff offundraisers, scientists, and communicators that areattracting substantial charitable and public contri-butions, financing product development, and keep-ing the field informed of activity and progress. They have also been instrumental in the develop-ment of similar initiatives in other countries.

UNAIDS/WHO

The multi-agency UNAIDS has represented theUnited Nations since 1996 in calling the world’sattention to the severity of this epidemic. In February, 2000, the UNAIDS AIDS vaccine program was reorganized as a joint program ofUNAIDS and the World Health Organization’sExpanded Program for Immunization called theWHO- UNAIDS HIV Vaccine Initiative. TheInitiative “will focus on strengthening the [research]capacity in developing countries to ensure that vac-cine trials are conducted with the highest ethicaland scientific standards.” Leaders of the Initiative


24

hope it will be able to“broker partnerships betweenpublic and private sectors,” in order to accelerateresearch.

Since 1989, WHO and UNAIDS have been estab-lishing international co-ordination and collabora-tion on HIV vaccines, and assisting selected devel-oping countries in establishing infrastructures whereHIV vaccine trails could be conducted with thehighest ethical and scientific standards. In 1992–3they assisted Brazil, Thailand, and Uganda in thedevelopment of their National AIDS Vaccine Plans.National plans provide, 1) policy frameworks forvaccine activities, 2) procedures and mechanismsfor review, approval and monitoring of vaccine pro-posals, and, 3) preparatory research (virology, epi-demiology, clinical trials, social behavioral studies).

These plans were instrumental in the conduct of trials in the countries noted above. Of the twelveHIV vaccine trials conducted in developing coun-tries since 1983, eight have been, or are being conducted in Thailand. The others were conductedin China (1993), Cuba (with technical supportfrom UNAIDS), Brazil, and Uganda. WHO-UNAIDS is currently assisting China, Ethiopia,Zambia, South Africa, Russia, and India in thedevelopment of national AIDS vaccine plans,strategies, and missions, and focusing on regionalapproaches, with development of an African AIDSvaccine strategy.

In February, 2000, UNAIDS released its GuidanceDocument on Ethical Considerations in HIV PreventiveVaccine Research. The document contains eighteen“guidance points” on HIV-vaccine-trial ethics.Among its conclusions: if a vaccine proves to beefficacious, all trial participants “as well as…otherpopulations at high risk of HIV infection” shouldreceive the vaccine as soon as possible; and, com-munity representatives should be involved “earlyand in a sustained manner” in research-design and planning.

The most controversial issue addressed by UNAIDSwas the extent to which researchers in all countriesare obligated to provide HIV-related health care tovaccine trial participants who become infected withHIV during the trial. After extensive debate, theUNAIDS Guidance document took a middle ground,calling for care and treatment for HIV for partici-pants, “with the ideal being to provide the bestproven therapy, and the minimum to provide thehighest level of care attainable in the host country.”

Advocates, researchers, and community membersmust press for the best possible care in every trial.At the same time, the West should not insist onprovision of Highly Active Anti-Retroviral Therapy(HAART) to every vaccine-trial participant incountries where HAART is unavailable to personsnot involved in the trials. Local governments,researchers and health authorities have a responsi-bility to strive for the highest quality care possible,as do researchers not from these countries. Webelieve local communities and authorities shoulddecide when to participate in trials.

This important work is done with less than $2 mil-lion per year, to serve all UN member nations.

INTERNATIONAL AIDS VACCINE

INITIATIVE

The Bill and Melinda Gates Foundation providedthe International AIDS Vaccine Initiative (IAVI) alarge grant to fund its HIV vaccine research. IAVIhas raised about $75 million to fund five to six vac-cine development projects. If any one proceeds towide testing, IAVI will need hundreds of millionsmore. IAVI continues to make an invaluable con-tribution by keeping the issue of HIV vaccinesbefore the public, scientific community, and govern-ments around the world. It has helped similarefforts in the UK and South Africa, and will contin-ue in other countries.


25

WORLD BANK

The World Bank has established an AIDS VaccineTask Force co-chaired by Amie Batson and MarthaAinsworth. They have been exploring ways thatthis international lending agency could acceleratedevelopment of an AIDS vaccine for developingcountries. Their work has helped clarify alternativeapproaches and shown governments and founda-tions how their contributions can influence theeffort. One part of their recommended program isestablishment of a purchase fund or low-interestloan replenishing fund to spur investment and tobuy a vaccine when available.

GLOBAL ALLIANCE FOR

VACCINES AND IMMUNIZATION

Every year, 6.7 million children under the age offive die of infectious diseases, almost entirely (99%)in the developing world. Approximately 4.1 million(70%) die from diseases preventable through immu-nization: Pneumococcus, Measles, Types of Haemo-philus, Pertussis, Tetanus, and Hepatitis B. Thiscurrent deficit is raised when planning for future

vaccines, such as HIV. In the past, it has typicallytaken many years and massive international effortswith intensive worldwide support to achieve broadaccess to critically needed vaccines.

Global Alliance for Vaccines and Immunization(GAVI) has received funding from the Bill andMelinda Gates Foundation, the InternationalFederation of Pharmaceutical ManufacturersAssociations, UNICEF, WHO, and the World Bank.GAVI is intended as a demonstration project todeliver existing vaccines and to pave the way fordelivery of new vaccines worldwide when theybecome available. (The Bill and Melinda GatesFoundation also pledged $750 million to a globalfund for children’s vaccines and has made a com-mitment of $100 million for the Bill and MelindaGates Children’s Vaccine Program, both of whichwill promote delivery of existing vaccines to chil-dren in low and middle-income countries.)

Somehow or other, most countries in the industrial-ized world allowed fifteen years to pass, before thediscovery that AIDS is a monumental problem inAfrica. Asia, Eastern Europe, and South Americaface the same unbearable catastrophe.


26

Many dedicated researchers aredevoting time and resources toimproving our knowledge aboutHIV and immune responses in aconcerted effort to help design anddevelop HIV vaccines. This workranges from basic immunology insmall animals and HIV pathogene-sis and epidemiological research, toexperimentation with various vac-cine techniques and concepts inthe test tube, in animals, and invaccinated or infected individuals.In this arena, every new bit of sci-entific evidence adds to our abilityto conceptualize and develop bet-ter vaccines. Without passingjudgment on the importance ofany individual work and with theawareness of being unable to men-tion many lines of research thatwill certainly be important, here isa very limited snapshot of what’sgoing on in several research areas.

Basic immunologyInvestigators are plumbing thecomplexities of the immune system, often in mouse models. This is leading, step-by-step: toimproved understanding of the roleof antigen presentation, immunehelp, development of memory cellswith their initial expansion andsubsequent reduction, mainte-nance of memory, and killing ofinfected cells by cytotoxic T lym-phocytes and other mechanisms.

Dynamics of infection Of great interest for designing vac-cines are the dynamics of earlyinfection. HIV can replicate inresting and activated CD4 cells atthe portal of entry, rapidly produc-ing chronically infected cells (Haasand others.) It would be useful toknow how much of infection isfrom cells vs. free virus; whereinfection begins; and how, where,

and how fast it spreads and estab-lishes itself in the lymph system.

HIV presentationInvestigators focusing on mecha-

nisms of cellular immunity and itsabsence in early and late HIVinfection are probing the functionof professional antigen-presentingcells. Recent work has identifiedthat dendritic cells can pick upHIV from mucosal linings andshuttle it to T cells in lymph nodeswithout becoming infected them-selves (Geijtenbeek and others.)

Neutralizing antibody The intractability of makingbroadly neutralizing antibodies toHIV with vaccines has capturedthe attention of another group ofinvestigators who are trying tounderstand how the few mono-clonal antibodies identified ininfected individuals work. Theseresearchers may be beginning tounderstand why HIV is so difficultto neutralize. Scientists are alsotrying to understand and confirmexperiments that captured “fusioncompetent” molecules on cell sur-faces that induced broadly cross-reactive antibodies in mice(Nunberg.) Some investigatorsbelieve that gp140 (gp120 withpart of gp41) looks to be a more

“Usually, we take a small amount of the tiny little monsters frompeople who are sick. We do lots of very complicated things to makethem weak. But none of the complicated things worked very wellwith the little monsters that caused mumps.”

Jean-Louis, Y. with Simon, D., The Story of Jeryl Lynn Based on a true story about the discovery of the Jeryl Lynn mumps strain and the creation of the combined vaccine againstmeasles, mumps, and rubella. Merck Vaccine Division, 1997.

T H E LO N G M A R C H O F


27

promising antigen and it is beingdeveloped by at least two groups(Progenics and Chiron.) Otherinvestigators are deleting variableloops from the virus which appearsto enhance immunogenicity(Desrosiers and others.)

Viral entry Structural biologists have recentlymade strides in understanding thecrystal structure of gp41 and iden-tifying sites to block viral entry for drugs and vaccines (Kim andothers.)

Immune signaling Other distinguished investigators,particularly Fauci, Levy, Paul, andGallo, are studying the complexand very important interaction ofimmune signals by cellularcytokines and chemokines.

Immune failureEpidemiologists and fieldresearchers are meanwhile tryingto piece together the mysteries oflong-term non-progressors and highly-exposed-but-uninfectedindividuals. Clinical researchersare re-examining the role of thera-peutic vaccination, which mightbe combined with highly effectiveantiviral drugs. Not only mightthis approach assist with immune

reconstitution and defense in infect-ed individuals, it also may helpanswer some key questions abouttheir value as preventive vaccinesto control subsequent infection.

VACCINE DESIGN DERBY

The use of viral and bacterial vec-tors is currently a very active areaof research, and a wide range ofvectors is being studied. Thesevectors have different safety pro-files, licensing statuses, and abili-ties to accept HIV genes orsequences. Now that safer, non-replicating Canarypox vectors arefar along in human testing, repli-cating vectors, such as attenuatedvaccinia, are getting much atten-tion. Other interesting vectorsthat may hold promise include:attenuated herpes viruses, aden-ovirus, and adeno-associated virus-es (AAV.) The alphaviruses,Venezuelan equine encephalitis(VEE), Semliki forest virus (SFV),and Sindbis also hold promisebecause of their apparent ability totarget antigen presenting cells.DNA vaccines are being refinedand explored on many fronts, in anattempt to optimize their geneticcomposition and delivery.

Adjuvants that can boost or directthe activity of an antigen are an

under-appreciated area for impro-vement. Dozens of potential adjuvants could be tested with avariety of antigens in animals andhumans. Some of these may pro-mote antibody formation, othersmay be more likely to promotecell-mediated immunity. Cytokinesmight also be used as adjuvants for vaccines.

ANIMAL TRIALS, ANDTRIBULATIONS

From animal researchers, the twomain lines of inquiry are attempt-ing to understand protection fromattenuated SIV, and comparativechallenge studies with intensiveimmunological analysis. Monkeyscan be challenged with virusstrains that display various levels of virulence, selected for theirgenetic type allowing sophisticatedimmunological analysis, and biop-sied or sacrificed to analyze effectsin tissue and other compartments.Parallel testing in human trials andanimal challenge experiments mayallow a better understanding of thetype of immune response induced.Such findings may also help us tobe more selective in the regimeswe choose to move forward intofuture efficacy trials.

S C I E N C E , W H AT ’ S N E W


28

THE LONG MARCH OF SCIENCE, WHAT’S NEW CONTINUED

The development of twin orcloned monkeys with identicalhistocompatibility (tissue) typeswould allow the kind of experi-mentation that is occurring insmaller animals to be validatedand extended to non-human pri-mates. Such experiments mighthelp focus the vaccine-develop-ment process by providing firmevidence of the relative roles ofdifferent immune responses inprotection against retrovirusinfection or disease.

Shortages of Indian macaques forvaccine experiments and insuffi-cient planning for future needsmay jeopardize or delay this essen-tial and informative research, mak-ing it almost prohibitively expen-sive to conduct experiments withlarge enough numbers to obtainstatistically significant results.The provision of adequate num-bers of non-human primates frompathogen-free colonies wouldimprove the ability to conductmore meaningful experiments.

ASSAYS NEEDED

It will probably be just as impor-tant to have good assays as good

immunogens. Hard work is finallybeing done, especially by BectonDickinson Biosciences, MerckResearch Laboratory, OregonHealth Sciences UniversityVaccine and Gene TherapyInstitute, Harvard MedicalSchool/Massachusetts GeneralHospital, the Vaccine TrialsNetwork, and NIAID Division ofAIDS to develop measurementsthat can efficiently and reliablybe used to measure immunogenic-ity more sensitively and morepractically in field situations.

As great as all this activitysounds, and is, there are reasonsfor reservations. There areavenues for future vaccine devel-opment that appear to be stuck inresearch labs without sponsors orchampions who have productdevelopment experience. IAVIand the government are assistingto some degree, but much morecould be done. Aside from therisk and lack of scientific certain-ty, companies want to havepatentable techniques orapproaches to protect their work,and seldom will move forwardwithout “intellectual property.”The lack of any validated surro-

gate measurements for efficacy orproven animal models hampersprogress. Unfortunately, becausethere is no alternative, somehuman efficacy trials will berequired to establish the relation-ship between vaccine responsesand efficacy. It is possible thatthis relationship will never beconclusively determined evenafter an efficacious vaccine hasbeen discovered, licensed, anddistributed.

That said, every year incrementalprogress is made toward under-standing the mechanisms of HIVinfection and varying degrees ofprotection. We’ve discoveredthat one of the most importantattributes of a good scientist isknowing which important ques-tions are amenable to getting ananswer with current techniques.The attribute of a brilliant scien-tist is to develop novel techniquesto answer an important, previous-ly-untestable question. While wecan’t afford to wait until the com-plete picture is clear to us, theseremarkable and varied contribu-tions advance our ability to makedecisions and move forward.


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Starting with the groundbreakingwork of IAVI and the World Bank,intense interest has been kindledin the desirability of creating amarket for AIDS vaccines inadvance. The reasons are twofold.First, it is generally agreed thatlack of a guaranteed profitablemarket slows the pace of researchand development. Second, thehistory of vaccines has been thattheir introduction into the devel-oping world has been unacceptablydelayed while developers recouptheir investments with sales inrich-country markets. There canbe no argument that a widely dis-tributed HIV vaccine for thedeveloping world is a top interna-tional public health priority.

These facts have spawned a num-ber of global initiatives: for a pur-chase fund; guaranteed low-costloans; a tax credit that purchaserscould pass on to sellers; “roamingmarket exclusivity,” which wouldallow extension of one patent inexchange for giving up the vaccinepatent for the developing world;and a liability fund similar to theone for childhood vaccines. Thepromise of widespread access at theend of the road is the chief benefitof these plans.

On the other hand, the market forglobal vaccines will never be as bigas for computers or the Internet. Itwill probably never be as big as for

the blockbuster lifestyle drugs.And it will be a managed market.A case can be made that we areundervaluing immediate incentivesin our rush to fill a pot of gold atthe end of the rainbow. Money forresearch and development, andincentives that make research anddevelopment less expensive, alsocan have a substantial impact onthe pace of research and develop-ment. At least one vaccine makerbelieves that an HIV vaccinecould more profitably be sold andcost-justified, country by country.

We continue to push for “push”interventions, especially directfunding for research and develop-ment and tax credits that are moregenerous and targeted than thoseavailable for general research anddevelopment. These efforts toentice more companies and inves-tigators into the effort give imme-diate incentives to those braveenough to try—not just to a singlewinner at rainbow’s end. For thisreason, The Gates Foundation isinvesting in push initiatives for allthree big killers, through IAVI,their newly formed MalariaVaccine Initiative, and theTuberculosis International VaccineCollaborative.

As described in BioCentury, theBernstein Report on BioBusiness,the cost of developing a vaccine can be justified only by

a market of $500 million to $1 billion a year at maturity, and itwill be difficult, if not impossible,for a purchase fund to maintainsuch expenditures. More promis-ing would be to create a bona fideglobal market by reducing costwith global distribution. The orig-inal cost of the Hepatitis B vaccinewas $40 per shot, but the price hasdecreased substantially for develop-ing-world markets. As BioCenturyrecognizes, the size of this marketis potentially immense, but phar-maceutical companies “do not nor-mally venture” there.

The immense investment to get allthe way to a vaccine can probablyonly be borne by a large pharma-ceutical company, even with sub-stantial government assistance.This means that “pull” mecha-nisms are largely of value to thefew biggest companies that canafford to run that course. Smallercompanies must count on acquisi-tion by a large pharmaceuticalcompany or by making investmentand marketing deals with them.

Do we really only want only ahandful of companies working onan AIDS vaccine, considering theywill have other, more lucrative fishto fry? Even the sixth biggest com-pany, Chiron, looks like it’s havinga hard time keeping pace.

T H E P U S H TO “ P U L L”

“Problems with liability and profitability have

sharply reduced the number of private firms in

the vaccine industry. Recognizing that monop-

olies inevitably place the public interest at

risk, I believe that interest is best served by

multiple manufacturers and competition, not

by monopolistic or universal government pur-

chase, which will limit development of new

and improved vaccines.”

Barry Bloom

Dean of the Harvard School of Public Health, in ScienceSeptember 4, 1994


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LARGE PHARMACEUTICAL

COMPANIES

Industry consolidation into goliath companies is notan encouraging trend. Private sector drug compa-nies are under growing pressure to maintain thesizeable profits of the last few years. This pressuredrives consolidation, a search for efficiencies inresearch and production, and an emphasis on blockbuster drugs. These mergers and acquisitionsdo not bode well for HIV vaccine research. Severalimportant industry vaccine research efforts arealready in jeopardy.

Glaxo Wellcome is merging with SmithKline

Beecham, to temporarily become the world’s largestpharmaceutical company with a stock market valueof $186 billion, annual sales of over $25 billion andan annual R&D budget of more than $3.6 billion.Pfizer is merging with Warner Lambert after outbid-ding American Home Products to create an evenlarger company. Monsanto is proposing to mergewith Pharmacia & Upjohn, having already digestedG.D. Searle. Aventis is a conglomeration ofHoechst, Rhone-Poulenc and DuPont. In the lastdecade, Novartis/Syngenta, American HomeProducts, and AstraZeneca were created to be massive “life sciences” companies.

The US giants, Merck, Pfizer, Bristol Myers Squibb,and Johnson & Johnson have surpassed the largeEuropean drug companies—Swiss Roche andNovartis, British Glaxo Wellcome, SmithKline, andAstraZeneca—each with over $135 billion marketcapitalization. This is largely because the US is theworld’s largest, most lucrative, and fastest expandingpharmaceutical drug market. The only large, indus-trial country without government health insurance,the US accounts for almost 40% of global drugsales, growing at 12–14% per year—greater thandouble the rate in Europe where cash-consciousgovernments rein in windfall profits. High domestic

0 S TAT U S Industry consolidation • Thirst for blockbusters • Seven research programs (mostly limited) at big pharma

• Scraping for resources at biotechs 0R E C O M M E N DAT I O N S Pass the Vaccines for the New Millennium Act •

Establish both “push” and “pull” incentives • Recruit internal company “champions” for vaccines • Urge wealthy companies

to step up efforts • Develop technology that facilitates vaccine design

INDUSTRY

“We will challenge America’s pharmaceuticalindustry, which leads the world in innovativeresearch and development, to work to makethe successful development of an AIDS vaccine part of its basic mission.”

President Bill ClintonMay 18, 1997


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growth has provided US pharmaceuticals with “atorrential income stream to reinvest in the evermore costly business of finding new drugs,” accord-ing to Financial Times.

In this monster market, vaccines are a relativelysmall, niche industry, which may be lost in the shuf-fle of merger mania. The global market for vaccineswas estimated at only $1.7 billion 10 years ago andit has not risen much above $3 billion today. Drugsgive larger profit margins, less liability risk, andpatent protection that is easier to maintain.

After a round of consolidations a decade ago, whenthere were three times as many vaccine companies,there are now only five big vaccine makers:

• Merck & Company

• Aventis Pasteur

• Wyeth-Lederle/American Home Products

• SmithKline Beecham

• Glaxo Wellcome.

Because of its parent, Novartis, and its history andactivity with HIV vaccines, we consider Chiron asixth. Because of its recently financed capital base,we consider VaxGen a seventh major vaccine com-pany in the AIDS vaccine arena.

This year, we are able to say that, at this moment, allseven major companies appear to be working onHIV vaccines. Though several of these programsare modest for them, the increased activity is anachievement. SmithKline and Glaxo Wellcomehave only begun their efforts, Wyeth’s remains verysmall, and the scope and depth of Chiron’s commit-ment is in question. In the last year, we have notedthe following activity and changes, among them:

MERCK

After some years testing DNA constructs, Merck &Company began its first clinical trial of an HIV vac-cine, an optimized gag vaccine. The company fundsall of its own research and the Phase 1 trial is atseveral sites. The company plans for results of thistrial to lead to a multi-gene DNA vaccine, whichmay be used ultimately with a vector boost. Merckhas a history of developing important vaccines overthe long haul and the resources to maintain thisprogram, probably as long as they believe they cancapitalize on their rights to the DNA immunizationtechnology, licensed from Vical.

Unfortunately, in March, 2000, Merck warned thattheir current candidate HIV vaccine represents onlya first step and is not likely to represent a final vac-cine candidate. A company spokesman also predict-ed that development of an AIDS vaccine will take anumber of years, but indicated Merck’s long-term,ongoing commitment to produce such a vaccine.

AVENTIS PASTEUR

The French government, through the AgenceNationale de Recherches sur le Sida (ANRS) andthe European Community, heavily support AventisPasteur’s HIV vaccine program which has also reliedheavily on the US government’s clinical trials networks. Aventis controls the rights to severalpoxvirus vectors and have focused on theirCanarypox vector, called ALVAC. It has taken thecompany almost a decade to improve this approachby adding to their constructs. They are now poisedto test their ALVAC in a Phase 2 trial in the US,Caribbean, and Brazilian sites through the US HIVVaccine Trials Network, which is in preparation foran efficacy trial planned for next year. AventisPasteur is also moving forward with WRAIR inThailand. (See Trials: page 19). The company has rights to most poxvirus vectors, including


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the attenuated vaccinia strain NYVAC, and to theSemliki Forest virus, but they have not been devel-oping them aggressively, choosing instead to focuson Canarypox and expand the large database accu-mulated on its safety and immunogenicity.

VAXGEN

VaxGen made remarkable accomplishments in thelast year. First and foremost, they received approvaland completely enrolled the first Phase 3 efficacytrial of a candidate HIV vaccine, their bivalent B-clade gp120, AIDSVAX. Its sister trial is beingconducted in intravenous drug users in Bangkokwith a combined B- and E-clade product. VaxGencompleted an initial public offering with net proceeds of $42 million and raised an additional $24 million in a private placement of stock to theinvestment organization of Paul G. Allen, co-founder of Microsoft. VaxGen has reported clinicalexpenses, largely for the Phase 3 trials in NorthAmerican and Thailand, of more than $9.1 millionfor two no-frills trials with 7,900 participants atmore than sixty sites. The CDC supports ancillarystudies for their trials by conducting behavioralresearch at selected US sites. While awaiting theinterim review (2001) and final results of these trials in 2003, Vaxgen hopes to make a trivalentclade A, C, and D version of their envelope vaccine for Africa.

CHIRON

The Chiron Corporation has taken the alternativeapproach to Vaxgen by stepping back from theiroriginal focus on stand-alone vaccines employinggp120 envelope proteins, instead, re-focusing their research on alternative mixed (“prime-boost”)approaches that use novel gene-delivery technolo-gies in combination with next-generation

recombinant proteins. Under the leadership ofMargaret Liu (who has recently departed), theChiron team has developed several new and inno-vative vaccine approaches in the last few years.These include potent new gene-based vaccines thatutilize plasmid DNA adsorbed to microparticles andalphavirus replicon particles to target human den-dritic cells—the professional antigen presentingcells of the immune system. These approaches showdramatic improvements in cellular response overconventional DNA vaccines. A prime-boost vac-cine strategy using these new gene deliveries, incombination with modified HIV envelope proteinsthat appear to induce primary isolate neutralizingactivity, should provide a strong candidate HIV vac-cine for clinical trials in the near future.

Nonetheless, in November, 1999, Chironannounced plans to cut spending for early-stageresearch in gene therapy and vaccines. Chironmade a substantial investment and contribution tothe field of HIV vaccines and should not lose heartnow, but redouble its efforts. A great deal of impor-tant background work is about to come to fruition.If this newly acquired technology base proves itself,Chiron may be able to join the top ranks of vaccinedevelopers, extend its new technologies to otherintractable diseases, and make an immeasurablecontribution to science and world health. We callon Chiron and their partner, Novartis, to make thatcommitment.

Whatever Chiron and other dedicated vaccinecompanies have been spending, it is, from the pointof view of public good, money well-spent. Thepotential societal cost of reduced activity clearlyillustrates the deficiencies of market dynamics. Ofthe relatively few papers presented at the Retrovirusmeeting about vaccines, Chiron had twelve, all ofwhich related to finding better HIV candidate vac-cines. We hope that this important work can con-tinue to move forward.


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AMERICAN HOME PRODUCTS,SMITHKLINE BEECHAM, ANDGLAXO WELLCOME

Of our big seven, that leaves American HomeProducts (AHP), SmithKline, and Glaxo Wellcome.None of these vaccine/drug giants come close tohaving the commitment of the other four, and eachneeds to reassess and expand its commitment toHIV vaccines. Though American Home Productshouses several pertinent subsidiaries, only its DNAvaccine effort from Wyeth-Lederle Vaccines hasmoved into human trials that will hopefully lead toimproved constructs and more rounds of Phase 1 tri-als. The company also has relationships with sever-al academic and NIH researchers, which they statedemonstrate a strong interest in developing an HIVvaccine. The subject of takeover speculation, AHPmust consolidate its conglomerate parts and committo a more aggressive approach. SmithKline hasstayed on the sidelines, but they have been develop-ing exciting adjuvants in their candidate malariavaccine that can be used to deliver HIV antigens—which we have heard they are beginning to explore.

Glaxo Wellcome stands alone as the single com-pany that has made the largest contribution andinvestment in AIDS therapeutics. The companyhas profited accordingly. While not a vaccine giant,they currently make a rubella vaccine not distrib-uted in the US. Glaxo may enter the HIV vaccinearena with the Powderject technology, that wasacquired a few years ago, to deliver DNA vaccines.

As vaccine or AIDS giants, these three companiesowe the world a more serious, scaled-up effort onHIV vaccines. AVAC, Congress and the currentAdministration are working to discover what com-bination of public opinion, incentives, and persist-ence can get them to step up to this challenge.

Pharmaceuticals have larger profit margins, less liability risk, and easier-to-maintain patent

protection than do vaccine makers. This situationled Merck, the most successful private vaccinedeveloper, to establish a separate business unit head-ed by a “champion” for vaccines. For years, this wasMaurice Hilleman, followed by Gordon Douglas.Douglas has now retired from Merck Vaccines andjoined Gary Nabel at the NIH Bumpers VaccinesCenter. Emilio Emini has taken that role at Merckfor HIV vaccines. The other companies should fol-low suit by creating their own vaccine champions.

SCIENTIFIC EQUIPMENT

Industry support is needed in another significantarea. Manufacturers of scientific equipment andtesting devices must make a commitment to devel-op products that will aid HIV vaccine research.HIV vaccine science needs to develop new meansfor assaying how the candidate immunogens work,particularly in the human immune system duringand after clinical trials. A promising technology forquantitatively assaying CTL activity, which is themechanism of most of the current vaccineapproaches, is ELISPOT visual imaging. This tech-nology needs to be improved, standardized, andmade available.

Scientists are working on sophisticated reagents andtechnology to measure CTL and T cell immunity.Technology to permit large-scale evaluation by flowcytometry could be the key that will bring us out ofthe thumbs-up/thumbs-down dark ages. These, andreliable mucosal testing techniques, will be neededto support and contribute to the worldwide scientif-ic effort. We call on industry and government tosupport development of this critical technology.NIH could place an order for CTL cell sorters forlarge clinical trials in advance, as the defensedepartment does with its contractors.


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BIOTECH COMPANIES

Vaccine development life is even more difficult forthe small biotechs and startups that are trying todevelop new approaches more or less independently.Given the innovative potential of this sector inother scientific arenas, this is a tragedy. Vaxgen’sability to raise venture capital and then publicinvestment seems to have been based solely onbeing in efficacy trials, due to early Genentech andgovernment support and the charismatic characterand business savvy of its founder, Don Francis, andCEO, Robert Nowinski.

The notables who are surviving in this arena are:Alphavax with its alphavirus VEE; TargetedGenetics Corp. with AAV supported by IAVI;Progenics Pharmaceuticals Inc. with monoclonalantibodies and gp140; CelSci with its HGP30; UBIwith its peptides (though it may be dropping thisapproach); Immune Response with its killed virus(that remains untested in HIV negatives); andTherion, which supports its HIV work in vacciniaand attenuated HIV vaccines solely with govern-ment support. This is a sad situation, given our cur-rent financial wealth, biotechnological expertise,and innovation capabilities.

Unique among the small biotechs is Therion, whichis primarily working on cancer vaccines, with ven-ture capital not available for HIV work. DennisPanicali, Therion’s president, has a commitment tomake HIV vaccines and is doing so with a variety ofscientific and public partners. The company has avaccine production contract and an Integrated Pre-Clinical/Clinical AIDS Vaccine Development(IPCAVD) grant from NIAID, to develop threeMVA products for clinical testing, a vaccinia-basedparticle vaccine TCB-IIIB in government Phase 1trials, and agreements to work with developers infowlpox and live attenuated HIV.

In a recent interview in IAVI Report, Panicali said

he believes a combination of poxviruses may givethe best results, but that “Therion is too small tocarry many programs simultaneously.” When askedwhat the US government could do to speed thingsalong, he says, “It’s just a matter of getting a coupleof strong leaders to say, ‘This looks good, I’ve seenthe data, let’s do the trials. And I’ll put my ass onthe line and do whatever has to be done to get thistrial ready in a year.’”

Government and industry must develop some good,new way to create a thriving competitive market forbiomedical prevention R&D. Otherwise, we won’thave bright new ideas to bring into the develop-ment pipeline quickly enough, if the currentpredilection for DNA and vectors comes up short.These, and more high-risk exploratory approachesneed stimulation with government and foundationsupport until they can be viewed as credible by “bigpharma” and the public. Senator Kerry’s andRepresentative Pelosi’s proposed R&D tax incentivehas a passthrough credit for investors in biotechsthat don’t pay tax, so it could very well spur thissegment of activity.

In Networks of Innovation: Vaccine Development atMerck, Sharp & Dohme, and Mulford, 1895–1995,authors Louis Galambos and Jane Sewell concludethat there are distinct advantages, over the longterm, of a mixed system that combines public, non-profit, professional, and profit-seeking institutionsin a manner that achieves specialization of functionand employs market constraints to ensure efficiency.They conclude that public institutions and those inthe private sector experience cycles of innovation,and that adequate returns for innovation wouldaccelerate new vaccine development by the privatesector. By way of example, the Merck varicella vaccine, Varivax, was approved in 1995 after more than a quarter-century of company support of research and development and five chief executive officers.


36

VaxGen is not your traditionalbiotech company. They have bro-ken the mold several times, com-mencing from their unorthodoxbeginnings in the halls ofGenentech, to the way CEORobert Nowinski raised their hugefirst-round of financing from hun-dreds of people with both invest-ment and philanthropic interests.Even tackling a high risk/high payoff project, such as making aneffective AIDS vaccine from a single recombinant protein, gp120,without a major back-up program,challenges the unwritten rules forstart-ups.

And yet, they seem to achieveresults year after year that wouldmake the largest pharmaceuticalcompany envious. VaxGen is cur-rently carrying out two large-scalePhase 3 clinical trials of itsAIDSVAX vaccines, one princi-

pally in North America and one inThailand. VaxGen has completedthe initial inoculation and enroll-ment of more than 5,000 volun-teers in their North AmericanPhase 3 clinical trial of their biva-lent gp120-based AIDSVAX vac-cine formulated with alum. Thereis still significant uncertainty aboutwhether the antibodies induced byAIDSVAX will be protective.

VaxGen has recently teamed upwith the CDC to conduct epidemi-ological, social and behavioralresearch at approximately one-tenth of their trial centers.Although work with the CDC hasnot yet started at these sites, itbroadens the useful informationthat will be gleaned from the firstPhase 3 HIV vaccine trial.

Founder Don Francis has alwaysbeen tenacious in dealing with the

many issues surrounding clinicaltrial design and implementation,and has overcome many hurdles.Breakthroughs (becoming infectedwith HIV some time after receiv-ing the vaccine when one wouldhope for protection) are expectedin any vaccine trial, and analysis ofHIV serotypes and time course of infection may lead to a betterunderstanding of the vaccine’s efficacy, or partial efficacy, or lackthereof.

One way or another, VaxGen willhave an answer regarding theeffectiveness of the first recombi-nant HIV vaccine, as well asprecedent for testing other AIDSvaccines as they move forward intothe clinic. This answer will be atriumph for AIDS vaccine devel-opment and will provide a rudderof sorts for the next generation ofAIDS vaccine researchers.

V A X G E N


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Representative Nancy Pelosi madehistory in March, 1999 by intro-ducing the Lifesaving VaccineTechnology Act of 1999 (HR 1274.)This was the first legislativeattempt to build a bridge betweenthe vaccine industry and govern-ment, to address the most urgentglobal public health needs. Lastfall, Senator Kerry, the bill’s Senatesponsor, attempted to add the billto expiring tax provisions.

This year, Kerry and Pelosi haveintroduced Vaccines for the NewMillennium Act (S. 2132 and H.R.3812), an expanded version of lastyear’s bill that would provide arange of important incentives forvaccine research and development.This legislation now becomes the focalpoint for HIV vaccine advocacy in the US legislative arena.

VACCINES FOR THENEW MILLENNIUM ACT

S. 2132 and H.R. 3812 would pro-vide a comprehensive package ofincentives to deliver and developvaccines against malaria, TB, HIV,and other diseases that kill overone million people each year. The bills would:

• Declare universal vaccinationand immunization of allchildren within ten years a

major goal of US foreign policy.

• Authorize $50 million in fiscalyear 2001 and $100 million infiscal year 2002 for GAVI.

• Authorize $10 million in fiscalyear 2001 and $20 million in2002 for the InternationalAIDS Vaccine Initiative.

• Provide a tax credit on R&Dcosts for priority vaccines toreduce the cost of research anddevelopment. (Senate billwould provide a 50% credit onincreased R&D on these vac-cines; House bill would provide30% credit on all qualifiedR&D on these vaccines.)

• Allow smaller firms to passthough a 25% tax credit totheir shareholders for invest-ments towards R&D on priorityvaccines in order to helpbiotech companies raise capitalfor needed research.

• Establish a tax credit for salesof priority vaccines, with thecredit equaling 100% of theamount paid by a qualifyingorganization for purchase of a priority vaccine to be

distributed in lower incomecountries —to a total value of$1 billion.

• Establish a purchase fundadministered by the TreasurySecretary, and authorize appro-priations of up to $100 millionper year, for ten years, to facili-tate the purchase and distribu-tion of priority vaccines.(Appropriations would begin ina year in which a priority vac-cine is determined to meettechnical requirements set inadvance.)

• Direct the President to initiatenegotiations with officials offoreign governments for theestablishment of an interna-tional vaccine purchase fundfor the priority vaccines.

• Establish a Lifesaving VaccineAdvisory Commission to reviewprogress of efforts to developpriority vaccines, examine themerits of innovative financingmechanisms, and develop con-sensus among industry and public health advocates on pol-icy recommendations toadvance public-private partner-ships toward the developmentof priority vaccines (House bill only.)

TA X I N C E N T I V E S F O R VAC C I N E R E S E A R C H A N D D E V E LO P M E N T


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In January, President Clintonannounced a set of initiatives in his2000 State of the Union and budg-et for 2001, including a tax crediton vaccine sales and a contributionto GAVI. These and other recom-mendations were modified andincluded in the new Kerry/Pelosilegislation outlined above.

AVAC still thinks that a tax crediton R&D for neglected vaccines,like that in both Kerry/Pelosi bills,could have an enormous impact:

• An R&D tax credit highlightsthe importance of work on vaccines for HIV, malaria, andTB and costs a fraction of theamount invested by companiesthemselves.

• It requires participants to justifytheir work in business terms,but makes it easier for them to do so.

• It rewards companies that havealready made this commitmentand believe in it, encouragingthem to persevere. It shouldcapture the attention of compa-nies that have not committed toresearch on priority vaccines fora variety of reasons.

• Unlike other push mechanisms,such as direct funding of privateR&D, a tax credit is availableto all and is not dependent onannual Congressional appropri-ations.

The R&D tax credit wouldn’tinterfere with a company’s rights totheir discoveries or product pricing,but it would require submission of aplan for global access and distribu-tion within one year of productlicensing.

We know an R&D tax credit isn’tthe complete answer, but it doesuse the taxing power of governmentto send a clear message to industry.This incentive holds the pharma-ceutical companies to their oft-stated humanitarian rhetoricwhile supporting their proven busi-ness methods for getting thingsdone efficiently and well.

TAX INCENTIVES FOR VACCINE RESEARCH AND DEVELOPMENT CONTINUED

“So why has doubt arisen about such a funda-

mental good? A lack of confidence in public

health policy is certainly part of the reason.

But so, ironically, is the remarkable success of

vaccines which has left parents who have never

seen a case of polio or measles to focus their

attention solely on the failures.”

Michael Specter

The New YorkerOctober 11, 1999


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Vaccine Activism Wanted

A high level of community activity has graced thebattle against AIDS almost from the beginning.Community activists critiqued and encouragedAIDS research and policy, which created a newmodel to combat disease. Activists played key rolesin decision-making about how to treat people withAIDS, medically and socially, since the mid-eighties.

The NIAID Division of AIDS pioneered inclusion ofcommunity representatives in research, throughCommunity Constituency Groups and CommunityAdvisory Boards, with varying degrees of success.AVAC’s existence speaks to community involvementin AIDS vaccine research.

Yet, in general, the sense of urgency about therapeu-tic research fails to animate vaccine work, for someobvious and subtle reasons:

• People with AIDS do not clamor for a vaccine.

• The science involved is difficult.

• Industry faces economic disincentives to developa vaccine.

• Americans have a predilection to solve problemsrather than prevent them.

All these factors contribute to inertia in the questfor an effective HIV vaccine.

Activism Promotes Success

Public engagement is critically important, especiallynow that vaccine research and delivery issues arereceiving increasing attention among the generalpublic and in the halls of Congress.

POSITIVE FACTORS

The President Boosts Vaccines

President Clinton used his bully pulpit to effect anunprecedented awareness about HIV vaccineresearch in the United States. He called for anincreased focus on and resources for vaccineresearch—using AIDS as a focal point—mostnotably in his last State of the Union address and a variety of domestic and international venues.

0 S TAT U S Increased visibility of international epidemic • Ongoing advocacy by affected communities • Successful

trial recruitment by VaxGen 0R E C O M M E N DAT I O N S • AIDS service-organizations should have staff dedi-

cated to vaccine issues • Social harm studies and alleviation efforts must continue • CDC should integrate vaccines as

a key part of the prevention agenda • NIH must continue to invest in communications • Interested people should:

demand action from elected officials: join a Community Advisory Board: consider the pros and cons of participating

in a trial: help build a social movement for vaccines

THE PUBLIC: BLUEPRINT FOR ACTION


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The US media followed suit with news articles andfeatures on the effort to develop an AIDS vaccinein outlets such as major daily newspapers, televi-sion’s 60 Minutes, and National Public Radio’sMarketplace.

Other factors in the mix include several founda-tions, which led in supporting the efforts of IAVI,PAF, and amfAR to provide direct funds for HIVvaccine research and development. Until There’s aCure Foundation provided start-up money for bothIAVI and AVAC. Many more foundations, espe-cially large foundations, are needed. Led by theGates Foundation, large, private foundations gar-nered publicity for increased attention and fundingfor vaccine work. The size of some awards madenews before a single dime was spent. VaxGen’s mar-keting campaign for sixty American test sites in-creased awareness in the gay and bisexual male com-munity, although it took one and a half years to fill5,400 slots in VaxGen’s US efficacy trial. VaxGen’srecord pales when compared to the Salk polio trialsin the fifties, which took only six months to fillwith hundreds of thousands of children.

Polls show Americans support vaccine developmentstrongly. In a Harris Poll conducted for amfAR inlate 1998–early 1999, an overwhelming majority (96%) of American adults of all ages and education-al levels think it is important to develop an AIDSvaccine. Seventy-two percent stated they would bevery or somewhat willing to take a vaccine them-selves or have their children vaccinated, and morethan one-third (36%) said they would considerbeing a participant in an HIV vaccine clinical trial.The Global Health Council (GHC) released stun-ning results from a June, 1999 poll. Conducted byLake Snell Perry and Associates, a Washington, DCfirm, the poll revealed that 80% of Americans fearthe global spread of infectious diseases, and the samenumber of people know that AIDS is a greater prob-lem today than 10 years ago. Some 90% said they

support fighting such diseases at their source—inpoor communities and the developing world.Eighty-five percent recognize that vaccines are cru-cial to the effort. GHC commissioned the poll inthe hope that these issues resonate with citizens, inorder to increase politicians’ receptivity about a vaccine. GHC found that 40% of respondents wereself-identified as conservative, compared to only 33% as liberal, and 23% as moderate.

One private poll showed large majorities of AfricanAmericans would participate in vaccine studies.This is significant, given that African Americanshave been the subject of unethical research studiesin the past, and, as a group, continue to suffer dis-parities in health care access.

NEGATIVE FACTORS

Anti-vaccine and Animal-rights Protests Increase

Despite the underlying foundation for positive pub-lic engagement, growing elements are decidedlynegative about vaccines. A nascent anti-vaccinemovement challenges the use of childhood vaccines.

Led by parents who probably have never known adeath from polio or measles, this movement hasmade a real splash. At their behest, the US HouseGovernment Reform Committee, led by chair Daniel Burton (R-IN), held hearings in 1999 onwhether childhood vaccinations should be required. Representative Burton, himself, made a heartfelt butspecious connection between vaccinations andautism in a member of his family.

In addition, some US military personnel resist taking required vaccinations against anthrax, a bio-logical warfare agent. Without doubt, widespreadmedia coverage of this issue encourages a negativeclimate for vaccines.


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Animal-rights activists in the US and UK havestepped up campaigns against animal research with-out offering the public alternative strategies foreffective medical research. Activists have made ter-rorist threats against animal researchers.

Both government and the private sector need lead-ers to build public support for an HIV vaccine. Forthe first time, AIDS was diagnosed in more AfricanAmerican and Hispanic gay men than in white gaymen, in 1999. To his credit, US Surgeon GeneralDavid Satcher called for African-American organi-zations to fight AIDS with the same zeal they broughtto the civil-rights struggle. Yet a recent St. LouisPost-Dispatch editorial excoriated African-Americanleaders, who were so instrumental in the civil-rightsmovement, for their aching silence with regards toAIDS—particularly in communities of faith.

Data show that younger, white, gay men account for the majority of new cases of AIDS in San Francisco —a city that may have the most edu-cated, organized population in the world with regardto AIDS. Still there is no outcry for a vaccine.

The void in government leadership is no lessastounding. It isn’t that messages about preventioncan’t reach a public. Countries with far less wealthand behavioral-research ability have shown it canbe done. Thailand, Uganda, and Senegal havesafer-sex promotion programs, which are orders ofmagnitude better than the US.

In Thailand, the success of prevention programshas caused seroconversion rates to decline so muchthat researchers are scrambling to adjust their strate-gies for trials. Thailand, Uganda, and Brazil havehad much more thorough press coverage, which hasenergized activists and nurtured a climate for politi-cal action. In the United States—at least when itcomes to AIDS—it seems that the “prevention” inCenters for Disease Control and Prevention hasgone AWOL, despite the millions spent.

The Division of AIDS at the National Institutes ofHealth has begun to make a stab at the task, withthe hiring of a consulting firm to advise on develop-ing public support for AIDS vaccine research. The Daystar Group returned a fine report and creditis deserved for commissioning it. The Division hasanother firm implementing the blueprint providedin the Daystar report, and, at this writing, the key staff position for this work remains unfilled atthat firm.

Shamefully, the “Big 6” AIDS agencies in theUnited States—AIDS Action Boston, AIDS ProjectLos Angeles (APLA), Gay Men’s Health Crisis(GMHC) in New York, Northwest AIDSFoundation in Seattle, San Francisco AIDSFoundation, and Whitman-Walker Clinic inWashington, DC—do not adequately acknowledgethe issue. None has a vaccine department or even acontact person working specifically on vaccines.

THE IMPERATIVE TO

ACTION

Consensus and Clarity Work

Clearly, there is fertile ground for public support ofthe AIDS vaccine research effort. But absent aconcerted effort by researchers and advocates, theground will yield a bitter crop.

This will be particularly true if the first real knowl-edge of HIV vaccine research reaches the public insome unpredictable and potentially sensational ordamaging way. Vaccine researchers and advocatesmust reach the public in the broadest manner withrealistic and responsible information or risk contin-uing negative definition of the issues and work bytheir detractors. The pieces are all in place—fromgovernment agencies to established private organi-zations—they are simply not being used.


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What must be communicated is, at its core, remark-ably uncomplicated. Infectious diseases are a clearand present danger, with AIDS leading the way;they can be prevented and there is real, tangiblevalue in doing so; and vaccines are by far the verybest and most effective way to do so. The work issubstantial and subtle in its detailed implementa-tion, but conceptually, is quite simple. The mostimportant thing all involved can accomplish rightnow is to reach consensus for action, clarity in themessage, and begin the work.

GOVERNMENT

NIH Must Lead

This and past AVAC reports point out that the USgovernment, through its programs at the NationalInstitutes of Health, has the most extensive vaccineresearch program in the world. Accordingly, it mustbe the touchstone for public education and aware-ness on research issues.

One can question why the work was not done soon-er, but the consultants hired by the Division ofAIDS have done their job well. The Daystar reportrecommends a focused message similar to that aboveand urges a thoroughly integrated strategic publicawareness campaign, which includes training for keypersonnel, written materials for internal and exter-nal dissemination, identification of lines of authori-ty to respond quickly to public communicationsneeds, and, perhaps most importantly, the use of aclear, consistent message.

However, the first target of the campaign must bethe researchers themselves. At the few sites thathave been conducting vaccine trials for many years,intense local efforts have enhanced visibility of vac-cine issues. Community awareness and educationcan no longer be thought of as an extra, an

“add-on.” It must be integral to all research. A general public campaign will succeed only in this context.

The CDC must adopt HIV vaccines as a key part of its prevention work. It has an extensive networkof prevention planning councils throughout thecountry, yet vaccine is not found on their agendas.Given that most people involved in researchbelieve that the first vaccine released for use will bemoderately efficacious at best, prevention educatorsmust begin the work now, to plan how to integratethat vaccine into communities.

The omission is especially glaring in light of the factthat large efficacy trials have begun in some fiftyUS cities, yet no prevention organizations havefocused on the impact of trials on overall preven-tion efforts. Fortunately, at least in initial data fromThailand, the presence of trials seems to haveincreased awareness of prevention in general andhad a desirable impact on seroincidence.

Different communities and cultures behave differ-ently, however. We don’t know what impact vac-cine trials will have on behavior in other affectedcommunities. It is entirely plausible, for instance,that in some communities safer behavior mightactually decrease with awareness of vaccine trialsbecause people come to believe that a vaccine is onthe way to solve the problem—making responsibledecisions about behavior unnecessary.

NON-GOVERNMENTAL

ORGANIZATIONS

AIDS organizations are struggling to maintain adequate funding. Meanwhile philanthropic foundations have clearly signaled their interest in vaccines, so this would seem a rich area for organi-zational investment from a financial position alone,


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in addition to the moral position of ending a pan-demic. The AIDS service organizations with a his-tory of effective community involvement must revisetheir strategic planning to respond to the impact ofHIV vaccine research on their constituents.

Just as government must have a holistic approachembracing community involvement and public edu-cation, so must non-governmental organizations.Research must be undertaken about how best toreach affected populations. Policy must be devel-oped about how to make vaccines accessible tothose in need. The public and political leadersmust be educated about how vaccines work andtheir immense promise to defeat AIDS. Researchersand advocates must work with those leaders toascertain cultural and community needs and con-cerns. This work is not happening.

The need for an HIV vaccine is most pressing inthe developing world. Work must be done now toassess how vaccine research will confront the realityof the international setting. There is more to siteinfrastructure than equipment. Issues of cultural dissonance, government support, and social accept-ance of trials—contentious in the United States—will only be magnified in the international context.

Models for community involvement in research arenew enough in the United States. They are non-existent in many other nations. Yet all the issues,problems, and tensions present in the US are present in those countries, undoubtedly along withnew ones we have yet to encounter.

A Compelling Argument

The logic of vaccines is compelling. It is almostinconceivable that anyone familiar with vaccines asa public-health tool with the potential to stop anepidemic in its tracks, would be deaf to a call forsupport. But one need not be deaf to ignore a callthat is not made.

Responsible, accurate information about HIV vac-cines and the research needed to develop them willengender the support needed for success only ifthose with the ability are wise enough to providethe information. Without the compelling argu-ment, success is far from guaranteed. Mistrust willcontinue, fear will grow, and more people will die.

Support from core constituencies and their involve-ment in the process is key to building and main-taining broader community and public support.Advocates, investigators and governments eachhave responsibilities and opportunities to build sup-port separately and collectively.

In the introduction to this report, we lamented thatno one stages die-in’s in the streets, as they did inthe past. People are still dying and experimentalagents are still not getting into people. FrederickDouglass wrote, “Power concedes nothing withoutthe demand. It never did and it never will. Peoplemight not get all they work for in this world, butthey certainly must work for all they get.”


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AVAC contributors to this report:

AVAC has had a productive year. We led the wayto support Congressional efforts to provide incen-tives for vaccine research and development, and webrought increased attention to the cause. We distributed over 5,000 copies of our book on HIVdevelopment and trials, the HIV Vaccine Handbook,which the CDC Clearinghouse is stocking and shipping free of charge.

Last year’s update, 8 Years and Counting, was distrib-uted to over 4,500 individuals in the field, organiza-tions, and press, and was mentioned in many publications including USA Today and the LosAngeles Times. We are very proud of our effort tohold NIH to established interim goals and mile-stones.

All this activity only increases our obligation to dothorough research and analysis and maintain ourreputation for unbiased, insightful public opinion.

To that end, we have increased our staff 50%, fromtwo to three, by adding a Policy Director, with plans to add a fourth person to work on communityoutreach and education planning. All this has been done without taking away from current AIDS prevention efforts or care, and without support fromthe companies or governmental organizations thatwe monitor.

We believe that developing a vaccine is only thefirst third of AVAC’s challenge. The second will be making the vaccine available through pricingand purchasing, which is in large part why we support current proposed legislation. The third will be to get the vaccine to those who need it. There is much more work to do and you can help. Please contact Rose McCullough, our ExecutiveDirector, to offer ideas, support, and/or your time([email protected]).

ABOUT AVAC

Bill Snow

Sam Avrett

Chris Collins

Adrian Marinovich

Mike Powell

Steve Wakefield

Jim Thomas

Dana Cappiello

David Gold

Rose McCullough

Luis G. Santiago

Allison Bauer

AIDS VACCINE ADVOCACY COALITION

WWW.AVAC.ORG

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