Global solutions to Rotavirus infections:An overview

Sirid Kellermann, PhD, MBA

“Innovation is the means, and equity is the end goal.”

- Bill Gates

Introduction: Setting the stage

Rotavirus is a major health concern in children

• Affects nearly every child by age 51

• Causes diarrhea & dehydration

• Cannot be treated with antibiotics / medications

Diarrhea: ~2M deaths1

Rotavirus: ~520,000 deaths39% of diarrheal deaths5% of total deaths2,3

2M hospitalizations

Global annual mortality, children age 5 & under

Total ~9M1

1PATH; WHO2Munos, B. (2010)

Children in Asia, Africa, & Latin America are disproportionately affected by rotavirus

Territory size: proportion of human poverty. Source: Worldmapper.com

These regions have greater poverty, poor quality water, and primitive sewerage systems

Why does rotavirus make us sick?

Rotavirus fast facts

~80 nm Ø

triple-layered protein capsid 11 segments of double-stranded RNA6 structural + 6 nonstructural proteins

There are 7 strains (A-G), but only A, B, C infect humans.

Group A causes most infections and is the target of current vaccines.

Groups B & C are less prevalent, and are not impacted by current vaccines.

Serotypes are defined based on sequence/antigenicity of the VP7 (glycoprotein, G) & VP4 (protease-sensitive, P) proteins.

Anatomy of a rotavirus infection

Rotavirus infects the villous epithelium of the upper small intestine.

Infectious particles are released & replicate further in the distal small intestine.

Symptoms are principally induced by the viral enterotoxin NSP4.

Trask, 2012

Rotaviruses can evade virostatic immune responses

The immune system produces Type I interferons that “interfere” with viral replication – BUT -

Rotaviruses express proteins that subvert this immune response!

Arnold, 2009

Janeway, 2001

Human resistance to rotavirus is primarily antibody-mediated

Antibody responses are to the VP4 (red) and VP7 (yellow) outer capsid proteins.

Humans fight back…

Maternal care:• Breastfeeding

Infrastructure:• Access to clean water• Proper sanitation

Nutrition:• Oral rehydration therapies

(ORS)• Zinc supplementation1

• Vitamin A

Health care:• Improved case management• Rotavirus vaccine

Reducing deaths from diarrheal disease:

cost of ORS + zinc = $0.30 per child (WHO)

Rotavirus vaccines can be an integral part of a child health program

1PATH

Two rotavirus vaccines are currently available

• Merck, approved by FDA 2006.

• Pentavalent = 5 reassortant rotaviruses from human & bovine rotavirus strains

• Protects against G1, G2, G3, G4 strains1

• Refrigerate

• 3 doses

• Ready-to-use

• GSK, approved by FDA 2008.

• Monovalent (RV1) - single human strain

• Protects against G1, G3, G4, G9 strains.Also efficacious against G2, G8, G12.2

• Refrigerate

• 2 doses

• Lyophilized, reconstitute

1Merck2www.medicines.org

Global vaccine initiatives

Key players in the global rotavirus vaccination initiative

Supports the introduction of rotavirus vaccines for 50M children in at least 44 low-income countries by 2015

Supports UN’s Millennium Development Goal 4 – reduce child mortality by 2/3 by 2015

GAVI’s leading private sector funderPATH funder

UN agency concerned with public health – runs Global Rotavirus Surveillance Network

International nonprofit; providing technical support to emerging-country manufacturers to expedite development of new rotavirus vaccines

Rotavirus Vaccine Program (PATH, WHO, CDC, GAVI $)“To generate & communicate the evidence required by global and national policymakers to make critical decisions about rotavirus vaccines.”

Disease burden, vaccine efficacy in developing countries, cost-effectiveness, role of rotavirus vaccines in the management of diarrheal disease

WHO recommends rotavirus vaccine in Europe and the Americas;

GAVI funding focuses on Nicaragua, Bolivia, Guyana & Honduras.

WHO SAGE recommends RV vaccine in all national immunization programs.

Sudan begins RV vaccination program.

33 countries projected to have rotavirus vaccination programs w/ GAVI1

A timeline of global RV vaccination progress

2011

2009

2007

2003-9

2015

1www.gavialliance.org

Butler D (2011). “Vaccine Campaign will target deadly childhood diarrhea.” Scientific American.

CIDRZ - evaluate the population effectiveness of rotavirus vaccine introduction in the context of a comprehensive diarrhea control pilot in Zambia’s Lusaka Province (3 yrs)

PATH - evaluate alternative vaccine candidates to address lingering safety and efficacy limitations with current vaccines (5 yrs)

PATH - advance clinical development of a rotavirus vaccine candidate by a developing-country manufacturer, to increase affordability & access (5 yrs)

PATH - develop evidence for improving the performance of live, attenuated, orally delivered rotavirus vaccines in infants in the developing world (4 yrs)

UVA - identify why oral polio- & rotavirus vaccines are less effective in the developing world, to develop new approaches (4 yrs)

Stanford - establish POC for the application of certain technologies to priority diseases, & large-scale characterization and phenotyping of immune T-cell responses to rotavirus and flu infection & vaccination (2 yrs)

WHO - convene an international symposium to discuss upstream rotavirus vaccine candidates and worldwide supply issues. (6 mos.)

Gates Foundation has already committed >$64M

11.2011

11.2010

11.2010

6.2010

2.2006 $65K

$1M

$14.7M

$8.8M

$30M

$15.7M

$3.8M

Source: Gates Foundation

Source: Gates Foundation

Pharma has also made commitments

3/11: MSD began offering RotaTeq to the private market in India at Rs900 per dose (~$20).1

1/25/11: MSD/Wellcome Trust’s Hilleman Lab in India announces it will develop an affordable, less bulky, heat-stable version of RotaTeq2

Collaboration with MEND (Medicine In Need),  an international non-profit organization specializing in the application of advanced vaccine formulation technologies

Est. $10-15M to reach POC stage; 4 yrs

6/6/11: GSK offers to supply Rotarix to the GAVI Alliance at $2.50 per dose (up to 125 M doses)3

1thehindu.com2hillemanlabs.org3gsk.com

The modelled impact of a vaccination programAll GAVI-eligible countries1: • Would prevent ~55% of rotavirus-associated deaths• 0.9M deaths averted (base case 280M children vaccinated)

over 10 years• Cost-effective in 68 countries

INDIA2:• Deaths projected to be reduced by 41% (base case)• Cost: ~12% of 2006-7 budget of Dept. of Health and Family

Welfare (but assumed $7/dose, not $2.50 as pledged by GSK)

VIETNAM3:• 66% reduction in mortality• Cost-effective b/w $5-32/dose• Key uncertainty: vaccine efficacy

All models based on single-cohort vaccination

So, how are things really going?

Current vaccines are less effective in poor countries

Not as effective in Africa and Asia compared to US, Europe, Latin America1,2,3

WHY?

• Comorbidities (other pathogens, protozoa, etc.)• Malnutrition• Breastfeeding – strong passive immunity neutralizes the vaccine• Strain diversity (serotypes)

Yen, 2011

1Armah, 20102Madhi, 20103Yen, 2011

Rotavirus serotypes are ever-shifting

Serotypes are defined based on sequence/antigenicity of VP7 (Glycoprotein) & VP4 (Protease-sensitive)

To date: 22 G genotypes and 31 P genotypes

Most common worldwide has been G1P[8] – but this is changing

Reassorting is a known phenomenon that could generate new serotypes; coinfection is more common in developing countries1

1Patton, 2012

Dynamic RotavirusSerotypes vary dramatically from year to year, country to country…

El Khoury, 2011M/O/U = mixed/other/unidentified

Rotateq won’t work; Rotarix may

What is this!!

Rotateq initiative in India will not (effectively) address 40% of cases..?

G12 emerging in Vietnam & India; G8 in Kenya

Rotarix targets G1, G3, G4, G9; also G2, G8, G12

RotaTeq targets  G1, G2, G3, G4

See comments for sources

New vaccines are in development…

Vaccine manufacturers in Brazil, China, Germany, India, Indonesia and Vietnam are working on new vaccines• Region-specific serotypes being targeted?

The original rhesus-based reassortant vaccine (RotaShield; Wyeth) is also undergoing renewed development (Germany)

NIH licensed its 2nd gen multivalent vaccine to multiple manufacturers – could these be customized for regional serotype prevalences?

Could vaccines become part of the problem?

The widespread deployment of e.g. Rotarix or RotaTeq may induce selective pressures on rotavirus, leading to emergence of antigenically distinct strains.1

John T. PattonChief, Rotavirus Molecular Biology Section, NIAID, NIH

This means that the efficacy of

current

(or any) vaccines could be self-

limiting.

1Patton, 2012

It’s time for some new ideas

“If all you have is a hammer, everything looks like a nail”1

“Our success [in developing effective

vaccines] has been limited mainly to those

cases in which the most highly pathogenic

strains of a virus or bacteria can be

identified and in which these limited

numbers of serotypes do not vary

substantially over time.”2

1Maslow, A.2Germain, R. (2012)

For example…Bypass serotype variability issues by focusing host immunity on invariant protein regions necessary for viral infectivity, e.g. by developing polypetides representing repeated critical epitopes:• VP4 trypsin cleavage site • VP4 region that binds to host cell receptors• NSP4 toxin active site/Ca++ channel mechanism

Vaccinology is in need of imaginative thinkingTraditional approach:“isolate – inactivate/attenuate – inject”

Alternatives?More sophisticated “vaccinomics” approach that considers genetic variability, epitope discovery, refined antigenic components, new routes of administration, novel adjuvants (Poland, 2011)

X

X

The Influenza model• Significant variation in

neutralizing determinants over short time frames

• Society has developed an “early warning system” that allows seasonal manufacture of the specific vaccine needed for that year

A role for Systems Biology?• Systems biology can identify

early correlates of efficacy• May help predict which

vaccines will be efficacious before large-scale deployment

• Useful e.g. when a new strain emerges

Vaccinology is in need of imaginative thinking

Pulendran, 2010

Beyond vaccines?

Less costly to make, can be genericized, orally administered, heat-stable

Able to access intracellular targets beyond 2 outer capsid proteins

Targets of potential interest:• Proteins critical for replication, translation, packaging

likely to be less variable than outer capsid structural proteins

• Enzymes are particularly amenable to small molecule targeting, e.g. RNA polymerase (RdRp;VP1), mRNA capping enzyme VP3; NSP5 autokinase

• Rotavirus double-layered particles (DLP) that catalyze RNA synthesis

• Mechanisms of viral blockade of interferon responses

Paradigm: HAART drugs for HIV

Small molecules have advantages over vaccines

Beyond vaccines?

Trask, 2012

A holistic perspective

Models generally find rotavirus vaccination to be cost-effective, but what’s the bigger picture?

What is the opportunity cost of a rotavirus vaccine program?

Health departments/Governments:Interventions foregone in public health – & other sectors, e.g. education1

• Relatively high cost of rotavirus vaccine• Vaccinations require trained personnel diverted from other activities• Transaction costs when dealing with international funders• Cold chain• Stockpiling a vaccine that may prove ineffective before inventory is

depleted• Post-GAVI cost burdenFamilies:• Vaccination co-payments (or outright cost, post-GAVI graduation)• Time spent traveling to vaccination centers

Pharma/Manufacturers:Opportunities foregone to research & develop more profitable drugs, etc.

& d

onor

s!

1Gauvreau, C. (2011)

Vaccine pricing is a critical variable

Vaccine pricing & efficacy, as well as discount rate, may be the most sensitive variables when determining the impact of rotavirus vaccination programs.

Kim et al., 2009

Funding & implementing rotavirus programs will benefit from decision analysis

Multi-criteria decision analysis can help set priorities (but data to build reliable models may be lacking for resource-poor countries)

Baltussen & Niessen, 2006

Any solution must adapt to economic, logistical, and financial constraints

Anti-rotaviral agents are ideally:

• Financially accessible & cost-effective

• Safe

• Heat-resistant, portable, easily administered

• Able to combat RV strains dominant in the target country/region

• Flexible dosing schedule w/o risking intussiception

Funding allocation should consider1:

• Ability of country/region to perform rotavirus strain surveillance

• Infrastructure to distribute & administer vaccine

• Ability to measure cost-effectiveness

• Health benefit of rotavirus vax vs other vaccination programs

• Relative benefit of vaccination over other, potentially less costly nutritional solutions (ORS, zinc, Vitamin A)

The ideal funding strategy would invest in near- and long-term solutions

Existing vaccines: increased deployment

Advances in public health , nutrition, infrastructure, sanitation, economic devt.

New vaccines: target regional serotypes

Existing vaccines: modify for robustness, portability, price

New biologics: vaccinomics

Small molecule inhibitors

Vaccination + probiotics &/or zinc to increase immune response

Implementation timeline

Thank you!