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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!