1. Global solutions to Rotavirus infections:
An overview
Sirid Kellermann, PhD, MBA
“Innovation is the means, and equity is the end goal.”
- Bill Gates

2. Introduction: Setting the stage

3. Rotavirus is a major health concern in children
• Affects nearly every child
by age 51
Global annual mortality,
children age 5 & under • Causes diarrhea &
dehydration
• Cannot be treated with
Total ~9M1
antibiotics / medications
Diarrhea: ~2M deaths1
Rotavirus: ~520,000 deaths
39% of diarrheal deaths
5% of total deaths2,3
2M hospitalizations
1PATH; WHO
2Munos, B. (2010)

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

5. These regions have greater poverty, poor
quality water, and primitive sewerage systems
Territory size: proportion of human poverty. Source: Worldmapper.com

6. Why does rotavirus make us sick?

7. Rotavirus fast facts
triple-layered protein capsid
11 segments of double-stranded RNA
6 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-
~80 nm Ø sensitive, P) proteins.

8. 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.

9. Trask, 2012

10. 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!
Janeway, 2001
Arnold, 2009

11. Human resistance to rotavirus
is primarily antibody-mediated
Antibody responses
are to the VP4 (red)
and VP7 (yellow)
outer capsid proteins.

12. Humans fight back…

13. Rotavirus vaccines can be an integral part
of a child health program
Maternal care:
• Breastfeeding
Reducing deaths from
Infrastructure:
diarrheal disease:
• Access to clean water
• Proper sanitation
Nutrition:
• Oral rehydration therapies (ORS)
• Zinc supplementation1
• Vitamin A
Health care:
• Improved case management
• Rotavirus vaccine
cost of ORS + zinc = $0.30 per child (WHO) 1PATH

14. Two rotavirus vaccines are currently available
• Merck, approved by FDA 2006. • GSK, approved by FDA 2008.
• Pentavalent = 5 reassortant rotaviruses • Monovalent (RV1) - single human strain
from human & bovine rotavirus strains
• Protects against G1, G2, G3, G4 strains1 • Protects against G1, G3, G4, G9 strains.
Also efficacious against G2, G8, G12.2
• Refrigerate • Refrigerate
• 3 doses • 2 doses
• Ready-to-use • Lyophilized, reconstitute
1Merck
2www.medicines.org

15. Global vaccine initiatives

16. Key players in the global
rotavirus vaccination initiative
International nonprofit; providing technical support to
emerging-country manufacturers to expedite
development of new rotavirus vaccines
UN agency concerned with public health –
runs Global Rotavirus Surveillance Network
Supports the introduction of rotavirus Supports UN’s Millennium
Development Goal 4 –
vaccines for 50M children in at least 44 reduce child mortality by
low-income countries by 2015 2/3 by 2015
GAVI’s leading private sector funder
PATH funder

17. A timeline of global RV vaccination progress
2003-9 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
2007 WHO recommends rotavirus vaccine in Europe and the Americas;
GAVI funding focuses on Nicaragua, Bolivia, Guyana & Honduras.
2009 WHO SAGE recommends RV vaccine in all national immunization
programs.
2011 Sudan begins RV vaccination program.
2015 33 countries projected to have rotavirus vaccination programs w/ GAVI1
1www.gavialliance.org

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

20. Gates Foundation has already committed >$64M
WHO - convene an international symposium to discuss upstream rotavirus
2.2006 $65K
vaccine candidates and worldwide supply issues. (6 mos.)
Stanford - establish POC for the application of certain technologies to priority
6.2010 diseases, & large-scale characterization and phenotyping of immune T-cell $1M
responses to rotavirus and flu infection & vaccination (2 yrs)
UVA - identify why oral polio- & rotavirus vaccines are less effective in the $14.7M
11.2010
developing world, to develop new approaches (4 yrs)
PATH - develop evidence for improving the performance of live, attenuated,
11.2010 $8.8M
orally delivered rotavirus vaccines in infants in the developing world (4 yrs)
PATH - advance clinical development of a rotavirus vaccine candidate by a
developing-country manufacturer, to increase affordability & access (5 yrs) $30M
PATH - evaluate alternative vaccine candidates to address lingering safety
11.2011 $15.7M
and efficacy limitations with current vaccines (5 yrs)
CIDRZ - evaluate the population effectiveness of rotavirus vaccine introduction in
the context of a comprehensive diarrhea control pilot in Zambia’s Lusaka $3.8M
Province (3 yrs)
Source: Gates Foundation

21. Source: Gates Foundation

22. Pharma has also made commitments
3/11: 6/6/11: GSK offers to supply Rotarix to the
MSD began offering RotaTeq to the private GAVI Alliance at $2.50 per dose (up to 125 M
market in India at Rs900 per dose (~$20).1 doses)3
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
1thehindu.com
2hillemanlabs.org
3gsk.com

23. The modelled impact of a vaccination program
All 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 All models based on
single-cohort vaccination
• Key uncertainty: vaccine efficacy

24. So, how are things really going?

25. Current vaccines are less effective in poor countries
Not as effective in Africa and Asia compared to US, Europe, Latin America1,2,3
Yen, 2011
WHY?
• Comorbidities (other pathogens, protozoa, etc.)
• Malnutrition
• Breastfeeding – strong passive immunity neutralizes the vaccine 1Armah, 2010
• Strain diversity (serotypes) 2Madhi, 2010
3Yen, 2011

26. 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

27. Dynamic Rotavirus
Serotypes vary dramatically from year to year, country to country…
M/O/U = mixed/other/unidentified El Khoury, 2011
Rotateq won’t work; Rotateq initiative in
Rotarix may India will not Rotarix targets G1, G3, G4, G9;
(effectively) address also G2, G8, G12
What is this!! 40% of cases..?
RotaTeq targets G1, G2, G3, G4
G12 emerging in Vietnam & India; G8 in Kenya See comments for sources

28. 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?

29. 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. Patton
Chief, Rotavirus Molecular Biology Section, NIAID, NIH
1Patton, 2012

30. It’s time for some new ideas

31. “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)

32. Vaccinology is in need of imaginative thinking
Traditional 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)
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 X
• NSP4 toxin active site/Ca++ channel mechanism

33. Vaccinology is in need of imaginative thinking
The Influenza model A role for Systems Biology?
• Significant variation in • Systems biology can identify early
neutralizing determinants correlates of efficacy
over short time frames • May help predict which vaccines will
• Society has developed an be efficacious before large-scale
“early warning system” that deployment
allows seasonal manufacture • Useful e.g. when a new strain emerges
of the specific vaccine
needed for that year
Pulendran, 2010

34. Beyond vaccines?
Small molecules have advantages over 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

35. Beyond vaccines?
Trask, 2012

36. A holistic perspective

37. What is the opportunity cost of
a rotavirus vaccine program?
Models generally find rotavirus vaccination to be cost-effective, but what’s the bigger picture?
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 burden
Families:
• 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.
1Gauvreau, C. (2011)

38. 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

39. 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

40. Any solution must adapt to
economic, logistical, and financial constraints
Anti-rotaviral agents are ideally: Funding allocation should consider1:
• Financially accessible & cost- • Ability of country/region to perform
effective rotavirus strain surveillance
• Safe • Infrastructure to distribute &
• Heat-resistant, portable, easily administer vaccine
administered • Ability to measure cost-effectiveness
• Able to combat RV strains • Health benefit of rotavirus vax vs
dominant in the target other vaccination programs
country/region
• Relative benefit of vaccination over
• Flexible dosing schedule w/o other, potentially less costly
risking intussiception nutritional solutions (ORS, zinc,
Vitamin A)

41. The ideal funding strategy would invest in
near- and long-term solutions
Implementation timeline
Existing vaccines: increased deployment
Existing vaccines: modify for robustness, portability, price
New vaccines: target regional serotypes
Vaccination + probiotics &/or zinc to increase immune response
New biologics: vaccinomics
Small molecule inhibitors
Advances in public health , nutrition, infrastructure, sanitation, economic devt.

42. Thank you!