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Structural insights into the coupling of virion assembly and rotavirus replicationhttp://www.nature.com/nrmicro/journal/v10/n3/full/nrmicro2673.htmlShane D. Trask, Sarah M. McDonald & John T. PattonNature Reviews Microbiology 10, 165-177 (March 2012)
Janeway, 2001. Immunobiology: The Immune System in Health and Disease. 5th edition. http://www.ncbi.nlm.nih.gov/books/NBK10757/ Arnold, 2009. Rotavirus antagonism of the innate immune response. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21994581/?tool=pubmed
1. Merck, product insert2. http://www.medicines.org.uk/emc/medicine/17840/SPC/Bovine strains are used in RotaTeq because rotavirus strains have a much weaker effect (ie are attenuated) in heterologous hosts.Development of these vaccines was funded in part by BMGF via GAVI’s rotavirus aDiP (accelerated Development and introduction Plan)
Source: Gates Foundation UVA: Univ. of VirginiaCIDRZ: Center for Infectious Disease Research in Zambia
1. http://www.thehindu.com/business/companies/article1523475.ece2. http://www.hillemanlabs.org/pdf/merck-to-fund-rotavirus-vaccine-project.pdf MEND = Medicine In Need, an international non-profit organization specializing in the application of advanced vaccine formulation technologies.3. http://www.gsk.com/media/pressreleases/2011/2011-pressrelease-462284.htm
Kim et al., 2010. http://www.biomedcentral.com/content/pdf/1471-2458-10-253.pdfWHO cost effectiveness is based on per-capita GDP.Rose et al., 2006. http://www.bmj.com/highwire/filestream/392593/field_highwire_article_pdf/0.pdf Kim et al., 2009. http://www.biomedcentral.com/content/pdf/1471-2458-9-29.pdf
1. Maslow, A. http://en.wikipedia.org/wiki/Law_of_the_instrument2.Germain, R. (2012). Vaccines and the Future of Human Immunology. http://www.cell.com/immunity/retrieve/pii/S1074761310003572
1.Poland (2011). “Vaccinomics and personalized vaccinology: is science leading us toward a new path of directed vaccine development and discovery?” http://dx.plos.org/10.1371/journal.ppat.1002344
Pulendran B (2010). Systems vaccinology. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21029962/?tool=pubmed
1. C. Gauvreau. PhD Thesis. https://188.8.131.52/bitstream/1807/29727/1/Gauvreau_Cindy_L_201106_PhD_Thesis.pdf
Kim, 2009. http://www.biomedcentral.com/content/pdf/1471-2458-9-29.pdfIf benefits accrue more that 2 years after the costs were incurred, it is good practice to discount benefits for the opportunity cost of money. Discounting is done at various rates, (3%, 6%, etc.) depending on the rate of inflation and interest rate that is anticipated (Dhanasiri & Puliyel, 2007. http://www.indianpediatrics.net/jan2007/jan-11-14.htm)
Kim, 2011. http://www.biomedcentral.com/content/pdf/1471-2334-11-174.pdfBaltussen & Niessen, 2006. http://www.resource-allocation.com/content/pdf/1478-7547-4-14.pdf Poliovirus appears to decrease the efficacy of the 1st dose of the RV vaccine. (WHO; http://www.who.int/wer/2009/wer8423.pdf)
Yen C.(2011) Rotavirus vaccines: Update on global impact and future priorities. Human vaccines 7:12, 1282-1290Tate JE (2012). Remaining Issues and Challenges for Rotavirus Vaccine in Preventing Global Childhood Diarrheal Morbidity and Mortality. http://www.medscape.com/viewarticle/759439
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 withTotal ~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 aredisproportionately affected by rotavirus
5. These regions have greater poverty, poorquality 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 rotavirusis 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: • BreastfeedingReducing 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 globalrotavirus 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 progress2003-9 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 disease2007 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
18. Butler D (2011). “Vaccine Campaign will target deadly childhood diarrhea.” Scientific American.
19. 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 $14.7M11.2010 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 safety11.2011 $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
20. Source: Gates Foundation
21. Pharma has also made commitments3/11: 6/6/11: GSK offers to supply Rotarix to theMSD began offering RotaTeq to the private GAVI Alliance at $2.50 per dose (up to 125 Mmarket in India at Rs900 per dose (~$20).1 doses)31/25/11:MSD/Wellcome Trust’s Hilleman Lab in Indiaannounces it will develop an affordable, lessbulky, heat-stable version of RotaTeq2Collaboration with MEND (Medicine InNeed), an international non-profitorganization specializing in the applicationof advanced vaccine formulationtechnologiesEst. $10-15M to reach POC stage; 4 yrs 1thehindu.com 2hillemanlabs.org 3gsk.com
22. 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 countriesINDIA2:• 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
23. So, how are things really going?
24. 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
25. 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 – but this is changing Reassorting is a known phenomenon that could generate new serotypes; coinfection is more common in developing countries1 1Patton, 2012
26. 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
27. 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?
28. 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
29. It’s time for some new ideas
30. “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)
31. Vaccinology is in need of imaginative thinkingTraditional approach:“isolate – inactivate/attenuate – inject”Alternatives?More sophisticated “vaccinomics” approach that considers geneticvariability, epitope discovery, refined antigenic components, new routes ofadministration, novel adjuvants (Poland, 2011)For example…Bypass serotype variability issues by focusing host immunity oninvariant protein regions necessary for viral infectivity, e.g. bydeveloping 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
32. Vaccinology is in need of imaginative thinkingThe 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
33. 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
34. Beyond vaccines? Trask, 2012
35. A holistic perspective
36. 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 burdenFamilies:• Vaccination co-payments (or outright cost, post-GAVI graduation)• Time spent traveling to vaccination centersPharma/Manufacturers:Opportunities foregone to research & develop more profitable drugs, etc. 1Gauvreau, C. (2011)
37. Vaccine pricing is a critical variableVaccine pricing &efficacy, as well asdiscount rate, maybe the mostsensitive variableswhen determiningthe impact ofrotavirus vaccinationprograms. Kim et al., 2009
38. Funding & implementing rotavirus programswill benefit from decision analysisMulti-criteria decision analysis can help set priorities (but data tobuild reliable models may be lacking for resource-poor countries) Baltussen & Niessen, 2006
39. Any solution must adapt to economic, logistical, and financial constraintsAnti-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)
40. The ideal funding strategy would invest innear- and long-term solutionsImplementation timelineExisting vaccines: increased deployment Existing vaccines: modify for robustness, portability, price New vaccines: target regional serotypesVaccination + probiotics &/or zinc to increase immune response New biologics: vaccinomics Small molecule inhibitors Advances in public health , nutrition, infrastructure, sanitation, economic devt.