Project Summary

RTS,S malaria vaccine trial – Malawi, Ghana, and Gabon

Global malaria elimination has little chance of success in the absence of an effective vaccine. The leading candidate vaccine (RTS,S) has shown only moderate efficacy in preliminary analysis of the recently completed Phase III trial and was recently given scientific support by the European Medicines Agency, allowing it to be assessed for the World Health Organization preferred medicines list. The vaccine does not work equally well in different populations; this variability may be due to parasite, environmental, or host factors. Furthermore, any malaria vaccine will not be used in isolation, but rather as part of an integrated program leveraging other control measures. Therefore, understanding the combinations of factors which modulate the effectiveness of a malaria vaccine is essential to guide appropriate vaccine use and formulating next-generation vaccines. This project is designed to improve our understanding of how RTS,S works by evaluating key ecological, host and parasite factors which likely impact effectiveness. The approaches will enhance our understanding of the effectiveness of RTS,S and can also be leveraged to improve the efficacy of future malaria vaccines. Recent Phase II data suggest that RTS,S efficacy varies based on transmission intensity. The first goal of this project is to expand these findings to a larger context. We will investigate ecological and behavioral factors that may influence vaccine efficacy at three RTS,S trial sites in Malawi, Ghana, and Gabon. These data, in conjunction with Phase III trial data, geographic information system (GIS) data and a concurrent transmission intensity study, will allow us to discern the impacts of individual and neighborhood factors on vaccine effectiveness in an “ecological” analysis of the trial. The second goal leverages the experience in the team of investigators for studying antigenic diversity in malaria to understand the importance of strain-specific protection to the vaccine antigen circumsporozoite protein (CS) during the trial. Recent evidence has shown strain selection by the vaccine, with a higher level of vaccine efficacy against vaccine type CS strains.  However, the longevity of strain specific immunity is not known. If immunity to vaccine type strain is longer-lasting than to non-vaccine type strains, this has important implications for vaccine design and suggests the need for a polyvalent vaccine. The third goal leverages expertise in second generation sequencing and human genetics at UMass to study the impacts of host polymorphisms associated with immune response and resistance to malaria on vaccine efficacy. The last goal is to provide an integrative analysis of the key factors identified in the first three aims of the project to assess their impact on vaccine efficacy in multivariate analysis. This study will be the most comprehensive evaluation to date of factors, including host, parasite and environmental, that affect RTS,S effectiveness. This information will be critical for future malaria vaccine trials for both CS and non-CS based vaccines. .

Cholera vaccine trial – Matlab, Bangladesh

In 1985, a community-based, individually randomized oral cholera vaccine trial was conducted in Matlab, Bangladesh. This study uses a geographic information system (GIS) to determine: (1) How cholera vaccine efficacy varies spatially in the study area; (2) What ecological socio-environmental variables are related to cholera vaccine efficacy (i.e., which variables are effect modifiers); (3) How protective efficacy varies with access to treatment facilities (i.e., whether access is a spatial confounder); and (4) Whether cholera incidence in the placebo group is related to vaccine coverage rates (i.e., is herd immunity important). Findings suggest that vaccine efficacy varies spatially in relation to vaccine coverage. Residents living in neighborhoods with higher levels of cholera vaccine coverage experienced lower infection rates regardless of vaccine status.

This research is presently being extended to integrate social networks into a spatial analytical framework for vaccine trial evaluation. The extended study uses social network analysis, participant location data, and remote sensing technologies to determine: (1) How cholera vaccine efficacy varies spatially within different spatial and environment contexts; (2) How protective efficacy varies within social networks; and (3) How spatial and social network information can jointly be used to assess the effectiveness of vaccines.

 

Project Team Members

Michael Emch

Griffin Bell

Veronica Escamilla

Mark Janko

Cory Keeler

Larry Han

Varun Goel

 

Publications

  1. Han L, Hudgens M, Emch M, Keeler C, Juliano J, Martinson F, Kathmunzi P, Tegha G, Hoffman I (2017) RTS,S/AS01 malaria vaccine efficacy and its interaction with seasonal precipitation: Results from a phase 3 randomized controlled trial in Lilongwe, Malawi. Scientific Reports. 7: 7200.
  2. Escamilla V, Alker A, Dandalo L, Juliano JJ, Miller WC, Kamthuza P, Tembo T, Tegha G, Martinson F, Emch M, Hoffman IF (2017) Effects of community level bed net coverage on malaria morbidity in Lilongwe, Malawi. Malaria Journal. 16 (1), 142.
  3. Parr J, Belson C, Patel J, Hoffman I, Kamthunzi P, Martinson F, Tegha G, Thengolose I, Drakeley C, Meshnick S, Escamilla V, Emch M, Juliano J. (2016, in press) Estimation of Plasmodium falciparum Transmission Intensity in Lilongwe, Malawi, by Microscopy, Rapid Diagnostic Testing, and Nucleic Acid Detection. American Journal of Tropical Medicine and Hygiene.
  4. Cash BA; Rodó X; Emch M; Yunus M; Faruque ASG; Pascual M. (2014) Cholera and Shigellosis:  Different Epidemiology but Similar Responses to Climate Variability. PLoS One. 9(9): e107223.
  5. Escamilla, V; Emch, M; Dandalo, L; Miller, WC; Martinson, F; Hoffman, I. (2014) Community level sampling using Google Earth satellite imagery and geographical methods in the absence of a Demographic Surveillance System. Bulletin of the World Health Organization. 92:690-694.
  6. Perez-Heydrich C; Hudgens MH; Halloran ME; Clemens J; Ali M; Emch, M. (2014). Assessing the effects of cholera vaccination in the presence of interference.  Biometrics. DOI: 10.1111/biom.12184.
  7. Ali, M; Emch, M; Park, JK; Yunus, M; Clemens, J. (2011) Natural Cholera Infection-derived Immunity in an Endemic Setting. Journal of Infectious Diseases. 204: 912-918.
  8. Root, ED; Giebultowicz, S; Ali, M; Yunus, M; and Emch, M. (2011) The Role of Vaccine Coverage Among Social Networks in Cholera Vaccine Efficacy. PLoS One. 6(7):  e22971.
  9. Giebultowicz, S; Ali, M; Yunus, M; Emch, M. (2011) A Comparison of Spatial and Social Clustering of Cholera in Matlab, Bangladesh. Health & Place. 17: 490–497.
  10. Huq, A.; Yunus, M.; Sohel, M. Bhuiya, A.; Emch, M.; Luby, S.P.; Russek-Cohen, E.; Nair, G.B.; Sack, R.B.; Colwell, R.R. (2010) Simple Sari Filtration is Sustainable and Continues to Protect Villagers from Cholera in Matlab, Bangladesh. mBio. 1(1):e00034-10.
  11. Ali, M.; Emch, M.; Yunus, M. and Clemens, J. (2009) Modeling Spatial Heterogeneity of Disease Risk and Evaluation of the Impact of Vaccination. Vaccine. 27(28): 3724-3729.
  12. Emch, M.; Ali, M.; Root, E.D.; Yunus, M. (2009) Spatial and Environmental Connectivity Analysis in Vaccine Trials. Social Science & Medicine. 68: 631-637.
  13. Emch, M.; Ali, M.; Yunus, M. (2008) Risk Areas and Neighborhood-level Risk Factors for Shigella dysenteriae 1 and Shigella flexneri: Implications for Vaccine Development. Health & Place. 14: 96-105.
  14. Ali, M.; Emch, M.; Yunus, M.; Sack, D.; Lopez, AL, Holmgren, J.; Clemens, J. (2008) Vaccine Protection of Bangladeshi Infants and Young Children Against Cholera: Implications for Vaccine Deployment and Person-to-Person Transmission. The Pediatric Infectious Disease Journal. 27(1): 33-37.
  15. Emch, M; Ali, M.; Yunus, M.; Sack, D.; Acosta, C.; and Clemens, J.D. (2007) Efficacy Calculation in Randomized Vaccine trials: Global or Local Measures? Health & Place. 13: 238-248.
  16. Emch, M; Ali, M.; Yunus, Park, J.K.; Yunus, M.; Sack, D.; and Clemens, J.D.  (2006) Relationship Between Neighbourhood-level Killed Oral Cholera Vaccine Coverage and Protective Efficacy: Evidence for Herd Immunity. International Journal of Epidemiology. 35: 1044-1050.
  17. Ali, M.; Emch, M.; von Seidlein, L.; Yunus, M.; Sack, D.A.; Holmgren, J.; Rao, M.; and Clemens, J.D.  (2005)  Herd Immunity Conferred by Killed Oral Cholera Vaccines in Bangladesh. Lancet. Jul 2-8;366(9479):44-9.

Funding

Bailey, J (P.I.), Emch, M (P.I.), Juliano, J (CoI), Kamthunzi, P (CoI), Hudgens, M (CoI) Impacts of Environment, Host Genetics and Antigen Diversity on Malaria Vaccine Efficacy, National Institute of Allergies and Infectious Disease, National Institutes of Health (NIAID), 1R01-AI137410-01, $3,632,091, 2018-2022 (fundable score pending council-5th percentile).

Hoffman, I. (P.I.); Emch, M. (CoI); Martinson, F. (CoI); Demster, D. (CoI); Krysiak, R. (CoI); Mofolo, I. (CoI); Sungitsa, M. (CoI) MAL55 Phase III clinical trial for malaria vaccine, PATH Malaria Vaccine Initiative, $6,033,760, 2009-14.

Hoffman, I. (P.I.); Emch, M. (CoI); Martinson, F. (CoI); Miller, W. (CoI); Demster, D. (CoI); Krysiak, R. (CoI); Mofolo, I. (CoI); Sungitsa, M. (CoI) MAL55 Phase III clinical trial for malaria vaccine, PATH Malaria Vaccine Initiative, $287,898, 2008-11.