What should vaccine developers ask? Simulation of the effectiveness of malaria vaccines

Abstract

Background: A number of different malaria vaccine candidates are currently in pre-clinical or clinical development. Even though they vary greatly in their characteristics, it is unlikely that any of them will provide long-lasting sterilizing immunity against the malaria parasite. There is great uncertainty about what the minimal vaccine profile should be before registration is worthwhile; how to allocate resources between different candidates with different profiles; which candidates to consider combining; and what deployment strategies to consider.

Methods and findings: We use previously published stochastic simulation models, calibrated against extensive epidemiological data, to make quantitative predictions of the population effects of malaria vaccines on malaria transmission, morbidity and mortality. The models are fitted and simulations obtained via volunteer computing. We consider a range of endemic malaria settings with deployment of vaccines via the Expanded program on immunization (EPI), with and without additional booster doses, and also via 5-yearly mass campaigns for a range of coverages. The simulation scenarios account for the dynamic effects of natural and vaccine induced immunity, for treatment of clinical episodes, and for births, ageing and deaths in the cohort. Simulated pre-erythrocytic vaccines have greatest benefits in low endemic settings (<EIR of 10.5) where between 12% and 14% of all deaths are averted when initial efficacy is 50%. In some high transmission scenarios (>EIR of 84) PEV may lead to increased incidence of severe disease in the long term, if efficacy is moderate to low (<70%). Blood stage vaccines (BSV) are most useful in high transmission settings, and are comparable to PEV for low transmission settings. Combinations of PEV and BSV generally perform little better than the best of the contributing components. A minimum half-life of protection of 2-3 years appears to be a precondition for substantial epidemiological effects. Herd immunity effects can be achieved with even moderately effective (>20%) malaria vaccines (either PEV or BSV) when deployed through mass campaigns targeting all age-groups as well as EPI, and especially if combined with highly efficacious transmission-blocking components.

Conclusions: We present for the first time a stochastic simulation approach to compare likely effects on morbidity, mortality and transmission of a range of malaria vaccines and vaccine combinations in realistic epidemiological and health systems settings. The results raise several issues for vaccine clinical development, in particular appropriateness of vaccine types for different transmission settings; the need to assess transmission to the vector and duration of protection; and the importance of deployment additional to the EPI, which again may make the issue of number of doses required more critical. To test the validity and robustness of our conclusions there is a need for further modeling (and, of course, field research) using alternative formulations for both natural and vaccine induced immunity. Evaluation of alternative deployment strategies outside EPI needs to consider the operational implications of different approaches to mass vaccination.

Figure 1. Effect of PEV (a,c,e) and BSV (b,d,f) on infectivity to vector over 20 years when delivered via EPI (black), EPI with boosters (blue) and EPI with 95% mass vaccination (red) for transmissions settings of EIR 5.25 (a,b), 21 (c,d) and 168 (e,f).

Results obtained assuming a vaccine efficacy of 80%, half-life of 10 years and homogeneity value of 10. Note that the blue and black lines almost overlap.

Figure 2. Effect of PEV with MSTBV (a,b,c) on infectivity to vector over 20 years when delivered via EPI (black), EPI with boosters (blue) and EPI with 95% mass vaccination (red) for transmissions settings of EIR 21 (a), 42 (b) and 168 (c).

Results obtained assuming a vaccine efficacy of 52%, half-life of 10 years and homogeneity value of 10.

Figure 3. Time to elimination given initial efficacies (x-axis) of vaccine for different transmission settings (square indicates combination with MSTBV and circle without).

All results are for vaccines delivered via EPI with mass vaccination, no elimination is achieved under these conditions for vaccines delivered via EPI or EPI with boosters. Results obtained assuming vaccine half-life of 10 years and homogeneity value of 10.

Figure 4. Effect of initial efficacy (a–c), vaccine half-life (d–f) and degree of heterogeneity (g–i) on the number of events averted per 1000 person years by PEV for the reference transmission setting of EIR 21.

Results obtained assuming vaccine efficacy of 52%, a vaccine half-life of 10 years and homogeneity value of 10, unless the values are varied along the x-axis. Vaccines are distributed via EPI (circles), EPI with boosters (*) and EPI with 70% mass vaccination (squares).

Figure 5. Effect of initial efficacy on effectiveness of PEV for different transmission settings delivered via EPI (a–c), EPI with boosters (d–f) and EPI with 70% mass vaccination (g–i).

Results obtained assuming a vaccine half-life of 10 years and homogeneity value of 10.

Figure 6. Effect of vaccine half-life on effectiveness of PEV for different transmission settings delivered via EPI (a–c), EPI with boosters (d–f) and EPI with 70% mass vaccination (g–i).

Results obtained assuming a an initial vaccine efficacy of 52% and homogeneity value of 10.

Figure 7. Effect of initial efficacy on effectiveness of all vaccines for different transmission settings delivered via EPI (BSV (a–c), BSV/TBV (d–f), PEV (g–i), PEV/TBV (j–l), BSV/PEV (m–o) and BSV/TBV (p–r)).

Results obtained assuming a vaccine half-life of 10 years and homogeneity value of 10.

Figure 8. Effect of initial efficacy on effectiveness of all vaccines for different transmission settings delivered via EPI with 70-% mass vaccination (BSV (a–c), BSV/TBV (d–f), PEV (g–i), PEV/TBV (j–l), BSV/PEV (m–o) and BSV/TBV (p–r)).

Results obtained assuming a vaccine half-life of 10 years and homogeneity value of 10.

Figure 9. Effectiveness of vaccines given different levels of mass vaccination coverage when delivered via EPI with community wide campaigns for different transmission settings (BSV (a–c), BSV/TBV (d–f), PEV (g–i), PEV/TBV (j–l), BSV/PEV (m–o) and BSV/TBV (p–r)).

Results obtained assuming an initial vaccine efficacy of 52%, a vaccine half-life of 10 years and homogeneity value of 10.