Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara

Abstract

Malaria is a major global health problem for which an effective vaccine is required urgently. Prime-boost vaccination regimes involving plasmid DNA and recombinant modified vaccinia virus Ankara-encoding liver-stage malaria antigens have been shown to be powerfully immunogenic for T cells and capable of inducing partial protection against experimental malaria challenge in humans, manifested as a delay in time to patent parasitemia. Here, we report that substitution of plasmid DNA as the priming vector with a specific attenuated recombinant fowlpox virus, FP9, vaccine in such prime-boost regimes can elicit complete sterile protection that can last for 20 months. Protection at 20 months was associated with persisting memory but not effector T cell responses. The protective efficacy of various immunization regimes correlated with the magnitude of induced immune responses, supporting the strategy of maximizing durable T cell immunogenicity to develop more effective liver-stage vaccines against Plasmodium falciparum malaria.

Fig. 1.

Immune responses after vaccination. (a) Summed IFN-γ ELISPOT responses 7 days after final vaccination in each group. (b) Summed IFN-γ ELISPOT responses 7 weeks after final vaccination in groups 3b and 4. In all groups prevaccination responses were very low (33). One FFM subject and one MMM subject did not proceed to malaria challenge and are not included in this data set.

Fig. 2.

Kaplan-Meier plot comparing time with patent parasitemia (by blood film) in FFM and DDMF-vaccinated subjects and in pooled controls from all challenge studies. Both vaccination regimes differ significantly from the nonvaccinated controls: P = 0.0013 for FFM and P = 0.0189 for DDMF. Subjects (18) received the FFM regime; five were challenged at 2 weeks, 11 were challenged at 7 weeks, and one was challenged at 6 months. Subjects (4) received the DDMF regime and were challenged after 2 weeks.

Fig. 3.

The correlation between the level of the ex vivo IFN-γ ELISPOT response (the peak responses to both T9/96 and 3D7 peptides) for each group plotted against delay with ELISPOT values on a log scale. d = 1 mg of DNA ME-TRAP i.m.; g = 4 μg of DNA ME-TRAP given i.d. by gene gun; m = 5 × 10⁷ plaque-forming units of MVA i.d.; D = 2 mg of DNA ME-TRAP i.m.; M = 15 × 10⁷ plaque-forming units MVA i.d.; and F = 10 × 10⁷ plaque-forming units FP9 i.d.. All vaccinations are given 3-4 weeks apart. Correlations of both peak T cell immune response to T9/96 strain peptides (correlation coefficient, 0.714; P = 0.0091) and 3D7 strain peptides (correlation coefficient, 0.659; P = 0.0198) with delay are significant.