Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults

Abstract

Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio, 0.24; 95% CI, 0.08 to 0.75; P = 0.016).

Fig. 1. Vaccine immunogenicity

ELISPOT and ICS assays were used to determine the numbers of cells producing IFN-γ (identified as spots on the ELISPOT assay) and percentages of cells on flow cytometry, respectively. Shown are geometric mean T cell and antibody responses with 95% CIs by time point and by vaccination group. Units are IFN-γ–producing cells (spots) per million PBMCs for the ELISPOT assay, %CD4/CD8 T cells for the ICS assay, and arbitrary units for the enzyme-linked immunosorbent assay (ELISA) detecting antibody. P < 0.05 is shown by a black circle for vaccinees receiving the ChAd63-MVA ME-TRAP vaccine versus control vaccinees receiving a rabies vaccine. Results are shown at screening (day 0), 14 days after priming with ChAd63 ME-TRAP (day 14), 7 days after boosting with MVA ME-TRAP (peak immunogenicity was at day 63), and after waning of the immune response (day 161). G, IFN-γ; L, IL-2; T, TNF-α.

Fig. 2. Kaplan-Meier plots of first episodes of PCR positivity after vaccination

(A to D) The figure shows (A) rainfall data (in millimeters per week) and (B to D) Kaplan-Meier plots of (B) first episode of PCR positivity at any threshold (P = 0.0006 by log-rank), (C) first episode of PCR positivity at >10 parasites/ml (P = 0.0004 by log-rank), and (D) first episode of PCR positivity where the parasite genotype was different from a parasite genotype seen in samples collected before the start of monitoring (P = 0.023 by log-rank). Analysis is shown beginning 1 week after the last vaccination when antimalarial drugs were given. *, significant differences (P < 0.05).

Fig. 3. Kaplan-Meier plot of first episodes of PCR positivity after immune response

(A to D) We split immunological responses according to tertile among the ChAd63-MVA ME-TRAP vaccinees and plotted survival functions for time to malaria infection by PCR according to tertile. Shown are (A) T cell responses to the TRAP peptide pool 21 to 30 from T9/96 parasites; (B) T cell responses to the TRAP peptide pool 21 to 30 from 3D7 parasites; (C) summed T cell responses to all TRAP peptide pools from T9/96 parasites; (D) ELISA results showing antibody responses to TRAP. *, significant differences (P < 0.05). Correlations are shown between peak immune response as measured on day 63 (1 week after boost) and subsequent infection.