This clinical trial provides further evidence for the safety of recombinant FP9 and MVA vectored vaccines in a healthy adult population. FP85A and MVA85A vaccines were well tolerated in all regimes. The frequencies of local and systemic AEs were comparable to previous clinical trials evaluating MVA85A vaccination and FP9 and MVA-vectored candidate malaria vaccines.11,15,16,18,19
Peak local reactions were larger in diameter in the FP85A-MVA85A regime in Group 3, compared with when MVA85A was the first vaccination. However, as previously discussed, this was not associated with increased frequency or severity of other local or systemic AEs; local reaction sizes were comparable by one week and the group size was small, so the significance is uncertain.20
All other local and systemic AEs in these subjects were mild and AEs were otherwise comparable between groups, as observed in previous clinical trials of FP9 and MVA vectored candidate malaria vaccines.19
MVA85A, but not FP85A vaccination induced strong 85A-specific cellular immunity. FP85A vaccination did not boost the responses to prior MVA85A vaccination (Group 2) and responses to MVA85A vaccination were inhibited by prior FP85A vaccination (Group 3). The same trend was observed in analysis of soluble cytokines, with IL-8 detected after MVA85A vaccination in Group 2 but not in Group 3.
Recombinant FP9-vectored vaccines induce weaker immune responses than recombinant MVA vaccines and MVA85A elicits unusually high responses compared with other recombinant MVA vaccines.11,13,15,16,21-23
In malaria vaccine clinical trials with a number of different antigen inserts, an increased IFNγ response compared with baseline was seen in FP9-MVA regimes with a similar interval between vaccinations with different viral vectors.6,18
Given the strong immune responses to MVA85A vaccination, we would expect at least modest antigen-specific immune responses following vaccination with FP85A.
Identity polymerase chain reaction (PCR) and sequencing assays had confirmed the presence of the 85A insert within the FP9 vector and no wild type FP9 was present. The clinical grade FP85A vaccine also passed annual murine potency assays, involving evaluation for antigen-specific cellular immune responses, which were lower for FP85A than MVA85A (data not shown). The antigen insert was therefore both present within the recombinant vector and recognizable by the adaptive immune system. In the clinical trial, FP85A induced local and systemic reactions typical of poxviruses, providing additional evidence that the viral vector was immunologically active. Positive and negative controls excluded technical problems with the assays and results were reproduced using frozen samples.
Serum was evaluated for the presence of the Th1 cytokines IFNγ and TNFα. The chemokine IL-8 was also measured because microarray analysis has previously demonstrated IL-8 to be one of the genes induced by MVA-infection of a cell.24
We speculate that IL-8 may be one of the mediators involved in directing the magnitude of the antigen-specific response to MVA85A. IL-8 is released by macrophages in response to M.tb
components, is chemotactic to neutrophils and thought to be important in granuloma formation and protection against disease.25,26
It would be interesting to evaluate further the role of IL-8 in early innate and adaptive cellular immune responses to MVA85A vaccination.
We used cryopreserved PBMC to investigate the inhibitory effect of prior vaccination with FP85A on the antigen-specific response to MVA85A vaccination. CD4+ and CD8+ T cell responses were detected upon stimulation of PBMC with Vaccinia epitopes following MVA85A vaccination in Group 2, but not in Group 3. No cell-mediated responses to Vaccinia epitopes were detected following FP85A vaccination. We therefore examined the serum IgG responses to MVA and FP9. Anti-MVA IgG antibodies were detected following MVA85A vaccination, but not after FP85A vaccination. Anti-FP9 IgG levels increased after MVA85A vaccination as well as after FP85A vaccination, suggesting anti-FP9 IgG is cross-reactive for MVA85A.
In conclusion, FP85A vaccination was safe and well tolerated in healthy adults. However, unlike MVA85A vaccination, FP85A vaccination did not increase 85A-specific immune responses. FP85A vaccination inhibited the antigen-specific and vector-specific cellular responses to subsequent MVA85A vaccination. We speculate that anti-FP9 IgG antibodies which are cross-reactive with MVA85A may be one factor mediating the inhibition of antigen-specific cellular immune responses to vaccination with MVA85A.