Safety and immunogenicity of an FP9-vectored candidate tuberculosis vaccine (FP85A), alone and with candidate vaccine MVA85A in BCG-vaccinated healthy adults: a phase I clinical trial

Abstract

The safety and immunogenicity of a new candidate tuberculosis (TB) vaccine, FP85A was evaluated alone and in heterologous prime-boost regimes with another candidate TB vaccine, MVA85A. This was an open label, non-controlled, non-randomized Phase I clinical trial. Healthy previously BCG-vaccinated adult subjects were enrolled sequentially into three groups and vaccinated with FP85A alone, or both FP85A and MVA85A, with a four week interval between vaccinations. Passive and active data on adverse events were collected. Immunogenicity was evaluated by Enzyme Linked Immunospot (ELISpot), flow cytometry and Enzyme Linked Immunosorbent assay (ELISA). Most adverse events were mild and there were no vaccine-related serious adverse events. FP85A vaccination did not enhance antigen 85A-specific cellular immunity. When MVA85A vaccination was preceded by FP85A vaccination, cellular immune responses were lower compared with when MVA85A vaccination was the first immunisation. MVA85A vaccination, but not FP85A vaccination, induced anti-MVA IgG antibodies. Both MVA85A and FP85A vaccinations induced anti-FP9 IgG antibodies. In conclusion, FP85A vaccination was well tolerated but did not induce antigen-specific cellular immune responses. We hypothesize that FP85A induced anti-FP9 IgG antibodies with cross-reactivity for MVA85A, which may have mediated inhibition of the immune response to subsequent MVA85A. ClinicalTrials.gov identification number: NCT00653770.

Keywords: heterologous prime-boost regimes; phase I clinical trial; poxvirus-vectored subunit vaccines; tuberculosis vaccines.

Figures

Figure 1. CONSORT flow diagram. Figure 1 shows the flow of subjects through the trial. Subjects were not randomized, but allocated sequentially into Group 1, then Group 2, then Group 3, in order of enrolment. All enrolled subjects completed follow up.

Figure 2. IFNγ ELISpot responses to 85A and soluble serum cytokines. (A) Longitudinal IFNγ ELISpot responses to the single 85A peptide pool. Each dot represents an individual subjects’ response and median responses are connected by lines. Group 1 = FP85A vaccination week 0; Group 2 = MVA85A vaccination week 0, FP85A vaccination week four; Group 3 = FP85A vaccination week 0, MVA85A vaccination week four. No increases in responses to antigen 85A were seen after FP85A vaccination in Group 1. MVA85A vaccination induced strong IFNγ T cell responses to antigen 85A in Group 2, which were maintained throughout the 52 week follow up, but were not boosted by subsequent FP85A vaccination at week four. There were no responses after FP85A vaccination in Group 3, but subsequent MVA85A vaccination at week four induced moderate IFNγ T cell responses to antigen 85A. (B) Proportion of subjects with detectable soluble serum cytokines. The bars show the proportion of subjects within each group, in whose serum, any cytokines were detectable. Group 1 = FP85A vaccination week 0; Group 2 = MVA85A vaccination week 0, FP85A vaccination week four; Group 3 = FP85A vaccination week 0, MVA85A vaccination week four; days = days since enrolment. Serum IFNγ and TNFα were detected in no more than one subject’s serum at any one time point. IL-8 was detected in all Group 2 subjects’ serum by day seven (one week after MVA85A vaccination).

Figure 3. IFNγ ELISpot responses to Vaccinia CD4+ and CD8+ T cell epitopes. (A) Longitudinal IFNγ ELISpot responses to known Vaccinia CD4 and CD8 epitopes Each dot represents an individual subjects’ response and median responses are connected by lines. Group 1 = FP85A vaccination week 0; Group 2 = MVA85A vaccination week 0, FP85A vaccination week four; Group 3 = FP85A vaccination week 0, MVA85A vaccination week four. Minimal, transient increases in Vaccinia CD8+ responses compared with baseline were observed after FP85A vaccination in Group 1. Transient responses to Vaccinia CD4+ and CD8+ epitopes were observed after MVA85A, but not FP85A vaccination in Group 2. In Group 3, responses to Vaccinia epitopes did not significantly increase after either FP85A or MVA85A vaccinations. (B) Correlation between IFNγ ELISpot responses to Vaccinia CD4+ and CD8+ at the time of MVA85A vaccination and IFNγ ELISpot responses to antigen 85A one week after MVA85A vaccination. Each dot represents an individual subjects’ responses. Pre-vaccination responses were from the day of MVA85A vaccination (Group 2 = week 0; Group 3 = week four). Post-vaccination responses were from samples taken one week after MVA5A vaccination (Group 2 = week one; Group 3 = week five). Circles = responses to Vaccinia CD4+ epitopes; diamonds = responses to Vaccinia CD8+ epitopes. No relationship between pre-vaccination anti-vector responses (y axes) and post-vaccination T cell responses (x axes) for MVA85A vaccination was found.

Figure 4. Serum IgG ELISA responses to r85A, MVA and FP9. (A) Longitudinal r85A IgG, FP9 IgG and MVA IgG responses detected by ELISA Each dot represents an individual subjects’ response and median responses are connected by lines. Group 1 = FP85A vaccination week 0; Group 2 = MVA85A vaccination week 0, FP85A vaccination week four; Group 3 = FP85A vaccination week 0, MVA85A vaccination week four. Anti-vector antibody responses were generally stronger than antigen-specific anti-85A IgG responses. In Group 1, FP85A vaccination induced an FP9 IgG response, but no MVA IgG antibodies. In Group 2, MVA85A vaccination induced FP9 IgG and MVA IgG responses. Subsequent FP85A vaccination boosted the FP9 IgG response but did not boost the MVA IgG response. In Group 3, MVA85A vaccination induced an MVA IgG response, but did not boost the FP9 IgG response to prior FP85A vaccination. (B) Correlation between FP9 IgG and MVA IgG levels detectable by ELISA at the time of MVA85A vaccination and IFNγ ELISpot responses to antigen 85A one week after MVA85A vaccination. Each dot represents an individual subjects’ responses. Pre-vaccination responses were from the day of MVA85A vaccination (Group 2 = week 0; Group 3 = week four). Post-vaccination responses were from samples taken after MVA5A vaccination (Group 2 = week four; Group 3 = week 12). Circles = FP9 IgG levels; diamonds = MVA IgG levels. There were trends toward negative correlations between pre-MVA85A FP9 and MVA IgG levels and post-MVA85A IFNγ ELISpot responses to single pool 85A in Groups 2 and 3.