A Phase I, Open-Label Trial, Evaluating the Safety and Immunogenicity of Candidate Tuberculosis Vaccines AERAS-402 and MVA85A, Administered by Prime-Boost Regime in BCG-Vaccinated Healthy Adults

Abstract

Background: MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing Mycobacterium tuberculosis antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB.

Methods: In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS-402.

Results: Most related adverse events (AEs) were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN-γ, TNF-α and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A.

Conclusions: Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries.

Trial registration: ClinicalTrials.gov NCT01683773.

Fig 1. CONSORT flow diagram.

CONSORT flow diagram showing subject recruitment and follow up. Subjects were allocated to Groups A and B in parallel and once both groups were complete, subjects were enrolled to Group C. *One subject was lost to follow up in Group B post day 14 follow up visit. All AEs post Day 0 vaccination had resolved prior to loss to follow up. **Two subjects withdrew from the study; one subject withdrew from Group B post first vaccination as did not wish to undergo any further venepunctures; one subject withdrew from Group C post second vaccination due to unexpected relocation. Both withdrawals were not considered related to vaccination and all AEs had resolved prior to withdrawal. The subject lost to follow up and the subject who withdrew from Group A was replaced; the subject who withdrew from Group C was not replaced as the study was nearing completion.

Fig 2. Ex-vivo IFN-γ ELISpot insert responses.

Responses to Ag85A (A), Ag85B (B) and TB10.4 (C) in BCG-vaccinated, healthy adults for Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Responses to Ag85A are also shown from TB022 (MVA85A). Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.

Fig 3. Ex-vivo IFN-γ ELISpot vector responses.

Responses to MVA peptides for CD4+ (A), and CD8+ T-cell epitopes (B) and summed responses to 3 pools of adenovirus peptides (C) in BCG-vaccinated, healthy adults for Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.

Fig 4. Total intracellular cytokine responses.

Total intracellular cytokine responses are presented as percentages of CD4+ T-cells or CD8+ T-cells producing mycobacteria-specific IFN-γ, TNF-α and IL-2 cytokines. Percentage of CD4+ (A, C and E) and CD8+ (B, D and F) responses in peripheral blood mononuclear cells to stimulation with Ag85A (A and B), Ag85B (C and D) and TB10.4 (E and F) peptides in healthy, BCG-vaccinated adults from Group A (AAM, green line), Group B (AM, blue line), Group C (AAA, red line) and TB022 (M, black line). Lines show median responses in each group, whiskers show inter-quartile range.

Fig 5. Polyfunctionality of peak and plateau intracellular cytokine responses.

Polyfunctionality of CD4+ (A, C, E and G) and CD8+ (B, D, F and H) T-cells in response to stimulation with Ag85A and Ag85B peptides in healthy, BCG-vaccinated adults from Group A (AAM, green), Group B (AM, blue), Group C (AAA, red) and TB022 (M, black). Panels A-D show peak responses to Ag85A (A and B) and Ag85B (C and D), whereas panels E-H show plateau responses to Ag85A (E and F) and Ag85B (G and H). Plots show box and whisker with inter-quartile range and minimum and maximum values.

Fig 6. Serum antibody responses.

Serum antibody responses to Ag85A (A), Ag85B (B) and TB10.4 (C) in the three study groups; Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Antibody responses were measured in optical density (OD), data is presented as fold change responses calculated by dividing each time point’s antibody response by its corresponding day 0 response. Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.