Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults

Abstract

Purpose: A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG.

Methods: Healthy BCG-vaccinated volunteers were vaccinated with either 1×10(7) or 1×10(8)PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5×10(7)PFU MVA85A had been administered.

Results: There were no serious adverse events recorded following administration of either 1×10(7) or 1×10(8)PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1×10(8)PFU of MVA85A when compared to either 5×10(7) or 1×10(7)PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1×10(8)PFU compared to the 5×10(7) and 1×10(7) doses. Additionally, a broader range of Ag85A epitopes are detected following 1×10(8)PFU of MVA85A.

Conclusion: A higher dose of 1×10(8)PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected.

Fig. 1

Fig. 2

Severity of adverse events induced by immunisation with different doses of MVA85A. Severity of the most frequently reported local adverse events following immunisation with (A) 1 × 10⁷ or (B) 1 × 10⁸ PFU of MVA85A. Severity of the most frequently reported systemic adverse events following immunisation with (C) 1 × 10⁷ or (D) 1 × 10⁸ PFU of MVA85A. White: mild, grey: moderate and black: severe.

Fig. 3

T cell responses in adults vaccinated with either 1 × 10⁷ or 1 × 10⁸ PFU of MVA85A. Antigen specific T cells were detected in PBMC from healthy, previously BCG vaccinated adults receiving either 1 × 10⁷ (panels A, C and E) or 1 × 10⁸ (panels B, D and F) PFU of MVA85A. T cells were detected using an overnight ex vivo IFN-γ ELISPOT assay with summed peptide pool (A and B), Ag85A protein (C and D) or PPD (E and F). Wilcoxon matched-pairs signed rank when compared to baseline (screening visit): ***p < 0005, **p < 005, *p < 05.

Fig. 4

T cell epitope display in adults vaccinated with either 1 × 10⁷ or 1 × 10⁸ PFU of MVA85A. A total of 66, 15-mer peptides overlapping by 10 amino acids (P1–P66) were used to map T cell responses to MVA85A. A) Open bars indicate individual peptide responses to 1 × 10⁷ (n = 12) and black bars 1 × 10⁸ PFU (n = 12) of MVA85A. B) The overall number of peptides detected in response to MVA85A is significantly higher in volunteers vaccinated with 1 × 10⁸ (black circles) compared to 1 × 10⁷ (white circles) PFU of MVA85A. Responses detected using an ex vivo IFN-γ ELISPOT assay, Mann–Whitney *p < 0.05.

Fig. 5

Dose related differences in T cell response to MVA85A. The fold increase in the frequency of antigen specific T cells detected following immunisation with different doses of MVA85A at the peak of response (1 week) and long term (52 weeks) over the screening pre-immunisation responses were calculated for each dose. There was a significant difference in the fold increase between the high and low dose groups at 52 weeks, but no significant difference between high, mid or low doses at 1 week post immunisation.