Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: different boosting intervals and implications for efficacy trials

Abstract

Objectives: To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination.

Design: There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naïve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime-MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG.

Results: MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination.

Conclusions: The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here.

Trial registration: ClinicalTrials.gov NCT00427453 (short boosting interval), NCT00427830 (long boosting interval), NCT00480714 (BCG alone).

Conflict of interest statement

Competing Interests: AP, AH and HM are named inventors on a composition of matter patent for MVA85A filed by the University of Oxford.

Figures

Figure 1. Consort flowchart for the BCG alone trial

Figure 2. Consort flowchart for the BCG prime–MVA85A boost (short interval) trial

Figure 3. Consort flowchart for the BCG prime–MVA85A boost (long interval) trial

Figure 4. Median IFN-γ ELISpot responses after vaccination in each vaccination group: BCG alone;BCG prime-MVA85A boost.

(a) timeline for vaccinations (weeks) in each group; (b)Tuberculin PPD responses; (c) Purified antigen 85 protein responses (d) summed pooled peptide responses; (e) For each of the three antigens measured, the responses between each vaccine group were compared 1 week after vaccination using Mann-Whitney statistic. (f) For each of the three antigens measured, the responses between each vaccine group were compared 24 weeks after vaccination using Mann-Whitney statistic.

Figure 5. Dot-plot showing data at (a) 1 week and (b) 24 weeks after vaccination in the MVA85A boosted group after recent and distant BCG vaccination.

Interval between BCG and MVA85A was four weeks for the short interval trial and a median of 18 years (range 6 months–38 years) in the long interval trial.