Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individuals

Abstract

Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care.

Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI.

Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNgamma and IL-2 ELISpot assays and FACS.

Measurements and main results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-gamma and IL-2 response that was durable for 52 weeks. The magnitude of IFN-gamma response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin-vaccinated individuals. Antigen 85A-specific polyfunctional CD4(+) T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination.

Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Clinical trial registered with www.clinicaltrials.gov (NCT00456183).

Figure 1.

The Consort E-Flowchart, August 2005. Consort diagram for study.

Figure 2.

MVA85A vaccination expands antigen 85A-specific IFN-γ–secreting T cells. Median IFN-γ ELISpot responses to (A) Ag85A, and the summed responses to (B) Ag85A peptide pools, for n = 12 for all time points except Week 4, where n = 11 due to subject unavailability. The responses to each antigen at 1 week, 24 weeks, and 52 weeks after vaccination were compared with Week 0 using the Mann-Whitney test.

Figure 3.

MVA85A vaccination is as effective at expanding antigen 85A-specific IFN-γ–secreting T cells in subjects with latent tuberculosis infection (LTBI) as in subjects who have been bacillus Calmette-Guérin (BCG) vaccinated, despite higher baseline antigen 85A–specific responses. Median IFN-γ ELISPOT responses to Ag85A and summed peptide pools in this trial (n = 12) compared with a previous trial of MVA85A in subjects vaccinated with BCG at (A) screening (n = 22), (B) 1 week (n = 17), and (C) 52 weeks (n = 9) after vaccination with MVA85A. The responses to each antigen at each time point for each trial were compared using the Mann-Whitney test.

Figure 4.

MVA85A vaccination expands antigen 85A–specific IL-2–secreting T cells. Median IL-2 ELISpot responses to (A) Ag 85A and the summed responses to (B) Ag85A peptide pools for n = 10 for all time points except Week 52, where n = 7 due to reagent unavailability. The responses to each antigen at 1 week, 24 weeks, and 52 weeks after vaccination were compared with Week 0 using the Mann-Whitney test.

Figure 5.

MVA85A vaccination expands multifunctional CD4⁺ T-cell populations. (A) The group functional profiles of Ag85A-specific CD4⁺ T cells throughout the vaccination time course are shown (n = 10 for Week 1, 11 for Week 4, and 8 for Week 24). Responding cells (able to produce any of the following cytokines: IFN-γ, IL-2, or TNF-α) were grouped and color coded according to the number of cytokines produced. (B) The absolute Ag85A-specific CD4⁺ T-cell responses are shown for each of the possible functional species (along the x axis) throughout the vaccination time course. Individual data points are shown with median line, interquartile range boxes, and minimum/maximum whiskers. Significant (P < 0.05) increases above baseline levels are shown (Wilcoxon signed rank test for matched pairs).

Figure 6.

MVA85A vaccination has no effect on early-secreted antigenic target (ESAT)-6– and culture filtrate protein (CFP)-10–specific IFN-γ–secreting T cells. Median IFN-γ ELISpot responses to summed peptide pools of antigens (A) ESAT-6, and (B) CFP-10 for n = 12 for all time points except Week 4, where n = 11 due to subject unavailability. The responses to each antigen at 1 week, 24 weeks, and 52 weeks after vaccination were compared with week 0 using the Mann-Whitney test.