We studied MVA85A vaccination of HIV-infected adults with or without M.tb infection, and those receiving ART. Five major findings emerged from our study: (1) MVA85A was well tolerated in HIV and M.tb-infected persons; (2) MVA85A vaccination did not influence the effectiveness of ART; (3) MVA85A vaccination induced robust, long-lived, and predominantly polyfunctional CD4 T-cell responses in all groups, and these responses were lowest in HIV-infected vaccinees; (4) the prevaccination T-cell response, which was associated with M.tb sensitization, was a major determinant of the postvaccination response; and (5) successful ART of HIV-infected individuals did not significantly improve the MVA85A-induced response.
We observed no vaccine-related SAEs on MVA85A vaccination of HIV-immunocompromised individuals with or without LTBI. Fluctuations in pVL or CD4 count were within ranges previously reported in untreated, chronic HIV infection (15
). The effectiveness of ART in group 4 participants was not markedly affected by MVA85A vaccination; pVL blips were similar to those observed after vaccination with other vaccines (17
). These fluctuations were not considered clinically significant and the HIV physicians managing the care of these individuals made no adjustments to their treatment regimen. Although interpretation of these data is limited by the small sample size in our study, this is an important finding given the increasing number of persons receiving ART in developing countries. Because the risk of TB in HIV-infected persons receiving ART remains higher than for HIV-uninfected persons (2
), effective TB vaccines are urgently required for this population.
The SAE involving diagnosis of TB of the spine was classified as not related to vaccination. This was based on the distal locality of disease and the 6-month timeframe between MVA85A vaccination and diagnosis. The individual had also previously received ART, but had stopped treatment 3 months before being screened for inclusion in the study. In addition, it emerged that the person had a previous episode of TB, a major risk factor for further episodes of TB in HIV-infected persons (20
With respect to the case of shingles in a group 4 participant, no CD4 count decrease was observed after MVA85A vaccination. To date, a total of 2,012 subjects and 108 HIV-infected adults have received MVA85A, with no reports of herpes zoster reactivation (H. McShane, personal communication). Further, to our knowledge no associations between other vaccinations and zoster reactivation are described. On the basis of these factors, this AE was classified as not related to vaccination.
No vaccine-related SAEs were recorded in immunocompetent individuals with documented LTBI. Given the hypothetical concerns of immunopathogenic inflammation on administration of mycobacterial antigens to individuals with LTBI, as originally described by Robert Koch (21
), this is an important finding. Nevertheless, we feel that reactions at the TST site should be carefully monitored in novel TB vaccine trials conducted in M.tb
-infected persons. Our data add to the safety results of MVA85A in M.tb
-infected adults from the United Kingdom, which also reported no vaccine-related immunopathology (11
Our results complement the excellent safety profile of MVA85A in adults (11
), adolescents, children (14
), and infants (24
) and pave the way for safety assessments of MVA85A in larger groups of M.tb
- and/or HIV-infected persons.
MVA85A induced predominantly polyfunctional CD4 T-cell responses in all groups. The pattern of IFN-γ, TNF-α, IL-2, and IL-17 expression by CD4 T cells observed in M.tb
-infected and/or HIV-infected vaccinees is similar to those reported previously (14
). However, lower response frequencies were observed in HIV-infected individuals. It should be noted that participation was limited to HIV subjects with CD4 counts greater than 300 cells/μl. The specific Th1 response in HIV-infected vaccinees also waned to low levels, although Ag85A-specific IFN-γ–producing cells still exceeded prevaccination levels 1 year postvaccination. M.tb
-specific CD4 T cells may be preferentially infected and depleted after HIV infection (26
) (reviewed in Reference 27
). It is unknown what the consequences of such lower responses on immunity against M.tb
might be. In HIV-infected individuals, the elevated risk for developing TB may be associated with lower and functionally impaired mycobacteria-specific Th1 responses in the lungs (28
). However, we showed that frequencies of polyfunctional Th1 cytokine-expressing T cells, measured 10 weeks after BCG vaccination in peripheral blood, did not correlate with risk of TB in infants (29
). We also showed that T-cell functional capacity was associated with antigen load. Polyfunctionality of mycobacteria-specific T cells was highest in persons with LTBI, and progressively decreased in patients with smear-negative, and smear-positive pulmonary TB, respectively (30
). Murine studies of vaccine-induced T-cell responses and their effect on control of M.tb
burden have reported variable and contrasting outcomes (31
). Until correlates of protection are identified in trials of effective vaccines, T-cell outcomes measured here may only be interpreted as vaccine take, even though these measures are known to be important in protection (35
We observed higher prevaccination frequencies of Ag85A-specific T cells in M.tb
-infected adults, compared with uninfected adults studied previously at our field site (16
). Furthermore, the magnitude of Ag85A-specific T cells correlated with the degree of M.tb
sensitization and the prevaccination Ag85A-specific T-cell response correlated with the postvaccination response. These data highlight the importance of measuring prevaccination responses to mycobacterial antigens in TB vaccine trials, and imply that immunogenicity should be interpreted in the context of this preexisting response and levels of mycobacterial exposure. This is supported by our previous observation of greater magnitudes of Ag85A-specific T cells before MVA85A vaccination in adults and adolescents, compared with infants (24
). We proposed that the frequency of Ag85A-specific cells before MVA85A vaccination may reflect BCG priming in infancy, while reflecting exposure to environmental mycobacteria and/or M.tb
in adolescents and adults. Our results from M.tb
-infected adults reinforce this finding. A limitation of these intergroup comparisons was the small number of individuals per group, which may have provided inadequate statistical power for detecting differences.
It has been proposed that the BCG-induced response may be blocked or masked in developing countries because of preexisting sensitization to mycobacterial antigens (36
). We observed that greater mycobacterial sensitization, in our case mostly M.tb
, was associated with greater MVA85A-induced Th1 responses. Whether this also applies to BCG-induced responses is not known. However, boosting the BCG-induced response with BCG elicited lower Ag85A-specific T-cell responses than boosting with MVA85A (38
), suggesting that vaccine formulation or nature of antigen may be important variables. Nevertheless, we propose that masking due to mycobacterial sensitization may be less important for vaccination with MVA85A, than has been suggested for BCG. Interestingly, sensitization of mice with nontuberculous mycobacteria interfered with immune responses induced by subsequent vaccination with BCG, but not a subunit TB vaccine (39
). Further investigation is required to understand this better.
Compared with ART-naive HIV-infected vaccinees, MVA85A vaccination of HIV-infected, ART-treated individuals did not induce profoundly greater frequencies of Th1 responses, with the exception of IL-2–expressing CD4 T cells. Loss of IL-2 expression by HIV-specific T cells is a well-described consequence of immune activation associated with high HIV replication (40
). Furthermore, IL-2–expressing CD4 cells, which were predominant among M.tb
-specific cells, were shown to be more susceptible to HIV infection than macrophage inflammatory protein-1β–expressing CD4 cells (26
). ART-mediated suppression of HIV replication may thus preferentially restore IL-2–expressing mycobacteria-specific CD4 T cells, which may be important for immunity against M.tb
Ag85A-specific CD8 T cells were not readily detectable after MVA85A vaccination. This contrasts with some previous MVA85A trials in different populations, in which low frequencies of specific CD8 T cells were reported (23
). We propose that frequencies of CD8 T cells induced by MVA85A were too low to be detected with our ex vivo
assay systems. This is supported by the observation that in vitro
expansion of specific T cells enabled detection of MVA85A-induced CD8 T cells (38
In conclusion, we show that MVA85A is safe and immunogenic in HIV- and/or M.tb-infected adults from a region where TB is endemic. These data support further studies to evaluate the safety and efficacy of MVA85A in HIV-infected and M.tb-infected populations.