# Tuberculosis Vaccines: An Update of Recent and Ongoing Clinical Trials
## 3 TB Novel Vaccines
### Recombinant Live Vaccines
#### 3.2.5. Mva85A  
The vaccinia virus was also identified as a promising vector to be used in the development of a TB vaccine. MVA85A has been, and continues to be, in clinical trial. This is a vaccine comprising a recombinant replication-deficient modified vaccinia virus, Ankara (MVA), expressing the _M. tuberculosis_ Antigen 85A (Ag85A) [24]. Previous clinical trials found that MVA85A is well-tolerated and highly immunogenic when administered as a boost to BCG-primed individuals, as well as capable of intramuscular, intradermal, and aerosol administration [24; 25]. With this information, a clinical trial was carried out to ascertain whether altering these administration and intradermal vaccination routes, and if specifically altering the aerosol route, would boost cellular immunity to the Ag85A (ClinicalTrials.gov: NCT01954563). In this phase I blinded trial, 36 BCG-vaccinated adults, aged 21-42 years, were randomized equally between three groups to receive two MVA85A vaccinations, one month apart, using the following regime: Group 1, aerosol-intradermal immunisation; Group 2, intradermal-aerosol immunisation; and Group 3, intradermal-intradermal immunisation [26]. Peripheral blood was collected, and AEs recorded over a six-month period [26]. Most AEs reported were mild injection site reactions after intradermal vaccination [26]. Short duration systemic AEs after vaccination by both routes were mild, as were respiratory AEs following primary aerosol MVA85A (Group 1) [26]. The most significant AEs were seen when boosting an intradermal MVA85A prime with an aerosolized MVA85A boost one month later (Group 2), which led to transient moderate, or severe respiratory, and systemic AEs [26]. No SAEs were reported [26]. A modest significant boosting of the cell-mediated immune response to Ag85A was verified, while all three groups were found to have systemic cellular immune responses to the MVA vector [26]. Serum antibodies to Ag85A and MVA were only found after intradermal vaccination [26]. Aerosolized MVA85A induced significantly higher levels of Ag85A lung mucosal CD4+ and CD8+ T cell cytokines compared to intradermal vaccination, while boosting with aerosol-inhaled MVA85A enhanced intradermal primed responses in Group 2 [26]. With the BCG vaccine contraindicated in HIV-infected infants, the MVA85A vaccine was studied as a candidate vaccine for HIV exposed infants [27]. A double-blind randomized controlled trial, in which 248 HIV-exposed infants were enrolled, compared MVA85A prime vaccination against a Candin(r) control, followed by selective deferred BCG vaccination at the age of eight weeks for HIV-uninfected infants, and a twelve-month follow-up for safety and immunogenicity (ClinicalTrials.gov: NCT01650389). Throughout the study, mild-moderate readecionicity events were seen after newborn MVA85A vaccination, but no significant difference was observed in the rate of SAEs, HIV acquisition, or incident TB disease compared to the control group [27]. Vaccination with MVA85A resulted in significantly higher Ag85A-specific IFNy and CD4+ T cells compared to the control, at weeks 4 and 8 (\(p<0.0001\)) [27]. BCG did not further boost this response in those vaccinated with MVA85A, whereas the BCG-induced Ag85A-specific IFNy+ CD4+ T cell response at weeks 16 and 52 was similar between the control group and the intervention groups [27]. A clinical trial evaluating the immunogenicity of the vaccination after aerosol and intramuscular administration in adults with latent TB was terminated (ClinicalTrials.gov: NCT02532036), while another phase IIa randomized clinical trial in adolescents and adults to assess the vaccines immunogenicity is currently recruiting (ClinicalTrials.gov: NCT03681860).