Evaluation of the Safety and Immunogenicity of a Candidate Tuberculosis Vaccine, MVA85A, Delivered by Aerosol to the Lungs of Macaques

Abstract

b Tuberculosis (TB) is a reemerging disease. The only available vaccine, Mycobacterium bovis BCG, is delivered intradermally and confers highly variable efficacy against pulmonary disease. There is an urgent need for improved vaccination strategies. Murine studies suggest that immunizations delivered directly to the respiratory mucosa might be a more effective route of vaccination. This study compared the immunogenicity of a leading candidate tuberculosis (TB) vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in rhesus macaques, delivered either as an aerosol or as an intradermal boost immunization 12 weeks after an intradermal BCG prime vaccine. Aerosol vaccination was well tolerated. MVA85A delivered by aerosol or by intradermal injection induced antigen-specific immune responses in the periphery and the lung, with a trend toward the highest response when the compartment and route of delivery were matched. The ability of poxvirus-vectored vaccines delivered by the systemic route to induce responses in the mucosal immune compartment in macaques is in contrast to the independent compartmentalization of mucosal and systemic immune systems described in mice. Unlike intradermal vaccination, aerosol vaccination did not induce a detectable serum anti-vector antibody response. The delivery of vaccines to the lungs might provide an immunization strategy that limits the induction of systemic anti-vector immunity, which would be extremely useful in the development of improved vaccine strategies. This is the first study to show a recombinant MVA-vectored vaccine to be highly immunogenic when delivered by the aerosol route to nonhuman primates. These results provide important safety and proof-ofconcept data for further evaluation of this route of immunization for use in human clinical trials.

Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial

“…The intradermal route also induced lung CD4 T-cell responses, although these were of a smaller size than those induced by the aerosol route. In non-human primates, systemic administration of MVA85A induced mucosal responses at a lower level than recorded in people; 8 however, in mice, systemic delivery of a recombinant adenoviral vector does not induce mucosal responses 21 …”

“…Recombinant MVA vectors delivered to mucosa induced high levels of mucosal immunity in animal models 7 . Aerosol administration of MVA in non-human primates was safe and induced potent and long-lasting antigen-specific immunity 8 . Aerosol delivery of a tuberculosis vaccine could offer logistic benefits over intradermal administration.…”

Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines

“…Recent studies have shown that a subunit vaccine can be delivered safely to the lung using an aerosol delivery device in both nonhuman primates and humans Although these studies were performed with MVA85A, the proof-of-concept safety and immunogenicity data generated from this study [94,95] will accelerate the clinical testing of aerosol vaccines emerging from the TBVAC2020 and EMI-TB consortiums.…”

Filling the Immunological Gap

“…The administration of MVA via mucosal routes proved to be efficient in generating protective immune responses to airborne viruses and M.tb in mice (Goonetilleke et al, 2003). Recently, MVA-based tuberculosis vaccine was shown to be highly immunogenic and safe when delivered by inhaled aerosol to nonhuman primates (White et al, 2013) and healthy human volunteers (http://clinicaltrials.gov/show/NCT01497769). Thus, due to its strong immunogenicity and safety, MVA-based vector is an attractive vaccine platform for respiratory mucosal immunization.…”