Immune responses to BCG immunisation and Mycobacterium tuberculosis infection in non-human primates

Abstract

The evaluation of new vaccines that are urgently needed against tuberculosis (TB) is hampered by the lack of an immune correlate of protection. One of the main measures of immune function utilised in TB vaccine studies is the assessment of interferon (IFN)-ɣ, as it is known that this cytokine is essential for immunity against infection. The studies conducted in this thesis uses the non-human primate model of TB to address whether two measurements of IFN-ɣ (the frequency of IFN-ɣ secreting cells and the concentration of IFN-ɣ secreted) can be related to survival and thus provide a correlate of protection. The Mycobacterium-specific IFN-ɣ profiles have been assessed in two primate species (rhesus macaques and cynomolgus macaques) following immunisation with BCG, or aerosol infection with Mycobacterium tuberculosis. Additionally, one of the most advanced novel TB vaccines (modified vaccinia virus Ankara expressing antigen 85A; MVA85A) has also been tested in this model. When human clinical trial data (provided by Oxford University) using BCG and BCG with an MVA85A boost were compared with results generated in similarly vaccinated macaques, it was observed that rhesus macaques have kinetically similar IFN-ɣ responses, but at different magnitudes. During a vaccine efficacy study, rhesus macaques were shown to be protected from M. tuberculosis infection by BCG vaccination. This allowed the opportunity for responses in animals protected against disease to be compared with those which were not protected. Although results showed that the capability to secrete larger concentrations of PPD-specific IFN-ɣ early after M. tuberculosis infection correlated with longer survival periods, this was not solely due to prior vaccination. Most of the IFN-ɣ responses during the vaccination periods did not relate to survival after challenge, except peak frequencies of IFN-ɣ secreting cells after BCG vaccination. Therefore, it was concluded that measuring IFN-ɣ alone does not provide the correlate of protection that is presently lacking in TB vaccine research.