Abstract
BCG is already established as a vaccine against a global epidemic of tuberculosis, but its efficacy remains variable. It has shown almost no protection against TB in tropical countries like Africa and India. One of the prime reasons postulated for the failure of BCG as a vaccine is associated with pre-exposure to environmental mycobacteria. Cross-sensitisation to shared mycobacterial antigens is regarded as an important factor for this variation in efficacy.
This study investigated the effects of environmental Mycobacterium avium exposure on immune responses to BCG and two novel TB vaccine candidates: Rabbit haemorrhagic disease (RHDV) virus-like particles conjugated with Antigen 85A (VLP/Ag85A) and Modified vaccinia virus Ankara expressing Antigen 85A (MVA/Ag85A). Ag85A peptide was used because it is known to be an effective immunogen. M. avium strain WAg206 was chosen for this study as it has previously been shown to interfere with BCG vaccination. RHDV VLP were generated using a recombinant baculovirus containing the VP60 capsid gene. VLP/Ag85A was prepared by chemical conjugation of mycobacterial peptide Ag85A to VLP. MVA/Ag85A is a genetically modified vaccinia virus expressing Ag85A. T cell proliferation assays, cytokine assays, total antibody and antibody isotype assays were carried out after vaccination to measure the immunogenicity.
The results suggest that among these novel vaccines, MVA/Ag85A is the best vaccine candidate following pre-exposure to WAg206 as it generated a stronger Th1 type of immune response than either BCG or VLP/Ag85A based on proliferation assays and cytokine assays specific to mycobacterial antigens. High levels of antigen-specific IFN-γ, a Th1 cytokine, were recorded when mice were vaccinated with MVA/Ag85A following pre-exposure to WAg 206. On vaccination with VLP/Ag85A, antigen-specific IFN-γ responses were low, but the presence of higher levels of total antibody specific to mycobacterial antigens suggested induction of a predominant Th2 response which is not protective.
Future work to improve the cell-mediated response to VLP/Ag85A may include using an adjuvant which enhances Th1 responses and overcomes the inhibitory effect of environmental mycobacteria.