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Title: Heterologous prime-boost vaccine regimens against Chlamydia trachomatis
Author: Badamchi-Zadeh, Alexander
ISNI:       0000 0004 5349 5676
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Chlamydia trachomatis is the most common bacterial sexually transmitted disease in man and despite decades of effort, there is still no protective vaccine. Left untreated, genital infection can lead to pelvic inflammatory disease, ectopic pregnancy, and infertility. However, infection-induced immunity in both animal models and humans indicates a strong role for CD4+ Th1-biased immune responses. Using a multi-component vaccine approach we assessed the immunogenicity and protective efficacy of novel plasmid DNA, Adenovirus 5 (HuAd5) and modified vaccinia Ankara (MVA) vectors each containing a major outer membrane protein (MOMP) transgene and recombinant MOMP protein in various heterologous prime-boost regimens in BALB/c and B6C3F1 mice. During the course of the prime-boost regimens, serum and vaginal MOMP-specific antibody titres, subtypes, avidities and neutralisation abilities were assessed, alongside IFN-γ ELISpot and CD4+ and CD8+ T cell polyfunctionality (IFN-γ, TNF-α, and IL-2). Regimens were grouped on the distinct MOMP-specific immune environments they elicited, with these regimens taken through into C. trachomatis vaginal challenge studies in two mouse models to shed light on the relative contribution of each environment to protective immunity. The DNA-HuAd5-MVA-Protein (D.A.M.P.) vaccine regimen resulted in a significant reduction in C. trachomatis vaginal shedding at day 3 post-infection in both BALB/c and B6C3F1 mouse strains. This significant reduction was lost when D.A.M.P. vaccinated mice were depleted of their CD4+ T cells prior to challenge, indicating the protection is CD4+ T cell mediated. C. trachomatis EB serum neutralisation profiles were similar between protective and non-protective vaccine regimens and combined with passive transfer experiments into naïve C57BL/6 mice and IFN-γ knock-out C57BL/6 mice we concluded that the antibody response did not play a significant role in this vaccine-induced protection. As well as infecting the genital tract, Chlamydia trachomatis is also the causal agent of trachoma, the leading cause of infectious blindness in the world. Recently, Kari et al. revealed serum anti-MOMP antibodies correlated with the reduction in chlamydial ocular burden in non-human primates, while anti-PmpD and anti-Pgp3 serum antibodies correlated with chlamydial eradication. We therefore investigated if we could induce such anti-chlamydial antibodies on the murine eye through heterologous prime-boost vaccinations. We uncovered a vaccination regimen that induced significantly greater anti-MOMP ocular antibodies, and employed this regimen for the additional chlamydial antigens, of which all induced ocular antigen-specific IgG antibodies. This is the first investigation into such vaccination regimens to induce chlamydial specific ocular antibodies and provides a new model for the screening of future potential trachoma vaccines.
Supervisor: Shattock, Robin Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral