ABSTRACT
Chlamydia trachomatis and Herpes simplex virus type 2 (HSV-2) genital infections pose a considerable public health challenge worldwide. Considering the high incidence of coinfections by the two pathogens, a combination vaccine that can be administered as a single regimen would be highly desirable. Recombinant Vibrio cholerae ghosts (rVCG) offer an attractive approach for the induction of humoral and cellular immune responses against human and animal pathogens. In this study, we evaluated a bivalent combination vaccine formulation comprising rVCG expressing chlamydial MOMP and HSV-2 glycoprotein D in mice for immunogenicity and protective efficacy against genital challenge with either pathogen. Mice immunized with the combination vaccine elicited secretory IgA and IgG2a antibodies to both chlamydial and HSV-2 antigens in serum and vaginal secretions. Robust antigen-specific mucosal and systemic T helper type 1 responses were induced in mice as measured by increased interferon-gamma levels produced by immune T cells in response to restimulation with target antigen in vitro. In addition, mice immunized with the combination vaccine were prophylactically protected from genital challenge with high doses of live Chlamydia and HSV-2. Thus, the combination vaccine regimen delivered by rVCG elicited adequate immune effectors that simultaneously protected against the individual pathogens.
Subject(s)
Bacterial Vaccines/pharmacology , Chlamydia Infections/prevention & control , Chlamydia trachomatis/immunology , Herpes Genitalis/prevention & control , Herpesvirus 2, Human/immunology , Porins/immunology , Viral Envelope Proteins/immunology , Viral Vaccines/pharmacology , Animals , Bacterial Vaccines/genetics , Bacterial Vaccines/immunology , Chlamydia Infections/immunology , Chlorocebus aethiops , Female , Genetic Vectors/genetics , HeLa Cells , Herpes Genitalis/immunology , Humans , Mice , Mice, Inbred C57BL , Porins/genetics , Th1 Cells/immunology , Vaccines, Combined/immunology , Vaccines, Combined/pharmacology , Vaccines, Subunit/immunology , Vaccines, Subunit/pharmacology , Vero Cells , Vibrio cholerae/genetics , Viral Envelope Proteins/genetics , Viral Vaccines/genetics , Viral Vaccines/immunologyABSTRACT
Immunity to intracellular microbial pathogens, including Chlamydia species, is controlled primarily by cell-mediated effector mechanisms, yet, the absence of antibodies results in inefficient microbial clearance. We investigated the hypothesis that certain Fc receptor functions promote the rapid induction of elevated T helper type 1 (Th1) response, which effectively clears chlamydiae. FcR(-/-) mice exhibited a delayed and reduced frequency of Chlamydia-specific Th1 cells, compared to FcR(+/+) mice. In vitro, antichlamydial antibodies increased the rate of Th1 activation by FcR(+/+) but not FcR(-/-) antigen-presenting cells. FcR(-/-) dendritic cells and the T cell-associated IgG2A and IgA mediate enhanced Th1 activation by antibodies. Immunization with chlamydia-antibody complexes induced elevated and protective Th1 response. These results provide a mechanistic basis for requiring both T cell and humoral immune responses in protective immunity and vaccine evaluation. Findings offer a paradigm in host defense wherein different effector components function indirectly to maximize the principal effector mechanism.
