Protective immunity elicited by recombinant bacille Calmette-Guerin (BCG) expressing outer surface protein A (OspA) lipoprotein: a candidate Lyme disease vaccine.

Abstract

The current vaccine against tuberculosis, Mycobacterium bovis strain bacille Calmette-Guerin (BCG), offers potential advantages as a live, innately immunogenic vaccine vehicle for the expression and delivery of protective recombinant antigens (Stover, C.K., V.F. de la Cruz, T.R. Fuerst, J.E. Burlein, L.A. Benson, L.T. Bennett, G.P. Bansal, J.F. Young, M.H. Lee, G.F. Hatfull et al. 1991. Nature [Lond]. 351:456; Jacobs, W.R., Jr., S.B. Snapper, L. Lugosi and B.R. Bloom. 1990. Curr. Top. Microbiol. Immunol. 155:153; Jacobs, W.R., M. Tuckman, and B.R. Bloom. 1987. Nature [Lond.]. 327:532); but as an attenuated intracellular bacterium residing in macrophages, BCG would seem to be best suited for eliciting cellular responses and not humoral responses. Since bacterial lipoproteins are often among the most immunogenic of bacterial antigens, we tested whether BCG expression of a target antigen as a membrane-associated lipoprotein could enhance the potential for a recombinant BCG vaccine to elicit high-titered protective antibody responses to target antigens. Immunization of mice with recombinant BCG vaccines expressing the outer surface protein A (OspA) antigen of Borrelia burgdorferi as a membrane-associated lipoprotein resulted in protective antibody responses that were 100-1,000-fold higher than responses elicited by immunization with recombinant BCG expressing OspA cytoplasmically or as a secreted fusion protein. Furthermore, these improved antibody responses were observed in heterogeneous mouse strains that vary in their immune responsiveness to OspA and sensitivity to BCG growth. Thus, expression of protective antigens as chimeric membrane-associated lipoproteins on recombinant BCG may result in the generation of new candidate vaccines against Lyme borreliosis and other human or veterinary diseases where humoral immunity is the protective response.

RecombinantMycobacterium bovisBCG Expressing the Sm14 Antigen ofSchistosoma mansoniProtects Mice from Cercarial Challenge

“…The marked differences noted for the two types of recombinant vaccines based on Sm14, in terms of the ability to stimulate humoral immunity, were not entirely unexpected given that they would be processed by and presented to the immune system by different mechanisms. In this context, it should be noted that the subcellular location of the recombinant antigen has been reported to influence both the quantity and quality of the immune response to a number of antigens produced by rBCG (15,17,29). Yet there are numerous examples of rBCG-based vaccines which are capable of inducing strong humoral immune responses to a variety of antigens (25).…”

“…Indeed, only a single candidate rBCG vaccine, based on the expression of the OspA antigen from Borrelia burgdorferi (29), has been evaluated in a phase I human clinical trial (13). Surprisingly, this vaccine failed to induce immunity in humans, despite having being shown to be highly immunogenic and protective in various strains of mice (29).…”

“…Indeed, only a single candidate rBCG vaccine, based on the expression of the OspA antigen from Borrelia burgdorferi (29), has been evaluated in a phase I human clinical trial (13). Surprisingly, this vaccine failed to induce immunity in humans, despite having being shown to be highly immunogenic and protective in various strains of mice (29). The reasons for this phenomenon remain unresolved, but they highlight the requirement for model systems with which to assess candidate rBCG vaccines in terms of their ability to infect, persist, and stably maintain their expression systems under conditions which resemble those encountered in the species for which the vaccine is being developed, or even as a preliminary step before embarking on costly smallanimal experimentation.…”

“…During the last 10 years, expression systems have been developed for the production of a variety of bacterial, parasitic, and viral antigens by BCG, and the capacity of these recombinant systems to induce both cellular and humoral im-mune responses in various experimental models is well documented (2,17,20,25). Furthermore, it has been demonstrated that recombinant BCG strains can induce protective immunity in animal models (1,24,29).…”

The next wave of recombinant and synthetic anticancer vaccines

“…89 Other antigens, including leishmania, Lyme disease OspA protein, and Borrelia burgdafori outer surface protein, delivered by rBCG elicited protective immunity from challenge with the respective pathogen. [92][93][94] Listeria monocytogenes is a gram positive, facultative intracellular bacteria that may also be useful in recombinant vaccine design. Listeria monocytogenes enters host cells and is taken up by the phagosomes where it then escapes into the cytoplasm by disrupting the phagosomal membrane primarily using hemolysin.…”