IgG Responses to Porins and Lipopolysaccharide within an Outer Membrane-Based Vaccine against NontyphoidalSalmonellaDevelop at Discordant Rates

Abstract

Antibodies acquired after vaccination or natural infection with Gram-negative bacteria, such as invasive Salmonella enterica serovar Typhimurium, can protect against disease. Immunization with naturally shed outer membrane vesicles from Gram-negative bacteria is being studied for its potential to protect against many infections, since antigens within vesicles maintain their natural conformation and orientation. Shedding can be enhanced through genetic modification, and the resulting particles, generalized modules for membrane antigens (GMMA), not only offer potential as vaccines but also can facilitate the study of B-cell responses to bacterial antigens. Here we show that the response to immunization with GMMA from S. Typhimurium (STmGMMA) provides B-cell-dependent protection and induces antibodies to two immunodominant antigens, lipopolysaccharide (LPS) and porins. Antibodies to LPS O antigen (O-Ag) markedly enhance protection in the spleen, but this effect is less marked in the liver. Strikingly, IgG responses to LPS and porins develop with distinct kinetics. In the first week after immunization, there is a dramatic T-cell-independent B1b-cell-associated induction of all IgG isotypes, except IgG1, to porins but not to LPS. In contrast, production of IgG1 to either antigen was delayed and T cell dependent. Nevertheless, after 1 month, cells in the bone marrow secreting IgG against porins or LPS were present at a similar frequency. Unexpectedly, immunization with O-Ag-deficient STmGMMA did not substantially enhance the anti-porin response. Therefore, IgG switching to all antigens does not develop synchronously within the same complex and so the rate of IgG switching to a single component does not necessarily reflect its frequency within the antigenic complex.

Outer membrane protein size and LPS O-antigen define protective antibody targeting to the Salmonella surface

“…An important and surprising implication of our results is that despite only a single Fab being able to access the LPS channel, it appears to be sufficient to promote complement-dependent killing. This conclusion is consistent with the experimental evidence showing similar binding of anti-STmOmpD IgG to WT or O-Agdeficient STm and that bacterial outer-membrane vesicle vaccines derived from bacteria lacking O-Ag can offer protection 27 . This could indicate that it is not necessary to have both arms of an antibody bound to a target antigen for it to be protective.…”

Fantastic voyage: the journey of intestinal microbiota-derived microvesicles through the body

“…Studies carried out to date using pathogen-derived and modified OMV vaccine formulations show that they are effective at inducing protective systemic and mucosal antigen-specific antibody and T-cell responses. Of interest, Schager et al [ 52 ] have recently shown that administration of OMVs produced by hyperblebbing strains of Salmonella Typhimurium can generate protective antibodies in mice. OMVs produced by different bacteria are equipped with specific sets of proteins that can bind to receptors on host intestinal antigen sampling M cells and DCs.…”

Pathogenic signature of invasive non-typhoidal Salmonella in Africa: implications for vaccine development

“…Unlike OAg-CRM197 glycoconjugates, in which variable amounts of high-, mixed-and low-molecular weight O-antigens can be present, the GMMA OAg population is mainly composed of highly glycosylated mixed-molecular weight molecules, 170,172 which have been associated with high immunogenicity. 148 Together with the possibility of inducing an immune response against surface components other than the OAg (such as porins), 173 these features may account for the enhanced immunogenicity and efficacy of GMMA vaccines in comparison with the OAg-CRM197 formulations. Schager and colleagues 173 showed that the protection conferred by iNTS GMMA could be achieved even in the absence of OAg, was predominantly B cell-dependent, and was long-standing, thereby further highlighting the potential of GMMA as an iNTS vaccine candidate.…”

“…148 Together with the possibility of inducing an immune response against surface components other than the OAg (such as porins), 173 these features may account for the enhanced immunogenicity and efficacy of GMMA vaccines in comparison with the OAg-CRM197 formulations. Schager and colleagues 173 showed that the protection conferred by iNTS GMMA could be achieved even in the absence of OAg, was predominantly B cell-dependent, and was long-standing, thereby further highlighting the potential of GMMA as an iNTS vaccine candidate. The power of this formulation is exemplified by the success of the GMMA-based Shigella sonnei vaccine, which is currently in clinical phase 2 and has yielded promising immunogenicity and safety data.…”