Immunology of gut mucosal vaccines

Abstract

Understanding the mechanisms underlying the induction of immunity in the gastrointestinal mucosa following oral immunization and the cross-talk between mucosal and systemic immunity should expedite the development of vaccines to diminish the global burden caused by enteric pathogens. Identifying an immunological correlate of protection in the course of field trials of efficacy, animal models (when available), or human challenge studies is also invaluable. In industrialized country populations, live attenuated vaccines (e.g. polio, typhoid, and rotavirus) mimic natural infection and generate robust protective immune responses. In contrast, a major challenge is to understand and overcome the barriers responsible for the diminished immunogenicity and efficacy of the same enteric vaccines in underprivileged populations in developing countries. Success in developing vaccines against some enteric pathogens has heretofore been elusive (e.g. Shigella). Different types of oral vaccines can selectively or inclusively elicit mucosal secretory immunoglobulin A and serum immunoglobulin G antibodies and a variety of cell-mediated immune responses. Areas of research that require acceleration include interaction between the gut innate immune system and the stimulation of adaptive immunity, development of safe yet effective mucosal adjuvants, better understanding of homing to the mucosa of immunologically relevant cells, and elicitation of mucosal immunologic memory. This review dissects the immune responses elicited in humans by enteric vaccines.

Fig. 1. Immune responses to S. Typhi following natural infection and vaccination

Immune responses following natural infection include: 1) serum antibodies to the O-antigen [lipopolysaccharide (LPS)], the H antigen (flagellar component), polysaccharide capsular Vi antigen, bacterial heat shock proteins (e.g. GroEL) and outer membrane proteins (Omp); 2) gut-derived antibody-secreting cells (ASCs) specific for LPS and Typhoid antigens; 3) secretory IgA to some of these antigens in intestinal fluids and bile, and 4) cell-mediated immune responses including T-cell proliferation and increased levels of pro-inflammatory and Th1-type cytokines. Chronic S. Typhi biliary carriers (80%) have high levels of serum IgG anti-Vi capsular polysaccharide; in contrast elevated serum IgG following acute typhoid fever is seen in only ~ 20% of subjects who do not become chronic carriers. Ty21a is the only licensed live oral typhoid vaccine. The most promising vaccine candidates to date include: CVD 908-htrA, CVD 909 (a further derivative of CVD 908-htrA that constitutively expresses Vi), M01ZH09 and Ty800. Oral immunization of adult volunteers with these vaccines showed the presence of mucosal and systemic immune responses.Mucosal immune responses include sIgA against bacterial antigens (e.g. LPS, flagella, Omp) and mucosally primed ASCs detected in peripheral blood mononuclear cells (PBMCs). Systemic responses include serum antibodies to different bacterial antigens (e.g. LPS, flagella, Omp, GroEL, HlyE). Cell-mediated immunity (CMI) (studied in depth for Ty21a, CVD 908-htrA and CVD 909) include proliferative responses by PBMCs, production of Th1-type cytokines (i.e. IFN-γ and TNF-α) in the absence of IL-4 and IL-5, and classical (HLA-Ia)- and non-classical (HLA-E)- restricted CD8⁺ cytotoxic lymphocytes (CTLs). Oral live vaccines also generate memory B and T cells; the latter include IFN-γ-secreting CD4⁺ and CD8⁺ T-central memory (T_CM)andT-effector memory (T_EM) subsets expressing the α₄/β₇ and/or CD62L. Immunological correlates of protection remain undefined. The relative contribution CMI responses and antibodies and their interplay in vaccine efficacy remains unclear. For purposes of comparison, the far right panel summarizes the immune responses to the licensed parenteral Vi polysaccharide typhoid vaccine. In contrast to the broad responses elicited by live attenuated strains, responses to parenteral Vi polysaccharide are restricted to systemic Vi antibodies (mainly IgG and IgA). A Vi polysaccharide conjugated to the recombinant exoprotein A from Pseudomonas aeruginosa elicited high levels of serum Vi IgG (compared with unconjugated Vi) in children of school age and pre-school age from highly endemic areas and these responses were long-lasting (248). Gradients of colors reflect the location of immune responses induced by natural infection and oral or parenteral immunization.