Live Oral Salmonella enterica Serovar Typhi Vaccines Ty21a and CVD 909 Induce Opsonophagocytic Functional Antibodies in Humans That Cross-React withS. Paratyphi A andS. Paratyphi B

Abstract

S almonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen, is the causative agent of typhoid fever, the most prevalent form of enteric fever, resulting in an estimated 21.7 million cases and 200,000 deaths per year worldwide (1). However, infection with Salmonella enterica serovar Paratyphi A (paratyphoid A fever) or Salmonella enterica serovar Paratyphi B (paratyphoid B fever) causes similar clinical manifestations (2). While less prevalent than typhoid fever, paratyphoid fever occurs in an estimated 5.4 million cases each year (3-6). Recent reports indicate that paratyphoid A fever is on the rise in areas of endemicity (e.g., South and Southeast Asia, China) and among travelers returning from those areas (3-6). The emergence of multiple antibiotic-resistant Salmonella strains has increased the health risks posed by these enteric fever infections (7).Currently, two licensed vaccines against typhoid fever are available worldwide, parenteral Vi polysaccharide (Vi) and oral live attenuated Ty21a. Nevertheless, each of these vaccines exhibits limitations that have fostered the development of a new generation of vaccines, including both of the engineered live oral typhoid vaccines (e.g., CVD 908-htrA [⌬aroC ⌬aroD ⌬htrA] and CVD 909 [CVD 908-htrA further engineered to constitutively express Vi]) (8) and the M01ZH09 (⌬aroC ⌬ssaV) (9) and Vi carrier protein conjugate vaccines (10). There are, however, no available licensed vaccines against S. Paratyphi A or B.Whole-genome comparative analysis has revealed a high degree of homology among S. Typhi, S. Paratyphi A, and S. Paratyphi B at the DNA level, suggesting the theoretical potential for vaccines against S. Typhi to offer some degree of cross-protection against S. Paratyphi A and S. Paratyphi B (11,12). Vi-based vaccines cannot confer cross-protection, since neither S. Paratyphi A nor S. Paratyphi B expresses Vi antigen. In contrast, large-scale field trials of the efficacy of the oral Ty21a vaccine have documented a moderate level of cross-protection against S. Paratyphi B but not against S. Paratyphi A (13-15). Therefore, the development of an effective vaccine against S. Paratyphi A has emerged as a public health priority (16).We and others have extensively studied the induction of S. Typhi-specific humoral and cellular immune responses (cell-mediated immunity [CMI]) following immunization with Ty21a and other live oral typhoid vaccines in humans (9,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) and have also begun to explore the cross-reactive immune responses elicited by the S. Typhi live oral vaccines against S. Paratyphi A and S. Paratyphi B that might explain the observed cross-protection and its serovar limitations (29,30).The capacity of oral typhoid vaccines to induce humoral responses has been well documented, but information on the functional capacity of the induced antibodies has been sparse except for a few reports on specific antibody-enhanced phagocytosis and intracellular killing. In the 1980s, Tagliabue et al. reported that the Ig...

Antibodies and tuberculosis

“…Even in intracellular bacterial infections such as S. typhi , surface-binding antibodies are able to trigger killing by opsonophagocytosis during the extracellular phase of their lifecycles [55]. M.tb presents the substantial challenge of a lipid-rich cell membrane and less potential exposure to antibodies via haematogenous spread.…”

Vaccines against Bacterial Enteric Infections

“…A new generation of live oral typhoid vaccines has also been developed, of which two candidate strains remain in clinical development, M01ZH09 (Hindle et al, 2002;Kirkpatrick et al, 2005Kirkpatrick et al, , 2006Tran et al, 2010) and CVD 909 (Tacket et al, 2004b;Wahid et al, 2007Wahid et al, , 2011Wahid et al, , 2014Wang et al, 2000). The aim of these live oral vaccines is to equal Ty21a in safety but to surpass it in efficacy and to achieve this with the administration of a single dose.…”

“…CVD 909 is unique among attenuated live oral S. Typhi vaccine candidates in having a mutation in the promoter of tviA, the first gene in the Vi biosynthesis locus; this results in the constitutive expression of Vi capsular polysaccharide. Both M01ZH09 and CVD 909 have been tested in phase 1 and 2 clinical trials and have been found to be well tolerated and immunogenic after ingestion of just a single oral dose (Kirkpatrick et al, 2005;Kirkpatrick et al, 2006;Tacket et al, 2004b;Tacket and Levine, 2007;Tran et al, 2010;Wahid et al, 2014). Oral single-dose immunization of adult volunteers with these vaccine strains elicits gut-derived IgA antibody-secreting cells and serum IgG and IgA antibodies to S. Typhi O antigen as well as S. Typhi-specific cell-mediated immune responses that are comparable to those obtained after immunization with four doses of Ty21a.…”

“…These immune response data support the notion that these newer recombinant S. Typhi strains might be as protective as the licensed Ty21a vaccine. CVD 909 primes the mucosal immune system to recognize Vi as well as eliciting potent cell-mediated immune responses (Tacket et al, 2004b;Wahid et al, 2008Wahid et al, , 2011Wahid et al, , 2014.…”

Opsonophagocytic Assay To Evaluate Immunogenicity of Nontyphoidal Salmonella Vaccines

“…As these vaccines enter clinical development, it is important to establish their immunogenicity through relevant, well-characterized immunological assays. There is a growing realization within the vaccinology community that in addition to determining antibody levels through binding assays, it is important to determine the functional, antimicrobial capacity of these antibodies.Although many studies have evaluated anti-Salmonella serum bactericidal and opsonophagocytic antibody activity (2,(8)(9)(10)(11)(12)(13)(14)(15), there is a need for reproducible assays that can be used routinely to characterize functional antibody responses to Salmonella in a standardized manner. We previously developed a complementdependent serum bactericidal antibody (SBA) activity assay that quantifies serum antibody responses to typhoidal (S. Typhi and S. Paratyphi A) and nontyphoidal (S. Typhimurium and S. Enteritidis) Salmonella (16).…”