Live Oral Typhoid Vaccine Ty21a Induces Cross-Reactive Humoral Immune Responses against Salmonella enterica Serovar Paratyphi A andS. Paratyphi B in Humans

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Enteric fever caused by<jats:named-content content-type="genus-species">Salmonella enterica</jats:named-content>serovar Paratyphi A infection has emerged as an important public health problem. Recognizing that in randomized controlled field trials oral immunization with attenuated<jats:named-content content-type="genus-species">S. enterica</jats:named-content>serovar Typhi live vaccine Ty21a conferred significant cross-protection against<jats:italic>S</jats:italic>. Paratyphi B but not<jats:italic>S</jats:italic>. Paratyphi A disease, we undertook a clinical study to ascertain whether humoral immune responses could explain the field trial results. Ty21a immunization of adult residents of Maryland elicited predominantly IgA antibody-secreting cells (ASC) that recognize<jats:italic>S</jats:italic>. Typhi lipopolysaccharide (LPS). Cross-reactivity to<jats:italic>S</jats:italic>. Paratyphi A LPS was significantly lower than that to<jats:italic>S</jats:italic>. Paratyphi B LPS. ASC producing IgG and IgA that bind LPS from each of these<jats:named-content content-type="genus-species">Salmonella</jats:named-content>serovars expressed CD27 and integrin α4β7 (gut homing), with a significant proportion coexpressing CD62L (secondary lymphoid tissue homing). No significant differences were observed in serum antibody against LPS of the different serovars. Levels of IgA B memory (B<jats:sub>M</jats:sub>) cells to<jats:italic>S</jats:italic>. Typhi LPS were significantly higher than those against<jats:italic>S</jats:italic>. Paratyphi A or B LPS, with no differences observed between<jats:italic>S</jats:italic>. Paratyphi A and B. The response of IgA B<jats:sub>M</jats:sub>to outer membrane proteins (OMP) from<jats:italic>S</jats:italic>. Typhi was significantly stronger than that to OMP of<jats:italic>S</jats:italic>. Paratyphi A but similar to that to OMP of<jats:italic>S</jats:italic>. Paratyphi B. The percentages of IgG or IgA B<jats:sub>M</jats:sub>responders to LPS or OMP from these<jats:named-content content-type="genus-species">Salmonella</jats:named-content>strains were similar. Whereas cross-reactive humoral immune responses to<jats:italic>S</jats:italic>. Paratyphi A or B antigens are demonstrable following Ty21a immunization, they cannot explain the efficacy data gleaned from controlled field trials.</jats:p>

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

“…The levels of antibodies to LPS have been shown to rise within the first 2 weeks following immunization with live oral typhoid vaccines (25,29,(36)(37)(38)(39)(40)(41)(42). Therefore, we explored whether the functional activity of antibodies described above correlated with anti-LPS titers.…”

“…The measurement of strain-specific humoral immune responses, including antibody-secreting cells (ASC) and/or serum antibodies, is a fundamental part of assessing the immunogenicity of live oral Salmonella vaccines. Ty21a and other candidate typhoid vaccines (including CVD 909) are capable of eliciting S. Typhi-specific antibodies (e.g., against O and H antigens) (25,29,36,39,41,43,44), as well as cross-reactive antibodies against S. Paratyphi A and S. Paratyphi B (29). Nevertheless, the role of such antibodies, if any, in protection from disease or in the elimination of intracellular bacteria is not well understood.…”

“…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 IgA antibodies induced following oral immunization with Ty21a mediate a CD4 ϩ T cell-dependent antibody-dependent cellular cytotoxicity (ADCC) against S. Typhi and against S. Paratyphi A and S. Paratyphi B, but not against S. Paratyphi C (31).…”

“…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).…”

Stable Chromosomal Expression of Shigella flexneri 2a and 3a O-Antigens in the Live Salmonella Oral Vaccine Vector Ty21a

“…Ty21a is a live attenuated bacterial strain that provides high-level durable protection against endemic typhoid fever. Additionally, there is evidence that Ty21a confers cross-protection against enteric fevers caused by Salmonella enterica serovar Paratyphi B (15) and provides crossreactive immune responses against S. enterica serovar Paratyphi A (16,17). Previously, we showed that Ty21a expressing S. sonnei or S. dysenteriae O-antigens provided robust immunity against virulent Shigella challenge in mice (13,18).…”