Abstract
Enhancement of mucosal immune responses in children and infants using novel adjuvants such as double mutant heat labile toxin (dmLT) is an important goal in the enteric vaccine field. dmLT has been shown to enhance mucosal IgA responses to the oral inactivated enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX. dmLT can enhance IL-17A production from adult T cells, which may increase the production and secretion of mucosal IgA antibodies. However, the adjuvant mechanism remains to be fully elucidated and might differ between infants and adults due to age-related differences in the development of the immune system. The main objective of this study was to determine how dmLT influences antigen presenting cells and T cells from infants compared to adults, and the role of IL-1β for mediating the adjuvant activity. Peripheral blood mononuclear cells (PBMCs) from Bangladeshi infants (6-11 months) and adults (18-40 years) were stimulated with the mitogen phytohaemagglutinin (PHA), the superantigen Staphylococcal enterotoxin B (SEB), ETVAX whole cell component (WCC) or E. coli lipopolysaccharide (LPS) ± dmLT, and cytokine production was measured using ELISA and electrochemiluminescence assays. The adjuvant dmLT significantly enhanced SEB- and PHA-induced IL-17A, but not IFN-γ responses, in PBMCs from both infants and adults. Blocking experiments using an IL-1 receptor antagonist demonstrated the importance of IL-1 signaling for the adjuvant effect. dmLT, ETVAX WCC and LPS induced dose-dependent IL-1β responses of comparable magnitudes in infant and adult cells. Depletion experiments suggested that IL-1β was mainly produced by monocytes. dmLT enhanced IL-1β responses to low doses of WCC and LPS, and the adjuvant effect appeared over a wider dose-range of WCC in infants. dmLT and WCC also induced IL-6, IL-23 and IL-12p70 production in both age groups and dmLT tended to particularly enhance IL-23 responses to WCC. Our results show that dmLT can induce IL-1β as well as other cytokines, which in turn may enhance IL-17A and potentially modulate other immunological responses in both infants and adults. Thus, dmLT may have an important function in promoting immune responses to the ETVAX vaccine, as well as other whole cell- or LPS-based vaccines in infants in low- and middle-income countries.
Highlights
Enteric infections are important causes of morbidity and mortality, in young children in low and middleincome countries, but so far only a limited number of licensed vaccines exist against such infections [1,2,3]
The production of IL-17A increased significantly in the presence of the lowest double mutant heat-labile toxin (dmLT) concentration tested (1 μg/ml, 2.1-fold mean increase compared to Staphylococcal enterotoxin B (SEB) alone) and addition of 10 μg/ml resulted in even higher IL-17A production (2.7-fold mean increase) (Figure 1A)
We showed for the first time that peripheral blood mononuclear cells (PBMCs) from infants and adults had similar capacity to be modulated by dmLT in vitro. dmLT promoted IL-17A production from PBMCs isolated from both infants and adults stimulated with SEB or PHA
Summary
Enteric infections are important causes of morbidity and mortality, in young children in low and middleincome countries, but so far only a limited number of licensed vaccines exist against such infections [1,2,3]. Oral vaccines induce immune responses locally in the gastrointestinal mucosa, but the responses are often lower in young children and infants compared to in adults [1, 4, 5]. Responses to oral vaccines are generally lower in children in low-resource countries compared to in more developed parts of the world [4, 6]. Enhancement of mucosal immune responses in children and infants using novel vaccine adjuvants that can be administered orally is an important goal in the field of enteric vaccination. Several strategies are currently used to enhance the immunogenicity of ETEC vaccines, including the addition of the oral adjuvant double mutant heat-labile toxin (dmLT). Recent results from clinical trials of ETVAX demonstrate promising adjuvant effects of dmLT on IgA responses in adults, as well as children of different ages [13, 16]. dmLT has been shown to improve the protection afforded by an oral live attenuated ETEC vaccine in adults in an experimental challenge study [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
