We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. The primary outcome was typhoid fever confirmed by blood culture. We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. *p<0.05, **p<0.01 and ns = non-significant by Mann-Whitney U test between individual groups (two-tailed). Data pooled from 2 experiments with n= 2 or 4 mice/group. (E) Spleen CFU counts of WT mice infected for 24 hours with 1x10 5 CFU TH177 opsonised with IgM depleted serum. Complete human serum (CHS) was used as a positive control. Representative of individual serum samples, showing change from the starting LogCFU/mL bacterial dose, normalised to the negative control values at each timepoint. (D) Pooled WT hyperimmune anti-Vi sera were depleted of IgM using antimouse IgM coated Sepharose beads, and serum bactericidal activity against TH177 measured by SBA. (C) Serum bactericidal activity of WT and IgM s-/-sera was measured against TH177, represented as mean change from the starting LogCFU/mL bacterial dose, normalised to the negative control values at each timepoint. (B) Serum anti-Vi IgG titres of WT and IgM s-/-mice were assessed by ELISA. Data pooled from 2 experiments with n = 2 or 4 mice/group. (A) Colony forming units (CFU) in the spleen of C57Bl/6 (WT) and IgM s-/-mice immunized i.p with 2 µg Vi-PS, Vi-TT or PBS, then infected for 24 hours with 1x10 5 CFU Vi+ S. *p≤0.05, **p≤0.01 and ****p≤0.001 by Mann-Whitney U test between individual groups (two-tailed).Īnti-Vi IgG induced by Vi vaccines is sufficient to impair infection. Bars represent mean relative antibody titre of each isotype, with SEM. Each timepoint is composed of 2-3 experiments with n = 2 or 4 mice/group. (D) ELISA was used to quantify anti-Vi IgG1, IgG2b and IgG3 in sera from mice 7 days post-immunization, or sera from C57Bl/6 mice immunized i.p with 2 µg Vi-PS, Vi-CRM 197, Vi-TT or PBS on day 0 and 35, then challenged with 1x10 5 CFU Vi+ S. (C) Representative immunohistological images of spleen tissue stained for IgM (brown) and Vi (blue), or IgD (brown) and PNA (blue). (B) Splenic antibody secreting cells (ASCs) producing anti-Vi IgM or IgG were enumerated by ELISPOT, with representative well images below each group. Data pooled from 3 experiments with n = 2 or 4 mice/group. (A) Sera from C57Bl/6 mice 7 days after i.p injection of 2 µg Vi-PS, Vi-CRM 197, Vi-TT or PBS were assessed by ELISA for anti-Vi IgM and IgG. TCV induce rapid IgM and IgG responses and GC. These findings suggest that enhancing our understanding of how responses to vaccines are maintained may inform on how to maximize protection afforded by conjugate vaccines against encapsulated pathogens such as S. Therefore, Vi-specific IgM or IgG are independently capable of protecting from infection and any superior protection from vaccination with TCV in adults may relate to responses being able to persist better rather than from differences in the antibody isotypes induced. These differences related to the maintenance of antibody responses at higher levels in mice boosted with TCV, with the rate of fall in IgG titres induced to Vi-PS being greater than for TCV. Only in the longer-term after immunization (>5 months) were differences observed in tissue bacterial burdens of mice immunized with Vi-PS or TCV. Unexpectedly, IgM or IgG alone were similarly able to reduce bacterial burdens in tissues, and this was observed in response to conjugated or unconjugated Vi vaccines and was independent of antibody being of high affinity. Here, we immunized wild-type (WT) mice and mice deficient in IgG or IgM with Vi-PS or TCVs (Vi conjugated to tetanus toxoid or CRM197) for up to seven months, with and without subsequent challenge with Vi-expressing Salmonella Typhimurium. Potential reasons for why TCV may be superior in adults are not fully understood. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Salmonella Typhi infections.
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