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Anti-O-specific polysaccharide (OSP) immune responses following vaccination with oral cholera vaccine CVD 103-HgR correlate with protection against cholera after infection with wild-type Vibrio cholerae O1 El Tor Inaba in North American volunteersBackground: Cholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. We therefore assessed whether antibody responses against OSP occur after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and whether such responses correlate with protection against cholera. Methodology: We assessed adult North American volunteers (n = 46) who were vaccinated with 5 × 108 colony-forming units (CFU) of oral cholera vaccine CVD 103-HgR and then orally challenged with approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961, either 10 or 90 days post-vaccination. Principal findings: Vaccination was associated with induction of significant serum IgM and IgA anti-OSP and vibriocidal antibody responses within 10 days of vaccination. There was significant correlation between anti-OSP and vibriocidal antibody responses. IgM and IgA anti-OSP responses on day 10 following vaccination were associated with lower post-challenge stool volume (r = −0.44, P = 0.002; r = −0.36, P = 0.01; respectively), and none of 27 vaccinees who developed a ≥1.5 fold increase in any antibody isotype targeting OSP on day 10 following vaccination compared to baseline developed moderate or severe cholera following experimental challenge, while 5 of 19 who did not develop such anti-OSP responses did (P = 0.01). Conclusion: Oral vaccination with live attenuated cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these anti-OSP responses correlate with protection against diarrhea following experimental challenge with V. cholerae O1. Copyright 2018 Public Library of Science. All Rights Reserved.
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Humoral Immune Responses to a Malaria Vaccine Candidate: Towards a Correlate of Vaccine-Induced ProtectionIntroduction: Identifying immune correlates of protection is a priority for malaria vaccine research. A successful pediatric Phase 2 clinical trial in Mali of FMP2.1/AS02A, a recombinant apical membrane antigen 1 (AMA1)-based vaccine candidate, provided a source of serum samples from subjects who may have developed vaccine-induced, strain-specific protective immunity to clinical malaria illness. We studied IgG subclass and avidity patterns of antibodies to the malaria protein AMA1 in a subset of participants, with the objective of identifying immune responses that may be associated with protection against malaria. We hypothesized that the AMA1 vaccine candidate would induce production of cytophilic antibody subclasses IgG1 and IgG3, as well as overall IgG avidity maturation. Methods: Titers of IgG1, IgG2, IgG3, and IgG4, as well as avidity of antibodies to AMA1, were determined by ELISA for ten AMA1 vaccine recipients and ten control subjects who had been randomized to receive a rabies vaccine in this double-blind trial at days 0, 90, and 150 after the first of three vaccinations. To identify statistically significant differences between the groups, responses in vaccine recipients were evaluated longitudinally and compared with responses in control subjects. Results: IgG1, IgG2, IgG3, and IgG4 were induced more strongly in vaccine recipients than in control subjects. Additionally, vaccine recipients had higher ratios of cytophilic to non-cytophilic antibodies than control subjects. Avidity indices were not significantly different between the two groups at the three time points tested, and there were no significant differences in avidity between time points in either group. Conclusion: Contrary to our hypothesis, both cytophilic and non-cytophilic antibodies were induced by the FMP2.1/AS02A vaccine candidate and immunization did not appear to stimulate avidity maturation. Therefore, IgG1, IgG2, IgG3, and IgG4 titers are candidate variables for a humoral immune correlate of vaccine-induced protection. These results are among the first reports of the subclasses and avidity of antibodies produced in response to a malaria vaccine candidate with allele-specific protective efficacy.
