Persisting antibody responses to Vi polysaccharide-tetanus toxoid conjugate (Typbar TCV®) vaccine up to 7 years following primary vaccination of children < 2 years of age with, or without, a booster vaccination


Krishna Mohan Vadrevu, Dugyala Raju, Sandhya Rani, Siddharth Reddy, Vamshi Sarangi, Raches Ella, Bhuvaneswara Javvaji, Niranjana S Mahantshetty, Sudhakar Battu, Myron M Levine


Background: Serum IgG anti-Vi titers attained by 327 children 6-23 months of age immunized with Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar TCV®), of whom 193/327 received a booster dose 2 years post-primary vaccination, were previously reported.

Methods: Anti-Vi IgG in boosted and unboosted children 3, 5, and 7 years post-primary immunization were monitored using three different enzyme-linked immunosorbent assays (ELISAs): Vacczyme™ kit ELISA (all specimens); “Szu” ELISA (all specimens), and National Institute of Biological Standards NIBSC ELISA (subset). Endpoints analyzed included: persisting seroconversion (titer remaining ≥ 4-fold above baseline), geometric mean titer (GMT), geometric mean-fold rise post-vaccination, and percent exhibiting putative protective anti-Vi level (≥2 µgSzu/ml) using Szu method and National Institutes of Health IgG reference standard. In assessing the persistence of elevated anti-Vi titers stimulated by Typbar-TCV®, four subgroups were compared based on whether or not the initially enrolled children were boosted on day 720 and whether they provided serum on all key timepoints, or if they missed one or more timepoints: i) Among boosted participants, an “All Specimens Cohort” (ASC) comprised 86 children who provided sera on days 42, 720 (booster), 762 (42 days post-booster), 1095, 1825 and 2555, to define kinetics of the Vi antibody response in a fully compliant cohort of boosted children monitored over seven years; ii) Among non-boosted subjects, a compliant All Specimens Cohort of 25 children provided sera on days 0, 42, 720, 1095, 1825, and 2555; iii) Among boosted children, an “Any Available Specimen” (AAS) subgroup consisted of boosted children who provided sera on days 0, 42, and 720 days and also on one or more of days 762, 1095, 1825, or 2555 but not on all those time points; iv) Among the non-boosted subjects, there was also an Any Available Specimen subgroup of 47 children who provided sera on days 0 and 42, of whom 41 subsequently contributed sera on one or more of days 1095, 1825 and 2555.

Results: Vacczyme™ GMTs among boosted ASC children (N = 86) increased significantly on day 762, and remained 32-fold, 14-fold, and 10-fold over baseline at 3, 5 and 7 years; among unboosted ASC children (N = 25), GMTs remained 21-fold, 8-fold and 5-fold over baseline, respectively. Post-primary vaccination, 72% and 44% of unboosted ASC subjects (N = 25) exhibited persisting seroconversion by Vacczyme™ at 5 and 7 years, respectively; the corresponding numbers for ASC boosted subjects were 84% and 71%. Amongst the four sub-groups, boosted subjects showed higher prevalence of persisting seroconversion at most time points with the gap widening by 7th year, though not statistically significant (except 3rd year). Tested by Szu and also NIBSC ELISAs, 92-100% of unboosted ASC children showed persisting seroconversion at 7 years with 100% also exceeding the Szu protective threshold.

Conclusion: To extend protection, administering a booster of Typbar TCV® to children ∼5 years after their primary dose, i.e., coinciding with school entry, may be advisable. Typbar TCV® is presently the only WHO pre-qualified Vi conjugate vaccine with reported efficacy, effectiveness, and long-term immunogenicity findings.

Keywords: Anti microbial resistance; Conjugate vaccine; Enteric fever, typhoid conjugate vaccine; Salmonella Typhi; Typhoid fever.

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