Review 1: "Safety and Immunogenicity of a Bivalent Paratyphoid A-Typhoid Conjugate Vaccine in Healthy Indian Adults: A Phase I, Randomized, Active Controlled Study"

RR:C19 Evidence Scale rating by reviewer:

• Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: 

This manuscript provides results from a Phase 1 safety and immunogenicity study for a bivalent typhoid and paratyphoid A conjugate vaccine. The study was conducted in 60 healthy Indian adults, who were blinded and randomised to receive either the bivalent investigational vaccine or a WHO prequalified typhoid conjugate vaccine (TCV), Typbar-TCV. The vaccine was found to be safe and generally well-tolerated, with no vaccine-related unsolicited adverse events or severe adverse events reported in either arm.

Immune responses against Salmonella Typhi (S. Typhi) and Salmonella Paratyphi A (S. Paratyphi A) were assessed at baseline, one month, and six months. For S. Typhi, serum antibody responses (anti-Vi IgG and IgA) were measured, and for S. Paratyphi A, serum IgG responses against lipopolysaccharide were measured, and functional antibody responses were assessed by serum bactericidal assay. Geometric Mean Titres (GMTs) and Geometric Mean Fold Rise (GMFR) to S. Typhi and S. Paratyphi A antigens were assessed, and seroconversion (defined as a four-fold rise in post-vaccination titres) was determined. Both components of the vaccine were highly immunogenic at one month and six months. In addition, the impact of pre-existing tetanus and diphtheria antibodies on immune responses to typhoid and paratyphoid antigens was measured, and no interference was found.

Overall, the study was appropriately designed, the results are well-supported, and the methods used are sound. This vaccine would appear to warrant further testing in Phase II/III clinical trials. The authors lay out a potential regulatory pathway to licensure in the discussion, considering the difficulty of conducting a Phase III field trial to measure efficacy against a relatively rare disease (Paratyphoid A), and suggest possible assessment in a Controlled Human Infection Model (CHIM) as a means of overcoming this challenge. This is all very sensible and helps to put the results into context. 

It would be great to see the immunogenicity results in graphical form (I think these might be represented in a Supplemental Figure, but it might help the reader to visualise the results more immediately). It would also be good to understand what if any plans for longer-term assessment of immunogenicity are, either through continued follow-up of Phase 1 subjects or incorporation of additional time points in a Phase 2 study. This would be useful given ongoing discussions about duration of immunity/protection for typhoid conjugate vaccines.

There is some language in the Introduction that suggests that Paratyphoid A incidence is increasing in some settings through potential replacement of S. Typhi – no citation is provided and the real-world data on this are inconclusive. In addition, mention of the problem of antimicrobial resistance (AMR) is raised for both S. Typhi and S. Paratyphi A, but no support is offered for the latter. In addition, there is a speculative statement about the future market share of a bivalent product that is overstated (e.g. that a bivalent vaccine would largely replace a monovalent TCV) given that Paratyphoid A seems to only be found in South and Southeast Asia. Addressing these minor points would further strengthen the manuscript.