Review 2: "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: 

Overall, this is a well-designed and well-executed phase 1 trial of a bivalent paratyphoid A-typhoid conjugate vaccine. Substituting this vaccine for the monovalent typhoid vaccine would further efforts to reduce typhoid fever in endemic areas. Overall, the manuscript is well written, and the conclusions are supported by the evidence provided.

Attention to the below comments would further clarify and strengthen the manuscript:

• All acronyms should be defined- such as DAIDS, ELISA, TMB, PBS, BAT (figure 1 legend). In the abstract findings section, the last sentence should say Typbar TCV “recipients”. On page 10, the authors should provide a reference for the adaptation of the Vaczyme ELISA for IgA measurements.

• In regards to the sentence: "The standard curve was created from a pool of serum from individuals exposed to the live oral typhoid vaccine M01ZH09
  added to each well. followed by 10μL of baby rabbit complement (Pel-Freez) giving a final concentration of 12.5%.", I’m confused as to why a standard curve for the paratyphoid assays would use serum from those who receive live oral typhoid vaccine? The authors should please clarify.

• Additionally, this sentence is confusing: “Seroconversion was observed in 96.7% and 100% for anti-Vi IgG in Sii-PTCV and Typbar-TCV® groups on Days 29 and 181.” There should be four values- one for each vaccine at two different time points. Please clarify which data points are the same.

• The comment in the first paragraph of the discussion, "This bivalent vaccine, if found safe, immunogenic and efficacious in late phase trials, would replace the existing monovalent typhoid vaccines," should be more focused on populations with both typhoid and paratyphoid fever. For example, bivalent vaccines may replace existing monovalent in areas with high incidence of paratyphoid A. Ultimately, cost and cost-effectiveness analyses will be important.

• Finally, women do frequently report higher rates of reactogenicity, so inclusion of women is important for the tolerability component.

• Enteric fever is an important public health problem caused by two different bacteria. We have an approved highly effective vaccine for one but not the other. This small trial in adults shows that a combination vaccine including both causative agents of enteric fever is well-tolerated, and immunogenic.