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Review 3: "Safety and Immunogenicity of a Bivalent Paratyphoid A-Typhoid Conjugate Vaccine in Healthy Indian Adults: A Phase I, Randomized, Active Controlled Study"

The general consensus among reviewers was that this study was reliable, highlights important evidence for the immunogenicity for this novel vaccine, and has important implications for future clinical development.

Published onFeb 14, 2024
Review 3: "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:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

This manuscript details findings of a Phase 1, first-in-human, randomized, controlled clinical trial of a bivalent Paratyphoid A-Typhoid Conjugate vaccine conducted in 60 adults in India. The authors report that single dose vaccination is safe and immunogenic, and importantly that the Paratyphoid A component does not negatively influence anti-Vi IgG or IgA immune responses to S. Typhi. The study provides evidence for advancement to next steps in clinical development for this bivalent vaccine.

Abstract: Were typhoid immune responses sustained at 6 months? It would be helpful to clarify. 

Introduction: I would suggest clarifying if current TCVs are recommended as a single dose vaccination for greater than or at 6 months of age.

In the second paragraph, I would suggest revising estimated typhoid morbidity and mortality noted on the WHO website and update reference. The current numbers are from 2022. Additionally, the authors mention that Asia had the highest mortality rate, however it is not completely clear if this refers to typhoid, paratyphoid, or both. Furthermore, it would be helpful to cite the actual rate in Asia compared to rates elsewhere. It might also be helpful for emergence of antimicrobial resistance to S. Paratyphi A to be referenced. 

In the third paragraph, the authors state that a standalone vaccine against S. Paratyphi is unlikely to be used- why? This is again stated in the discussion section without explanation. 

Methods: In the “Participants” section, in regards to clinically significant systemic disease, it would be helpful to provide 1-2 examples for context. Some other questions pertaining to the “Participants” section include:

  • Were baseline laboratory values required to be normal before vaccination, or was this based on investigator decision?

  • As diary cards were used to document adverse events, were participants required to be literate at a certain level?

In the “Study Visits” section, was a visit window allowed for planned study visits? Did any participant visits occur outside of this window?

Results: For the solicited events of moderate severity in the Sii-PTCV group, did the fever, headache and myalgia occur in a single individual? This would be helpful to specify. 

For the unsolicited AEs of lymphadenitis, GGT increased, and transaminases increased, how did the investigators determine that these were unrelated to vaccination? Were other etiologies diagnosed? Lymphadenitis is a common side effect of vaccination, for example. Vaccination can also be associated with increased liver transaminases. 

For Table 4, it is interesting that the participants with no preexisting anti-TT Ab seemed to achieve higher anti-Vi IgG and IgA compared to the other participants. The numbers are very small, and it is difficult to say with confidence that this is true. However, as immune responses to TCV wane over time, it would be helpful to know if these same participants demonstrated sustained increased anti-Vi IgG and IgM at day 181 compared to participants with preexisting anti-TT Ab. If yes, this suggests that alternative carrier proteins should be prioritized for vaccine development in lieu of TT, particularly for pediatric populations who frequently receive multiple doses of tetanus-containing vaccines as part of routine immunization and because pediatric populations represent the target population for salmonella vaccines.

Discussion: In the third paragraph, the authors should spell out IM at first use. The authors should also consider specifying the lower age limit for TCV use in children.

One of the major strengths of this study is the 100% follow-up at all study visits. This should be highlighted.

Table 3 suggests no evidence of impairment of immune responses to vaccination based on preexisting anti-LPS or SBA. If this is the case, it would be important to highlight, as Sii-PTCV is planned for possible implementation in endemic areas. 

The authors should also consider the question- what are the target populations for the planned Phase 2 and 3 clinical studies of Sii-PTCV.

Summary: Adding a Paratyphoid A component to a typhoid conjugate vaccine was well tolerated by adults who were vaccinated and provides a strong immune response to both Paratyphoid A and S. Typhi. The study provides evidence for the next phases in testing this product in more people and eventually in children who would eventually receive this vaccine if it continues to show safety and a strong immune response.

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