Review 1: "Efficacy, Public Health Impact and Optimal Use of the Takeda Dengue Vaccine"

RR\ID 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.

***************************************

Review: “Efficacy, public health impact and optimal use of the Takeda dengue vaccine” by Daniels, Ferguson, and Dorigatti provides an excellent analysis that describes the expected benefits of vaccinating populations with Qdenga, one of two licensed dengue vaccines (the other currently licensed vaccine is Dengvaxia). Vaccinating for dengue is complicated by the potential for antibody-dependent enhancement, where the presence of antibodies against one serotype of dengue may increase the severity of infection by other serotypes.

This study uses mathematical modeling to infer population-level outcomes from clinical trial data, providing valuable insight into the likely benefits of various policy choices related to using Qdenga. The technical details and model characterization are outstanding but perhaps so dominant that they detract from understanding some important points. Outcomes are presented for a broad range of transmission intensities, recognizing that transmission can vary greatly between and even within contexts. Simulations focus on Brazil and the Philippines, though these labels primarily describe population structure, not transmission intensity or prevalence. The modeling does not account for seasonal transmission variations.

All four serotypes of dengue are assumed to have equal prevalence. Authors note that serotypes 1 and 2 accounted for 75% of prevalence during Qdenga clinical trials, but further characterization of the model's sensitivity to serotype prevalence would be very welcome. These results are heuristics for policymakers across a variety of settings but are sufficiently general to describe nowhere in particular.

Examining the benefit of individual-level screening on the impact of vaccination is also an important part of this work. Guidance for Dengvaxia use involves pre-screening for prior infection, while this analysis emphasizes that pre-screening for Qdenga may reduce its overall benefit. Those contrasting outcomes arise from differences between vaccines, which ought to have a greater emphasis. Pre-screening identifies neutralizing antibodies. Both Dengvaxia and Qdenga have the potential for increasing risk because of antibody-dependent enhancement, but for the Qdenga vaccine, that risk is largely confined to serotypes 3 and 4. Qdenga reduces the burden of serotypes 1 and 2, even in seronegative individuals; however, pre-screening for neutralizing antibodies could exclude those individuals from receiving a beneficial vaccination.