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Review 1: "Understanding the Key Determinants of an HPV Therapeutic Vaccine: A Modeling Analysis"

The reviewers found this study makes a good case in favour of such potential interventions to prevent cervical cancer. However, they also expressed concerns regarding some assumptions made by the model and how these might impact the results.

Published onMar 04, 2024
Review 1: "Understanding the Key Determinants of an HPV Therapeutic Vaccine: A Modeling Analysis"
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Understanding the key determinants of an HPV therapeutic vaccine: a modeling analysis
Understanding the key determinants of an HPV therapeutic vaccine: a modeling analysis

Abstract Despite incredibly effective tools to prevent HPV infection and treat precancerous lesions, the scale-up of existing interventions in most low and middle-income countries has been slow, leaving a residual burden of invasive cervical cancer that will persist for decades. An HPV therapeutic vaccine may overcome some of the scalability and infrastructure challenges of traditional screening and treatment programs, though its potential public health value depends upon its characteristics, delivery strategy, and the underlying immunity of the population on which it would act. This analysis uses HPVsim, an open-access agent-based simulation framework, to evaluate the impact of a range of potential HPV therapeutic vaccines with varying scale-up of existing preventive interventions in nine high-burden low- and middle-income countries (LMICs). For each setting, the model is populated with context-specific demographic and behavioral data, and calibrated to fit estimates of HPV and cervical disease by age. We find that an HPV therapeutic vaccine that clears 90% of virus and regresses 50% of high-grade lesions, reaching 70 percent of 35-45 year old women starting in 2030, could avert 1.2-2.2 million incident cases of cervical cancer, 500,000-1.2 million cervical cancer deaths and 20-40 million disability adjusted life years (DALYs) in the modeled high-burden LMICs over 30 years. The size of the impact is sensitive to rates of background intervention scale-up and the characteristics of the vaccine, including ability to establish long-lasting immune memory.

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.


Review: In this analysis, the authors use a complex agent-based simulation model to assess the impact of a range of potential therapeutic HPV vaccine (TxV) under multiple intervention scenarios in different high-burden settings. The paper makes a strong case for the development of TxV to supplement the prophylactic HPV vaccines (PxV) and screening and testing (S&T) which are currently available. The analysis demonstrates that TxV interventions can prevent 1 million+ of cases of cervical cancer over 30 years independent of assumptions about screening, ages targeted, and the efficacy of the vaccine. However, there is a broader question about the optimal allocation of resources and what proportion should be directed towards the development of TxV rather than increasing PxV coverage or S&T. We believe that this question is not properly addressed by this analysis. In order to make the case that resources should be put towards therapeutic vaccination, the authors need to be consistent about what metrics are important and show the impact of offering TxV, expanding PxV coverage, expanding S&T and combined interventions on those metrics. Therefore, simulations with different levels of PxV coverage are important. Setting the preventative vaccine to 90% in all scenarios, given that authors admit that scale-up to date has been challenging, is not justified. In the current form, the analysis suggests that both achieving 90-70-90 and adding TxV are essential for reducing cervical cancer burden by 2060. The challenges with potential scale ups and the cost associated with overcoming them should be further discussed in order to inform realistic intervention scenarios.

We also find that no sufficient details are provided in the main text and the supplement for readers to understand the assumptions integrated in the model and decide if they are reasonable. One example, is that the assumed properties of the prophylactic HPV vaccines, including their efficacy and durability are not presented. It is mentioned that several interventions components reach target coverage immediately (e.g HPV screening that occurs twice in a lifetime) without clear explanation how this is implemented in the model. Finally, the authors present good model fits of the cervical cancer cases in 2020 without discussing how well the model captures the growth/decline of cases over prior periods. Significant increase in cases projected with highly effective PxV intervention (presented in Fig.1) suggests an even faster growth in absence of vaccination prior to 2020. Important to show that this matches the data from the simulated settings.

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