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Background: Recent evidence suggests that 1 dose of the human papillomavirus (HPV) vaccine may have similar effectiveness in reducing HPV infection risk compared to 2 or 3 doses., Objective: To evaluate the public health impact and cost-effectiveness of implementing a 1-dose or a 2-dose program of the 9-valent HPV vaccine in a low- and middle-income country (LMIC)., Methods: We adapted a dynamic transmission model to the Indonesia setting, and conducted a probabilistic sensitivity analysis using distributions reflecting the uncertainty in levels and durability of protection of a 1-dose that were estimated under a Bayesian framework incorporating 3-year vaccine efficacy data from the KEN SHE trial (base-case) and 10 year effectiveness data from the India IARC study (alternative analysis). Scenarios included different coverage levels targeted at girls-only, or girls and boys. Costs and benefits were computed over 100 years from a national single-payer perspective., Results: Depending on the coverage and target population, the median number of cancer cases avoided in 2-dose programs ranged between 600,000-2,100,000, compared to 200,000-600,000 in 1-dose programs. The 1-dose programs are unlikely to be cost-effective compared to 2-dose programs even at low willingness-to-pay (WTP) thresholds. The girls-only 2-dose program tends to be cost-effective at lower WTP thresholds, particularly in scenarios with high coverage, dose price and discount rate, while the girls and boys 2-dose program is cost-effective at higher WTP thresholds. In the alternative analysis, 1-dose programs have higher probability of being cost-effective compared to the base-case, particularly for low WTP thresholds (less than 0.5 GDP) and for high coverage, dose price and discount rate., Conclusion: Adoption of 1-dose programs with 9-valent vaccine in an LMIC resulted in more vaccine-preventable HPV-related cancer cases than 2-dose programs. The 2-dose programs were more likely to be cost-effective than 1-dose programs for a wide range of WTP thresholds and scenarios., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Vincent Daniels and Kunal Saxena are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and shareholders in Merck & Co., Inc., Rahway, NJ, USA. Oscar Patterson-Lomba and Andres Gomez-Lievano are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Merck & Co., Inc, which funded the development and conduct of this study and manuscript. Jarir At Thobari, Nancy Durand, and Evan Myers have received consultancy fees from Merck & Co., Inc., (Copyright: © 2024 Daniels et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Human papillomavirus (HPV) is a prevalent sexually transmitted infection with significant implications for public health. In Poland, a nationwide vaccination program offers a choice between the 9-valent (9v) and 2-valent (2v) HPV vaccines. We aimed to assess the cost-effectiveness of the 9v vs 2v vaccine from the public payer perspective in Poland., Material and Methods: A cost-effectiveness analysis was conducted to compare the public health and economic benefits of using 9v vs 2v vaccine in Poland over 100-year horizon using a previously published deterministic dynamic transmission model. A target population of girls and boys aged 12-13 years was considered. The model was populated with local epidemiological inputs, utilities, and costs, including vaccine and administration costs, as well as costs related to medical procedures for HPV-related diseases., Results: The 9v vaccine reduced the prevalence of HPV infections and HPV-related diseases substantially more than 2v vaccine when both are compared to no vaccination strategy. The total discounted cost savings of using the 9v vaccine instead of 2v, excluding the vaccine costs, amounted to EUR 66 million. The incremental cost-effectiveness ratio amounted to 8094 EUR per quality-adjusted life year, much below the official cost-effectiveness threshold in Poland set up at the three times the annual gross domestic product per capita. 9v cost-effectiveness ratio remained unchanged when shorter time-horizons of 20, 40, 60, or 80 years were considered., Conclusions: Using 9v HPV vaccine in Poland is highly cost-effective compared to the 2v vaccine.

Importance: Patients who have been treated for high-grade cervical intraepithelial neoplasia (CIN grade ≥2) are at a high risk for subsequent CIN and other cancers and diseases related to human papillomavirus (HPV). HPV vaccination can reduce the risk of subsequent disease in patients surgically treated for grade 2 or greater CIN; however, there is no formal recommendation for prophylactic HPV vaccination in this high-risk population, and the cost-effectiveness is unknown., Objective: To assess the incremental lifetime outcomes, costs, and cost-effectiveness of integrating peritreatment 9-valent HPV (9vHPV) vaccination in combination with posttreatment surveillance for the prevention of cervical cancer and other HPV-attributable diseases in patients surgically treated for grade 2 or greater CIN vs posttreatment surveillance alone from a UK payer perspective., Design, Setting, and Participants: This economic evaluation used 3 independent Markov model structures. Model inputs for vaccine efficacy, utilities, and costs were obtained from published sources, and cervical cancer screening data were obtained from the National Health Service Cervical Screening Program. Costs were adjusted to 2022 to 2023 reference years. Data were analyzed from October 2022 to September 2023., Exposure: Peritreatment vaccination with 9vHPV in combination with posttreatment surveillance compared with posttreatment surveillance alone., Main Outcomes and Measures: Clinical outcomes included grade 1, 2, or 3 CIN; cervical cancer; vaginal cancer; vulvar cancer; anal cancer; head and neck cancer; genital warts; and recurrent respiratory papillomatosis. Incremental cost-effectiveness ratios (ICERs) using a willingness-to-pay threshold (WTP) of £20 000 (US $26 200) per quality-adjusted life-year (QALY) were estimated. Deterministic sensitivity analysis and probabilistic sensitivity analysis were performed., Results: Vaccination with 9vHPV in conjunction with posttreatment surveillance was cost-effective, with a favorable ICER of £13 789.07 (US $18 064.68) per QALY gained (ie, below the WTP of £20 000 per QALY) vs posttreatment surveillance alone. The resulting ICER was £52 358.01 (US $68 588.99) per HPV-related cancer averted and £64 090 (US $83 958.18) per HPV-related cancer death averted. The ICER was most sensitive to discount rate, incidence of HPV infection, vaccine price, and age at initial treatment for grade 2 or greater CIN. Results of the probabilistic sensitivity analysis showed peritreatment 9vHPV vaccination was cost-effective at the WTP recommended by the UK's Joint Committee on Vaccination and Immunisation (90% of iterations <£30 000 [US $39 300] per QALY) in 100% of iterations., Conclusions and Relevance: These findings suggest that peritreatment prophylactic 9vHPV vaccination is a cost-effective option for preventing subsequent HPV-attributable diseases in patients surgically treated for grade 2 or greater CIN.

Human papillomavirus (HPV) is a common sexually transmitted virus that can cause cervical cancer and other diseases. Dynamic transmission models (DTMs) have been developed to evaluate the health and economic impacts of HPV vaccination. These models typically include many parameters, such as natural history of the disease, transmission, demographic, behavioral, and screening. To ensure the accuracy of DTM projections, it is important to parameterize them with the best available evidence. This study aimed to identify and synthesize data needed to parametrize DTMs on the natural history of HPV infection and related diseases. Parameters describing data of interest were grouped by their anatomical location (genital warts, recurrent respiratory papillomatosis, and cervical, anal, vaginal, vulvar, head and neck, and penile cancers), and natural history (progression, regression, death, cure, recurrence, detection), and were identified through a systematic literature review (SLR) and complementary targeted literature reviews (TLRs). The extracted data were then synthesized by pooling parameter values across publications, and summarized using the range of values across studies reporting each parameter and the median value from the most relevant study. Data were extracted and synthesized from 223 studies identified in the SLR and TLRs. Parameters frequently reported pertained to cervical cancer outcomes, while data for other anatomical locations were less available. The synthesis of the data provides a large volume of parameter values to inform HPV DTMs, such as annual progression rates from cervical intraepithelial neoplasia (CIN) 1 to CIN 2+ (median of highest quality estimate 0.0836), CIN 2 to CIN 3+ (0.0418), carcinoma in situ (CIS) 2 to local cancer+ (0.0396), and regional to distant cancer (0.0474). Our findings suggest that while there is a large body of evidence on cervical cancer, parameter values featured substantial heterogeneity across studies, and further studies are needed to better parametrize the non-cervical components of HPV DTMs., (© 2024. The Author(s).)

The high prevalence of human papillomavirus (HPV) infection in China suggests there would be a substantial positive health impact of widespread vaccination against HPV. We adapted a previously described dynamic transmission model of the natural history of HPV infection and related diseases to the Chinese setting to estimate the public health impact in China of 2-valent (with and without cross-protection), 4-valent, and 9-valent HPV vaccination strategies. The model predicted the incidence and mortality associated with HPV-related diseases, including cervical and noncervical cancers, genital warts, and recurrent respiratory papillomatosis (RRP), based on the various vaccination coverage rate (VCR) scenarios, over a 100-year time horizon. The public health impact of the 4 vaccination strategies was estimated in terms of cases and deaths averted compared to a scenario with no vaccination. Under the assumption of various primary and catch-up VCR scenarios, all 4 vaccination strategies reduced the incidence of cervical cancer in females and noncervical cancers in both sexes, and the 4-valent and 9-valent vaccines reduced the incidence of genital warts and RRP in both sexes. The 9-valent vaccination strategy was superior on all outcomes. The number of cervical cancer cases averted over 100 years ranged from ~ 1 million to ~ 5 million while the number of cervical cancer deaths averted was ~ 345,000 to ~ 1.9 million cases, depending on the VCR scenario. The VCR for primary vaccination was the major driver of cases averted.

Competing Interests: The authors declare no conflict of interest.

Background: The United Kingdom (UK) switched from using the 4-valent human papillomavirus (HPV) vaccine (Gardasil®) to the 9-valent vaccine (Gardasil 9®) in 2021. Objective: To estimate and compare the health and economic outcomes of 2 HPV vaccination programs in the UK targeting girls and boys aged 12-13 years from the perspective of the UK National Health Service. The 2 vaccination strategies were (1) universal vaccination 4-valent (UV4V), using the 4-valent HPV vaccine (4vHPV), and (2) universal vaccination 9-valent (UV9V), using the 9-valent HPV vaccine (9vHPV). Methods: A deterministic heterosexual compartmental disease transmission model was used to track health and economic outcomes over a 100-year time horizon. Outcomes were discounted at an annual rate of 3.5% and 1.5%. All costs were adjusted to 2020 British pounds (£). Health outcomes were measured in quality-adjusted life-years (QALYs), and the summary results were presented as incremental cost-effectiveness ratios (£/QALY gained) when comparing UV4V with UV9V. Results: Using the same vaccine coverage for both programs, the total cumulative cases of HPV-related health outcomes tracked over the 100-year horizon indicated that the relative number of cases averted (UV9V vs UV4V) ranged from 4% (anal male cancers and deaths) to 56% (cervical intraepithelial neoplasia [CIN1]). Assuming that 9vHPV cost £15.18 more than 4vHPV (a cost differential based on discounted list prices), the estimated incremental cost-effectiveness ratio was £8600/QALY gained when discounted at 3.5%, and £3300/QALY gained when discounted at 1.5%. The estimated incremental cost-effectiveness ratios from the sensitivity analyses remained <£28000/QALY over a wide range of parameter inputs and demonstrated that disease utilities, discount rate, and vaccine efficacy were the 3 most influential parameters. Discussion: Consistent with other published studies, the results from this study found that the 9vHPV vaccine prevented a substantial number of cases when compared with the 4vHPV vaccine and was highly cost-effective. Conclusions: These results demonstrate that replacing universal 4vHPV with 9vHPV can prevent a substantial additional number of HPV-related cases/deaths (in both women and men) and remain cost-effective over a range of 9vHPV price premiums., Competing Interests: This study was performed by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey. KOE, CP, OO, and VD are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey, and may hold stock or stock options in Merck & Co, Inc, Kenilworth, New Jersey.

The Advisory Committee on Immunization Practices (ACIP) recommended catch-up 9-valent Human Papillomavirus (HPV) vaccination through age 26 years, and shared clinical decision-making for adults aged 27-45 years, compared with catch-up through age 26 years and 21 years for females and males, respectively (status quo; pre-June-2019 recommendations). This study assessed the public health impact and cost-effectiveness of expanded catch-up vaccination through age 45 years (expanded catch-up) compared with status quo. We used an HPV dynamic transmission infection and disease model to assess disease outcomes and incremental cost-effectiveness ratio (ICER) of expanded catch-up compared with status quo. Costs (2018 USD), calculated from a healthcare sector perspective, and quality-adjusted life years (QALY) were discounted at 3% annually. Historical vaccination coverage was estimated using NIS-TEEN survey data (NHANES data for sensitivity analysis). Alternative scenario analyses included restricting upper age of expanded catch-up through 26 years (June-2019 ACIP recommendation), 29 years, and further 5-year increments. Our results show expanded catch-up vaccination would prevent additional 37,856 cancers, 314,468 cervical intraepithelial neoplasia-2/3s, 1,743,461 genital warts, and 10,698 deaths compared with status quo over 100 years at cost of $141,000/QALY. With NHANES coverage, the ICER was $96,000/QALY. The June-2019 ACIP recommendation also provided public health benefits with an ICER of $117,000/QALY, compared with status quo. The ICER for expanded vaccination through age 34 years was $107,000/QALY. Expanding catch-up vaccination program through age 45 years-old in the US is expected to provide public health benefits, and cost-effectiveness improves with expanding catch-up through age 34.

Background: In 2017, varicella vaccination became mandatory for all children in Italy, based on a two-dose schedule administered at 12-15 months of age and 5 to 6 years of age. Varicella vaccines are available in different formulations (as a single vaccine or as a combination vaccine together with measles, mumps, and rubella) and are made by multiple manufacturers with different effectiveness profiles. This study calculates the cost-effectiveness of a range of varicella vaccination strategies to identify the optimal strategy for Italy., Methods: A dynamic transmission cost-effectiveness model was applied in Italy to simulate the long-term (50 years) costs and outcomes associated with different varicella vaccination strategies. Five vaccination strategies were evaluated using the model: two doses of two different combination Measles-Mumps-Rubella-Varicella vaccines (either Vaccine A (MSD) [denoted QQVa] or Vaccine B (GSK) [denoted QQVb]); a first dose of a single Varicella vaccine followed by a second dose of a combination vaccine (either Vaccine C (MSD) followed by Vaccine A [denoted MQVa] or Vaccine D (GSK) followed by Vaccine B [denoted MQVb]); or no vaccine at all (NV). The model was adapted for Italy using publicly available Italian data and expert opinion., Results: Over the 50-year time-horizon, in the absence of universal varicella vaccination, there would be 34.8 million varicella cases, 142 varicella-infection-related deaths, and €23 billion in societal costs. The cost per capita from a societal perspective ranged from €164.55 to €392.18 with NV being the most expensive and QQVa the least expensive. The most effective strategy was QQVa, which resulted in a 66% decrease in varicella cases and 30% reduction in varicella-related deaths compared to NV strategy. QQVa led to a net saving in societal cost around €13 billion compared to NV as the cost of vaccination was more than offset by the savings that resulted from the reduced burden of illness., Conclusion: Varicella vaccination has a major impact on reducing varicella incidence, prevalence, and societal costs. This analysis supports the policy for universal varicella vaccination in Italy as the NV strategy was the most expensive and resulted in the poorest outcomes. QQVa offers the greatest benefits at the lowest cost and should be considered as a potential priority strategy for Italian population., Competing Interests: CA, VB, and SG report financial support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, RG and EOB are employees of Evidera, Modelling and Simulation, Inc, and participated in the study under contract to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USAND (at the time of the study), VJD and LJW are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, who may own stock and/or hold stock options in Merck & Co., Inc., Kenilworth, NJ, USA. The authors report no other conflicts of interest in this work., (© 2020 Azzari et al.)

Padsevonil is an antiepileptic drug (AED) candidate synthesized in a medicinal chemistry program initiated to rationally design compounds with high affinity for synaptic vesicle 2 (SV2) proteins and low-to-moderate affinity for the benzodiazepine binding site on GABA A receptors. The pharmacological profile of padsevonil was characterized in binding and electrophysiological experiments. At recombinant SV2 proteins, padsevonil's affinity for SV2A was greater than that of levetiracetam and brivaracetam (pKi 8.5, 5.2, and 6.6, respectively). Unlike the latter AEDs, both selective SV2A ligands, padsevonil also displayed high affinity for the SV2B and SV2C isoforms (pKi 7.9 and 8.5, respectively). Padsevonil's interaction with SV2A differed from that of levetiracetam and brivaracetam; it exhibited slower binding kinetics: dissociation t 1/2 30 minutes from the human protein at 37°C compared with <0.5 minute for levetiracetam and brivaracetam. In addition, its binding was not potentiated by the allosteric modulator UCB1244283. At recombinant GABA A receptors, padsevonil displayed low to moderate affinity (pIC 50 ≤6.1) for the benzodiazepine site, and in electrophysiological studies, its relative efficacy compared with zolpidem (full-agonist reference drug) was 40%, indicating partial agonist properties. In in vivo (mice) receptor occupancy studies, padsevonil exhibited SV2A occupancy at low ED 50 (0.2 mg/kg) and benzodiazepine site occupancy at higher doses (ED 50 36 mg/kg), supporting in vitro results. Padsevonil's selectivity for its intended targets was confirmed in profiling studies, where it lacked significant effects on a wide variety of ion channels, receptors, transporters, and enzymes. Padsevonil is a first-in-class AED candidate with a unique target profile allowing for presynaptic and postsynaptic activity. SIGNIFICANCE STATEMENT: Padsevonil is an antiepileptic drug candidate developed as a single molecular entity interacting with both presynaptic and postsynaptic targets. Results of in vitro and in vivo radioligand binding assays confirmed this target profile: padsevonil displayed nanomolar affinity for the three synaptic vesicle 2 protein isoforms (SV2A, B, and C) and micromolar affinity for the benzodiazepine binding site on GABA A receptors. Furthermore, padsevonil showed greater affinity for and slower binding kinetics at SV2A than the selective SV2A ligands, levetiracetam, and brivaracetam., (Copyright © 2019 The Author(s).)