JNCI Monographs

A cervical cancer control strategy for lower-resource settings: interventions to complement one-dose HPV vaccination

Abstract One-dose prophylactic HPV vaccination of pre-adolescents may reduce cervical cancer deaths dramatically in lower-resource settings, but the benefits of achieving immediate high coverage among pre-adolescents would not be realized for 20 to 40 years. Prophylactic vaccine efficacy is reduced after sexual debut, and current therapeutic intervention candidates designed to treat existing HPV infections or precancerous lesions have yielded insufficient evidence to warrant widespread use. However, we are developing a feasible, scalable, high-quality cervical screening approach that could prevent hundreds of thousands of deaths, while we work to achieve high coverage of one-dose vaccination for adolescent cohorts. A time-limited “one screen” campaign approach for lower-resource settings could complement parallel efforts to achieve high coverage with one-dose vaccination. This screen-triage-treat strategy would target the highest risk groups of screening age (ie, 25 to 49 years) for once-in-a-lifetime HPV testing of self-collected samples using a low-cost accurate HPV test; subsequent triage relying on extended genotyping and a validated deep-learning algorithm for automated visual evaluation (AVE) would stratify management based on risk to provide treatment for those most likely to develop cancer without overburdening health care systems. Early efficacy of this approach has been demonstrated in 9 countries within the HPV-AVE (PAVE) Study Consortium. We estimate that the cost per death averted of a screen-triage-treat campaign is of similar magnitude to prophylactic vaccination. We do not envision perpetual investment in ubiquitous brick-and-mortar screening programs if “one dose, one screen” is implemented with high coverage and targets the highest-risk populations. In collaboration with in-country stakeholders, efforts to ensure acceptability, risk communication, and cost-effectiveness are underway.

Human papillomavirus prophylactic vaccines: update on new vaccine development and implications for single-dose policy

Abstract Human papillomavirus (HPV) prophylactic vaccines were first licensed in 2006 with the primary goal of preventing HPV-related cancers, with cervical cancer accounting for the highest morbidity and mortality globally. Six HPV vaccines have been licensed; 4 of these have been prequalified by the World Health Organization, and additional products are in the pipeline. This article provides an overview of HPV vaccine coverage and current and anticipated vaccine supply vs expected demand. Given that the 2022 World Health Organization position paper on HPV vaccines includes a 1-dose regimen as an alternate schedule, we will discuss the evidence for using licensed vaccines in single-dose regimens and the approach to generating similar supportive data for other current and future vaccines. The broad adoption of a single-dose HPV vaccine regimen would expand access to vaccines by improving the supply-demand balance, increasing affordability, and simplifying logistics, which will ultimately impact HPV-related morbidity and mortality.

Population-level health impact of hypothetical waning 1-dose human papillomavirus vaccination and 2-dose mitigation strategies in a high cervical cancer burden setting

Abstract Background We simulated the impact of hypothetical waning scenarios of a 1-dose human papillomavirus (HPV) vaccination paired with switching to 2-dose mitigation strategies guided by empirical vaccine trial reporting timelines. Methods Using 2 independent mathematical models fitted to a high-burden setting, we projected the cumulative cervical cancer cases averted over 85 years for alternative HPV vaccination scenarios under 2 program adoption timelines: 1) de novo introduction of a 1-dose HPV vaccination and 2) a switch from an existing 2-dose HPV vaccination program to a 1-dose vaccination. We assumed 80% vaccination coverage with the bivalent vaccine and an average duration of a 1-dose HPV vaccine protection of either 30 or 25 years with 100% efficacy. We varied the eligible age group(s) at program introduction and the 2-dose mitigation (single-age cohort or multi-age cohort). If needed for mitigation, reintroduction of 2-dose vaccination was assumed to occur in 2036 (ie, 30 years after initiation of the Costa Rica Vaccine Trial). Results Under both vaccine adoption timelines, the models projected that countries could achieve the same level of health benefits by switching to 2 doses in 2036 using a multi-age cohort approach as with initiating a 2-dose or 1-dose vaccination program with no waning. With only a single-age cohort 2-dose mitigation approach, 98%-99% of cases would be prevented compared with the health benefits of 2 doses or a noninferior, durable 1 dose. Conclusions Countries hesitant to adopt a 1-dose HPV vaccination program may have opportunities to leverage the benefits and efficiency of a 1-dose schedule while awaiting longer-term reporting from 1-dose durability studies, including Costa Rica Vaccine Trial.

Population-level impact of switching to 1-dose human papillomavirus vaccination in high-income countries: examining uncertainties using mathematical modeling

Abstract Background A concern in high-income countries is that switching to 1-dose human papillomavirus (HPV) vaccination could cause a rebound in HPV infection and cervical cancer if 1-dose efficacy or duration were inferior to 2 doses. Using mathematical modeling and up-to-date trial-based data, we projected the population-level effectiveness of switching from 2-dose to 1-dose vaccination under different vaccine efficacy and duration assumptions in high-income countries. Methods We used HPV-ADVISE (Agent-based Dynamic model for VaccInation and Screening Evaluation), a transmission-dynamic model of HPV infection and cervical cancer, varying key model assumptions to identify those with the greatest impact on projections of HPV-16 and cervical cancer incidence over time: 1) 1-dose vaccine efficacy and vaccine duration, 2) mechanisms of vaccine efficacy and duration over time, 3) midadult (>30 years of age) sexual behavior, 4) progression to cervical cancer among midadults, and 5) vaccination coverage and programs. Results In high-income countries, 1-dose vaccination would cause no appreciable rebound in HPV-16 infection, except for a limited rebound under the most pessimistic assumptions of vaccine duration (average, 25 years), because 1) the switch would occur when HPV prevalence is low because of high 2-dose vaccination coverage and 2) individuals would be protected during their peak ages of sexual activity (<35 to 40 years of age). Our model projects a more limited rebound in cervical cancer because of a shift to older age at infection, resulting in fewer life-years left to potentially develop cancer. Projections were robust when varying key model assumptions. Conclusions High protection during peak ages of sexual activity in high-income countries would likely mitigate any potential rebounds in HPV infection and cervical cancer under the most pessimistic assumptions of 1-dose efficacy and duration.

Acceptability of single-dose HPV vaccination schedule among health-care professionals in Kenya: a mixed-methods study

Abstract Background The World Health Organization recommends a single-dose human papillomavirus (HPV) vaccination schedule for girls and boys to accelerate progress toward cervical cancer elimination. We applied the Theoretical Framework of Acceptability (TFA) within the context of HPV vaccination to assess the acceptability of a single-dose schedule among health-care professionals in Kenya. Methods A REDCap survey was developed using relevant Theoretical Framework of Acceptability domains and validated with health-care professionals. Descriptive analyses and multivariate Poisson regression were conducted to assess factors associated with increased acceptability. Free-text responses were analyzed using a rapid qualitative approach, and findings were presented using a joint display. Results Among 385 responses, 74.2% of health-care professionals were female and 48.6% were nurses. On average, respondents had been in their position for 60 months, and one-third (33.2%) were based at level-4 facilities. The majority (75.84%) thought that giving a single-dose of the HPV vaccine to adolescent girls and young women was either acceptable or very acceptable. Qualitative findings highlighted that lack of information was the underlying reason for health-care professionals who were resistant, and most clinicians thought that a singled-dose schedule was less burdensome to clinicians and patients. Hospital directors had a non–statistically significantly lower acceptability likelihood than nurses (incident rate ratio = 0.93, 95% confidence interval = 0.45 to 1.71) and health-care professionals at urban facilities had a non–statistically significantly lower acceptability likelihood than clinicians in rural facilities (incident rate ratio = 0.97, 95% confidence interval = 0.83 to 1.13). Conclusion Although not statistically significant, predictors of increased acceptability provide information to tailor strategies to increase HPV vaccination coverage and accelerate progress toward cervical cancer elimination.

Leveraging single-dose human papillomavirus vaccination dose-efficiency to attain cervical cancer elimination in resource-constrained settings

Abstract Background In low- and middle-income countries, resource constraints remain a critical factor limiting access to cervical cancer preventive measures. The option of single-dose immunization could help improve access to human papillomavirus vaccination and attain cervical cancer elimination. Methods With simulation models adapted to country-specific data and scenarios for single-dose protection derived from International Agency for Research on Cancer India vaccine trial data, we estimated the expected impact of single-dose vaccination in India, Rwanda, and Brazil, three countries with varying profiles of cervical cancer risk and vaccination timelines. In combination with single-dose vaccination, we explored different resource reallocation strategies based on dose efficiency, elimination attainment, and cervical cancer cases prevented, with the existing 2-dose program as a comparator. Results Assuming lifelong single-dose protection, switching from 2-dose to 1-dose vaccination and reallocating resources to female catch-up could prevent 467-1336, 94-194, and 15-207 additional cervical cancer cases (per 100 000 women born) in cohorts aged 11-30 years in India, Rwanda, and Brazil, respectively. Resource reallocation to improve the current routine coverage could help eliminate cervical cancer in India and across all Brazilian states but not in Rwanda. For each country, we found a dose-efficient reallocation strategy (or a combination of strategies) together with 1-dose vaccination that could prevent more cervical cancers vs 2-dose vaccination, even in the worst-case scenario of single-dose protection. Conclusion Adopting single-dose vaccination with resource reallocation is a resource-efficient approach to enhance progress toward cervical cancer elimination. The overall impact of vaccination can be maximized by fine-tuning resource reallocation to a country’s needs.

Approaches to developing de novo cancer population models to examine questions about cancer and race in bladder, gastric, and endometrial cancer and multiple myeloma: the Cancer Intervention and Surveillance Modeling Network incubator program

Abstract Background We are developing 10 de novo population-level mathematical models in 4 malignancies (multiple myeloma and bladder, gastric, and uterine cancers). Each of these sites has documented disparities in outcome that are believed to be downstream effects of systemic racism. Methods Ten models are being independently developed as part of the Cancer Intervention and Surveillance Modeling Network incubator program. These models simulate trends in cancer incidence, early diagnosis, treatment, and mortality for the general population and are stratified by racial subgroup. Model inputs are based on large population datasets, clinical trials, and observational studies. Some core parameters are shared, and other parameters are model specific. All models are microsimulation models that use self-reported race to stratify model inputs. They can simulate the distribution of relevant risk factors (eg, smoking, obesity) and insurance status (for multiple myeloma and uterine cancer) in US birth cohorts and population. Discussion The models aim to refine approaches in prevention, detection, and management of 4 cancers given uncertainties and constraints. They will help explore whether the observed racial disparities are explainable by inequities, assess the effects of existing and potential cancer prevention and control policies on health equity and disparities, and identify policies that balance efficiency and fairness in decreasing cancer mortality.

A prospective cohort study comparing efficacy of 1 dose of quadrivalent human papillomavirus vaccine to 2 and 3 doses at an average follow up of 12 years postvaccination

Abstract Background While recommending a human papillomavirus (HPV) single-dose vaccination schedule in 2022, the World Health Organization highlighted the need for long-term follow-up studies to monitor waning of protection. We report on vaccine efficacy against HPV infections in 1-, 2-, and 3-dose schedules and protection against cervical precancers at a median follow-up of 12 years postvaccination. Methods This randomized multicenter study in India was originally designed to vaccinate unmarried girls aged 10-18 years with either 2 or 3 doses of quadrivalent HPV vaccine. A ministerial decree to halt vaccination in trials resulted in the creation of cohorts receiving different doses, including just a single dose. Cohorts were assessed for incident and persistent infections by genotyping cervical samples collected yearly for 4 consecutive years after participants were married. Cervical screening with an HPV test was initiated at age 25 years for married participants. Age- and site-matched unvaccinated married women were recruited to be compared with vaccinated cohorts. Vaccine efficacy was assessed using proportional incidence ratios. Results The number of participants in the 1-, 2- (at 0 and 6 months), and 3-dose cohorts was 4949, 4980, and 4348, respectively. Of the recipients, 71%-82% in the different cohorts were eligible to provide samples for genotyping. Vaccine efficacy against persistent HPV 16 and 18 infection was 92.0% (95% confidence interval [CI] = 87.0% to 95.0%) in 3022 recipients of the single dose; and comparable with that observed in the 2-dose arm (94.8%, 95% CI = 90.0% to 97.3%) and the 3-dose arm (95.3%, 95% CI = 90.9% to 97.5%). No high-grade precancer associated with HPV 16 and 18 was detected among vaccinated participants compared with 8 precancers detected among the unvaccinated women. Conclusion This observational cohort study has established that a single dose of HPV vaccine provides high protective efficacy against persistent HPV 16 and 18 infections and associated neoplasia 15 years postvaccination.

Muscle loss during cancer therapy is associated with poor outcomes in advanced ovarian cancer

Abstract Data evaluating change in body composition during treatment of advanced cancer are limited. Here we evaluated computed tomography (CT)–based changes in muscle mass during treatment for advanced ovarian cancer (OC) and association with outcomes. We analyzed the preoperative and posttreatment skeletal muscle index (SMI), skeletal muscle area normalized for height of 109 patients with advanced OC who underwent primary surgery and platinum-based chemotherapy from 2006 to 2016. Based on an SMI less than 39 cm2/m2, 54.1% of patients were never sarcopenic, 24.8% were sarcopenic on both CT scans, and 21.1% were newly sarcopenic upon treatment completion. Patients who lost muscle during treatment had the worst survival of the 3 groups identified: median survival 2.6 years vs 4.6 years if sarcopenic on both CT scans and 4.8 years if never sarcopenic. Loss of muscle portends a poor prognosis among patients with OC. Additional research is needed to better understand and best mitigate these changes.

Adapting a model of cervical carcinogenesis to self-identified Black women to evaluate racial disparities in the United States

Abstract Background Self-identified Black women in the United States have higher cervical cancer incidence and mortality than the general population, but these differences have not been clearly attributed across described cancer care inequities. Methods A previously established microsimulation model of cervical cancer was adapted to reflect demographic, screening, and survival data for Black US women and compared with a model reflecting data for all US women. Each model input with stratified data (all-cause mortality, hysterectomy rates, screening frequency, screening modality, follow-up, and cancer survival) was sequentially replaced with Black-race specific data to arrive at a fully specified model reflecting Black women. At each step, we estimated the relative contribution of inputs to observed disparities. Results Estimated (hysterectomy-adjusted) cervical cancer incidence was 8.6 per 100 000 in the all-race model vs 10.8 per 100 000 in the Black-race model (relative risk [RR] = 1.24, range = 1.23-1.27). Estimated all-race cervical cancer mortality was 2.9 per 100 000 vs 5.5 per 100 000 in the Black-race model (RR = 1.92, range = 1.85-2.00). We found the largest contributors of incidence disparities were follow-up from positive screening results (47.3% of the total disparity) and screening frequency (32.7%). For mortality disparities, the largest contributor was cancer survival differences (70.1%) followed by screening follow-up (12.7%). Conclusion To reduce disparities in cervical cancer incidence and mortality, it is important to understand and address differences in care access and quality across the continuum of care. Focusing on the practices and policies that drive differences in treatment and follow-up from cervical abnormalities may have the highest impact.

Evaluating potential program cost savings with a single-dose HPV vaccination schedule: a modeling study

Abstract Background There is limited evidence on the magnitude of the potential program cost savings associated with the World Health Organization–endorsed single-dose schedule for the human papillomavirus (HPV) vaccine. The objective of this analysis was to model the delivery and vaccine procurement cost implications of the new schedule. Methods The analysis leveraged primary data during a study evaluating the HPV vaccine delivery costs and operational context in 5 countries (Ethiopia, Guyana, Rwanda, Sri Lanka, and Uganda) implementing a two-dose schedule. To estimate the cost for the single-dose schedule, we adjusted the two-dose schedule cost estimates to account for differences in the frequency of activities, whether activities differed by HPV vaccine dose or session, and differences in relative quantity or storage volume of HPV vaccines delivered. We estimated the cost per dose and cost per adolescent receiving the full (single-dose or two-dose) vaccination schedule in 2019 US dollars from a health system perspective. Results Modeled results found that cost per dose would increase under a single-dose schedule, whereas cost per adolescent receiving the full schedule would decrease. The financial cost for vaccine procurement and delivery per adolescent receiving the full schedule ranged from $9.64 (Sri Lanka) to $23.43 (Guyana) under a two-dose schedule and decreased to $4.84 and $12.34, respectively, under a single-dose schedule, reflecting savings up to 50%. For economic costs, the range for a single-dose schedule was $7.86 (Rwanda) to $28.53 (Guyana). Conclusion A single-dose HPV vaccination schedule could provide cost savings to immunization programs and enhance program affordability and sustainability.

Single-dose human papillomavirus vaccination: an update

Abstract Human papillomavirus (HPV) vaccines received regulatory approval and were recommended for use in young girls nearly 2 decades ago. Uptake is mostly high in resource-rich settings. In resource-limited settings, where the burden of cervical cancer is disproportionately high, access to and uptake of HPV vaccines are nowhere near satisfactory, despite evidence that HPV vaccination is highly cost-effective and a significant value-for-money investment. The discovery that only a single dose of the HPV vaccines may be needed to confer adequate protection may make equitable access to HPV vaccines possible. Indeed, the recent World Health Organization recommendation allowing for 1 or 2 doses is already gaining traction. This monograph aims to update the state of the science related to single-dose HPV vaccine protection and includes both primary data and modeling efforts that address key gaps in the knowledge regarding 1) durability of protection of a single dose of the HPV vaccine, 2) single-dose HPV vaccine effectiveness in both high-income and low-income settings, 3) implementation of single-dose HPV vaccination, and 4) how to accelerate control of cervical cancer by integrating a 1-time screen for cervical disease. The content published in this monograph will continue to advance the science of HPV vaccination and will be vital as new countries make informed decisions about how best to use this remarkable vaccine.