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Catch-up human papillomavirus (HPV) vaccination is challenging in many low- and middle-income countries (LMICs). Pay-it-forward offers an individual a subsidized vaccine, then an opportunity to donate to help others access vaccinations. Our randomized control trial assessed the effectiveness of pay-it-forward in improving HPV vaccination among girls aged 15-18 years in China. This study was conducted from July 6, 2022, to June 9, 2023, in four community health centers (CHCs) in Chengdu, western China. Eligible participants were unvaccinated girls living in the service areas of CHCs. Participants were initially recruited via telephone and, after providing verbal consent, attended in-person visit where they were randomly assigned using the sealed envelope method to either the pay-it-forward arm (received a community subsidy of 47.7 USD covering the first vaccine and an opportunity to support others) or control arm (self-paid vaccination at the market price). Participants were unblinded only after the envelope was opened, while the CHC staff coordinators, physicians prescribing the vaccine, outcome assessors, and data analysts were blinded to the intervention allocation. The primary outcome was the first-dose HPV vaccination rate, verified against clinical records. Data were analyzed using the intention-to-treat approach. We identified 662 participants per phone invitation. A total of 321 participants showed up in the health centers and randomly assigned to the pay-it-forward arm (n = 161) or control arm (n = 160). Most caregivers were female (80.1%, 257/321). In the pay-it-forward arm, 55 of 161 (34.2%) girls received the HPV vaccine, compared with 28 of 160 (17.5%) girls in the control arm (adjusted proportion difference = 17.9%, (95% CI [8.7%, 27.0%]; P < 0.001). Among 55 girls in the pay-it-forward arm who received the vaccination, 37 (67.3%) wrote a postcard message, and 39 (70.9%) of their caregivers donated to support future girls. The financial cost per person vaccinated was $294 in the control arm and $230 in the pay-it-forward arm. The trial had several limitations, including a 54% clinic attendance rate (360 of 662 consented participants attended) and its conduct in a single western province of China. The pro-social pay-it-forward strategy was effective to increase catch-up HPV vaccination among teenage girls. This approach also enhanced vaccine confidence among participants. Pay-it-forward demonstrates promise as an effective intervention to improve vaccine uptake through community engagement. Chinese clinical trial registry ChiCTR2200055542 (https://www.chictr.org.cn/hvshowproject.html?id=183292&v=1.3).

Pay-for-performance (P4P) incentives can be paid as a bonus (gain) or a penalty (loss). Diminishing marginal utility of wealth suggests that, starting from the same initial wealth, individuals dislike losses more than they like equivalent gains. This study reports the minimum financial gain or loss required to motivate primary care providers and clinical staff to try to increase their human papillomavirus (HPV) vaccination rates. In 2022, we conducted a national U.S. survey through WebMD's Medscape Network of clinical staff working in primary care clinics that provided HPV vaccination to children ages 9 through 12 years (N = 2,527; response rate = 57%). We randomized respondents to one of two hypothetical HPV vaccine incentive designs: a bonus for reaching an unspecified target HPV vaccination rate and a penalty for failing to reach the unspecified target. The primary outcome is the self-reported smallest incentive amount (U.S. dollars) that would motivate participants to try and increase their HPV vaccination rates. We tested for differences across P4P designs using unadjusted responses and linear regressions adjusting for clinic and respondent characteristics. We also tested for heterogeneous responses by experience with incentizves, training, and rurality. The mean amount required to motivate effort was $2,155 in the gain P4P design and $1,185 in the loss P4P design (unadjusted difference =  $970 [p < 0.001], adjusted difference =  $967 [p < 0.001]). There were no heterogeneous effects by rurality or experience with incentives. Physicians reported the highest differences (in dollars) between gain and loss P4P designs. Stated preference data from primary care clinical staff suggests that effective P4P incentives could be half as large if designed as losses rather than gains.

ObjectiveTo explore whether vaccine confidence and vaccine delay intention mediated the effect of the pay-it-forward intervention on human papillomavirus (HPV) vaccine uptake.DesignThis secondary mediation analysis of a two-arm randomised controlled trial was conducted among female adolescents aged 15–18 years in Chengdu, China, from July 2022 to June 2023.SettingThis study was conducted in four residential areas representing diverse economic backgrounds in Chengdu.ParticipantsA total of 321 parents of girls aged 15–18 years who had not received the HPV vaccine participated in the study.InterventionParticipants were randomly allocated into two arms. Pay-it-forward participants received a community-contributed subsidy (47.7 USD) to support the HPV vaccination, along with educational postcards and an opportunity to donate to support others. In the standard-of-care arm, participants paid for their vaccination.Primary and secondary outcome measuresPrimary outcome was the receipt of the first HPV vaccine dose within a 3-month period following an intervention. Based on previous literature, we hypothesised that vaccine confidence and vaccine delay intention were potential mediators. Vaccine confidence was measured using the vaccine confidence index. Vaccine delay intention refers to the caregiver’s preference to postpone HPV vaccination for their daughter until the preferred vaccine type becomes available, rather than accepting the immediately accessible HPV vaccine. Data on these mediators were collected via a self-administered online questionnaire conducted after the intervention but before vaccination.ResultsAmong urban participants, when compared with the standard-of-care arm, about 39% of the effect of the pay-it-forward intervention on vaccine uptake was mediated by a reduction in vaccine delay intention. Notably, vaccine confidence did not appear to mediate the effect of the intervention on vaccine uptake. Among suburban participants, no mediation effects were observed. In the suburban setting, caregivers who vaccinated their daughters showed poorer prior awareness of the HPV vaccine before participating in the trial compared with those who did not vaccinate their daughters (41.5% vs 21.1%; p=0.011).ConclusionOur findings indicate that among urban participants, the pay-it-forward may have effectively reduced vaccine delay intention, which was associated with an increased uptake of the HPV vaccine. However, in suburban areas, enhanced awareness might be a potential contributing factor to improved vaccine uptake, but further research is necessary to affirm this.Trial registration numberChinese Clinical Trial Registry: ChiCTR2200055542.

This study reports how 3 design features (size of incentive, who is responsible, and target goal) affect clinical staff perceptions of pay-for-performance (P4P) for HPV vaccination. We conducted a national survey of clinical staff in 2022 (N = 2527; response rate = 57%). Respondents worked in pediatrics, family medicine, or general medicine specialties in the United States and had a role in HPV vaccination for children ages 9 through 12 years. Respondents were randomized to 1 of 8 P4P scenarios representing 3 design features with 2 levels each. We used ordered logistic regression to model respondents’ agreement with each of 11 statements about the P4P scenario. Statements represented domains of the Theory of Planned Behavior (attitudes, perceived behavioral control, and norms) plus 2 equity items. Relative to a $1000 incentive, a $5000 incentive was associated with favorable perceptions in 8/11 items: 5/5 attitude items and 1/2 items for each of control, norms, and equity. Incentives based on an individual provider’s patients, rather than the entire clinic’s patients, were associated with more agreement for 1 attitude item and 1 perceived behavioral control item. Relative to an absolute goal of 80%, a goal of 5% relative increase in HPV vaccination rates was associated with favorable perceptions for 3/5 attitude items and 1 equity item. Clinical staff perceptions of P4P for HPV vaccination were more favorable the larger the size of the incentive, when it was focused on a provider’s own patients, and when the goal was a relative, rather than absolute, target.

Background Cervical cancer is the leading cause of female cancer-related deaths in Tanzania. Vaccination against human papillomavirus (HPV) offers a new opportunity to control this disease. This study aimed to estimate the costs of a school-based HPV vaccination project in three districts in Mwanza Region (NCT ID: NCT01173900), Tanzania and to model incremental scaled-up costs of a regional vaccination program. Methods We first conducted a top-down cost analysis of the vaccination project, comparing observed costs of age-based (girls born in 1998) and class-based (class 6) vaccine delivery in a total of 134 primary schools. Based on the observed project costs, we then modeled incremental costs of a scaled-up vaccination program for Mwanza Region from the perspective of the Tanzanian government, assuming that HPV vaccines would be delivered through the Expanded Programme on Immunization (EPI). Results Total economic project costs for delivering 3 doses of HPV vaccine to 4,211 girls were estimated at about US$349,400 (including a vaccine price of US$5 per dose). Costs per fully-immunized girl were lower for class-based delivery than for age-based delivery. Incremental economic scaled-up costs for class-based vaccination of 50,290 girls in Mwanza Region were estimated at US$1.3 million. Economic scaled-up costs per fully-immunized girl were US$26.41, including HPV vaccine at US$5 per dose. Excluding vaccine costs, vaccine could be delivered at an incremental economic cost of US$3.09 per dose and US$9.76 per fully-immunized girl. Financial scaled-up costs, excluding costs of the vaccine and salaries of existing staff were estimated at US$1.73 per dose. Conclusions Project costs of class-based vaccination were found to be below those of age-based vaccination because of more eligible girls being identified and higher vaccine uptake. We estimate that vaccine can be delivered at costs that would make HPV vaccination a very cost-effective intervention. Potentially, integrating HPV vaccine delivery with cost-effective school-based health interventions and a reduction of vaccine price below US$5 per dose would further reduce the costs per fully HPV-immunized girl.

•These 4vHPV and 2vHPV vaccines evaluation considered health system perspective.•The bivalent vaccination was found to be cost-effective at Gavi-negotiated prices in Bangladesh.•This vaccine offers substantial future benefits for preadolescents in Bangladesh. Cervical cancer is one of the most prevalent cancers in women caused by the human papillomavirus (HPV) that leads to a substantial disease burden for health systems. Prevention through vaccination can significantly reduce the prevalence of cervical cancer. The objective of this study is to evaluate the potential health and economic impacts of introducing two-dose bivalent (Cervarix) and quadrivalent (Gardasil) HPV vaccines in Bangladesh. The study uses the Papillomavirus Rapid Interface for Modelling and Economics (PRIME) model to assess the cost-effectiveness of introducing HPV vaccination. The incremental cost-effectiveness ratios (ICERs) were estimated per disability-adjusted life years (DALYs) averted using the cost-effectiveness threshold (CET). The analyses were done from a health system perspective in terms of vaccine delivery routes. Introduction of bi-valent HPV vaccination was found highly cost-effective (ICER = US$488/DALY) at Gavi (The Vaccine Alliance for Vaccines and Immunizations) negotiated prices. The value of ICERs were US$710, US$356 and US$397 per DALY averted for school-based, health facility-based, and outreach-based programs, respectively, which is consistent with the CET range (US$67 to US$854). However, bivalent and quadrivalent vaccines at listed prices were not found cost-effective, with ICERs of US$1405 and US$3250 per DALY averted, respectively, that exceeds the CETs values. Introducing a two-dose bi-valent HPV vaccination program is cost-effective in Bangladesh at Gavi negotiated prices. Vaccine price is the dominating parameter for the cost-effectiveness of bivalent and quadrivalent vaccines. Both vaccines are not cost-effective at listed prices in Bangladesh. The evaluation highlights that introducing the two-dose bivalent HPV vaccine at Gavi negotiated prices into a national immunization program in Bangladesh is economically viable to reduce the burden of cervical cancer.

Introduction of human papillomavirus (HPV) vaccination has been slow in low-income and middle-income countries (LMICs) because of resource constraints and worldwide shortage of vaccine supplies. To help inform WHO recommendations, we modelled various HPV vaccination strategies to examine the optimal use of limited vaccine supplies and best allocation of scarce resources in LMICs in the context of the WHO global call to eliminate cervical cancer as a public health problem. In this mathematical modelling analysis, we developed HPV-ADVISE LMIC, a transmission-dynamic model of HPV infection and diseases calibrated to four LMICs: India, Vietnam, Uganda, and Nigeria. For different vaccination strategies that encompassed use of a nine-valent vaccine (or a two-valent or four-valent vaccine assuming high cross-protection), we estimated three outcomes: reduction in the age-standardised rate of cervical cancer, number of doses needed to prevent one case of cervical cancer (NNV; as a measure of efficiency), and the incremental cost-effectiveness ratio (ICER; in 2017 international $ per disability-adjusted life-year [DALY] averted). We examined different vaccination strategies by varying the ages of routine HPV vaccination and number of age cohorts vaccinated, the population targeted, and the number of doses used. In our base case, we assumed 100% lifetime protection against HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58; vaccination coverage of 80%; and a time horizon of 100 years. For the cost-effectiveness analysis, we used a 3% discount rate. Elimination of cervical cancer was defined as an age-standardised incidence of less than four cases per 100 000 woman-years. We predicted that HPV vaccination could lead to cervical cancer elimination in Vietnam, India, and Nigeria, but not in Uganda. Compared with no vaccination, strategies that involved vaccinating girls aged 9–14 years with two doses were predicted to be the most efficient and cost-effective in all four LMICs. NNV ranged from 78 to 381 and ICER ranged from $28 per DALY averted to $1406 per DALY averted depending on the country. The most efficient and cost-effective strategies were routine vaccination of girls aged 14 years, with or without a later switch to routine vaccination of girls aged 9 years, and routine vaccination of girls aged 9 years with a 5-year extended interval between doses and a catch-up programme at age 14 years. Vaccinating boys (aged 9–14 years) or women aged 18 years or older resulted in substantially higher NNVs and ICERs. We identified two strategies that could maximise efforts to prevent cervical cancer in LMICs given constraints on vaccine supplies and costs and that would allow a maximum of LMICs to introduce HPV vaccination. World Health Organization, Canadian Institute of Health Research, Fonds de recherche du Québec–Santé, Compute Canada, PATH, and The Bill & Melinda Gates Foundation. For the French and Spanish translations of the abstract see Supplementary Materials section.

•This is one of the few original investigations of vaccine manufacturing and costs.•Manufacturing costs of Gardasil-4 are much lower than the “no profits” price to Gavi.•Lower sales make per-unit costs of Cervarix much higher than Gardasil.•This study may have relevance to the costs and fair pricing of other vaccines. Nearly all of the 500,000 new cases of cervical cancer and 270,000 deaths occur in middle or lower income countries. Yet the two most prevalent HPV vaccines are unaffordable to most. Even prices to Gavi, the Vaccine Alliance, are unaffordable to graduating countries, once they lose Gavi subsidies. Merck and Glaxosmithkline (GSK) claim their prices to Gavi equal their manufacturing costs; but these costs remain undisclosed. We undertook this investigation to estimate those costs. Searches in published and commercial literature for information about the manufacturing of these vaccines. Interviews with experts in vaccine manufacturing. This detailed sensitivity analysis, based on the best available evidence, finds that after a first set of batches for affluent markets, manufacturing costs of Gardasil for developing countries range between $0.48 and $0.59 a dose, a fraction of its alleged costs of $4.50. Because volume of Cervarix is low, its per unit costs are much higher, though at comparable volumes, its costs would be similar. Given the recovery of fixed and annual costs from sales in affluent markets, Merck’s break-even price to Gavi could be $0.50–$0.60, not $4.50. These savings could support Gavi programs to strengthen delivery and increase coverage. Outside Gavi, prices to lower- and middle-income countries, with profit, could also be lowered and made available to millions more adolescents at risk. These estimates and their policy implications deserve further discussion.

•HPV16/18 bivalent vaccine is based on self-assembling VLPs in vitro derived from E. coli.•Scalability, and process and lot consistency are confirmed in a pilot scale.•Cryo-EM structures of both HPV16 and -18 VLPs demonstrate a T=7 icosahedral arrangement.•Immunogenicity in mouse and in monkey is comparable with that of licensed vaccines.•E. coli-derived HPV16/18 bivalent vaccine is feasible and potentially cost-effective. Human papillomavirus (HPV) types 16 and 18 account for approximately 70% of cervical cancer worldwide. Neutralizing HPV prophylactic vaccines offer significant benefit, as they block HPV infection and prevent subsequent disease. However, the three licensed HPV vaccines that cover these two genotypes were produced in eukaryotic cells, which is expensive, particularly for low-income countries where HPV is highest. Here, we report a new HPV16 and -18 bivalent candidate vaccine produced from Escherichia coli. We used two strategies of N-terminal truncation of HPV L1 proteins and soluble non-fusion expression to generate HPV16 and HPV18 L1-only virus-like particles (VLPs) in a scalable process. Through comprehensive characterization of the bivalent candidate vaccine, we confirm lot consistency in a pilot scale-up of 30L, 100L and 500L. Using cryo-EM 3D reconstruction, we found that HPV16 and -18VLPs present in a T=7 icosahedral arrangement, similar in shape and size to that of the native virions. This HPV16/18 bivalent vaccine shares comparable immunogenicity with the licensed vaccines. Overall, we show that the production of a HPV16/18 bivalent vaccine from an E. coli expression system is robust and scalable, with potentially good accessibility worldwide as a population-based immunization strategy.

Most cervical cancers can be prevented by population-wide vaccination of pre-adolescent girls with highly efficacious HPV vaccines. In South Africa, first-dose coverage of bivalent HPV vaccination among girls aged 10 is ∼80 %. We investigated the additional impact and cost-effectiveness of different bivalent and nonavalent vaccination strategies among the general population and women with HIV (WHIV). We used an individual-based, population-level model for HPV and HIV transmission in South Africa to estimate the epidemiological impact of HPV vaccination. The costs of interventions in the cervical cancer care cascade are estimated in 2024 USD based on resource use and prices obtained from research studies. To estimate cost-effectiveness of different bivalent strategies, we calculated the median cost per disability adjusted life-year averted (DALY) between 2024 and 2120 and compared it to an opportunity cost (OC) threshold of USD 3015. We calculated a threshold price at which nonavalent vaccination will be cost-effective in South Africa. Current interventions are projected to reduce age-standardised cervical cancer incidence from 54 to 12 per 100,000 women by 2120. Increasing girl-only bivalent coverage to 90 % would prevent an additional 5 % of cases and be cost-saving. Gender-neutral vaccination at 80 % coverage would yield similar impact, with a USD/DALY averted of USD 2782 compared to girls-only vaccination. Vaccinating WHIV up to age 45 could prevent 10 % of cervical cancer cases in this group and remains cost-effective. The nonavalent vaccine would be cost-effective if priced below USD 40 per dose. Enhanced HPV vaccination strategies—including higher coverage, gender-neutral programs, and targeted vaccination of WHIV—are cost-effective in South Africa. However, no vaccination strategy alone will reach elimination, which will require integrated approaches combining vaccination with cervical cancer screening and treatment. •Transmission modelling of HPV vaccination strategies in South Africa.•Show cost-effectiveness of different bivalent & nonavalent vaccination strategies.•Increasing bivalent coverage by vaccinating boys and WHIV is cost-effective.•Nonavalent vaccine needs substantial price reduction to be cost-effective.