Single-Dose HPV Vaccine EVALUATION CONSORTIUM

Accumulating evidence suggests a single dose of human papillomavirus (HPV) vaccine may elicit an immune response to protect against incident and persistent HPV infection, which are the necessary prerequisites to the development of cervical lesions and, in the longer term, cervical cancer.

Clinical trials, observational studies, and modeling analyses are being conducted to evaluate the efficacy, immunogenicity, effectiveness, and cost-effectiveness of single-dose HPV vaccination. If demonstrated to be effective, single-dose HPV vaccination could facilitate new options for current national programs by simplifying delivery and lowering

program costs. For LMICs that have delayed introducing HPV vaccines because of financial, logistical, or other barriers, a single-dose HPV vaccination schedule could accelerate introduction of HPV vaccines into national immunization schedules, potentially protecting even more girls against cervical cancer and other HPV-related diseases.

This brief summarizes a comprehensive review and assessment of current, published evidence on a single-dose HPV vaccination schedule. The review was undertaken by researchers in the Single-Dose HPV Vaccine Evaluation Consortium.

Cervical cancer is a leading cause of cancer death among women in low- and middle-income countries (LMICs). More than a half-million new cases and 311,000 deaths occur annually, with more than 85% of deaths occurring in LMICs.

A general summary of current, published evidence on single-dose HPV vaccination

GENERAL SUMMARY

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CURRENT, PUBLISHED EVIDENCE ON SINGLE-DOSE HPV VACCINATION

Background

HPV vaccines

Preventing the development of cervical cancer is now possible through vaccination with any of three licensed HPV vaccines: the bivalent vaccine, the quadrivalent vaccine, and the nonavalent vaccine.

Currently, the World Health Organization (WHO) recommends two doses of HPV vaccine for girls aged 9 to 14 years, with dosing flexibility for dose 2 as early as five months after dose 1. Girls aged 15 years or older and girls who are immune-compromised, including those who are HIV infected, should continue to receive three doses per the original dosage recommendations.

Current evidence

Rationale for single-dose HPV vaccination

HPV vaccines are highly effective. Since introduction, they have significantly reduced vaccine-type HPV infections and precancerous cervical lesions. The strong, consistent, and durable antibody responses to the three HPV vaccines are well documented. In healthy young women, seroconversion rates are virtually 100%. Immune responses in pre-adolescent girls and boys are even stronger. The stability of antibody responses has been observed for over ten years post-vaccination. This pattern of antibody response is evident even after a single dose of HPV vaccine, as seen in observational data from several clinical studies.

Evidence on single-dose HPV vaccination from clinical trials

The available evidence from randomized controlled trials (RCTs) on the immunogenicity and efficacy of single-dose HPV vaccination compared to either no vaccination or to multidose schedules was systematically reviewed in a recent study. As of March 2019, there were no data that originated from specifically designed RCTs. However, data from RCTs where participants failed to complete their allocated schedule of two or three doses provide some evidence that one dose of HPV vaccine may provide protection against persistent HPV infection with vaccine genotypes and protective immune responses.

The review includes four studies: one each in India [International Agency for Research on Cancer (IARC) India HPV Trial], Costa Rica [Costa Rica Vaccine Trial (CVT)], and the United States, and one multinational study [PApilloma TRIal against Cancer In young Adults (PATRICIA)]. These studies provide evidence that one dose of HPV vaccine may be as effective in preventing HPV infection as two or three doses in healthy young females up to seven years post-vaccination. Incident, persistent, and prevalent infection with HPV 16 and 18 were extremely low in all efficacy trial participants who received any HPV vaccine, and significantly lower than participants who were either unvaccinated or received a control vaccine. All included efficacy studies reported comparable efficacy against HPV 16 and 18 infection in one-dose and two- or three-dose arms.

Immunogenicity evidence after receipt of a single dose of HPV vaccine was also assessed in the CVT and IARC India HPV Trial. The proportions of participants reportedly seroconverting to HPV 16 and 18 were generally high in all HPV vaccine dosage arms. However, the definition for seroconversion differs between studies, so caution must be applied in interpreting these results. Antibody titers were lower with one dose than with two or three doses, but titers in one-dose arms remained

About the Single-Dose HPV Vaccine Evaluation Consortium The Single-Dose HPV Vaccine Evaluation Consortium encompasses eight leading independent public health and research institutions working together to collate and synthesize existing evidence and evaluate new data on the potential for single-dose HPV vaccination. The consortium’s goal is to evaluate this evidence to inform global policy discussions and program guidance, as well as to raise awareness and understanding of its implications.

As the project unfolds, the consortium is coordinating relevant scientific groups and evaluating new data as they become available. Modeling experts within the consortium are generating new evidence through exploratory analyses to estimate the impact and cost-effectiveness of single-dose schedules to alternative dosing schedules to inform decision-making. The consortium will update the evidence base throughout the project period (2018–2021).

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GENERAL SUMMARY PAGE 3

stable throughout follow-up. Furthermore, observed antibody titers were significantly higher in participants vaccinated with one dose of HPV vaccine compared to prevaccination titers in participants with natural infection.

Evidence from immunogenicity studies of partially vaccinated non-trial populations

As of March 2019, seven observational studies have reported humoral immunogenicity results after receipt of a single dose of HPV vaccine—one in Uganda, and two each in Fiji, Canada, and the United States. One study from Fiji also presented cellular humoral immunogenicity data.

These studies demonstrate that single-dose HPV vaccination results in high rates of seroconversion and sustained seropositivity, with one study presenting data up to eight years after vaccination. As observed in the data from RCTs described above, antibody titers are mostly lower for single-dose recipients compared to multidose recipients. However, where immunogenicity studies have used the same laboratory methods as the clinical trials described above, they have been able to demonstrate higher antibody titers among adolescents who had received a single dose of HPV vaccine through national campaigns or programs than the titers associated with protection in previous clinical trial participants.

Evidence from postlicensure vaccine effectiveness evaluations and other observational studies

Twenty-three studies published between January 1, 2007, and March 20, 2019, identified through a systematic review and its recent update, provide evidence of HPV vaccine effectiveness by number of doses.

Most of the 23 studies found the highest effectiveness with three doses, followed by two doses, and then one dose. Importantly, more recent studies with younger vaccine recipients, or with analyses stratified by age at vaccination, have found small or no differences by number of doses.

Of the 23 studies, 9 studies found significant vaccine effectiveness for single-dose HPV vaccination in some or all analyses. Across all endpoints (prevalence, anogenital warts, and cervical abnormalities), variation in effectiveness by number of doses was observed in most studies. The more recent studies overcome some of the limitations and biases in earlier studies, which likely included more women who had prevalent infection at the time of vaccination.

Mathematical modeling of impact of reduced-dosing schedule

Mathematical models have been used extensively to evaluate the impact of strategies to prevent HPV-related diseases, including reduced dosing schedules. Some of the outcomes that modelers have been able to project include how widely HPV viruses will spread in populations, how common HPV-related diseases will be in the future, what impact these strategies will have on national health care budgets, and whether the strategies represent good value for money to governments. A few of these models have looked at single-dose HPV vaccination strategies; we now have results from such models for the United States, United Kingdom, Uganda, and South Africa.

Initial analyses suggest that the duration of protection afforded by reduced dosages is a critical factor in determining impact and cost effectiveness. The initial findings of these models suggest that giving a single dose of HPV vaccine to women will yield much greater health benefits than none at all, even if the vaccine does not protect as well as two doses. The models suggest that

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Figure 1. Countries with existing and forthcoming evidence on single-dose HPV vaccination

single-dose HPV vaccination represents good value for money according to standard benchmarks that health authorities in these countries and global organizations use. The models were also used to evaluate the added impact and value of two-dose HPV vaccination. The models suggest that one dose is the optimal strategy if two doses do not give recipients any additional or longer-term protection against HPV or HPV-related diseases. If two doses will protect women for longer than one dose, or if the initial level of protection is greater for two doses than for one dose, then the optimum number of doses to give depends on exactly how much extra protection the second dose provides and what level of vaccine coverage can be achieved with each strategy.

A modeling analysis also suggested that in places where many people are infected with HIV, giving 9-year-old girls a single dose of nonavalent HPV vaccine can still help to prevent many cases of, and deaths due to, cervical cancer. These reductions will even be seen in women who are infected with HIV, regardless of how advanced their HIV is or whether or not they are receiving drugs used to treat HIV.

Gaps and forthcoming evidence

While several studies have examined single-dose regimens, further studies are warranted on the durable efficacy and population-level effectiveness of single-dose HPV vaccination.

Ongoing clinical trials assessing the efficacy and immunogenicity of single-dose HPV vaccination will provide additional data to fill knowledge gaps. However, research on efficacy of, and immune responses to, single-dose HPV vaccination may need to be expanded to other target groups, such as boys, alternative age groups, and HIV-positive individuals. This research also should evaluate all licensed HPV vaccines, as well as new vaccines currently in development. Standardization of laboratory assays to measure seropositivity and immune responses comparatively between the different vaccines is also needed.

Observations on longer-term efficacy as well as long-term immunogenicity evidence are forthcoming from the CVT and the IARC India HPV Trial. New prospective efficacy trials are underway in Costa Rica (ESCUDDO, or Estudio de Comparacion de Una y Dos Dosis de Vacunas Contra el Virus de Papiloma Humano) and Kenya (KEN-SHE, or Kenya Single-dose HPV vaccine Efficacy), which are randomizing young women to single-dose schedules. Single-dose HPV vaccine effectiveness trials have also begun in Thailand (IVIHPV1, or Effectiveness of Single Dose or Two Doses of Bivalent HPV Vaccine in Thailand) and South Africa (HOPE, or The HPV One/Two Dose Population Effectiveness). Other trials in The Gambia (HANDS, or HPV Vaccination in Africa – New Delivery Schedules) and Tanzania (DoRIS, or Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls) will immunobridge to efficacy trials, and a common immunoassay will be used across vaccines to directly compare immune response regardless of vaccine received.

An updated systematic review will include any newly published studies on efficacy and immunogenicity; single-dose effectiveness studies from population-based HPV vaccination programs in the United States, Canada, and Australia; and new quality assessments of the evidence.

Evidence generated by future modeling work will focus on integrating new trial, non-trial, and effectiveness data into existing models, as well as conducting model-based analyses in LMICs with different sexual behavior and epidemiological profiles. In South Africa and other countries with high prevalence of HIV infection, it will be critical to generate more evidence on the health and economic impacts of reduced-dose HPV vaccination in HIV-positive individuals.

The evidence for single-dose schedule HPV vaccination is encouraging. The limitations of previous studies are being overcome by new studies with more robust data. The Single-Dose HPV Vaccine Evaluation Consortium will continue to monitor and update the evidence base and share results widely.

The consortium, coordinated by PATH, includes Harvard University, London School of Hygiene & Tropical Medicine, Université Laval, University of British Columbia, US Centers for Disease Control and Prevention, US National Cancer Institute, and Wits Reproductive Health and HIV Institute.

In addition to the consortium members, representatives from the following institutions serve as advisors: the World Health Organization; International Agency for Research on Cancer; Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine; Instituto Nacional de Salud Pública de Mexico; Quebec Institut National de Santé Publique;Victorian Cytology Service, Australia; University of Washington; and International Vaccine Institute.

Disclaimer: The content, findings, and conclusions of this report are those of the authors and do not necessarily represent the official position of their agencies or institutions of employ.

For information about the Single-Dose HPV Vaccine Evaluation Consortium and access to the full review of current evidence, visit path.org/singledosehpv. Inquiries about this project can be directed to: Evan Simpson, PATH, 2201 Westlake Avenue, Suite 200, Seattle, WA 98121, USA, esimpson@path.org

December 2019

Single-Dose HPV Vaccine EVALUATION CONSORTIUM