Supplement Canadian Human Papillomavirus Vaccine Research Priorities Workshop Final Report November 17-18, 2005 Quebec City Volume: 32S1 - July 2006 Full version: PDF Version 66 pages (820 KB)

Table of Contents

Executive Summary
Introduction
November 17: Plenary Presentations

• Frameworks used to structure the knowledge base
  • HPV vaccines: from development to implementation, from research to action: Bernard Duval
  • Models of epidemics: epidemic ofmodels: Babak Pourbohloul
  • Role of economic studies in decision-making for publicly funded immunization programs: Philippe DeWals
• Knowledge synthesis: available Canadian evidence for decision-making on the use of vaccine
  • Burden of HPV-related disease: Patricia Goggin
  • Do the characteristics of the HPV vaccine permit implementation of an effective and safe immunization program?Marc Dionne
  • HPV vaccine - considerations for program implementation and delivery: Greg Hammond
  • HPV/cervical cancer surveillance and monitoring in Canada: TomWong
• How other countries are addressing decision-making on HPV vaccine use
  • Development of HPV vaccine recommendations in the US: LauriMarkowitz
  • HPV vaccine - the UK perspective: David Salisbury

November 17: Break-out Sessions
November 18: Plenary Presentation of Research Questions

• Break-out session A: fundamental research
• Break-out session B: intervention research.
• Break-out session C: programdelivery research

November 18: Wrap-up

• Next steps
• Concluding remarks
• Workshop Evaluation
• Voting Results

Appendix 1: Workshop Participants
Appendix 2: Break-out Session Agendas
Appendix 3: Workshop Evaluation Summary
Appendix 4: Additional Voting Results Tables

Executive Summary

Background

Human papillomavirus (HPV) has been identified as a causative agent of cervical cancer. The virus also causes anogenital warts in both sexes and is associated with anal cancer and cancer of the vulva, vagina and penis. Two new vaccines against HPV are nearing the end of the clinical trials stage, and at least one is expected to be submitted for approval over the next year. There is an urgent need to plan now for the introduction of the vaccines in Canada, and this will necessitate collaboration among experts in vaccines, immunization programs, sexually transmitted infections and cancer, as well as decision-makers, public health, academia and industry. The Public Health Agency of Canada (PHAC) and the Canadian Association for Immunization Research and Evaluation (CAIRE), in partnership with the Canadian Institutes of Health Research (CIHR) Institute of Infection and Immunity and the Institute of Cancer Research, held an invitational HPV Vaccine Research Priorities Workshop on November 17-18, 2005, in Quebec City. It was attended by 53 Canadian and international HPV experts and researchers from the areas of vaccines, cancer, and sexually transmitted infections. The purpose of the meeting was to examine the current Canadian and international status of HPV vaccine research and develop national research priorities before the vaccines become approved for use in Canada.

Workshop Structure/Process

The Workshop consisted of a plenary session at which various speakers provided background information. This was important context for participants, who came from diverse disciplines, and served as a frame of reference for the brainstorming required in the break-out sessions held later that day. Participants heard about the two frameworks (one for decision-making in cancer control and one for evaluating immunization programs) that would guide the structure of the break-out sessions and their deliberations; the value of infectious disease modelling and economic studies in evaluating potential immunization programs; the burden of disease associated with HPV; rates of HPV infection and cervical cancer, as well as the benefits of screening; the characteristics of the HPV vaccine; and other considerations for vaccine program implementation and delivery. The plenary session ended with an account from experts from the United States (US) and the United Kingdom (UK) on how those two countries are addressing decision-making on HPV vaccine use.

Participants were allocated to one of three break-out groups representing fundamental research (burden of disease), intervention research (vaccines), and program delivery research (immunization programs). Each of these sessions began with a presentation about current research activities and possible areas that would merit further investigation. A template had been created for each of the groups highlighting the areas of the evaluation framework specific to that group in order to facilitate discussion. Each group was asked to discuss the issues raised by particular criteria from the framework and to consider existing research gaps, as well as to identify pertinent infrastructure gaps. The research questions and infrastructure gaps identified during the break-out sessions were presented in plenary the following day, and participants were asked to vote on both the importance and feasibility of each of the research questions and infrastructure gaps according to a 5-point Likert scale. This allowed for some degree of ranking of the research areas.

Research Priorities

Fundamental research: Baseline data are needed on the transmission of HPV in specific groups, the distribution of HPV types, and the prevalence, duration, natural history and costs (in terms of screening, diagnosis and treatment) of HPV-associated disease. It would be useful to know the comparative costs of improving the effectiveness and coverage of cervical screening versus a combined immunization and screening approach to the disease. Associated with this is the impact of migration and ethnicity on the effectiveness of primary and secondary prevention programs, and the psychosocial burden on particular groups of identified precursors of disease and medical interventions.

Intervention research: The short- and long-term immunogenicity, efficacy, and effectiveness associated with a two-dose rather than three-dose schedule need to be examined. Research is required on whether the two new vaccines are interchangeable for protection against HPV types 16 and 18, on the consequences for safety and immunogenicity of co-administration with other vaccines, and on the safety and immunogenicity of the vaccine during pregnancy and among immunocompromised individuals, as well as in Aboriginal populations. The herd immunity according to level of coverage and the effect of natural infection on the antibody level in vaccinated individuals should be documented. Other areas of priority are the incidence of adverse events following immunization and the impact of HPV immunization programs on cervical screening, not only in terms of compliance and screening intervals but also with respect to the sensitivity, specificity and predictive value of the Papanicolaou test.

Program delivery research: In order to deliver an HPV immunization program efficiently there should be research into the optimal age cohort, schedule, and delivery setting for immunization, and the feasibility/cost-effectiveness of catch-up programs. The potential effect of an immunization program on sexual behaviour, cervical screening programs and health care services needs to be investigated. The costs and savings associated with this immunization program and the knowledge/attitudes/beliefs of providers and parents are other priorities for research.

Analysis/Findings

After the Workshop, the Planning Committee reviewed the voting results and determined the best method of further analyzing and presenting the results. For clarity, there were minor editorial adjustments made to the wording of some research questions. A complete summary of the voting results is provided in this report, and Appendix 4 includes additional analysis of the results. The tables presented in the text depict the 10 highest ranked research questions and infrastructure gaps, by importance and feasibility. Results are also given by research components (fundamental, intervention and program delivery research) and by participant subgroups. The total means of all research questions and infrastructure gaps are provided.

Next Steps

Participants felt that national goals for an HPV immunization program should be clearly articulated as the next step, as should the impact of a vaccine program on cervical screening programs. Many questions need to be answered before administration of the new vaccine can be justified, and some of this information may soon be available from the results of follow-up studies from vaccine clinical trials and other international research activities. The results of the voting showed that program delivery research issues were perceived as some of the most important. Possible sources of funds for such research might be CIHR, perhaps in collaboration with PHAC and the private sector. There was a strong feeling that PHAC should have a stronger role in research funding, but that provinces/territories could also lobby for additional funds for post-marketing research. Another alternative is to conduct pilot projects in one or more provinces/territories with collaboration between cancer and immunization experts for monitoring the interaction between immunization and screening services.

Introduction

As early as 1975, evidence suggested that human papillomavirus (HPV), a common sexually transmitted virus spread through direct contact, might be linked with cervical cancer. More recently, improvements in DNA amplification techniques, such as polymerase chain reaction, have allowed investigators to determine that HPV DNA is present in the majority of cervical cancers examined. Almost half a million women worldwide developed cervical cancer in 2002, and approximately 270,000 died; 83% of these cases occurred in developing countries. Estimates of the prevalence of HPV vary depending on the age of the cohort studied, the study population and the country, from 3% in Spain to 43% in Mozambique. In Canada, according to a limited number of studies, the prevalence of HPV is relatively high and varies dramatically with the type of cohort studied, from 13% to 33%; the latter included Aboriginal women (42% of the group). HPV is also associated with anogenital warts and anal cancer.

Large-scale clinical trials of two new HPV vaccines, manufactured by Merck Frosst and GlaxoSmithKline Inc., have been under way for a number of years, and the manufacturers are preparing for submission to the regulatory authorities within the next year. The vaccines have been developed with the use of DNA-free virus-like particles, synthesized from self-assembling protein subunits of the L1 capsid antigen. One of the vaccines is bivalent and protects against the HPV genotypes 16 and 18, which occur in more than 70% of cervical cancer cases. The other vaccine is quadrivalent and protects against these two genotypes and types 6 and 11, which cause genital warts in both sexes. The trials to date have found both vaccines to successfully prevent persistent infection with HPV (100%) and to provide protection (> 90%) against cervical intraepithelial neoplasia, cervical abnormalities that are predictive of cervical cancer.

A number of issues need to be addressed before the new vaccines become available for use in immunization programs. These include the epidemiology of HPV disease in the population and the dynamics of HPV infection in particular subgroups; the effect of population immunity to vaccine genotypes on other circulating HPV genotypes; the population groups that should be the target of an HPV immunization program; the need for booster doses of vaccine; the optimal dosage schedule; and the value of catch-up campaigns. As well, the new vaccine has unique implications not applicable to previous vaccines, i.e. the effect on cancer prevention efforts in the form of cervical cancer screening with the Papanicolaou (Pap) test.

Planning for the introduction of the HPV vaccines in Canada requires both scientific information in order to answer the above-mentioned questions and collaboration among diverse groups, such as those who work in the fields of vaccines, sexually transmitted infections and cancer; between scientists and decision-makers; and among public health at the federal/provincial/territorial level, academia and industry. In the past, new immunization programs have been introduced differently by individual provinces and territories, leading to inequitable access. Part of the mandate of the National Immunization Strategy (NIS) is to encourage the adoption of necessary immunization programs across Canada and to develop, in collaboration with the provinces and territories, a consistent and logical means of evaluating what a necessary program might be. To this end, and to foster both the collaborative and the research planning components, the Public Health Agency of Canada (PHAC) and the Canadian Association for Immunization Research and Evaluation (CAIRE), in partnership with the Canadian Institutes of Health Research (CIHR), held an invitational HPV Research Priorities Workshop on November 17 and 18, 2005, in Quebec City. A multidisciplinary expert scientific committee was formed to establish the Workshop agenda and process, and to provide scientific/technical input (see Appendix 1: Participant List).

The goal of theWorkshop was to develop research priorities for HPV vaccine use in Canada. Its objectives were as follows:

• to take stock of past and current research on HPV vaccine-related issues;
• to identify the key elements to support decision-making on the use of new HPV vaccines;
• to identify the implications to the cervical cancer screening programs in the era of HPV vaccines and to support evaluation activities;
• to identify the gaps remaining among those key elements and translate them into priorities for future research activities;
• to suggest organizational models of collaboration among Canadian researchers from industry, academia and public health to answer those priorities efficiently, despite the usual constraints of confidentiality, conflict of interest, competition, etc.;
• to foster an increased interpersonal knowledge and communication between the key decision-makers and scientists of the various fields and organizations;
• to identify research priorities and suggest mechanisms by which they could be achieved within Canadian funding structures; and
• to identify the next steps required in the short and long term to realize the above objectives.

Fifty-three participants from a variety of backgrounds attended theWorkshop, and all participants signed a mandatory conflict of interest form prior to the event.

The Workshop began with a plenary session during the first morning, providing participants with a broad overview by speakers considered experts in their field of work. Presentations included information on the use of frameworks for evaluating potential immunization programs; a review of the available Canadian data about HPV-related disease; a review of epidemiologic modeling and economic analysis; a review of surveillance/monitoring of vaccines, screening and cancer; a review of decision-making for publicly funded immunization programs; and ways in which other countries are approaching the implementation of HPV vaccine programs.

During the afternoon of the first day, participants were split into three break-out groups representing fundamental research, intervention research, and program delivery. They were asked to develop research questions relevant to optimal decision-making both before and after introduction of the HPV vaccine, as well as to identify infrastructure gaps (i.e. capacity, funding, networks) for the research.

On the morning of the second day, participants assembled again in plenary to rank each of the research questions and infrastructure gaps identified during the break-out sessions according to its importance and feasibility. This was followed by general discussion of the next steps towards conducting the necessary research.

Full version: PDF Version
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