Vaccines of the 21st Century : Taking Canada to the Next Level

Report prepared for CIHR Institute of Infection and Immunity by Michelle French, Scientific Communication

Table of Contents

List of Abbreviations
Executive Summary
About This Report
Background
Vaccins Overview
Steps in Vaccine Research and Development
Reasons for Renewed Interest and the Need to Support Vaccine Research
Data Collection Methods
Survey Results
Vaccine-Related Organizations in Canada
Selected Key Accomplishments
Research Strengths
Vaccine-Related Challenges and Recommendations
Funding
Existing Funding Opportunities
New Funding Opportunities
Recent Vaccine-Related Developments
Conclusion
Next Steps
Appendix 1: Representatives Interviewed from Vaccine-Related Organizations
Appendix 2: Interview Questions for Representatives from Vaccine-Related Organizations
Appendix 3: Web Survey Questions for Individual Researchers
Appendix 4: Funding Agencies and Organizations Who Were Contacted
Appendix 5: Questionnaire for Representatives of Funding Organizations
Appendix 6: Members of the IAB Subcommittee on Vaccines of the 21st Century
Appendix 7: Major Vaccine-Related Organizations in Canada: Current Projects and International Linkages
Appendix 8: Key Accomplishments of Vaccine-Related Organizations
Appendix 9: Key Accomplishments of Individual Vaccine Researchers

List of Abbreviations

BCG
bacillus Calmette-Guérin
BSL 3 biosafety level 3
CAIRE Canadian Association of Immunization Research and Evaluation
CDC Centers for Disease Control and Prevention
CFIA Canadian Food Inspection Agency
CHVI Canadian HIV Vaccine Initiative
CIC Canadian Immunization Committee
CIDA Canadian International Development Agency
CIHR Canadian Institutes of Health Research
CIHR-III CIHR Institute of Infection and Immunity
CIII2 Canadian International Immunization Initiative Phase 2
CIN cervical intraepithelial neoplasia
CPS Canadian Pediatric Society
CTA cancer-testis antigen
CTL cytotoxic lymphocyte
DRDC Defense Research and Development Canada
FDA Federal Drug Administration
FRSQ Fonds de la recherche en santé du Québec
HC Health Canada
HCV hepatitis C virus
HDP host defense peptides
HIV human immunodeficiency virus
HPV human papilloma virus
HSV herpes simplex virus
IAB Institute Advisory Board
IDRC International Development Research Centre
IMPACT Immunization Monitoring Program, Active
GHRI Global Health Research Initiative
GMP good manufacturing practices
LD lethal dose
LPS lipopolysaccharide
NACI National Advisory Committee on Immunization
NCIC National Cancer Institute of Canada
MHC major histocompatibility complex
MRSA methicillin-resistant Staphylococcus aureus
NK natural killer
NIAID National Institute of Allergy and Infectious Diseases
NIH National Institutes of Health
NRC National Research Council Canada
NSERC Natural Sciences and Engineering Research Council
OHASIS Occupational Health And Safety Information System
PHAC Public Health Agency of Canada
PIV3 human parainfluenza virus type 3
PREVENT Pan-Provincial Vaccine Enterprise
RSV respiratory syncytial virus
RI retro-inversed
SARS Severe Acute Respiratory Syndrome
TB tuberculosis
TLR Toll-like receptor
UBC University of British Columbia
UNICEF United Nations Children’s Fund
UIIP universal influenza immunization program
VIC Vaccine Industry Committee
VIDO Vaccine and Infectious Disease Organization
WHO World Health Organization

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Executive Summary

About this report

In its Strategic Plan for 2007-2012, the Canadian Institutes of Health Research (CIHR) Institute of Infection and Immunity (CIHR-III) made Vaccines of the 21st Century a research priority. The Institute surveyed representatives from vaccine-related organizations, individual researchers and representatives from funding organizations. They were asked to:

  • Summarize their accomplishments and/or investments in research;
  • Identify challenges; and
  • Make suggestions for facilitating and supporting research and translating knowledge into new products and services.

Their responses form the basis of this report and will guide the activities of this strategic priority area for the Institute.

The broad nature of this report, however, also makes it useful for government policy makers, those who support research and development, members of the research community and "end users" of vaccines such as health-care professionals and governments.

The time is right

The Vaccines of the 21st Century strategic research priority is well-timed. Renewed interest in research and development is being driven by several converging factors including:

  • A lack of new antibiotics to fight infections;
  • A dearth of vaccines for several major diseases;
  • Threats from emerging infectious diseases, pandemic influenza and bioterrorism;
  • New uses for vaccines (e.g. to prevent and to treat cancer);
  • Renewed interest in global health; and
  • A need to maintain national capacity to develop, manufacture and test vaccines.

Basic research to vaccination

From basic research to the implementation of immunization programs, a number of organizations engage in vaccine-related activities. Canadian universities, research institutes, governments and vaccine companies do basic research. Clinical trials are conducted by vaccine manufacturers and at vaccine evaluation centres. Others play a role in vaccine approval and make recommendations to health-care professionals and governments.

Strong track record

Canada has a history of making significant contributions to vaccine research and development. Accomplishments over the past decade include:

  • Developing an acellular pertussis vaccine from basic research to manufacture by sanofi pasteur;
  • Developing vaccine technology to prevent meningitis by Dr. Howard Jennings at the National Research Council of Canada;
  • Preparing for and assessing the impact of human papilloma virus (HPV) immunization in Canada by Dr. Babak Pourbohoul at the BC Centre for Disease Control, Dr. Marc Brisson at Laval University and Dr. Eduardo Franco at McGill University;
  • Assessing and making recommendations for influenza immunization programs by Dr. Noni Macdonald at the Canadian Centre for Vaccinology, Dalhousie University and Dr. Jeff Kwong at the Institute for Clinical Evaluative Sciences;
  • Developing a vaccine candidate for Severe Acute Respiratory Syndrome (SARS) by the SARS Accelerated Vaccine Initiative led by Dr. Brett Finlay and Dr. Robert Brunham at the University of British Columbia (UBC) Centre for Disease Control;
  • Developing and licensing a cattle vaccine against E. coli 0157:H7 by Dr. Andrew Potter at the Vaccine and Infectious Disease Organization (VIDO) and Dr. Brett Finlay at the UBC Centre for Disease Control;
  • Developing candidate vaccines against hemorrhagic fevers by Dr. Heinz Feldmann and Dr. Steven Jones at the Public Health Agency of Canada (PHAC) National Microbiology Laboratories;
  • Researching and developing adjuvants, which are added to vaccines to enhance immune responses, by GlaxoSmithKline Inc. and several individual researchers at universities; and
  • Developing therapeutic cancer vaccines by manufacturers and researchers at universities including Dr. Jonathan Bramson at McMaster University.

The research accomplishments described by representatives of vaccine-related organizations and individual researchers highlight specific research strengths in Canada. There is strength in research into novel adjuvants and methods of antigen delivery, as well as determining how to evoke specific types of immune responses. Epidemiology, vaccines for special populations and evaluation research are also strong areas. Over 25 different infectious agents are under study with the most common being influenza, therapeutic cancer vaccines, HPV and human immunodeficiency virus (HIV).

Challenges and recommendations

Survey respondents identified challenges and made suggestions on how CIHR and partners can facilitate vaccine research and development. These include:

Challenges Recommendations
Research efforts need to be better coordinated. Organize and facilitate vaccine research workshops and facilitate communication. Foster linkages between all stakeholders. Establish a vaccine research network.
Vaccine research and development is costly. Create partnerships with funding organizations, industry, academic institutions and government to drive research and development.
There are still several major diseases for which there currently are no vaccines. As well, improved methods to formulate and deliver vaccines are needed. Continue to support basic research. Also, develop and support strategic research initiatives.
The public lacks accurate knowledge about the safety and efficacy of vaccines. Support behavioural, social and ethics research.
There is a gap between basic research and Phase I/II clinical trials. Partner with industry to bridge the gap between basic science and clinical trials. Establish facilities and guidelines to allow researchers to take discoveries towards clinical trials. Create new funding mechanisms.
There are many clinical research questions that require public funding. Provide additional and ongoing support for pre-clinical and post-licensure trials.

Additional challenges not specifically related to research

  • Up-to-date and standardized data on the epidemiology and burden of disease is often lacking.
  • It is increasingly difficult for industry to do clinical trials in Canada.
  • Industry needs faster and more transparent vaccine approval.
  • Canada must retain and develop its own vaccine production facilities.
  • Immunization programs across the country need to be harmonized.

Additional recommendations not specifically related to a challenge

  • Improve the grant application process, review and approval times.
  • Train more vaccinologists and develop additional scientific and regulatory expertise.

Funding and Recent Announcements

Vaccine-related research is funded by several agencies and organizations operating at provincial, national and international levels. Several new funding opportunities for vaccine research were identified by representatives from funding organizations. These include the Influenza Research Network launched by PHAC and CIHR-III and the Canadian HIV Vaccine Initiative.

In addition, several exciting announcements regarding vaccine research and development were made in early 2008. For example, a new Centre of Excellence for Commercialization and Research called The Pan-Provincial Vaccine Enterprise (PREVENT) will conduct pre-clinical and proof-of-concept clinical trials for promising early-stage vaccine candidates. A Canadian Network on HPV Prevention, operated by the International Centre for Infectious Diseases, is also in development. As well, the Alberta Heritage Foundation for Medical Research (AHFMR) has awarded an Interdisciplinary Team Grant in Vaccine Design and Implementation to study how bacteria evolve within the human population and design vaccine products to protect against different strains and species.

Conclusion

Canada continues to make significant contributions to vaccine research and development. These accomplishments have saved lives, decreased human suffering and reduced health-care costs. Exciting new funding initiatives and a renewed interest in vaccines combine to make this an ideal time for CIHR-III to launch its strategic research priority. The new-found enthusiasm must be maintained, however, and many individuals, organizations and countries will have to work together to succeed.

Next steps

CIHR-III will use this report – which will be distributed to stakeholders in vaccine research and development and immunization – to develop an action plan and build partnerships for the Vaccines of the 21st Century strategic priority. The goals of the priority are to help to coordinate research efforts, foster linkages, facilitate vaccine research and development and support the transfer of research knowledge to governments, health-care providers and the public.

These activities will take vaccine research and development in Canada to the next level, and ultimately, improve health and well-being in Canada and around the world.


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About This Report

The purpose of this report is to help CIHR-III plan a strategic initiative for Vaccines of the 21st Century, one of five priorities in its Strategic Plan for 2007-2012. The broad nature of this report, however, also makes it useful for policy makers, organizations that support research and development, members of the vaccine research community and all who are interested in and benefit from vaccines and immunization programs.

This report provides an overview of vaccine-related research and development in Canada, and is based on surveys of researchers and representatives from vaccine-related organizations and funding agencies. The strength of Canadian research is showcased in a summary of research activities and recent accomplishments. Current challenges in vaccine research and development and in immunization are discussed, along with recommendations on how these can be addressed and overcome. Recent and anticipated investments in research by funding agencies are also summarized. The background section provides an overview of vaccines, the steps in vaccine research and development and reasons for the renewed interest in vaccines.


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Background

Vaccines Overview

Over the past century, vaccination has saved more lives than any other health-care intervention. Its effectiveness and low cost have made it essential to maintaining public health. Smallpox has been eradicated, and the suffering and death caused by over 30 other infectious diseases, including typhoid, diphtheria, polio, measles, mumps, rubella, hepatitis A, hepatitis B, pneumococcus, meningococcal disease and tetanus has been drastically reduced.

A vaccination stimulates the immune system with a particular agent (e.g. bacterium, virus, toxin) causing it to develop immunological memory. Anything that stimulates an immune response, whether naturally or via vaccination is called an antigen. Vaccinated individuals produce a much stronger immune response if they encounter the agent again and will have a much lower chance, if any, of developing disease.

There are two main types of immune responses: cell-mediated, in which specific cells called cytotoxic T cells attack cells in the body that have become infected, and humoral, in which the body develops antibodies that neutralize and help eliminate antigens in the blood, on epithelial surfaces and in the fluid that bathes tissues.

Several classes of vaccines exist. In some cases, bacteria or viruses are heat-inactivated or killed with chemicals (inactivated vaccines) or grown in cell culture (attenuated vaccines) in order to disable their virulent properties. In other cases, only the toxin produced by a bacterium or a protein portion of an agent (subunit vaccines) is used in the vaccine. Sometimes a subunit is attached to a toxin (conjugate vaccines) in order to evoke a stronger immune response. Vaccines usually contain adjuvants such as aluminum salts or oil and water emulsions. These enhance the immune response or elicit a specific type of immune response, either cell-mediated or humoral. Newer approaches use DNA or RNA coding for a component of the agent in the vaccine. The DNA or RNA can be transferred using a viral vector in which a non-pathogenic form of a virus is used.

Vaccines are generally administered via injection or are taken orally, and sometimes boosters are needed to develop and maintain immunological memory. Vaccines can be preventative (prevent occurrence of disease) or therapeutic (administered after infection or disease onset to enhance natural immunity).

Steps in Vaccine Research and Development

Vaccine research and development is a continuum from basic research to clinical trials (Figure 1). The research begins with the identification of an infectious agent or disease. Methods to detect the agent are needed to understand the causes and transmission of the disease and for subsequent clinical vaccine trials. An understanding of the agent's biology and how it infects and causes pathogenesis is useful in identifying candidate antigens. In addition, understanding the types of immune responses that confer protection against infection is useful for formulating an effective vaccine and for subsequent clinical vaccine trials.

Once antigens have been chosen, methods to formulate and deliver the vaccine are developed and tested in animal models. Vaccines produced for human trials must be manufactured according to good manufacturing practices (GMP). Human clinical testing involves four phases. Phase I trials examine safety of the vaccine in a small number (20-100) of healthy individuals. Phase II trials examine safety and immunogenicity (the ability to stimulate the immune system) in a larger number of individuals (100-300). In Phase III trials, the vaccine is administered to many individuals (2,000-10,000) and information about safety and immunogenicity is gathered. If the candidate vaccine is deemed effective in Phase III clinical trials, then an application for licensure is submitted to regulatory bodies such as Health Canada (HC) and the Federal Drug Administration (FDA). Post-licensure trials (i.e. vaccine evaluation) are often performed to assess long-term vaccine effectiveness, as well as the health, social and economic effects of the vaccine.

Basic Science

Figure 1: The vaccine research and development continuum. Modified from figures from SARS Accelerated Vaccine Initiative (SAVI) website and CIHR website.

Reasons for Renewed Interest and the Need to Support Vaccine Research

Only five multinational companies currently develop and manufacture most of the vaccines used today, down from the approximately 30 companies that existed about 35 years ago. The decline stems from the introduction of GMP for vaccine production in the 1980s, which substantially increased production costs, and traditionally low profit margins because governments are bulk purchasers of vaccines. The threat of liability lawsuits has also played a role. Interest in vaccines, however, has been renewed over the past few years for the following reasons:

Antibiotic resistance and lack of new antibiotics
Microorganisms including bacteria develop resistance to antibiotics over time. Over the past five to ten years, there has been a decline in the development and approval of new antibiotics. Alternatives for antibiotics, such as vaccines, are urgently needed.

There are several major infectious diseases for which vaccines are still needed
There are no vaccines for several major infectious diseases, including HIV, hepatitis C and malaria. These diseases have devastating effects on health, the economy and society. Vaccines would be an effective and relatively low-cost method to combat these diseases.

Emerging infectious diseases and potential threats such as pandemic influenza
The emergence of SARS and its rapid spread between countries via global travel heightened awareness of the potential threat of emerging diseases. In addition, many experts agree that the next influenza pandemic is overdue, and recent human deaths caused by a highly pathogenic strain of avian influenza have intensified concerns.

Bioterrorism threat
Increased concern over potential bioterrorism attacks has led to renewed government support for research and the development of methods to counter biological agents that threaten national security and public safety.

Newer uses for vaccines
Vaccines are now being developed and marketed to prevent and treat cancer. Preventative vaccines include vaccines against hepatitis B to prevent liver cancer and vaccines against HPV to prevent cervical cancer. Many therapeutic cancer vaccines are being developed, including one for the treatment of kidney cancer that received Russian approval in April 2008. These vaccines have opened a new avenue for research and development.

Renewed interest in global health
Private philanthropic organizations such as the Bill and Melinda Gates Foundation have targeted malaria, tuberculosis, HIV and other vaccine-preventable and infectious diseases for investment. As a result, more researchers have made these areas a focus of their research.

Need to maintain capacity to develop, manufacture and test vaccines in Canada
Given the potential threats and opportunities for new vaccine therapies, there is a renewed drive for Canada to maintain and enhance capacity to develop, manufacture and test vaccines in order to optimally protect and treat its citizens.


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Data Collection Methods

This report was researched and written by Dr. Michelle French, Scientific Communication. Information was gathered in three phases. In the first phase, over 20 phone interviews were conducted with key representatives from vaccine-related organizations with a broad range of expertise (Appendix 1). See Appendix 2 for the interview questions. In the second phase, approximately 240 researchers engaged in vaccine-related research were asked via e-mail to complete a web-based survey (see Appendix 3 for survey questions). For the final stage, over 40 representatives from funding agencies (Appendix 4) were contacted via e-mail and asked to complete a questionnaire (Appendix 5). All questions and lists were prepared in consultation with the CIHR-III Advisory Board Sub-Committee on Vaccines of the 21st Century (IAB Sub-Committee, Appendix 6).

A draft of this report was circulated to all individuals who were originally contacted. Errors and omissions that were identified were corrected in the final version. While attempts were made to collect data from as many organizations and researchers as possible, some research and information will have been omitted because researchers declined to participate or could not be contacted via e-mail. The report contains as many comments and suggestions as possible from those who participated.

The report includes vaccine and related immunization research programs, but excludes immunotherapy such as passive immunization with antibodies.

The views expressed herein do not necessarily represent those of all respondents, CIHR-III, or the report writer (Michelle French). Most of the data was collected by the end of February 2008.


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Survey Results

Vaccine-Related Organizations in Canada

There are a number of organizations in Canada that are engaged in vaccine-related activities from basic research through to the implementation and evaluation of immunization programs. See Table 1 for a list of the organizations and their main vaccine-related activities. Further details including the current activities of each organization and their international linkages are described in Appendix 7. Information for this section came from responses by representatives of vaccine-related organizations who were asked to briefly describe the vaccine-related research programs of their organization.

Basic research (e.g. microbiology, immunology, vaccinology) is conducted at universities and research institutes, government organizations and in the private sector. Clinical trials are conducted by vaccine manufacturers and by teams at vaccine evaluation centres in Vancouver, Montreal, Quebec City and Halifax. Once vaccines have been approved for use, organizations such as the National Advisory Committee on Immunization (NACI) make recommendations to provinces and health-care workers regarding immunization programs and protocols. Most of the research performed at universities and research institutes is included elsewhere in this report (see "Selected key accomplishments").

Table 1: Vaccine and immunization organizations in Canada and their vaccine-related activities

Organization Vaccine-related activities
BIOTECanada Consists of representatives from small and medium size enterprises (biotech) and core multinational companies, including vaccine developers and producers. Represents industry to government.
Canadian Association of Immunization Research and Evaluation (CAIRE) An association of over 100 vaccine-orientated researchers. Many engage in evaluating new vaccines, building the rationale for new public programs and optimizing public immunization programs.
Canadian Centre for Vaccinology/Clinical Trials Research Center, Dalhousie University Includes scientists and experts in diverse fields who conduct research programs to develop, evaluate and generate new vaccines and vaccine technologies.
Canadian Coalition for Immunization Awareness and Promotion A partnership of national non-governmental, professional, health, consumer, government and private sector organizations with a specific interest in promoting the understanding and use of vaccines amongst health-care providers and the public.
Canadian Food Inspection Agency (CFIA) Dedicated to safeguarding food, animals and plants in Canada. This includes supporting vaccine research and animal vaccination, which prevents the spread of disease to humans.
Canadian HIV Vaccine Initiative (CHVI) A partnership between the Canadian International Development Agency (CIDA), PHAC, Industry Canada, CIHR and Health Canada (HC) with the goal to develop a safe, effective, affordable and globally accessible HIV vaccine. Canada's contribution to the Global HIV Vaccine Enterprise.
Canadian HIV Trials Network (CTN) A partnership of clinical investigators, physicians, nurses, people living with HIV/AIDS, pharmaceutical manufacturers and others that facilitate HIV/AIDS clinical trials including vaccine trials.
Canadian Immunization Committee (CIC) A group of provincial, territorial and federal immunization organizations that guide the implementation of a national immunization strategy.
Canadian Pediatric Society An association of pediatricians involved in professional and public education, advocacy, surveillance and research. Monitors infectious diseases in children that are vaccine preventable and records adverse events following immunization.
Centre for Immunization and Respiratory Infectious Diseases, PHAC Collaborates with the provinces and territories, other federal departments, and others to prevent, reduce or eliminate vaccine-preventable and infectious respiratory diseases; reduce the negative impact of respiratory infections; and maintain public and professional confidence in immunization programs.
Defence Research and Development Canada, Department of National Defense Performs research and develops technology for national security. Includes research on and acquisition of vaccines against organisms that could be used in biological warfare.
GlaxoSmithKline Inc. A global pharmaceutical company involved in vaccine research, development and manufacture in Canada. This includes clinical research on new vaccine products and epidemiological research on the burden of disease. Canada's annual influenza vaccine supplier.
McMaster Centre for Gene Therapeutics Conducts research and develops gene- and cell-based vaccines for therapeutic intervention in cancer and infectious diseases. Primary interest in vaccines to provide mucosal immunity. Established in 1998, provides the infrastructure for cell-based cancer vaccine trials in Canada.
Merck Frosst Canada Ltd A global pharmaceutical company involved in vaccine research, development and manufacture. In Canada, performs clinical trials (mostly Phase III, some Phase I/II). Committed to working with academic and clinical researchers in collaborative projects concerning vaccine-preventable diseases in order to assist Canadian decision makers (i.e. epidemiologic research, outcomes research).
National Advisory Committee on Immunization (NACI) Consists of recognized experts in the fields of pediatrics, infectious diseases, immunology, medical microbiology, internal medicine and public health. Makes recommendations for the use of vaccines currently or newly approved for use in humans in Canada.
National Research Council of Canada (NRC) Institute for Biological Sciences Engaged in research focused on infectious diseases, cancer vaccines, immunotherapeutics and neurodegenerative diseases. About 60% of the research is directed towards discovery of new vaccine strategies.
PHAC National Microbiology Laboratory Performs reference microbiology and surveillance, support to epidemiology programs and conducts applied and discovery research including research for vaccines against pathogenic viruses and bacteria.
sanofi pasteur A global pharmaceutical company involved in vaccine research, development and manufacture. In Canada, conducts basic research, epidemiological studies and clinical trials. Also, develops and manufactures vaccines.
UBC Centre for Disease Control Performs vaccine research from antigen discovery to pre-clinical studies, as well as the evaluation of the impact of vaccines.
Vaccine and Infectious Disease Organization (VIDO) Conducts research and develops vaccine and immunity enhancing technologies for humans and animals. Works to ensure that discoveries are commercialized.
Vaccine Evaluation Centre, BC Children's Hospital Conducts research to determine vaccine safety and effectiveness; evaluates new vaccines; studies vaccine preventable infections and enhances public immunization programs. Was established in 1988, making it the first formal centre for independent vaccine research in Canada.
Vaccine Industry Committee (VIC) A sub-committee of BIOTECanada consisting of industry representatives with a focus to create a vaccine environment conducive to the goals of public health and manufacturers.
Wyeth Canada Wyeth is a global pharmaceutical company that is involved in vaccine research, development and manufacture. Wyeth Canada performs Phase I-III clinical trials.

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Selected Key Accomplishments

Canadian researchers working in universities, research institutes, government organizations, industry and clinical settings have made many significant contributions to the field of vaccine research and development. The information for this section was selected from responses made by representatives from vaccine-related organizations and individual researchers.

Representatives from vaccine-related organizations were asked:

  • What are the major accomplishments that your organization has made in the area of vaccines and immunization programs over the past five years?
  • What are the anticipated or realized impacts of the research accomplishments of your organization?

Individual researchers were asked to:

  • Summarize your top one to three research projects/accomplishments from the past five years.

Selected key accomplishments are described below. See Appendix 8 for a summary of all key accomplishments described by representatives from vaccine-related organizations and Appendix 9 for a summary of all key accomplishments described by individual researchers.

Development of an acellular pertussis vaccine: From basic research to manufacture
In the late 1990s, sanofi pasteur marketed the first acellular pertussis vaccine in the world. It was researched, developed and is manufactured in Canada. The vaccine contains purified antigenic components of the bacterium Bordetella pertussis. In addition to protecting against whooping cough, it has other antigens that afford protection against diphtheria, tetanus, polio and Haemophilus influenzae type B.

The acellular vaccine (PentacelTM) replaced whole-cell pertussis vaccines introduced in the 1940s. Although the older vaccines drastically reduced the incidence of pertussis infections, frequent local and systemic reactions, which were occasionally severe, were reported. As well, small outbreaks occurred every three to five years because some individuals were not protected. The acellular vaccine is safer and more effective than the whole-cell vaccine, has virtually prevented small outbreaks of whooping cough in children over the age of two months and all but eliminated Haemophilus influenzae type B infections.

Dr. Scott Halperin at the Canadian Center for Vaccinology at Dalhousie University and his team participated in the clinical trials associated with the licensure of the vaccine. The vaccine is now licensed in 52 countries around the world, including the United States and the United Kingdom.

Development of vaccine technology against Neisseria meningitidis type C
Led by Dr. Harold Jennings, a team of scientists at the NRC developed an innovative technology that attaches a polysaccharide from the bacterium Neisseria meningitidis group C to a non-toxic form of tetanus toxoid. Neisseria meningitidis group C causes meningitis. A few years ago, approximately 10% of Canadians (many under the age of 5) who contracted meningitis died, while those that survived suffered serious health complications such as deafness or permanent brain damage.

The NRC technology was licensed to Baxter Healthcare Corporation who used it to develop a vaccine called NeisVac-CTM. The vaccine replaced previous vaccines that were not very effective in children. NeisVac-CTM was one of three conjugate vaccines that were used in the United Kingdom in the late 1990s to combat meningococcal disease, which at that time was the number one killer of children between the ages of one to five. The vaccines helped to reduce the incidence of disease by about 75%, avoiding an estimated 500 cases and 50 deaths in a two-year period. The vaccine was approved for use in Canada in 2002, where it is manufactured by GlaxoSmithKline Inc.

Preparing for and assessing the impact of HPV immunization in Canada
In July 2006, Merck's quadrivalent recombinant vaccine (GardasilTM), which protects against HPV types 6, 11, 16 and 18, was approved for use in Canada. It is the first HPV vaccine to be licensed for use. HPV types 16 and 18 cause 70% of all cervical cancers and types 6 and 11 cause ano-genital warts.

In 2005, to prepare for the anticipated Canadian approval of vaccines for HPV, PHAC and CAIRE, in partnership with CIHR, held a Canadian HPV Vaccine Research Priorities Workshop, which brought together over 50 Canadian and international HPV experts and researchers from the areas of vaccines, cancer and sexually transmitted diseases to develop national research priorities and identify infrastructure gaps.

One of the areas identified was program delivery research. To address this priority and assess the potential impact of immunization programs, Dr. Babak Pourbohloul at the UBC Centre for Disease Control and Dr. Marc Brisson at Université Laval worked independently to develop mathematical models of HPV transmission and the impact of HPV immunization. The model outcomes helped policy makers make decisions regarding implementation of HPV immunization programs in Canada.

GlaxoSmithKline has developed a bivalent recombinant HPV vaccine to protect against HPV types 16 and 18. It is in the final stages of review at the FDA. Dr. Eduardo Franco at McGill University assisted GlaxoSmithKline during the clinical development phase of the vaccine by co-leading a randomized control clinical trial. His research, which demonstrated the efficacy of the vaccine, was selected by The Lancet medical journal as among the most important contributions in medicine in 2006.

Assessment of and new recommendations for influenza immunization programs
Annual epidemics of influenza continue to cause worldwide morbidity, mortality and societal disruption. In October 2000, Ontario initiated the world's first large-scale universal influenza immunization program to provide free influenza vaccinations for the entire population six months of age or older. Dr. Jeff Kwong and his research team at the Institute for Clinical Evaluative Sciences evaluated this program and found decreases in influenza-associated mortality, health-care use (hospitalizations and visits to emergency departments and physician offices), and antibiotic prescriptions relative to other provinces. The results will assist policy makers to develop recommendations for the implementation of influenza immunization programs.

Research results generated by Dr. Noni Macdonald and her team at the Canadian Centre for Vaccinology, Dalhousie University were the basis of a change in policy by NACI who, in 2007, recommended that all pregnant women receive influenza vaccines. The team performed a large study on pregnant women using administrative databases to determine risk of hospitalization and/or physician visit for respiratory illness during the flu season versus risk in the flu season prior to pregancy. The researchers found that there was a significant increase in risk of serious illness caused by influenza in pregnant women especially in the third trimester.

Development of candidate SARS vaccines
SARS was a new respiratory disease that emerged in China at the end of 2002 and quickly spread to several countries, including Canada. Worldwide, about 8000 people were infected with SARS and 800 people died during the outbreak. An early research success by Canadian clinicians and scientists was the sequencing of the SARS virus. Building on this knowledge, Dr. Brett Finlay and Dr. Robert Brunham at the UBC Centre for Disease Control co-directed the SARS Accelerated Vaccine Initiative to rapidly develop SARS vaccines. The initiative consisted of a group of over 40 scientists, including researchers at UBC, VIDO and McMaster University. Within six months, the team developed three prototype vaccines using whole killed virus, adenovirus expressing SARS spike protein and recombinant spike protein. Fortunately, human transmission of SARS was halted in July 2003 due to a massive public health effort and further development of the vaccines has not been necessary. The experience, however, allowed the researchers to develop a new way of doing rapid response vaccine development science. If SARS reappears, the vaccines will be developed further.

Development of vaccines against hemorrhagic fevers
In 2005, Dr. Heinz Feldmann and Dr. Steven Jones from the PHAC National Microbiology Laboratory, in collaboration with Dr. Thomas Geisbert from the U.S. Army Medical Research Institute of Infectious Diseases, announced that they had developed vaccines against Ebola and Marburg viruses that had proven 100% effective in protecting monkeys from these often deadly viruses. The viruses are potential public health and bioterrorism threats. The vaccines are based on attenuated recombinant vesicular stromatitis virus vectors expressing either Ebola or Marburg glycoproteins. Pre-clinical trials of these vaccines are underway. Once fully developed, vaccines against these viruses will help stop outbreaks where they originate and reduce the risk of disease spread in the event of a bioterrorism attack.

Development and licensure of a cattle vaccine against Escherichia coli O157:H7
The transmission of disease from animals to humans has become a major source of infection in Canada, particularly in high-risk populations. Presently, there are few methods for the control of these diseases. Vaccination of both animal and human populations would have a significant impact on environmental safety (i.e. Walkerton-type outbreaks), foodborne illness and travellers' diarrhea. A major goal of the research conducted by Dr. Andrew Potter and his research team at VIDO is to produce a comprehensive family of vaccines for these types of pathogens that can be used in animals, to lessen the environmental load of these organisms, and in humans, to prevent disease in high-risk populations. To illustrate, the team, in collaboration with Dr. Brett Finlay at UBC, developed a vaccine for Escherichia coli O157:H7. The technology has been transferred to the private sector for commercialization. It is anticipated that the Escherichia coli O157:H7 vaccine will be in widespread veterinary use in Canada within two years.

Research and development of vaccine adjuvants
Adjuvants are critical components of vaccines: they enhance the immune response to an antigen and have a role in triggering specific types of immune responses. Researchers at GlaxoSmithKline have spent more than 20 years developing adjuvants that will evoke the required type of immune response to a particular antigen. For example, they tested three different adjuvants for their malaria vaccine, which is in clinical trials. They have also developed new adjuvants for pandemic influenza vaccines. A new adjuvant is also being used in their HPV vaccine that is in the final stages of review at the FDA.

In Canada, several individual researchers have also been engaged in developing new adjuvants. For example, Dr. Denis Leclerc at Université Laval has improved the intrinsic adjuvant properties of papaya mosaic virus-like particles to develop a novel vaccine platform that can trigger both arms of the immune system: cell-mediated and humoral. He and his research team are currently planning to bring the adjuvant into Phase I trials in humans. They believe that, when fully developed, the new system could be used to make a universal influenza vaccine and aid in the development of vaccines that trigger strong cell-mediated immune responses, which will be needed in vaccines for hepatitis C, HIV and cancer.

Dr. Girish B. Patel and colleagues at the NRC have developed an adjuvant and mucosal delivery system using archaeal polar lipids. The system is efficient at eliciting long-lasting mucosal and systemic immune responses upon intranasal vaccination in mice. The technology is being evaluated for applications in human and veterinary vaccines.

Therapeutic cancer vaccines
The first therapeutic vaccine to treat human cancer received Russian approval in April 2008 when the American biotechnology company Antigenics was permitted to market Oncophage for the treatment of kidney cancer. All of the vaccine companies interviewed for this report were developing therapeutic cancer vaccines, and many vaccines are in clinical trials, some at the Phase III stage. In Canada, sanofi pasteur has a cancer vaccine research program that focuses on melanoma and colorectal cancer, and efforts are also being directed at breast cancer. Vaccines that the company has developed employing modified canary pox viral vectors (ALVAC) to deliver tumour antigens or other immunomodulatory molecules are currently in Phase II clinical trials in Canada and elsewhere.

Individual researchers in Canada are also conducting studies to develop therapeutic cancer vaccines. Dr. Jonathan Bramson at McMaster University is developing recombinant adenovirus vaccines that are highly efficient at evoking immunity against cancer antigens in mice. He and his research team are also developing vaccines with dendritic cells (a type of immune cell that stimulates immune responses). The dendritic cells are removed from mice, genetically modified to express tumour cell antigens and then transferred into mice. This approach elicits helper T cell immunity (needed for both cell-mediated and humoral immune responses) and stimulates a unique population of anti-tumour natural killer cells. Given the success of dendritic cell vaccines in pre-clinical models, Dr. Bramson has been working with colleagues at McMaster University (Drs. Yonghong Wan, Ronan Foley, Bindi Dhesy, Graeme Fraser and Mark Levine) to evaluate dendritic cell vaccines in early phase human trials. The group has successfully completed a Phase I/IIa trial for melanoma demonstrating the feasibility of this approach and is in the midst of a similar trial for breast cancer.


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Research Strengths

The accomplishments described in this report identify current research strengths in Canada. There is a great deal of strength in early discovery research, especially in the areas of identifying the best antigens to be used in vaccines against infectious agents and for cancer therapy; discovering and developing novel adjuvants and methods for antigen delivery; and in studying the immune system in order to evoke specific types of immune responses and to develop assays to examine immune responses to vaccination. There is also strength in the areas of epidemiology, vaccines for special populations and vaccine evaluation. Approximately 25 infectious agents or diseases were targeted in the accomplishments described. The most common ones were: influenza, therapeutic cancer vaccines, HPV and HIV. In the case of influenza, HPV and HIV, accomplishments included basic science discoveries, epidemiological findings, development of mathematical models and vaccine evaluation.


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Vaccine-Related Challenges and Recommendations

The purpose of this section is to outline vaccine-related challenges in Canada and to provide suggestions on how CIHR-III, its partners and others can address and overcome these challenges. The information is based on the responses made by representatives from vaccine-related organizations, individual researchers and representatives of funding organizations to the following questions:

Representatives from vaccine-related organizations were asked:

  • What vaccine-related scientific challenges require attention in Canada?
  • How can CIHR-III help to facilitate vaccine-related research in your organization or in general within existing programs?
  • How can CIHR-III help in translating your organization's research accomplishments into new products or health services so that they are utilized to their fullest potential?

Individual researchers were asked:

  • How can CIHR-III facilitate/support you to be more successful and capitalize on existing opportunities?

Representatives from funding organizations were asked:

  • What vaccine-related scientific challenges require attention in Canada?
  • How can CIHR-III help in translating vaccine research accomplishments into new products or health services so that they are utilized to their fullest potential?

The answers have been compiled and categorized. Because many of the recommendations relate directly to the identified challenges, both are presented together. The challenges and recommendations are ordered to follow the chronology of the vaccine research and development continuum (Figure 1), with research planning and basic research challenges listed before vaccine development and clinical trial challenges. Challenges not directly related to research, and recommendations that do not match a specific challenge are described last. The number of respondents, who made a comment related to the challenge or recommendation, is shown in brackets. (Note that the numbers do not match because challenges and recommendations were described in answers to separate questions.)

Challenge: Research efforts need to be better coordinated (9 respondents)

There are a number of excellent vaccine researchers and specialists in Canada in a number of organizations, but their efforts are fragmented and there is a general lack of communication among different groups. The 2005 decision not to renew funding of the Canadian Network for Vaccines and Immunotherapeutics (CANVAC), a Network of Centres of Excellence that included 75 researchers, contributed to this fragmentation. It eliminated a mechanism for researchers to share ideas and establish collaborations. Related to the need to coordinate research efforts, is a need to identify research priorities for the next five to eight years.

The United States does vaccine research and development well. Basic science research is performed at the National Institutes of Health (NIH), and vaccine trials are then undertaken at associated vaccine trials units and vaccine evaluation centres. Also, the Centers for Disease Control and Prevention (CDC) perform research on the epidemiology of infectious disease and vaccine effectiveness, which supports vaccine research and development.

Recommendation: Organize and facilitate vaccine research workshops and facilitate communication (13 respondents)
CIHR and partners should organize and facilitate workshops to help vaccine researchers and stakeholders identify gaps and set vaccine research priorities, foster cross-disciplinary collaboration and help develop research programs. The workshop for the Safe Food and Water Initiative that was organized by CIHR and partners could serve as a model. That event, which respondents described as a tremendous success, brought together individuals from many areas.

A vaccine research workshop should include basic scientists (microbiologists, immunologists, vaccinologists, etc.), industry representatives, public health experts, clinicians, nurses, members of the National Advisory Committee on Immunization and government representatives. The expanding use of vaccines to prevent and treat diseases such as cancer means that there is a need to include organizations and individuals with expertise in relevant fields in the workshops and discussions.

CIHR and partners should also provide opportunities for knowledge sharing during the research process. Showcasing researchers and their results in this manner would allow stakeholders such as industry and other end users to learn about the research that CIHR and other organizations are funding and help them identify Canadians who can provide scientific guidance in specific areas. Having a database that documents the expertise of Canadian researchers/physicians and their research output would also facilitate the communication of preliminary research results to interested stakeholders.

Recommendation: Foster linkages between all stakeholders (8 respondents)
To coordinate research efforts, CIHR and partners should foster linkages among national and international researchers, public health organizations, industry, end users, decision makers, funding organizations and international research-related organizations. For example, groups such as CIHR, PHAC, HC, industry and others could work together to identify sources of infection and morbidity and determine the best approach to deal with each disease or potential threat. This could take the form of a collaborative consortium modeled on the Canadian HIV Vaccine Initiative, which includes CIHR, PHAC, HC and industry. The CIHR/PHAC collaboration on influenza pandemic preparedness has worked well and could also be used as a model of best practices on how to establish collaborations. One respondent mentioned that he would like to see the Canadian Vaccine Initiative revived and developed further.

There should be continued support for research collaborations between academia and industry including support for clinical trials. Industry should be involved in early-stage discussions regarding vaccine research priorities and needs. One participant suggested that high-level discussions between the Scientific Directors of CIHR-III and CIHR Institute of Population and Public Health and a public sector consortium might foster collaborations with academia and industry.

Recommendation: Establish a vaccine research network (3 respondents)
Respondents suggested that a network of centres of excellence for vaccine research and development should be established. This could be accomplished informally by providing funds for researchers in complementary areas to get together to discuss a project. If the project is large, it will require a project manager/coordinator.

A more formal, integrated, vaccine research centre with a full spectrum of research encompassing basic science, clinical, and population and public health research, as well as Phase I-III clinical trials would be ideal. Current key players, such as the vaccine evaluation centres in Halifax, Quebec City, Montreal and Vancouver, the PHAC National Microbiology Laboratory and VIDO, could be brought together to drive the initiative. The centre would have two mandates: discovery and translation.

Challenge: Vaccine research and development is costly (4 respondents)

It costs $750 million to $1 billion to develop a vaccine. Even early-stage research, which is performed by both academic and industry researchers, requires millions of dollars and must be sustained for longer than the typical research grant of three to five years.

The vaccine business is highly competitive: companies are concerned about funding, purchasing, vaccine development and approval times and costs. The multinational nature of the companies means that the needs of individual countries, which are considered a small part of the market, may be ignored. As well, Canadian vaccine prices traditionally have been the lowest in the world because of bulk purchases, so there is less incentive to sell to Canada. On the whole, specific vaccines are developed by companies based on the potential market for the vaccine and projected profits. As a result, Canadian priorities are often no longer considered.

Companies need incentives to do early development work and clinical trials in Canada. Scientific Research and Experimental Development (SR & ED) tax credits help, but they are insufficient. In many cases, a push from others outside of industry is needed. For example, with emerging diseases such as SARS, companies might be reluctant to develop a robust research and development program for a vaccine because of market uncertainty. Similarly, vaccines for the developing world have a greater chance of being developed if there is collaboration in the early stages with government, funding organizations and industry.

Recommendation: Create partnerships with funding organizations, industry, academic institutions and government to drive vaccine research and development
CIHR has funded and facilitated the development of networks, including the Canadian HIV Trials Network, to support research including clinical studies. CIHR and others should continue to establish partnerships with funding organizations, industry, academic institutions and government to drive vaccine research and development in order to meet the needs of Canadians. For example, CIHR could champion vaccine research and development within the context of broader science and technology initiatives or international development activities supported by the Government of Canada. CIHR should also consider partnering with provincial health research agencies to support a coordinated research agenda. Internationally, there has been renewed interest in vaccine research and development. International initiatives have been useful in helping to leverage funds from national sources. For example, it is unlikely that the Canadian HIV Vaccine Initiative would have been established without support from the Bill and Melinda Gates Foundation. Governments should commit funds before international visits and partnerships are established. In addition, information about the existing networks and how they could contribute to the clinical evaluation of promising vaccine strategies developed in Canada would be of tremendous help to many investigators currently developing new vaccines.

All of these partnering activities would provide funds and encourage academic researchers and industry to focus their research activities. This will ultimately lead to the development of new vaccines and technologies for Canada and the rest of the world.

Challenge: There are still several major diseases for which there are currently no vaccines (8 respondents)

The vaccines developed in the last century were generally relatively easy to make. The tough ones remain. Respondents identified the following infectious agents and diseases for which vaccines are needed (the number in brackets indicates the number of times the infectious agent or disease was mentioned): West Nile virus (4), methicillin-resistant Staphylococcus aureus (3), HIV (3), hepatitis C (2), cancer (2), avian influenza (2), meningococcal group B (2), respiratory syncytial virus (1), equine encephalitis (1), plague (1), tuberculosis (1), SARS (1), dengue (1) and prions (1). Knowledge about host/pathogen relationships, human immunology and the epidemiology of these and other emerging infectious diseases is needed to develop vaccines.

There is also a need to develop appropriate animal models to test vaccines, and for research on animal reservoirs and vector competencies. Directing research attention to the animal/human interface, and the development of animal vaccines and methods to decrease the populations of vectors such as insects, arthropods and ticks would help to prevent the spread of disease to humans.

Challenge: Improved methods to formulate and deliver vaccines are needed (3 respondents)

Vaccine formulation and delivery are key challenges. For example, research is needed to develop methods to spare antigen, stimulate different types of immunity (e.g. mucosal immunity), vaccinate special populations (e.g. newborns and the elderly) and deliver antigens (e.g. intranasal vaccines, microparticles or skin patches). Newborns are especially important because infants and children receive the majority of routinely administered vaccines. Technologies that are low-cost or make vaccines easier to deliver would be of great benefit in the developing world.

Methods to modulate the immune response to a vaccine, such as the development of new adjuvants, are also needed. Better ways to determine the correlates of protection would be useful for early vaccine development and clinical trials. Surrogate markers of protection are needed when clinical efficacy studies cannot be performed because of the highly pathogenic nature of the infectious agent.

The pain associated with immunization contributes to a negative experience and poor compliance. There is a scarcity of clinical trials on the pain caused from vaccines and modulating impact of different formulations and local anaesthetics. There is also a lack of knowledge on how the physical environment (setting) effects pain felt during immunization and minimal knowledge on pain management in the hours to days post vaccination. Also, national pain management guidelines and educational materials are needed to ensure that vaccines are administered with minimal pain.

Recommendation: Continue to support basic research (6 respondents)
CIHR must continue to support basic research, especially in the areas of microbiology, immunology and vaccinology. Research on pathogens is essential because it identifies critical biological pathways that can be targeted by vaccines. Research on immunology will help to identify ways to modulate the immune system and also provide the basis of technologies to assess correlates of protection. The development of animal models is often suited to academic researchers who examine specific diseases. The research should also include studies on human immune responses to infection. One respondent suggested that vaccine research be included in the recent funding opportunities on immunotherapy with a focus on adjuvants, which are now recognized to be as important as the antigen in vaccines. For example, a systems biology approach could be used to understand how adjuvants successfully modify the immune response during vaccination. Research is also needed to determine the optimal ways to manage pain during immunization and on how to communicate the results to health-care professionals so that the new research knowledge is applied in the clinical setting. One respondent stated that CIHR should focus on basic research and leave most translational research to voluntary health agencies and to provincial research agencies.

Recommendation: Develop and support strategic vaccine research initiatives (4 respondents)
Respondents were pleased that CIHR-III has made vaccines part of its strategic plan because funding for vaccine research has been underrepresented. One respondent suggested that funds should be focused on two to three areas where Canada can be a world leader instead of funding small grants on a broader range of areas. Others thought that CIHR should introduce strategic funding opportunities to which industry could directly apply. Another thought that CIHR could use existing peer review panels, select highly ranked vaccine applications that missed the funding cut off and provide institute support (similar to the HIV/AIDS initiative) or facilitate partner support for these grants. Strategic initiatives from CIHR should focus on the large infrastructure required to support high quality vaccine research and perhaps provide infrastructure support for translational research groups in different provinces to meet for strategic planning. This could help reduce duplication of expensive translational infrastructure being created in different provinces.

Challenge: The public lacks accurate knowledge about the safety and efficacy of vaccines (7 respondents)

Public concern over vaccine safety has increased over the past ten to 15 years. Paradoxically, part of the problem has been the success of vaccines. Many parents today have never witnessed a major threat of infectious disease. This change in attitude and beliefs has happened in one generation. One of the participants stated that "My parents could not wait to line me up for the polio vaccine." Health-care professionals and public health experts need to do a better job at educating the public and, in some instances, other health-care providers about the safety and efficacy of vaccines. This is critical because, as one respondent stated, "We can have the best vaccines in the world, but they will remain on the shelf if people do not want them."

Recommendation: Support behavioural, social and ethics research (8 respondents)
CIHR and partners should support research that examines public perceptions concerning vaccines, and identifies the best methods to inform the public. The Canadian Immunization Guide produced by NACI is a highly technical, 300-page book. Research is needed to determine ways in which the information can be translated so that it is understandable and useful to health-care professionals. Funding opportunities should be developed and aimed at the dissemination of research results. As well, research that models the health and economic impact of vaccines, which is independent of vaccine companies, should be supported. Related to this, vaccine researchers require information to counter the accusations of vaccination critics that they are biased towards industry. This entails promoting the relevant scientific messages concerning the benefit and safety of vaccines and helping to dismiss the myths concerning side effects of vaccination. It also involves providing an ethical framework for researchers conducting vaccine studies. CIHR should provide organizations with funds so that the organizations can communicate information themselves.

Challenge: There is a gap between basic research and Phase I/II clinical trials (4 respondents)

Many academic researchers become stalled relatively early in vaccine development because they lack the resources, expertise, funds and, in some cases, the desire to take their discoveries through pre-clinical trials. For example, an individual researcher can take an antigen, put it in a delivery system and elicit a good immune response in mice, but where do they go from there? Road blocks arise because the vaccine must be produced under stringent GMP for human trials and regulatory approval must be sought. This is intimidating.

In terms of facilities, many researchers do not have access to biosafety level 3 (BSL 3) laboratories or GMP facilities. Although BSL 3 facilities exist, researchers must sometimes wait a year to get in. One respondent said that he had been denied access. Vaccines for emerging diseases and infectious agents, such as avian influenza, prions, SARS and West Nile virus, require researcher access to BSL 3 facilities and will likely require a multidisciplinary approach that involves both academic researchers and industry. As well, it is difficult for researchers to get access to non-human primates for studies.

Adding to these challenges, there is currently no funding mechanism for the later stages of vaccine development. The vaccines of the 21st century will be difficult to create and fiercely expensive due to the technical challenges and rigorous pre-licensure regulatory requirements. Currently researchers have to go to the US or elsewhere to ensure that their discoveries are commercialized. The loss of the immune monitoring facility created by CANVAC was also a big setback.

Recommendation: Partner with industry to bridge the gap between basic science and clinical trials (13 respondents)
If academic researchers could progress further through the vaccine research and development continuum and demonstrate the potential of their discoveries, there would be a greater chance that the research knowledge would be taken up by industry for vaccine development. This might be accomplished via strategic initiatives through industry. CIHR should allow industry to fund a strategic initiative, in order to get them more involved and facilitate vaccine development. Industry should be involved at the application phase because they know what is required in the later stages.

NRC does a good job in partnering with industry to get discoveries into the marketplace. NRC may be able to provide expertise to CIHR in this regard. One respondent stated that he would like to see consultation with end users and the private sector early in the research development stages. If industry is on board early and progress can be made more quickly, it is likely they will be motivated to continue the project. Another respondent said that there is expertise and facilities to do pre-clinical work in Canada, but researchers and industry have to work together to have an impact.

CIHR should also consider becoming involved in the pre-clinical stages of vaccine development. Traditionally, CIHR has directed its investment at the basic level, but has stopped long before a discovery gets to Phase I and II clinical trials.

Recommendation: Establish facilities and guidelines to allow researchers to take discoveries towards clinical trials (2 respondents)
A transitional facility should be established to take discoveries from the laboratory to pre-clinical trials. The facility should contain BSL 3 laboratories to test vaccines in animal models and have the equipment for making vaccines according to GMP. This would allow for the final stage of development of candidate vaccines including late-stage clinical trials. This approach would be more likely to attract investments, because the work will have been done according to GMP. The facilities could be part of a vaccine manufacturing research centre, which would attract industry.

Some trials need access to existing GMP vaccine production at BSL level 2. Limited availabilty exists (e.g. McMaster) for small-scale manufacture of clinical lots of vaccines for Phase I/II trials in Canada. Such facilities could be incorporated into a national approach thus avoiding duplication of existing efforts.

The NIH and FDA in the US have developed clear guidelines and procedures for the initiation of clinical trials and most vaccine Phase I clinical trials are conducted there. The development of clear guidelines as well as a central point to help move forward towards clinical evaluation of candidate vaccines in Canada would also greatly facilitate the emergence of novel vaccines and technologies.

Recommendation: Create new funding mechanisms to bridge the gap between basic science and clinical trials (2 respondents)
If CIHR were to increase funding for translational research, basic investigational research likely would be compromised – which is not acceptable. A separate funding envelope should be opened to support a competitive funding process aimed at translational investigations. In the case of cancer immunotherapies, for example, this could involve partnering with the National Cancer Institute of Canada (NCIC) and other interested parties. For these types of grants, researchers should be asked to provide a knowledge translation plan in the grant application that includes a detailed process for commercialization. This process should be clearly reflected in the budget, with requests for the necessary support. For example, necessary personnel to commercialize research may include: a technical expert with experience in developing products, someone to help with the patenting process and possibly someone with business expertise to manage the process.

Challenge: There are many clinical research questions that require public funding (5 respondents)

Many vaccine-related clinical research questions are of more interest to public health and governments than industry. Examples include:
  • Are fewer doses of a vaccine effective?
  • Why are there low coverage rates in certain groups?
  • Would it be possible to develop delivery methods that combine vaccines?
  • Why have there recently been so many cases of mumps among the vaccinated in Nova Scotia?
  • Which company has the best vaccine against a specific disease?
  • What is the best way to vaccinate special populations such as pregnant women, Aboriginals, people infected with HIV, the very young and the elderly?
  • What is the role of persistent exposure to naturally occurring infectious agents in maintaining immunity?
  • Are vaccines compatible and can products be interchanged?
  • What is the long-term effect of HPV vaccination on cervical cancer rates?

Public funding is needed to support research to answer these and other questions. The answers will help governments and others make informed decisions regarding the purchase of vaccines and delivery of immunization programs.

In addition, there is an assumption of capacity for vaccine evaluation in Canada, but each of the four main evaluation centres is economically fragile and living a day-to-day existence. The capacity could disappear overnight. For example, those developing pandemic influenza vaccines assume that evaluation centres will be available to evaluate the vaccines, but this is not a given. Program and safety evaluation research conducted independently from vaccine companies is likely to be better accepted by the public. This type of information is also needed by vaccine providers.

Another related difficulty is that clinical trials are discrete. Researchers cannot go onto the next one without ongoing funding. Stopping and starting means that teams have to be dismantled and then rehired.

Recommendation: Provide additional and ongoing support for pre-clinical and post-licensure vaccine trials (9 respondents)
CIHR should consider providing support for research that addresses the clinical questions outlined. As well, PHAC and provinces should join together to support this type of clinical research. In Quebec, for example, 1% of funds for immunization programs are directed towards specific clinical questions related to vaccines and immunization programs. This model works well and should be considered by other provinces. Ultimately, it is the government that buys vaccines and accurate information is needed to inform these decisions.

Since Canada has excellent health-care databases and good screening, agencies should facilitate use of the information for long-term, follow-up studies of vaccine efficacy. Vaccine evaluation centres should be provided with funds for operating expenses to ensure that clinical trial capacity is maintained. Canada should also foster development of clinical trial capacity in developing countries. For example, this would give them the capability of doing high quality clinical HIV vaccine trials.

CIHR (with PHAC) should consider the funding of a small number of "centres" for the in-depth evaluation of vaccine adverse events. Contingency funding should be available to address new allegations of adverse events quickly.

Additional challenges

Respondents identified additional vaccine-related challenges in Canada that are not specifically related to research, and therefore, fall outside the mandate of CIHR-III. These are listed below.

Up-to-date and standardized data on the epidemiology and burden of disease is often lacking (2 respondents)
There is a need to ensure that methods of detecting disease-causing agents are standardized across all public health laboratories and that the results are available to decision makers and industry in a timely manner. For example, the development of vaccines against meningococcus and pertussis require knowledge of the current, most prevalent serotypes, but there is a three-year lag in the reporting of this information. Up-to-date information should be provided via a high quality nation-wide immunization registry. The Manitoba/Quebec registry is excellent and could serve as a model.

It is increasingly difficult for industry to do clinical trials in Canada (3 respondents)
In the past, Canada was a large contributor to vaccine trials, but the number of trials has eroded because of the length of time to get ethics approval, prolonged times to recruit subjects and overhead costs. Instead, companies are turning to countries where trials will be of good quality, low cost, and can be performed quickly. Canada has the quality, but not the latter two criteria. For example, it took one company three to four months to enroll 600 patients for a vaccine trial in Canada. In contrast, 300-400 subjects were enrolled in one day in Poland because parents do not have access to universal vaccine programs and want their children vaccinated. One way to keep vaccine trials in Canada is to coordinate ethics boards for all sites (i.e. have a common protocol). This would allow trials to get started more quickly. It currently takes about eight weeks for ethics approval (in some universities it can take up to six months). Four weeks would be better. Timing is crucial for seasonal influenza. There should be a single place to go to for ethics approval for all academic networks in order to speed the process. We need to attract more clinical studies including global vaccine trials to Canada. To do this, we should emphasize the quality of our clinical research, the multi ethnicity of our inhabitants, our robust medical databases and universal health-care system.

Faster and more transparent vaccine approval is needed by industry (3 respondents)
Industry needs both good quality and timely review by regulators. The recommendations by NACI should be timely and grounded in research knowledge. Part of the problem is that regulatory groups are under-funded. As well, manufacturers need to know why an application was rejected, but usually they are not given any reasons for rejection. Approval is required from several bodies such as the Patented Medicine Prices Review Board, Common Drug Review and HC, and companies wonder whether this effort is worth the small market share. Industry representatives also would like to have better working relationships with public health agencies and decision makers, especially scientists and clinicians, so that industry can better explain the scientific reasons for recommended vaccine doses and schedules.

Canada must retain and develop its own vaccine production facilities (2 respondents)
We should not be at the mercy of other countries for our vaccine supply. The need for self-sufficiency will be critical in a time of crisis when countries will supply their own citizens with vaccines before shipping vaccines to another country. One way to accomplish this would be to create a critical mass of vaccine centres to attract vaccine companies and big pharmaceutical companies.

Immunization programs across the country need to be harmonized (6 respondents)
Several respondents stated that immunization programs across Canada are fragmented; each province and territory funds a different set of vaccines and has its own vaccine schedule and suggested population groups. A more harmonious structure is needed because the current approach is confusing and complicated. It also makes it difficult to immunize individuals who move from one region to another. It would be useful to develop a national funding platform for immunization programs. The National Immunization Strategy needs to be refreshed. NACI requires up-to-date information about the burden of disease. Its members should have special expertise, such as a high-level understanding of immunology, to make informed decisions regarding complex new vaccine technologies (e.g. new adjuvants). Related to this, efforts should be made to ensure equitable access to existing, under-utilized vaccines.

Additional recommendations
Respondents made two additional recommendations that were not directly linked to the vaccine-related challenges that they had identified. These are listed below.

Improve the grant application process, review and approval times (12 respondents)
CIHR should create a faster application and review process for grants so that research can be performed in a timely fashion. Some research questions, especially those of a clinical nature, require immediate answers. One respondent suggested that the grant application itself be streamlined and made more user-friendly. For example, it took her a long time to complete the common CV section. Another felt that there should be more flexibility with the current grant system, because it is difficult to get funds for research that falls under both CIHR and NSERC mandates. For example, researchers working on animal vaccines against E. coli 05187 have found it difficult to get money from either agency. One respondent suggested that CIHR set up a review panel with experts that understand all aspects of vaccine research including transitional research projects. He stated that the lack of expertise on current panels has been frustrating. Another asked that the review process be made more transparent and that better efforts be made to communicate priorities. Regarding specific programs, one respondent thought that the proof of principle program was useful for supporting translational research, but the amount of the grants and their duration should be increased to enhance researcher success. Respondents thought that the requirement to have application outlines approved in the CIHR clinical trials program should be removed because it adds at least six months to the grant approval time.

Train more vaccinologists and develop additional scientific and regulatory expertise (3 respondents)
CIHR has a good program to support training and should use it to train individuals in the areas of vaccinology, emerging diseases, wildlife management in relation to vectors of disease, and other areas relevant to vaccines and immunization programs. Many current vaccinologists are more that 50 years of age, so new researchers must be trained, and ways to retain older researchers should be considered. In this regard, partnerships with vaccine companies could be established to create additional endowed chairs and provide salary support for students, post-doctoral fellows and junior investigators. There is also a need to develop scientists with strong regulatory expertise so that they will be able to make informed recommendations to decision makers in the health-care system. Individuals with high-level scientific knowledge and a thorough knowledge of regulatory affairs will also be necessary for vaccine review panels, especially considering the current and projected advances in vaccine technology.


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Funding

A number of funding agencies and organizations that support their vaccine-related research were identified by representatives from vaccine-related organizations and individual researchers (see Appendix 4). A representative from each funding agency and organization was contacted and asked to provide information about their organization's vaccine research investments. Table 2 lists the names of the agencies and organizations that responded, their vaccine-related research priorities, the amount they invested in vaccine research in fiscal year 2007-2008 and future funding commitments. Information for this section came from answers to the following questions:

  • Provide a list of your organization's current vaccine research grants and awards, including the amount disbursed between April 1, 2007 and March 31, 2008.
  • Has your organization committed future funding to vaccine research? If so, please provide annual totals.
  • What are your organization's vaccine research priorities?

Table 2: Organizations that support vaccine research and development in Canada, their vaccine-related research priorities, recent investments and future commitments

Funding agency/
organization 		Vaccine-related research priorities Funding in fiscal year 2007-2008 Future funding already committed
Federal
Canadian Foundation for Innovation (CFI)
(funds research infrastructure at institutions, colleges and research hospitals)		 Funding discipline-specific research activities is beyond the scope of CFI, but health research is currently a top priority. $684,877
(represents 40%: a matched funding partner is required).		 None, however, $440,000,000 is committed over the next two years to the Research Hospital Fund (a part of which will undoubtedly support vaccine research).
Canadian Institutes of Health Research (CIHR) Related strategic priorities:
Pandemic influenza preparedness, HIV/AIDS,
Vaccines of the 21st century, Emerging infections and microbial resistance.		 $23,000,000 2008-2014:
$48,000,000
Defense Research and Development Canada (DRDC), Department of National Defense Novel platforms for rapid, post-exposure immunization and broad spectrum vaccines. Advanced development, support for Canadian licensure and acquisition of initial stockpile. $4,040,000 2008-2010:
$8,500,000
The Global Health Research Initiative (GHRI) a partnership between CIHR, HC, International Development Research Centre (IDRC) and CIDA No vaccine priorities as such, but rather supports innovative research as it relates to strengthening health systems and building global health research capacity. $1,290,678
HIV Prevention Trials Capacity Building Grants Program launched in 2006.		 2008-2012:
$17,000,000
National Research Council of Canada (NRC) Priorities include: adjuvants, immunomodulation and vaccine delivery; glyco-vaccine strategies for childhood diseases; and vaccine strategies for intracellular pathogens. $5,200,000 $5,200,000 per year
Provincial
Alberta Heritage Foundation for Medical Research Not a named priority area. $250,000 2008-2012:
$5,000,000
Fonds de la recherche en santé du Québec (FRSQ) None in particular. $2,268,451 None.
Genome British Columbia (BC) Vaccine research is not a specific priority, but research proposals within the framework of competitions either within Genome Canada, or Genome BC research competitions are welcome. Not provided. Not provided.
Manitoba Health Research Council No funding targeted specifically to vaccine research. $228,930.00 Not provided.
Medical Research Fund of New Brunswick None. None. None.
Nova Scotia Health Research Foundation None at this time. $78,325 None.
Ontario Institute for Cancer Research (OICR) Support research on vaccines or other immunological attacks of cancer and clinical trials of cancer vaccines.
A major strategic research priority is biotherapies. This program, led by Dr. John Bell in Ottawa focuses on oncolytic viruses and on adoptive immunotherapy approaches from the group at McMaster University. Also have a commercialization program to invest (up to $500,000) in promising new therapies with a goal of either developing an industry partnership or creating a new company in Ontario.		 $1,653,804 (Competitive grants)
$3,000,000 to $4,000,000 (Biotherapy priority)		 Usually fund one or two competitive grants each year. The grants are approximately $500,000, spread equally over three years.
$3,000,000-$4,000,000 (Biotherapy priority)
Saskatchewan Health Research Foundation Public health including infectious disease, water safety and food safety is one of the foundations five priority areas. $884,720 Committed future funding to vaccine research. Preference is given to research that falls into a priority area, but there is no annual total that is allotted for each one.
International
Bill and Melinda Gates Foundation Acute lower respiratory infections, diarrheal diseases, HIV, malaria, neglected tropical diseases and tuberculosis. $4,510,133 (Canada)
$214,969,511 (total)		 2008-2014:
$9,031,422,263 (total)
Private sector
Dow AgroSciences Animal health vaccines. Strategic alliance with NRC and research collaborations with Plantigen, SemBioSys and Agrisoma. Confidential Confidential
Merck Frosst Canada Ltd. Working with Canadian academic and clinical researchers to build the body of evidence supporting the complete vaccine research and development life-cycle. Includes epidemiologic research and outcomes-based research to document the Canadian burden of illness and health-care resource utilisation and clinical research studies on safety and efficacy as well as post licensure surveillance and evaluation of immunization programs. In Canada, $2,125,000+ to support research collaborations, clinical trials, in-kind contributions and investigator-initiated research projects spanning several different vaccine-related therapeutic areas. $1,250,000+ per year.
sanofi pasteur     $3,800,000
Wyeth Canada In Canada: ongoing surveillance studies on invasive and non-invasive pneumococcal disease, and ongoing participation in a global study with a new pneumococcal conjugate vaccine. Globally: Wyeth Vaccines developing new vaccines for meningococcal B disease, Staphylococcus aureus, HIV, hepatitis C and B-hemolytic Streptococcus. $825,000+
(support to academic researchers, including investigator-originated proposals, two vaccine chairs and one fellowship).		 $695,000 to $895,000 per year.

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Existing Funding Opportunities

Individual researchers were asked to describe the existing opportunities that would allow them to take their research accomplishments to the next stage. Most of the researchers stated that they intend to apply to CIHR for additional funding support. They listed several programs and initiatives within CIHR including proof of principle, knowledge translation, team and catalyst grant programs, as well as targeted initiatives including pandemic preparedness and HIV. Other funding agencies to which researchers intend to apply include: NIH, NCIC, NSERC, the Bill and Melinda Gates Foundation and the Quebec Department of Health and Social Services (MSSS). Other researchers intend to form partnerships with the private sector. A few stated that there were no existing opportunities to take their research accomplishments further because of meagre support for areas such as clinical trials, surveillance or knowledge translation. One respondent stated that the provinces and territories have decided to allocate 2% of federal money for HPV vaccination to research and program evaluation and suggested that CIHR would be an ideal place to administer the requests for applications.


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New Funding Opportunities

Representatives from funding organizations and from vaccine-related organizations identified new funding opportunities for vaccine research. These are described below.

Pandemic Influenza Preparedness
Pandemic influenza preparedness is a strategic research priority of both CIHR and PHAC. Together, they are already supporting critical research in this area. CIHR and PHAC recently announced a new funding opportunity to support an Influenza Research Network. The Network will conduct applied public health research with the goals of developing and testing methods to rapidly evaluate candidate pandemic influenza vaccines for safety and population-based methods to evaluate vaccine effectiveness and safety following release of a pandemic vaccine for general use. The deadline for the letter of intent was May 1, 2008. See the CIHR-III website for more details about this funding opportunity.

Canadian HIV Vaccine Initiative (CHVI)
Several funding opportunities will be launched under this new initiative. CHVI will focus on five areas:

  • Discovery and social research ($22 million);
  • Clinical trials capacity building and networks ($16 million);
  • Pilot scale manufacturing facility for clinical trials ($89.1 million);
  • Policy and regulatory issues, community and social dimensions ($8.5 million); and
  • Planning, coordination and evaluation ($3.4 million).

A funding opportunity for pilot scale manufacturing of clinical trials was announced in April 2008. The deadline for the letter of intent was June 10, 2008. See the CHVI website for more details about this initiative.

Canadian International Immunization Initiative Phase 2 (CIII2)
This is a Canadian International Development Agency (CIDA)-funded initiative in partnership with the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), the Pan American Health Organization and the Canadian Public Health Association. Phase 1 of CIII was initiated in 1998 to increase and intensify routine immunization for all children of the world. Phase 2 of the initiative supports research to increase access to and enhance immunization services in CIDA's priority countries. The CIII2 program is being expanded to include Haiti ($1 million over five years), and there are preliminary negotiations to launch a subsequent phase of funding for CIII2, but details concerning its focus have not been announced.


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Recent vaccine-related developments

Several announcements regarding vaccine research, development and manufacture were made in early 2008 after the survey phase of this report was completed.

The Pan-Provincial Vaccine Enterprise (PREVENT)
In February 2008, PREVENT, one of 11 new Centres of Excellence for Commercialization and Research was announced. It will be an incorporated, non-profit organization that will conduct pre-clinical and proof-of-concept clinical trials for promising early-stage vaccine candidates. Beginning operation in mid-2008, PREVENT will capitalize on expertise at VIDO at the University of Saskatchewan, the Canadian Center for Vaccinology in Halifax and the UBC Centre for Disease Control. By partnering with Canadian stakeholders and shouldering the risk of early-stage vaccine development, PREVENT will strengthen Canada's vaccine industry, promoting growth, investment and improved global competitiveness.

Sanofi Pasteur Human Vaccine Challenge Unit at the Canadian Center for Vaccinology
Also in February 2008, the IWK Health Centre Foundation announced a $3.8 million donation from sanofi pasteur to the Canadian Center for Vaccinology. $1 million of the donation will support the completion of the construction of the Sanofi Pasteur Human Vaccine Challenge Unit at the Canadian Center for Vaccinology. The purpose of this facility is to do very early clinical trials on candidate vaccines. The Sanofi Pasteur Human Vaccine Challenge Unit will be a 5,400 square foot, ten-bed, in-patient facility with isolation rooms, including full disease containment and full physiological monitoring. The remaining $2.8 million of the donation will support the Canadian Maternal Immunization Study, which will determine whether immunization of pregnant women against pertussis will protect newborns from developing whooping cough.

Canadian Network on HPV Prevention
The Canadian Network on HPV Prevention, hosted by the International Centre for Infectious Diseases (ICID), is in development. Some of the proposed activities of the network include: funding identified HPV research priorities, building capacity within the HPV community, facilitating the evaluation of implementation strategies and enabling knowledge translation to clinical practice and to the public. The overall goal of the network is to improve the health of Canadians by optimizing prevention strategies and technologies related to HPV-associated diseases.

New Research Facilities at sanofi pasteur in Toronto
In April 2008, sanofi pasteur announced that it is investing $100 million in a new, state-of-the-art research facility at their Connaught Campus in north Toronto to boost innovation in vaccine research for the benefit of global health. The investment includes the construction of an $80 million facility, the purchase of specialized research and development equipment, and support for research and development jobs over the next five years.

Interdisciplinary Team Grant in Vaccine Design and Implementation
Also in April 2008, the Alberta Heritage Foundation for Medical Research (AHFMR) announced that it had awarded an AHFMR Interdisciplinary Team Grant in Vaccine Design and Implementation to researchers at the University of Calgary, the University of Alberta, the University of Saskatchewan and the University of Toronto. The initiative, led by Drs. Anthony Schryvers, Lorne Babiuk and James Kellner, will study how the bacteria evolve within the human population in order to design vaccine products capable of providing protection against different strains and species. They will use a detailed understanding of basic biology to target essential processes shared by different disease-causing bacteria. At the same time they will improve vaccine evaluation strategies and develop new approaches to predict the impact of vaccines.


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Conclusion

Canada continues to make significant contributions to vaccine research and development. These accomplishments have saved lives, decreased human suffering, reduced health-care costs and protected the health of societies both in Canada and around the world. Several vaccine-related challenges remain, but exciting new funding initiatives and a renewed interest in vaccines make this an ideal time for CIHR-III to launch its Vaccines of the 21st Century Strategic Research Initiative. It is essential that Canada maintain this new-found enthusiasm by continuing to support and develop both basic and clinical vaccine research, promote vaccine development, and ensure that the country retains its own vaccine manufacturing capability. Many individuals, organizations and countries will have to work together to make the vaccines of the 21st century a reality.


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Next Steps

This report will be distributed widely to all those with an interest in vaccine research and development and in immunization. CIHR-III will use the report to develop an action plan and partnerships for the Vaccines of the 21st Century Strategic Research Initiative. The goals of the Initiative are to help coordinate research efforts, foster linkages, facilitate vaccine research and development and support the transfer of research knowledge to governments, health-care providers and the public. These activities will take vaccine research and development in Canada to the next level, and ultimately, improve the health and well-being of individuals in Canada and the rest of the world.