CIHR-BMGF Information Session and Consultation: Future Investments in Mucosal Immunology and HIV Vaccine Development – Summary report, November 25, 2013

Background

The Canadian Institutes of Health Research (CIHR) and the Bill & Melinda Gates Foundation (BMGF) are developing a joint initiative to support research related to mucosal immunology and HIV vaccine development. CIHR, Canada’s leading health research funding organization, is working with the BMGF to further advance the Canadian HIV Vaccine Initiative (CHVI), a partnership between the Government of Canada and the BMGF.

CIHR has received a grant from the BMGF to support a new CHVI Team Grant funding opportunity. The purpose of the grant and funding opportunity is to stimulate new and innovative high quality research that addresses current gaps and priorities relevant to the development of vaccines that prevent HIV infections at mucosal surfaces.

Prior to the web-based information session and consultation, CIHR and the BMGF consulted international experts (N=7) on this initiative during the AIDS Vaccine 2013 conference and by telephone to help identify priority areas for investigation to advance research and address gaps in the field (see Appendix 1 for a list of participants and summary of feedback).

Initial consultations indicated that further vaccine-related research is required on the early stages of HIV exposure and infection at mucosal surfaces. A revised list of 10 potential priority research areas was shared with participants in the web session in advance as part of a consultation guide.

Consultation Summary

On November 25, 2013, a web-based consultation was facilitated by the CHVI Alliance Coordinating Office (ACO). The consultation was open to anyone interested in participating and was promoted in advance to the research community and stakeholders by the ACO and CIHR. There were a total of 43 confirmed participants including a mix of researchers, HIV community representatives, CHVI government partners and industry representatives (see Appendix 2 for a list of participants). The web consultation’s main objective was to seek further input on priority areas for investigation and investment that will leverage Canadian and international expertise and maximize the impact of investments.

Introductions

The web consultation commenced with an overview of the CHVI and the CHVI Alliance Coordinating Office (ACO) by Dr. Greg Hammond. Subsequently, Dr. Magda Moutaftsi discussed the involvement of the BMGF in HIV vaccine research. She indicated that the BMGF had identified the topic of mucosal immunology as an important area for investigation that is currently not well funded. Recognizing existing Canadian expertise in this area, the BMGF determined that a partnership with CIHR was a good opportunity to address the identified gap and make a significant contribution to the field.

Overview of CIHR-BMGF Partnership

Dr. Marc Ouellette provided an overview of CIHR’s role in the Vaccine Discovery and Social Research Component of CHVI and the partnership with the BMGF. Dr. Ouellette explained that the partnership was enabled by CIHR submitting a proposal to the BMGF for a new CHVI funding opportunity on mucosal immunology, which was approved. Dr. Ouellette indicated the goal of the partnership is to contribute to the global effort to reduce HIV infections by supporting research addressing the role of mucosal immunology in HIV protection. The research funded is expected to contribute new and important scientific knowledge and advance the commercialization of current discoveries in the field of HIV vaccines. Dr. Ouellette also indicated that, as per the proposal to the BMGF, the funding opportunity will support team grants of up to three years in duration and $400,000 per year.

Dr. Ouellette thanked Dr. Hammond at the ACO for his initial help in the literature review and identification of potential priority areas and provided an overview of the consultation conducted to date. Prior to this web session, consultation involved in-person interviews with international experts during the AIDS Vaccine Conference in October 2013 and telephone interviews in November 2013. A total of seven experts were interviewed. The consultation with international experts provided the opportunity for CIHR and the BMGF to learn about significant recent developments in the field of mucosal immunology related to HIV vaccines and whether there are advancements outside of HIV research that could be applied to advance HIV vaccine development. The initial list of potential priority areas for investigation were discussed and rated by the international experts, who also provided suggestions of additional priority areas (see Appendix 1 for a list of participants and a summary of feedback).

After providing this overview, Dr. Ouellette encouraged the web consultation participants to ask questions and discuss key aspects of a future CHVI funding opportunity focused on mucosal immunology. It was noted that the funding opportunity is not yet developed as the organizations are in the consultation phase, therefore, some details were not available. However, the following points were clarified during the discussion:

  • Team eligibility: teams will likely require a minimum of 3 investigators; community participation will be encouraged; involvement of an international researcher will be required and will not be limited to low- and middle-income country researchers.
  • Eligible research areas: research involving humans and clinical studies will be eligible for funding but, as per conditions of the grant from BMGF, clinical trials will not be eligible.
  • Administration of funding: as per CIHR guidelines, Nominated Principal Investigators (NPIs) at eligible Canadian institutions will receive the funding. NPIs have the flexibility to transfer funds to institutions of other team members, including international collaborators.

In addition, a recommendation was made to include training as a key component of the funding opportunity and also to encourage the use of Good Participatory Practice Guidelines.

Priority Research Areas

Following the discussion, Dr. Ouellette reviewed each priority area listed in the consultation guide and provided the opportunity for participants to discuss and provide feedback. After each area was presented, participants were asked to rate it using the web-based polling technology as low, medium or high priority for future investments and research. Not all participants chose to participate in the polling activity. A few participants that joined the discussion via teleconference and one that did not submitted their ratings to the ACO via email following the session.

The following are the potential priority areas listed in the consultation guide and the recommendations from the web consultation (see Appendix 3 for detailed polling results):

  • Area 1: Innovative methods to induce protective immune quiescence at mucosal sites

    There was substantial discussion of this priority area with some noting it to be a high priority and one led by Canadian experts. It was also suggested that the issue is likely more complex than quiescence and involving innate immune response. There was general agreement that the word “protective” should be removed from the priority topic. With the word “protective” removed, this area was rated one of the highest priorities by participants in the poll.

  • Area 2: Approaches to measure and stimulate the induction of memory innate immune responses

    Participants were supportive of this priority area but discussed the appropriateness of the focus on “memory” responses. In general, there was agreement that “memory” should be replaced by “mucosal” for this area. With the word “memory” removed prior to polling participants, this area was rated the highest priority in the poll.

  • Area 3: Understanding mucosal immunity (humoral and cellular) in animal models in HIV vaccine challenge studies

    During the discussion it was clarified that challenge studies referred to those where vaccinated animals would be challenged with the virus of interest (eg SIV). This was noted as an important area but also a challenging one when considering implications of previous vaccination of animals. In the poll, ratings were split among high, medium and low.

  • Area 4: The use of human subjects (e.g. , testing scientific hypotheses/experimental medicine) to study mucosal immunity induced by early stage vaccines

    Participants discussed the coverage of this topic already by international investigators and one noted that it is currently a contested area. Some participants suggested Canada would have little to contribute in addition to what is already being done. However, it was noted that currently there is not much focus on mucosal samples. Overall, this area was rated the lowest priority in the poll.

  • Area 5: Immunologic or systems biology platforms for measurement of local mucosal immunity generated during HIV infection and immunization

    This area was noted as complex but one where not a lot is being done internationally and where Canada could potentially do well. In the poll, this area received moderate support.

  • Area 6: The very early events of HIV exposure at mucosal sites that allow mucosal transmission or protection

    A couple of participants commented that this area has recently been demonstrated as important for HIV vaccine development and noted that some aspects are being investigated by researchers in the United States. There were varying opinions as to whether there are aspects of this broad topic where Canadian researchers would be well placed to contribute. This area was rated among the top five in the poll.

  • Area 7: Role of inflammation at mucosal sites in HIV transmission and protection

    There was not a lot of discussion of this area during the web consultation but a couple of participants noted it to be of high importance. In the poll, it was rated among the top five priority areas.

  • Area 8: How to induce and target IgAs and IgGs at mucosal sites

    Discussion of this area was limited but one participant suggested it is one where there is a Canadian advantage. It was suggested that the area include both the neutralizing and non-neutralizing antibodies. This area was rated among the top five in the poll.

  • Area 9: The implications of sex hormones (e.g., during the menstrual cycle and use of oral contraception) in susceptibility to infections and in vaccine efficacy

    Participants noted that the term “oral contraception” should be replaced with “hormonal contraception”. It was suggested that a better understanding of fundamental aspects of sex hormones on mucosa are required but others noted that this is not required prior to investigating their implications for vaccines. Overall, the poll indicated this area to be of moderate priority.

  • Area 10: Comparing adaptive and innate immunity at the levels of the rectal and vaginal mucosa

    One participant noted this area to be of high priority, particularly as not much is known about immunity within the rectal mucosa. In the poll, this area received moderate support.

Towards the end of the web conference, participants had the opportunity to identify and discuss other gaps in current research and areas of investigation perceived as important to direct future research investments related to mucosal immunology for HIV vaccine development. The following suggestions were provided by participants:

  • Vaccine route - this represents a key element in vaccine strategy to elicit an immune response at the mucosa (Follicular B helper T cells - TFH cells)
  • Vector delivery of broadly neutralizing antibody genes
  • Influence of HSV/HPV upon mucosal environment and immune activation - co-infections
  • Potential role of ADCC in protecting HIV-1 transmission
  • Capacity building needs to be a focus in all of the priority areas
  • Assay development for mucosal responses
  • Basic understanding of immunology B cell and T cell biology at the genital tract and gut is important and fundamental, particularly in response to viruses
  • Influence of the vaccine adjuvant on the HIV vaccine protection
  • HIV reservoir at mucosa
  • The role of the microbiome might prove important
  • Mechanism and role of mucosal barrier disruption in HIV pathogenesis
  • Understanding the mechanism for vector-vaccine induced susceptibility for HIV infection (as was the case with adenovirus 5)
  • Agree that understanding how certain vaccine constructs might increase susceptibility is important and do-able.

Next Steps

The discussion and feedback from the consultation process will be considered and used in the development of the new CHVI team grant funding opportunity. The overall aim is to encourage high quality applications from Canadian researchers in areas of relevance to the advancement of mucosal immunology research and vaccine development for the prevention of HIV infections.

A summary report of the information and consultation session will be prepared and posted on the CIHR website. The CIHR HIV/AIDS Research Initiative intends to launch the CHVI funding opportunity by spring 2014.

Appendix 1 – October-November 2013 Consultation with International Experts: Participant List and Summary of Feedback

  • Dan Barouch, Harvard University
  • Kristina Broliden, Karolinska University Hospital
  • J Victor Garcia, University of North Carolina
  • Tom Hope, Northwestern University Medical School
  • George Lewis, University of Maryland
  • Julie McElrath, Fred Hutchinson Cancer Research Centre
  • Ruth Ruprecht, Texas Biomedical Research Institute
Potential Areas of Investigation for HIV Preventive Vaccines Priority # Comments
Strategies for vaccines/adjuvants to stimulate and boost adaptive immunity at local genitourinary and gastrointestinal mucosal sites (e.g. neutralizing Ab, non-neutralizing Ab, etc.) Low 1
Medium 1
High 3
Innovative methods to induce protective immune quiescence at mucosal sites Low 2 Difficult to do
Medium 0
High 3
Approaches to measure and stimulate the induction of memory innate immune responses Low 0 Difficult to do in mucus
More basic research required
Medium 3
High 1
Understanding mucosal immunity in animal models in HIV vaccine challenge studies Low 0 Focus on primate model
Medium 0
High 6
The use of human subjects (e.g. , testing scientific hypotheses/experimental medicine) to study mucosal immunity induced by early stage vaccines Low 0 Difficult
Medium 0
High 6
Innovative sampling and standardization of procedures for collection of genital and anal specimens, including self-sampling, for measurement of mucosal immunity Low 3 Low – as a lot of funding for this already.
High – but compliance with this is not trivial
Medium 0
High 4
Immunologic or systems biology platforms for measurement of local mucosal immunity generated during HIV infection and immunization Low 1
Medium 1
High 3

Appendix 2 – November 25, 2013 Information Session and Consultation: Participant List

  • Ancuta, PetronelaCentre Hospitalier de l’Université de Montréal (CHUM), Université de Montréal
  • Angel, Jonathan – Ottawa Hospital Research Institute
  • Ball, Blake – Department of Medical Microbiology, University of Manitoba & National Laboratory for HIV Immunology, National HIV & Retrovirology, Laboratories Public Health Agency of Canada
  • Brunham, Robert – British Columbia Centre for Disease Control, University of British Columbia
  • Burgener, Adam – Department of Immunology, University of Manitoba & Laboratories Public Health Agency of Canada
  • Coleman, Gina – Clinical Evaluation Division – Vaccines, Health Canada
  • Chauhan, Bobby – Biologics and Genetic Therapies Directorate, Health Canada
  • Diaz-Mitoma, Francisco – Advanced Medical Research Institute of Canada
  • Douglas, Deborah – Canadian HIV Vaccine Initiative (CHVI) Alliance Coordinating Office
  • Dos Santos, Suzete – HIV/AIDS Research Initiative, Canadian Institutes of Health Research
  • El-Far, Mohamed – Research Institute of the McGill University Health Centre
  • Estaquier, Jerome – Department of Microbiology, Infection and Immunology, Université Laval
  • Finzi, AndrésCentre de Recherche de Centre Hospitalier de l’Université de Montréal (CRCHUM)
  • Fowke, Keith R. – Department of Medical Microbiology, University of Manitoba
  • Fraser Valiquette, Mary – Canadian Institutes of Health Research
  • Gaudreau, Marc Andre – Strategic Issues and Integrated Management Division, Public Health Agency of Canada
  • George, Rajan – Akshaya Bio Inc. (Edmonton)
  • Gray, Clive – University of Cape Town
  • Gunning, Jennifer – HIV/AIDS Research Initiative, Canadian Institutes of Health Research
  • Gurwith, Marc – PaxVax
  • Hammond, Gregory – Canadian HIV Vaccine Initiative (CHVI) Alliance Coordinating Office
  • Hassell, Tom – International AIDS Vaccine Initiative
  • Jenabian, Mohammad-Ali – Research Institute of the McGill University Health Centre
  • Kaushic, Charu – McMaster University
  • Kaul, Rupert – Department of Medicine, University of Toronto
  • Lajoie, Julie – University of Manitoba
  • Luo, Ma – Department of Medical Microbiology, University of Manitoba & National Microbiology Laboratory, Public Health Agency of Canada
  • Manrique, Amapola – Global HIV Vaccine Enterprise
  • Merke Epp, Tanya – Canadian HIV Vaccine Initiative (CHVI) Alliance Coordinating Office
  • Mouland, Andrew – Department of Microbiology and Immunology, McGill University
  • Moutaftsi, Magda – Bill & Melinda Gates Foundation
  • Ng, Anita – Electronic Submission Policy Unit, Health Canada
  • Ostrowski, Mario – Department of Medicine, Immunology, University of Toronto
  • Ouellette, Marc – Institute of Infection and Immunity, Canadian Institutes of Health Research
  • Pantophlet, Ralph – Department of Molecular Biology and Biochemistry, Simon Fraser University
  • Pinto, Jorge – Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela
  • Prodger, Jessica – Department of Medicine, University of Toronto
  • Reinhard, Robert – Department of Immunology, University of Toronto
  • Roger, MichelCentre Hospitalier de l’Université de Montréal (CHUM), Université de Montréal
  • Rogers, Timothy D. – CATIE
  • Rosenthal, Ken – Department of Pathology and Molecular Medicine, McMaster University & Michael G. DeGroote Institute for Infections Disease Research, McMaster University
  • Smith, Dean – Biologics and Genetic Therapies Directorate, Health Canada
  • Zinszner, Hélène – Global HIV Vaccine Enterprise

Appendix 3 – November 25, 2013 Information Session and Consultation: Priority Area Polling Results

Potential Areas of Investigation for HIV Preventive Vaccines Priority # %
1 Innovative methods to induce protective immune quiescence at mucosal sites Low 2 7.7
Medium 8 30.8
High 16 61.5
2 Approaches to measure and stimulate the induction of memory innate immune responses Low 3 13.6
Medium 3 13.6
High 16 72.7
3 Understanding mucosal immunity (humoral and cellular) in animal models in HIV vaccine challenge studies Low 6 31.6
Medium 5 26.3
High 8 42.1
4 The use of human subjects (e.g. , testing scientific hypotheses/experimental medicine) to study mucosal immunity induced by early stage vaccines Low 10 47.6
Medium 8 38.1
High 3 14.3
5 Immunologic or systems biology platforms for measurement of local mucosal immunity generated during HIV infection and immunization Low 6 27.3
Medium 9 40.9
High 7 31.8
6 The very early events of HIV exposure at mucosal sites that allow mucosal transmission or protection Low 1 4.8
Medium 8 38.1
High 12 57.1
7 Role of inflammation at mucosal sites in HIV transmission and protection Low 3 13
Medium 6 26.1
High 14 60.9
8 How to induce and target IgAs and IgGs at mucosal sites Low 1 4
Medium 10 40
High 14 56
9 The implications of sex hormones (e.g., during the menstrual cycle and use of oral contraception) in susceptibility to infections and in vaccine efficacy Low 8 36.4
Medium 4 18.2
High 10 45.5
10 Comparing adaptive and innate immunity at the levels of the rectal and vaginal mucosa Low 4 18.2
Medium 10 45.5
High 8 36.4
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