Presentation or Meeting title Name of presenter (dd-mmm-yyyy)

1
Why is there still no effective HIV vaccine?

• Ken Legg
• MRC Clinical Trials Unit

2
Outline of presentation

• Why is there still no effective HIV vaccine
• Brief history
• Why is it so difficult?
• Current situation
• Whats happening in UK?
• VaccNet volunteer network
• What it is
• Need for advocate input
• Timely to create an overarching HIV vaccine
  advisory group, although membership of the
  various oversight committees for funded work
  still needed

3
HIV Vaccine history

• In 1984, after scientists at the U.S. National
  Institutes of Health and the Pasteur Institute
  identified HIV, the United States Health and
  Human Services Secretary Margaret Heckler
  declared that a vaccine would be available within
  two years.
• 25 years later no effective vaccine has been
  licensed and the majority of scientists cannot
  envisage one becoming available in the next 10
  years

4
HIV Vaccine history

• The first HIV vaccine trial was conducted in 1987
• Since then over 30 different candidate vaccines
  have been tested in over 60 phase I and IIa
  trials
• There have been 5 phase IIb and III trials in
  which efficacy was tested, the last of which will
  report at the end of 2009

5
HIV structure
6
Vaccine history

• VaxGen was a Phase III study exploring using a
  recombinant envelope protein (rgp120) and found
  it to be safe but not effective. Although
  disappointing, this was an important safety
  result as enhancement of infection had been seen
  in neonatal macaques
• STEP and Phambili were Phase IIb, both exploring
  the Merck Adenovirus (common cold) strain 5
  vector (V520) vaccine, with core proteins
  (gag/pol/nef). Although not statistically
  significant overall, there was a trend towards
  enhanced infection. This was most marked in
  uncircumcised men with pre-existing immunity to
  Adenovirus 5

7
Why is it so difficult?

• It did take a long time with other diseases,
  especially in the trial and error days prior to
  modern lab techniques
• Hepatitis B and HPV have been successful because
  it was clear what immune responses protected
  individuals exposed to these viruses from
  developing disease, so scientists knew what they
  were aiming for
• In HIV there is much less to go on, but studying
  long term non-progressors, and exposed but not
  infected populations helps

8
Current situation

• The envelope protein that HIV uses to attach to
  the CD4 cells was the obvious first target, but
  most of this protein is highly variable meaning
  it is different between people and even between
  the strains that exist in one infected person.
  Hence the immune response to the vaccine protein
  is limited to the strain used to develop the
  vaccine.
• Scientists are working on the more stable part
  and trying to boost the response using adjuvants
  (an extra component that helps present the
  vaccine)

9
Current situation

• The next target was to stimulate a T-cell
  response such as those that long term
  non-progressors have. The Merck Ad5 vaccine was
  good at doing this, and hopes were high for
  control of viral load. As the cellular response
  was mainly to core proteins not envelope, and
  unlikely to be quick enough to prevent infection
• Scientists are now working on ways to broaden the
  cellular response (core and envelope)
• In parallel they are looking for better
  techniques to measure the cellular immune
  response

10
Current situation

• The Thai Phase III is exploring a combination
  regime with an avian vector prime and protein
  boost. It has gone through 2 futility analyses
  which suggests the trend is in the right
  direction.
• This trial will report late 2009

11
Whats happening in the UK

• EUROVACC (EV) bench to clinic programme funded
  by European Commission now in Phase IIa
• AfrEVacc (African-European HIV Vaccine
  Development Network) capacity building and
  Phase I trial funded by EDCTP, using EV products
• Grand Challenges in Global Health Initiative
  pathogenesis and discovery funded by
  Gates/Wellcome Trust/Canadian Government
• UKHVC (UK HIV Vaccine Consortium) bench to
  clinic funded by Wellcome Trust EUROPRISE
  bringing EV and Grand Challenge products together
  in combination regimens

12
Whats happening in the UK

• Europrise network of excellence funded by
  European Commission
• CAVD (Collaboration for AIDS Vaccine Discovery)
  discovery funded by Bill and Melinda Gates
• CHAVI (Center for HIV/AIDS Vaccine Immunology)
  pathogenesis funded by US NIH
• IAVI not for profit organisation funded by
  Governments and Foundations has their central lab
  in UK and are doing a phase I/II study
• CutHIVac just funded by European Commission to
  explore cutaneous delivery system of DNA HIV
  vaccine through to Phase I in negative and
  positive volunteers

13
MRC current involvement

• AfrEVacc
• UKHVC
• EuroVacc
• CutHIVac
• Europrise coordinates WP7
• IAVI (MRC Uganda Unit)
• VaccNet
• Plus other prevention activities
• MDP
• PopArt

14
Plan to facilitate HIV and other vaccine trials
in UK

• VaccNet
• We have applied to NIHR for a grant to fund the
  development and implementation of a UK wide
  volunteer network
• Recruitment through a national advertising
  campaign on billboards, buses and newspapers
• Volunteers log onto the VaccNet home page and
  learn about current UK vaccine research and
  recruiting trials, HIV news option to join the
  network as a potential volunteer
• Volunteers that register will be referred to the
  nearest clinical site for a basic screening visit

15
VaccNet

• A screening assessment will be carried out which
  includes a risk assessment, blood tests for liver
  function tests, full blood count and rapid POC
  HIV test
• Everyone will be asked to complete a
  psychological assessment (probably a
  questionnaire) if required they can be referred
  to a psychologist
• If eligible they will be invited to join the
  network as a potential volunteer, and informed
  via e-mails when a suitable study is looming, and
  invited for a screening visit specific to that
  trial

16
VaccNet

• Primary focus of the network is HIV but other
  trials will also be listed e.g. malaria and TB
  vaccine trials, microbicide trials and discordant
  couple studies
• If funded, we plan to be running by September
  2010
• Need to develop the website, the secure database
  and prepare the sites and support structure

17
HIV Vaccine advisory board

• In support of the future trials that will be
  developed by all these groups we would like to
  initiate a community advisory board specifically
  for HIV vaccines
• The board will include members of the HIV
  community, members of the VaccNet network and
  members of the trial teams
• The role of the board is to help in the
  development of the protocols and to help develop
  the recruitment strategies for trials

18
HIV vaccine advisory board

• Questions
• Do you think there is a role or a need for such a
  board?
• Would it be a good idea to be involved in the
  development of protocols or better to review the
  draft protocol or be involved in developing
  generic guidelines for the community activation
  of such projects?
• How many people should be on it and what division
  of responsibility should there be?