Why is there still no effective HIV vaccine?

Why is there still no effective HIV vaccine? Ken Legg MRC Clinical Trials Unit

Outline of presentation • Why is there still no effective HIV vaccine • Brief history • Why is it so difficult? • Current situation • What’s 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

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

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

HIV structure

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

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

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)

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

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

What’s 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

What’s 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

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

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

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

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

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

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?

Why is there still no effective HIV vaccine?