The gloom that has dominated the AIDS vaccine field since the pessimistic AIDS Vaccine ’04 conference in Lausanne began to lift further last week with the confident statement by a leading researcher that 2006 has been “a vintage year for vaccine development.” Why are vaccine researchers beginning to feel more optimistic?
The first reason is the impressive immune responses, or immunogenicity, demonstrated by at least three vaccines presented at the meeting. After years of fruitless attempts to develop vaccines that stimulate broadly protective neutralising antibodies which prevent HIV infection, vaccine researchers have begun to concentrate on vaccines that will stimulate T-cell responses, in the hopes that these will either prevent HIV infection altogether (as in exposed but uninfected individuals) or slow HIV disease progression greatly (as observed in long-term non-progressors).
These promising results suggest that the success of the Merck adenovirus-based HIV vaccine is not a flash in the pan, and that the strategy of using a strongly immunogenic vector to stimulate T-cell responses is working.
What’s less clear is what the end result of vaccination will be: prevention of infection or control of HIV disease progression?
We should know by 2008 or 2009 whether this vaccine has some protective effect against HIV transmission, at which point it could move into much larger phase III trials required for licensing.
However, its effect on disease progression in people not receiving treatment could take longer to determine. Proof of concept trials will look at the viral set-point of vaccine recipients who become infected during the study to determine whether this group have significantly lower viral load set points than people in the placebo group. The assumption is that a low viral set point in vaccinated individuals, as in people who have not received a vaccine, indicates a slower disease course.
The conference was also excited by research showing that it is now possible to measure the quality, or `polyfunctionality` of the immune responses induced by T-cell vaccines in a much more comprehensive way. Viral control, whether in animals or in HIV-positive humans, depends on a broad array of T-cell functions being maintained in good working order.
However, determining which immune responses correspond with true immune protection is still a puzzle for researchers, and Jerald Sadoff of the Aereas Global TB Vaccine Foundation told the conference that while correlates of protection help a lot in proving that a vaccine works, “often you don’t have your correlate until you prove it works – you assume it works until you prove it.”
Sadoff’s advice? “Look to your milkmaids, they are your strongest predictor,” he argued, referring to Edward Jenner’s oberservation in the 1790s that milkmaids exposed to cowpox were protected from smallpox.
The search for `milkmaids` has been going on for over 15 years, and recently entered a new phase with the launch of the Elite Controllers research cohort by Professor Bruce Walker and a network of colleagues in the US and Europe.
Until now, the only factor found in common among people who control HIV after infection has been strong T-cell responses to HIV gag proteins, while people with strong responses to HIV envelope proteins tend to have higher viral load levels, presumably because immune responses to envelope proteins drive the virus to diversify its coat to escape immune detection much more quickly.
This finding, together with the recent discovery that envelope proteins – specifically HIV gp120 – shift the immune system response away from vigorous HIV-specific T-cell responses, have led some researchers to question whether envelope proteins should be included in vaccines at all, according to Dr Jill Gilmour of the International AIDS Vaccine Initiative.
Professor John Moore of Cornell University agrees that the HIV envelope remains a major problem in vaccine design. “The responses are essentially fiendish. We have to make a global influenza vaccine every year to respond to variation; in comparison, HIV envelope variation is vastly greater.”
Yet there are human neutralising antibodies that can bind to HIV envelope spikes, and the International AIDS Vaccine Initiative is funding a research consortium to search more intensively for HIV antigens that generate neutralising antibodies. The most conserved sites, however, are well hidden and much less frequently displayed to the immune system, making it very difficult to apply neutralising antibodies to these sites.
Whether it will be necessary for a successful AIDS vaccine to induce a healthy neutralising antibody response alongside a T-cell response remains to be seen.
The other reason for optimism is the development of a humanised mouse model for vaccine testing, reported at the conference by a team from the University of Texas Southwestern Medical Center. Animal modelling of HIV infection is limited by the fact that HIV is a human immunodeficiency virus, and primates are not susceptible to infection by it, so primate experiments must use a genetically engineered simian immunodeficiency virus in order to deliver HIV genes, commonly called a SHIV.
The University of Texas group has at last succeeded in transplanting human CD34+ stem cells into the haematopoietic systems of immunodeficient mice that have laready receuved transplants of human liver and thymic tissue, leading to an immune reconstitution with human lymphocytes. HIV infection of the mice results in a predictable pattern of disease progression, and the mouse model, say vaccine researchers, has the potential to allow much faster animal testing of vaccine candidates.