Senior scientist Shahid Jameel says the partially successful HIV vaccine trial in Thailand has offered a direct opportunity to understand the correlates of protection in humans. The initial trial results, though modest, will surely energise HIV vaccine research towards a more complete analysis of the successful immune response
The human immunodeficiency virus (HIV), which causes AIDS, has been a difficult target for vaccine developers.
Vaccines are substances that mimic a disease-causing agent (pathogen) in order to raise immunity in the host (human), which disables (neutralises) and clears the pathogen from the host in the event of a natural infection.
Two types of immune responses are usually required for complete protection from an infecting pathogen. In humoral responses, antibodies develop to neutralise pathogens before they get into cells, in other words, extracellular pathogens. Cellular responses are also required in which special cytotoxic cells are recruited by the host immune system to kill those cells that have become infected. This is critical for removing infection reservoirs, especially in the case of chronic/persistent pathogens such as HIV. An ideal mix of the two types of responses is required, and this mix is different for different pathogens.
The HIV vaccine field is limited by a poor understanding of the correlates of protection. In other words, we do not understand the quality and quantity of humoral and cellular responses that are required to prevent HIV infection. The problem is compounded by the extremely variable nature of HIV, which enables it to evade both arms of host immunity. Clinical trials of candidate vaccines carried out thus far have shown no efficacy in humans.
The good news was released on September 24, 2009 of a vaccine trial conducted jointly by the US Military HIV Research Program and Thailand’s Ministry of Public Health. This trial initiated in late 2003 was a Phase III efficacy study of a prime-boost combination of two vaccine candidates, ALVAC manufactured by Sanofi-Pasteur and AIDSVAX manufactured by VaxGen (now called Global Solutions for Infectious Diseases). Both these candidate vaccines were earlier tested individually and showed no efficacy.
The Rv144 trial included more than 16,000 Thai men and women who were randomly divided into two groups. One group received the prime-boost vaccine combination and the other received a similar placebo regimen. In the final analysis, 74 persons in the placebo group became infected with HIV, while only 51 persons in the vaccine group showed infection. This difference was calculated as an efficacy of 31.2%. Though not impressive, this is the first time any candidate AIDS vaccine has shown any level of protection in humans. That is the hope.
The caution? We do not yet know the reason(s) for this difference between the two groups. Curiously, there was no difference between the amounts of virus (viral load) in people who got infected in the two groups. One would have expected a functional vaccine to at least reduce the viral load even in the absence of a protection from infection.
The real question is why the vaccine group showed lower numbers of infection. Though participants in such trials are randomised, humans being genetically out-bred have slight differences in their genetic makeup. The effects of this on protection from HIV infection are well known. For example, the human leukocyte antigen type 1 (HLA1) alleles B57 and B27 are known to be protective; similarly other genetic markers are known to be associated with increased predisposition to infection and disease progression.
Is it possible that just by random chance, the vaccine group had more persons with the protective alleles? Alternatively, it is also possible that the placebo group similarly had more persons with the predisposing alleles. Only a complete genetic polymorphism analysis of those who became infected and a section of those who were protected will answer this question.
The trial also offers an opportunity to directly determine the correlates of protection. These studies have thus far relied entirely on animal studies and on special groups of individuals who remain HIV-negative despite repeated presumed exposure to the virus. This is the first direct opportunity to test why a vaccine works in some people but fails to work in others.
The Rv144 trial has, for the first time, shown that it is possible to make a vaccine that will protect against HIV infection. It has also offered a direct opportunity to understand the correlates of protection in humans. The initial trial results, though modest, will surely energise HIV vaccine research towards a more complete analysis of the successful immune response.
But this may still not be the vaccine the world is looking for. For example, we still do not understand whether the vaccine response in the Thai population can be directly translated to genetically different African or Caucasian populations.
There is hope and optimism, but mix it with caution. We may be one step closer, but we are not there yet. Sustained research, funding and the opportunity to carry out trials of promising candidates is the only way forward.
We may again fail along the way, but the only way to succeed is to keep trying.
More details on the antibody discovery and the vaccine trial are available from the following sources: International AIDS Vaccine Initiative: http//www.iavi.org, the US Military HIV Research Program: http://www.hivresearch.org/ and Science magazine:
(Shahid Jameel is Senior Scientist and Group Leader, International Centre for Genetic Engineering and Biotechnology, New Delhi)
Infochange News & Features, October 2009