AIDS kills more than 3 million people each year and, according to the latest UNAIDS figures (December 2002), an estimated 42 million people live with HIV throughout the world. In 2002, 5 million people, including 800,000 children were infected, i.e. 14,000 new cases per day. No vaccine has yet been produced despite more than sixty clinical tests in recent years in the world, testing roughly 30 potential vaccines. At Institut Pasteur, where the HIV-1 was discovered in 1983 (followed by HIV-2 in 1985), various research programmes are underway.
Low cost vaccines for developing countries
Today, more than 95% of individuals infected by HIV live in developing countries. Access to treatment is being restricted in these countries for financial reasons, the need for a low cost vaccine available for global distribution is more important than ever.
In this view, the Institut Pasteur has developed a project aiming to produce an anti-AIDS vaccine based on the measles vaccine - low cost, and widely distributed as part of WHO vaccination campaigns. The measles vaccine is made up of an attenuated live virus providing high immunity and life-long protection with just one injection. The aim is to produce a "recombining" vaccine, i.e. to introduce two or three HIV genes in the attenuated measles virus genome. This would create a mixed HIV-measles vaccine, the HIV proteins being present in the infected cells due to the recombining virus. The measles vaccine has long proved its inoffensiveness and effectiveness, which suggests that a recombining measles vaccine should also be well accepted and effective.
This suggests many advantages, but also one disadvantage: this vaccine would possibly be targeted at children, as most adults are already vaccinated against measles.
This project receives financing from the ANRS in France and the American National Institute of Health (via the "New live viral vectors as candidates AIDS vaccine" programme including similar research on yellow fever, MVA and chicken pox led by other teams on an international basis). This brings together several Institut Pasteur laboratories in a cross-sector research programme co-ordinated by Frédéric Tangy (Lentivirus unit): Bruno Hurtrel (Physiopathology of Lentiviral Infections expertise and research unit ), Pierre Langlade (Anti-viral Cell Immunity unit), Pierre Charneau (Vectorology and Molecular Virology 5-year team), Yves Jacob (Papillomavirus unit).
Initial results found in mice and primates are encouraging: humoral and cell responses (antibodies able to neutralise primary HIV isolates and killer lymphocytes) were obtained against HIV proteins after one injection of the potential HIV-measles vaccine. Animals previously vaccinated against measles were also able to be effectively immunised against HIV, which suggests that the use of these potential HIV-measles recombining vaccines in adults previously vaccinated against measles may be possible, meaning the new vaccine is not for children only.
To test the effectiveness of this immunity in terms of protection, Pasteur researchers began infectious experiments in primates: the idea is to test the ability of a potential recombining measles vaccine (using HIV proteins and the simian equivalent, SIV) to protect against infection by a chimera virus, SHIV (a SIV simian virus containing part of the genetic data of HIV). The results of these tests will be available in early 2004. If positive, Phase I clinical testing will be considered.
Selecting new potential vaccines
In parallel, the Anti-viral Cell Immunity unit led by François Lemonnier led rational research to find HIV fragments able to activate cell immunity specifically against the virus. These fragments are known as "epitopes". The first step means identifying virus sequences - potential epitopes - shared by a maximum of virus strains. We are aware that one of the problems of developing an anti-HIV vaccine lies in the extreme variability of the virus, and that one of the objectives of researchers is to develop vaccines which may protect against the majority of viruses existing in the world. This research is based on computerised data bases containing the sequences of all HIV characterised until now. Software capable of forecasting reactions allows epitopes to be identified: the presence of epitopes in the immune system depends on self-recognition molecules (normal cell) and non-self (cell infected by a virus) - "HLA" molecules -, present at the surface of the cells of the immunity system; the idea is to select virus sequences likely to attach to HLA molecules. Finally, the methods developed by the unit allow for optimised immunological capacities for certain epitopes, precisely by improving their attachment to HLA molecules.
"Humanised" mice to accelerate research
Once identified, potential epitopes are tested on mice developed in the unit and whose immune system has been partly "humanised" (their HLA molecules with epitopes are human molecules). The most immunogenic epitopes are thus selected and the aim is to assembly these epitopes to produce polyepitopes (10 - 40 epitopes) and multiply the probability of activation of the immune system. Researchers have already found potential epitopes. One of these has been combined with a protein from the hepatitis B virus (acting as a vector) in order to create a DNA vaccine. Injected in the muscle of a mouse, this potential vaccine led to long-term cell responses against most epitopes involved. Although these "humanised" mice do not allow for the protection provided by trial vaccines to be assessed - mice cannot be infected by HIV - they make the selection of potential vaccines, which are likely to be immunogenic in humans and could be subject to clinical testing, easier.
Hunting for the ideal vector
Different forms of administration for polyepitopes will be studied to find the best possible type of vaccination. The construction of potential polyepitopes, with the help of other vectors (adenovirus, lentivirus, etc.), will also be assessed in mice and primates in order to find the optimal vector before any possible clinical testing in humans.
In the Mycobacterian Genetics unit, the team of Natalie Winter suggests the use of the BCG as a vector of HIV antigens. For the moment, research focuses on the macaque model with the Simian Immunodeficiency Virus (SIV). BCG recombining strains using SIV genes were administered to macaques: they were able to provide a certain level of protection against a virulent attack by the virus. This research was undertaken in collaboration with the CEA (Atomic Energy Commission) teams at Fontenay-aux-Roses and the Medicine faculty of Paris Sud.
In the
same way, the team of Marie-Louise Michel, of the Hepatic carcinogenesis and
Molecular virology unit, and the Viral Immunopathology laboratory managed
by Yves Rivière, use the protein of the surface of the hepatitis
B (HBs) virus as a vector to present HIV fragments or the simian equivalent,
SIV, to the immunity system. The injection of coding DNA vectors for SIV/HB
chimerical proteins combined with live viral vectors (MVA vaccine virus) led
to significant protection against infection by a Simian Immunodeficiency
Virus (SHIV) in immunised macaques. In animals vaccinated with
this combined protocol, T CD4+ cells remain constant.
Vaccination testing is undertaken with the support of the ANRS and in collaboration
with the CEA teams at Fontenay-aux-Roses and B. Moss in the NIH (USA).
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We reiterate that, beyond producing vaccines, many Pasteur teams focus on different aspects of HIV research and the infection caused by HIV. More fundamental research than that mentioned here may also contribute to further progress in developing a vaccine against AIDS.