THE ROLE OF VACCINE PERSISTENCE IN PROTECTION CONFERRED BY LIVE ATTENUATED SIV

The World Health Organisation recognises HIV/AIDS as the number one infectious disease in the world. Doctors and scientists know that the best way to stop this disease would be to develop a vaccine to stop the 14,000 new infections with AIDS virus that occur each day worldwide.

The difficulty is that scientists do not know whether an AIDS vaccine needs to stimulate the production of antibodies, molecules in the blood that recognise the virus and stop it from infecting new cells or killer T cells that eliminate virus infected cells before the infection spreads further. Alternatively the vaccine may need to do something different to be fully effective.

The team at NIBSC are studying an animal model of HIV and have found that animals vaccinated with a disabled form of the virus first are resistant to disease causing strains. They are collaborating with scientists in Amsterdam who have a genetically engineered AIDS virus that can only grow if it is given a special drug. The team at NIBSC will use this new virus to understand how the disabled AIDS virus works as a vaccine. That information will put us one step closer to the vaccine that the world desperately needs.

A safe and effective vaccine that will prevent infection with and the transmission of HIV is urgently needed to control the AIDS pandemic. However, progress has been hampered by the absence of a clear paradigm of the types of host responses required to prevent or clear infection. Using simian models of AIDS, the most potent vaccine protection has been obtained by vaccination with live, attenuated simian immunodeficiency virus (SIV). However, attempts to characterise the mechanism of protection have, so far, failed. The purpose of this proposal is to investigate the role of the persistence of the attenuated vaccine virus in the vaccine protection observed. To do so, we propose to collaborate with a team led by Prof B Berkhout at the Amsterdam Medical Centre, The Netherlands, to establish, in cynomolgus macaques, a model using a conditional, live, attenuated SIV vaccine that will enable us to modify vaccination schedules and allow us to dissect the process of vaccination. Careful molecular engineering by the Dutch team has yielded a virus that is absolutely dependent upon the presence of the antibiotic doxycycline for replication in vitro. The team at NIBSC will be the first group in the world to use this virus for studies in vivo. We propose to investigate: (1) the kinetics of replication of this virus over 25 weeks in a group of macaques treated with doxycycline. (2) the kinetics of virus replication decay following withdrawal of doxycycline 3 weeks after inoculation of the virus. (3) adaptive immune responses and other host responses (eg. innate immunity, occlusion of viral receptors and depletion of target cells) in groups vaccinated for either 25 weeks or 3 weeks whilst under continuous treatment on doxycycline and compare these responses with those in a group vaccinated for 3 weeks in the presence of doxycyline before withdrawal of the antibiotic for a further 22 weeks. (4) the ability of the 3 vaccine groups described above to prevent and/or control infection following intravenous challenge with a heterologous wild-type SIV stock. The successful outcome of this study will be the establishment of a novel simian model for dissecting host responses to vaccine protection mediated by live attenuated SIV. In addition, we shall have determined the duration of vaccination required to protect against wild-type virus challenge and, critically, whether persistence of the vaccine virus is central to this protection.