Carolyn Williamson, University of Cape Town Robert Johnston, University of North Carolina Michelle Galloway, Medical Research Council, SA
Why a vaccine?
It's 20 years since the first evidence of acquired immune deficiency syndrome (AIDS) and the discovery of the virus that causes this clinical syndrome, the human immunodeficiency virus (HIV). Since then, over 60 million people have become infected, 40 million of whom are currently living with HIV - 70% of them in Africa. Southern Africa is the worst affected region with South Africa, Zimbabwe and Botswana reporting infection rates of over 25% of women attending antenatal clinics in the public health services.
Vaccines are generally accepted as the most effective public health intervention for controlling viral epidemics. This has been illustrated by the elimination of other viral infections such as smallpox. In 1967 there were 10 million cases of smallpox worldwide but after an organised global vaccine programme the last case was reported in 1975.
What is a vaccine and what will an HIV vaccine need to do?
Vaccines arm the body so that it can defend itself against an invading infectious agent (or pathogen) by stimulating an effective immune response. In HIV vaccines, two types of responses against HIV antigens are important, the antibody response and cellular immune response. Antibodies bind to the outside of the virus with the aim of 'neutralising' the virus and preventing it from infecting new cells. The cellular response includes cells called T-cells which act as either 'helpers' or 'killers'. The T-helper cells play a central role by regulating the immune response and the killer cells (cytotoxic T-cells or CTLs) kill virus-infected cells, preventing the production of more virus. Although both arms of the immune response are thought to be necessary, the CTL response may be more important for controlling HIV.
Challenges in HIV vaccine development
Developing an effective vaccine against HIV has proven to be a difficult task. The virus is a challenging enemy that has evolved many ways to avoid detection and elimination. Vaccines against other diseases work by rapidly eliminating infection once it occurs so that the person doesn't get sick. Because HIV incorporates its genetic material into the genetic material of an infected person, established HIV infection is impossible to eliminate. An ideal HIV vaccine therefore would provide sterilising immunity, i.e. completely blocking infection. This may be difficult to achieve and if this is not possible, then an HIV vaccine that assists the body to control virus replication could keep the infected person from getting sick and might also prevent transmission of the virus to other persons. HIV continually changes, and evolves, posing a major challenge to vaccine developers. Based on its genetic sequence, HIV-1 has been grouped into different subtypes named alphabetically (subtypes A to K). Ideally, a vaccine needs to protect against multiple subtypes, especially in Africa where there are a high number of subtypes circulating. In southern Africa the epidemic is primarily caused by subtype C virus (estimated to be responsible for over 95% of new infections in the region) and therefore vaccine development in this region is focusing specifically on this subtype.
Another challenge is defining the immune responses that predict vaccine efficacy. Although there is evidence that both antibodies and CTLs provide protection, it's not clear if both responses are necessary and what level of response is needed. Designing a vaccine that stimulates an effective antibody response to neutralise the virus is difficult due to the nature of the viral envelope - the outer coat of the virus that neutralising antibodies target. It's also not clear how strong and broad the cellular immune response needs to be to provide protection. This makes it difficult to predict whether a vaccine will work. The lack of an ideal experimental animal model of HIV infection has also hampered progress.
Is an HIV vaccine feasible?
Several groups of individuals are being studied who provide hope that resistance to HIV infection is possible. There are rare individuals who, despite repeated exposure to HIV, appear able to resist infection. There are also HIV-infected individuals who remain disease free for over 15 years (so-called long-term non-progessors), suggesting that it's possible to control virus replication. Research is aiming to determine the mechanisms of resistance in these groups as these might provide the key to an effective vaccine.
Although there is no successful HIV vaccine yet, some candidate vaccines have been shown to protect against AIDS in animal models. So, despite the difficulties, there is optimism that developing an effective vaccine against HIV is feasible.
Replicon vaccines: A good candidate?
As it takes years to develop and test a vaccine, and because no one knows what approach will work, different types of candidate vaccines are being developed around the world.