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Therapeutic vaccines
Most vaccines are given to children or to travellers before they are likely to be exposed to the agent the vaccine protects against. Some – like rabies, and like hepatitis B vaccine given to newborn infants – may be administered after exposure to a virus, but before it is fully established in the body. However, the same hepatitis B vaccines that protect infants and unexposed adults have no effect in people who are longstanding carriers of the virus.
A modern definition of a vaccine would focus on its ability to act against a disease by inducing a specific immune response to a micro-organism, a protein or other substance, or a class of cells. Thus interleukin 2, which has a variety of effects on cells of the immune system but is not specifically related to HIV, should not be described as a vaccine.
There is no strong precedent for a vaccine stopping a disease by inducing new immune responses to an established viral infection and, as already noted, some clear cases where they don't. However, the idea of a ‘therapeutic vaccine’ has been around for a long time in relation to HIV and has recently gained some credibility.
Parallel developments are taking place in other diseases such as HPV (linked to cervical and anal cancers) and HSV-2 (genital herpes). In some animal models, and in some clinical trials, it has been shown that new immune responses can be generated against established infections.
The strongest evidence so far in relation to HIV concerns a DNA vaccine based on an SIV – a monkey virus related to HIV - administered on scraped skin to SIV-infected macaque monkeys. When used in combination with antiviral treatment on a three weeks on three weeks off cycle, the vaccine seems to have enabled the monkeys to control viral load to below 200 whereas monkeys treated with the antivirals alone did not. The vaccine was given while the animals were on treatment, at the end of weeks 2 and 3 in each cycle. Another group of animals, treated with the vaccine alone, also showed some control of viral load although their CD4 count declined in a way that did not happen with the two ARV groups.
In the case of people with HIV receiving effective antiretroviral treatment, it does appear to be possible to use a vaccine to induce specific cellular immune responses to HIV although their clinical significance, if any, is unknown. The hope is, essentially, that the use of a vaccine can reduce the burden of the disease and of its treatments. For example, if it prevented or delayed the emergence of drug-resistant viruses, it would ensure that people would not have to switch treatment for any reason other than side effects. This would, on balance, be a benefit for people’s quality of life. Similarly, if it meant that people could continue to take less expensive first-line treatments rather than having to switch to more expensive drugs, this could be a major benefit to treatment programmes, especially in countries with limited resources.
A Thai trial of Remune given to people with HIV, not on antiviral treatments, seemed to show an effect in sustaining CD4 counts which might, for some people, delay the time when they would need antiviral treatment (Churdboonchart, Sukeepaisarncharoen). Either Remune or a placebo was given initially on a randomised, double-blind, basis to people with HIV with a relatively high CD4 count. The results showed a significant difference between the rates of decline of CD4 counts between the Remune treated group and the controls, with more Remune-treated people maintaining a high CD4 count. In the much longer follow-up study, where Remune was given every twelve weeks to all participants, a minority (39 people) seemed to have a stable viral load. It is hard to know what to make of these results, since they fly in the face of the main rationale for giving therapeutic vaccines to people with HIV on treatment. This latter is based on the observation that antiviral drugs seem able to suppress the virus so deeply, that the body’s own immune response to HIV declines over time.
A larger randomised placebo-controlled clinical trial of Remune combined with antiviral treatments may or may not show that progression of HIV disease is slower, that viral loads are lower or that the effectiveness of antiviral therapy is sustained for longer in those vaccinated than in those given placebos.
Remune itself has not been given to HIV-negative people, due to safety concerns. However, other newer vaccines may be more obviously suitable for preventive use. If some of these products were to receive the backing of pharmaceutical companies as therapies, credible candidate vaccines could become available for preventive trials, almost as a by-product.
Therapeutic use of vaccines, especially in conjunction with antiviral drugs, is far less problematic for pharmaceutical companies than development of vaccines for preventive use. People are willing to pay more for treatments than for any form of prevention and the ethical and other issues involved in clinical trials are considered minimal in comparison.
There are, however, at least three major risks in such a course of development.
The first is that a vaccine aimed at a therapeutic market in countries which already have access to antiviral drugs may be inappropriate for use as a preventive vaccine in another country where different viruses are circulating.
The second is that it may skew vaccine research into a narrow area, delaying the proper evaluation of entirely different vaccine designs which are less likely to be of therapeutic value but could be effective preventive vaccines.
The third is that a vaccine which is found to be ineffective as a therapeutic vaccine may be perceived as ‘useless’ to an extent that makes it impossible to evaluate it properly as a preventive vaccine.
There is therefore a responsibility on the part of the media and treatment advocates to explain the difference between therapeutic and preventive vaccines and to consider the case for each on their own merits.