How a vaccine might work

A vaccine could protect against HIV in several ways. Firstly, it might prevent a person becoming infected with HIV in the first place (sterilising immunity). Measuring this effect is simple in principle. A population of individuals at risk is recruited into a clinical trial, and a proportion is vaccinated. After follow-up for a number of months or years, the number of new infections in the vaccinated group is compared to the number in a control group. If there are fewer infections in the vaccinated group, this may be evidence for the efficacy of the vaccine.

Vaccines that generate sterilising immunity usually do so by stimulating the humoral immune response and generating antibodies to the pathogen involved.

The prototype for a trial to measure this was the VaxGen Phase III trial discussed later¹ where the primary endpoint was the number of people who became HIV positive in the vaccine recipient group compared to the placebo recipient group.

Secondly, a vaccine might delay or prevent the progression of illness, despite HIV infection (functional immunity). This means in some cases that recipients might test HIV-positive, if certain types of antibody response were generated, but might never suffer immune depletion or progress to AIDS, or do so extremely slowly. This effect is likely to be the one created by a vaccine that generates a cellular immune response directed against HIV-infected cells. There is evidence from animal studies that such effects can be achieved.

In a clinical trial an effect would be detected using viral load tests, comparing individuals who had been infected after taking a vaccine with those infected without first having received the vaccine.

Extracting the true protective effect of a vaccine that delays progression is obviously more difficult, as the ultimate test of efficacy would be time to the development of AIDS, which could take decades. However surrogate markers such as the slope of CD4 decline, or a reduced viral load, in people who became infected with HIV during the trial could be used.

Thirdly, a vaccine might reduce the chance of onward HIV transmission, for example to a sexual partner or from mother to baby. Vaccines, of course, eventually do this anyway, and indeed the success of many vaccines in containing disease depends on the generation of ‘herd immunity’ where few people remain vulnerable. A cellular HIV vaccine could also do it, however, in a similar way to widespread HIV treatment, by generating a reduced viral load in vaccinated individuals compared to those who had not been vaccinated.

The greatest benefit from a vaccine would be if it reduced viral load in vaccinees in the period immediately after infection and before antibodies were produced. If so, this should be reflected relatively rapidly in lower rates of new HIV diagnoses over the course of the study, in communities that have received the vaccine compared to those which have not.

The greatest value of a vaccine, which had this as its main effect, would be seen at a population level. The ideal way to test it would therefore be to compare populations in which a vaccine is available with those in which it is not. It would be necessary to ensure a continuing high uptake of HIV testing, which is likely to depend on excellent and expanding access to treatment. The proper comparison would then be between populations, all of which had high levels of access to treatment, some of which were also provided with a vaccine and in which the majority of the HIV-negative population were persuaded to take that vaccine.

The success of a clinical trial based on this principle would depend on identifying and randomising populations which were large enough for most sexual contact to be taking place within them but small enough for the trial to be feasible.