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What a vaccine can do
A vaccine is a substance or organism that gives rise to specific immune responses. These may take the form of antibodies or cellular immune responses (CD8 or "killer" T-cells) or both. Responses may operate in specific locations - such as mucosal surfaces, thought to be important for sexual transmission - or throughout the body. Those immune responses may then protect against disease in three different ways.
Preventing infection
Firstly, a vaccine might prevent a person becoming infected with HIV. This may require that the virus is prevented from infecting any cells, which would depend on producing sufficient antibodies that can 'neutralise' the virus (as distinct from merely binding to it like those detected in antibody tests).
Alternatively, an early HIV infection might be cut short with neutralisation of the virus and the death of those cells that had been infected. This may require a cellular immune response as well as antibodies.
Measuring this effect is simple in principle. A population of individuals at risk is recruited into a clinical trial, and a proportion are 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.
The prototype for a trial to measure this was the VaxGen Phase III trial discussed below, where the primary endpoint was the number of people who became HIV positive in the vaccine recipient group compared to the placebo recipient group.
Delaying illness
Secondly, a vaccine might delay or prevent the progression of illness, despite HIV infection. This effect is likely to depend on 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 they would be detected using viral load tests, comparing individuals who had received a vaccine and then went on to be infected to others who became infected without first having received the vaccine.
A statistician working for the US HIV Vaccine Trials Network has argued that an initial trial might still randomise people individually, in a similar design to the AIDSVAX trials, to receive vaccine or placebo. In a population with a 2% risk of HIV infection every year, it should be possible to get answers from a trial that recruited 5,000 people over 12 months and followed them for another four years. This would show if the vaccine did, in fact, have an impact on HIV infection rates – and would be large enough to tell the difference between a vaccine that was 30% effective and one that was 60% effective.
One of the possible differences between vaccines that prevent infection and those which may influence the later course of disease, is that the former can be boosted to extend their effect while the latter probably cannot be boosted, once the person is infected with HIV. (Some might question this, especially if the person is treated with ARVs.)
With no protection against infection, this trial design would also make it possible to compare two groups of people with HIV for an average follow-up of around 18 months. This might be long enough to look at some markers of progression (viral load and falling CD4 counts) although this could be obscured by treatment. As follow-up increased, the likelihood of treatment obscuring any effect of the vaccine could become greater (Self). (It might also be reduced, if treatment is driven by CD4 counts, since better control of the virus should lead to deferred treatment.)
A vaccine effect delaying illness could, according to the same group, be obscured if there is some degree of prevention of infection combined with an effect delaying illness. People who become infected despite vaccination might then form a distinct population with a less effective immune response (or exposed to more virulent viruses) compared to those who were completely protected against infection. When these two distinct vaccinated subgroups are compared to people who have received only a placebo, then although there will be a larger proportion of infected individuals among the placebo recipients they could become ill more slowly than the infected vaccine recipients despite a real protective effect of the vaccine for the latter. It could therefore appear that the vaccine made things worse for those who became infected despite vaccination, when the reverse was true (Hudgens).
If it were possible to show that the need for antiviral treatment was delayed through vaccination, hopefully by years, at least this would provide a clear cost-benefit rationale for providing such a vaccine to populations at risk.
A vaccine in this category might also, in principle, be directed at making HIV disease easier to treat, for example, by specifically blocking the development of drug-resistant viruses. It might also be possible to direct the immune response against specific parts of the virus that are responsible for its virulence, so that viruses which escape from the vaccine-induced response cause less damage than would otherwise be the case.
Blocking transmission
Thirdly, a vaccine might reduce the chance of onward HIV transmission. For example, from a mother to her baby, or through sexual transmission. This, like the second effect, would be likely to follow from a reduced viral load seen in vaccinated individuals compared to those who had not been vaccinated.
Mother-to-baby transmission could be studied at an individual level, if a sufficiently large number of girls and young women could be enrolled in a trial before becoming either HIV positive or pregnant.
Sexual transmission could be studied by enrolling discordant couples into a study (Barth-Jones). although such couples are likely to be highly motivated to use condoms, especially when provided with condoms and appropriate counselling. Other important factors such as prevalence of other sexually transmitted infections may similarly not truly represent the population at risk.
The greatest value of a vaccine with 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 (Self). 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.
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.
This proposed trial design sets up a number of challenges. Results could vary, as for different STI control strategies, depending on the maturity of the epidemic. The size of the communities compared, the actual level of vaccine coverage achieved, and the extent to which community membership and patterns of sexual mixing remain stable over the period of the study, may all be issues. So, too, is the question of how and from whom consent should be sought for such a study.
Nonetheless, this proposal would eliminate the conflict sometimes perceived between treatment and care, including ARV access, and prevention, including vaccines. It could also strengthen the case for providing HIV/AIDS treatment and care in smaller and more rural communities, where such trials would be most likely to give clear results.
In practice, this would probably need to follow on after a trial which had demonstrated a reduced early viral load in people infected with the virus, and in which lower levels of the virus in semen and/or vaginal fluids can be linked to vaccination.
Regardless of whether such trials can be carried out, this proposal rightly draws attention to the ultimate test of the value of such a vaccine. This must be whether it reduces the burden both of disease and of its treatment, in populations where it is made available as compared to those where it is not.