Highly effective vaccine might delay AIDS by twelve years, but postpone starting treatment by only three years

A vaccine that could induce strong cell-mediated immune responses to HIV might delay the onset of AIDS by twelve years when compared to no vaccination, researchers from vaccine developer Merck and several US universities have calculated. Their projections are published in the February 15^th edition of the Journal of Infectious Diseases.

Merck is one of several research groups working on an HIV vaccine that could stimulate strong cell-mediated immune responses to the virus. The vaccine may not be able to stop HIV infection, but it could allow the immune system to mount a very strong response to HIV, leading to a much lower viral set point after infection and much slower disease progression.

The viral set point represents a stand-off between the virus and the immune system – it’s the point at which the immune system has brought viral load down to its lowest level without the aid of medication. The set point is usually reached six to nine months after infection, and the level of the set point can be used to predict the risk of developing AIDS within a specific period.

After reaching the set point viral load will gradually rise, and the rate of increase is determined in part by the ability of HIV to mutate to evade cellular immune responses targeting viral proteins. Vaccine designers now know that the proteins which vary least between viral strains – the so-called `conserved` regions of the virus – are the areas that can be most profitably targeted by an HIV vaccine.

However, they are still trying to identify which proteins vary least between viral strains, and which cellular immune responses to these proteins most strongly predict long-term suppression of viral load at levels associated with long-term non-progression of HIV infection (below 1,500 copies/ml).

Clinical trials of the Merck HIV vaccine that seeks to raise cellular immune responses are now underway, but it is still unclear whether viral load reductions after seroconversion in vaccinated individuals will have the same prognostic significance as changes in unvaccinated individuals.

In order to provide a baseline for future research, researchers from Merck and several medical schools in the United States carried out an analysis of data from the Multicenter AIDS Cohort Study (MACS), looking at the association between varying degrees of viral load reduction approximately nine months after infection and subsequent risk of disease progression.

Natural history data from 311 seroconverters with available viral load data were used to model the effects. None had taken antiretroviral therapy prior to the viral load measurements, which date from samples collected between 1984 and 1990 in men whose date of seroconversion could be narrowed down to within one year by use of antibody testing. A median of 5.5 years of follow-up was available on participants.

The effects of varying reductions in the set point were compared with the outcomes of individuals who had a viral set point around 30,000 copies/ml, which corresponds to the median set point observed across a number of cohort studies for adult males.

The table below shows the estimated effects of four lower set points on varying parameters of HIV disease progression using data from the cohort. A clinical indication to start treatment was defined in this analysis as a CD4 cell count below 350 cells/mm³ or clinical symptoms or a viral load above 55,000 copies/ml.

The authors says that similar analyses need to be conducted in women and in cohorts infected with non-B HIV subtypes in order to identify any ethnic or gender differences that might affect interpretation of subsequent clinical trial results.

They also caution: “Although the results of this study strongly suggest that a vaccine that reduces viral load set point by at least 0.5 log₁₀ will reduce the risk of disease progression, it should be noted that in order for clinical effects of this magnitude to occur, the vaccine would need to mimic cell-mediated immune-based responses seen in natural infection. It is possible that vaccine efficacy could wane over time due to the emergence of viral escape mutants.”