HIV immunology: what lessons can we learn from recent vaccine trials?

AuthorKelleher, Peter
PositionLEADING ARTICLE - Human immunodeficiency virus - Report

Results from two large HIV vaccine studies, the STEP and RV144 trials, gave surprising and divergent results that have raised more questions than answers in efforts to understand the immunology of HIV-1 infection and to develop successful vaccines against this condition.

The STEP trial was a double-blind Phase 2 study, in which 3000 high-risk healthy uninfected volunteers were randomly allocated to receive three injections of an adenovirus serotype 5 viral vector expressing three HIV-1 genes (gag, pol, nef) or placebo [1]. The aim of the study was to test the capacity of the vaccine to reduce acquisition of HIV-1 infection or to decrease viral load set-point in vaccinated individuals who subsequently had breakthrough infection. A major issue for this vaccine was the high prevalence of adenovirus-specific antibodies as a result of prior exposure to the virus, particularly in sub-Saharan Africa, which would have been expected to lead to reduced immunogenicity.

The STEP trial was stopped early when a planned interim analysis showed vaccinated trial participants with high adenoviral antibody titres had increased rates of HIV-1 acquisition compared to subjects with low or absent adenoviral antibody titres [2]. The adenoviral 5 HIV-1 gag/pol/nef vaccine induced strong, durable HIV-1-specific CD8 and CD4 immune responses in a large proportion of vaccine recipients; however, there was no difference in magnitude and quality of CD8 T cell immunity between vaccinated persons who developed HIV-1 infection and those who did not [3]. Finally, viral load in vaccine recipients with HIV-1 infection was similar to that observed in subjects who were allocated to the placebo arm [1].

The results of the STEP trial have raised a number of critical issues for the field of HIV-1 immunology, namely the interaction between immune responses to viral vector and HIV-1 immunogens, the utility of currently used immune monitoring assays to measure potential correlates of protective HIV-1 immunity and the suitability of nonhuman primate models of infection to guide the development of HIV-1 vaccines [4].

The RV144 trial enrolled 16,402 low-risk subjects in Thailand into a multicentre double-blind placebo-controlled efficacy study. Vaccine recipients received, over a 6-month period, four doses of a canarypox viral vector. It encoded the HIV-1 subtype B gag and protease proteins and a chimeric envelope protein consisting of subtype E gp120 linked to subtype B gp41 domain (ALVAC). It was designed to prime HIV-1-specific cell-mediated immunity and was then followed by two injections of a recombinant glycoprotein gp120 subunit vaccine containing concentrations of subtype B and E antigens designed to boost HIV-1 cell-mediated immunity and stimulate neutralising HIV-1 antibodies (AIDSVAX) [5]. The HIV-1 immunogens were chosen to match strains circulating in North America and Thailand.

The aim of the study was to determine if this prime boost vaccine combination reduced HIV-1 infection and early HIV-1 viraemia. The decision to proceed with the study was highly controversial as a previous version of the AIDSVAX failed to show any benefit in two previous studies and the ALVAC was considered be insufficiently immunogenic to proceed to an efficacy trial [6].

The results of RV144 showed that the prime boost HIV-1 vaccine combination led to a modest reduction (26-31%) in acquisition of HIV-1 infection and when subjects with HIV-1 infection at the time of randomisation were excluded, the reduction in rate of new HIV-1 infections in vaccine recipients was statistically significant (P=0.04). The vaccine did not have any effect on early HIV viral load or CD4 T cell count in vaccinated subjects who eventually became infected. This suggests that vaccination may have induced good mucosal immune responses that do not influence HIV-1 replication in peripheral blood.

As with the STEP study, the results of RV144 have significant implications for HIV-1 immunology and vaccine research which include an opportunity to identify markers of protective immunity, the need to study HIV-1-specific immune responses in mucosal specimens, a re-evaluation of the role of innate immunity in control of HIV-1 infection and agreement on laboratory tests that could be used to look for correlates of protective immunity. In addition, follow-up studies of the RV144 will need to answer a number of questions, such as:

* Are the needs for protection against HIV-1 transmission different in high-risk as opposed to...

To continue reading

Request your trial