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AIDS 2016: New HIV Vaccine Efficacy Trial Set to Start this Year

A new efficacy trial for an HIV vaccine -- only the seventh ever conducted in the history of the epidemic -- will start this November, delegates heard at the 21st International AIDS Conference (AIDS 2016) taking place this week in Durban. The HVTN 702 study will enroll 5400 men and women in southern Africa, and is planned to last for 4 years. In May it was announced that a pilot study, HVTN 100, had met the criteria for the vaccine being taken forward into the larger study. But this week was the first time researchers revealed how well it had met those criteria.

[Produced in collaboration with Aidsmap.com]

Presenter Linda-Gail Bekker from the Desmond Tutu HIV Foundation told the conference that the story of HVTN 100 goes back to 2009, when the RV144 vaccine study was the first to show signs of efficacy, with 31% fewer infections in people given the vaccine than in those given placebo. Subsequent investigations showed that the vaccine’s effects were real and due to an unpredicted kind of immune response.

However RV144’s effect was very weak and tailed off rapidly over time; at the end of the first year it was 60%, but a post-hoc analysis showed that after 2 years it had stopped contributing any further degree of protection against HIV.

There was clearly a need for a more potent vaccine of the same type. It took a long time to develop this, partly because few people had expected RV144 to be successful and partly because a decision was taken to refashion the vaccine so it was tuned to HIV subtype C, the predominant subtype found in southern Africa, rather than to subtypes B and E, the ones most common in Thailand where RV144 was conducted.

HVTN 702 will be conducted in countries where subtype C predominates, namely southern Africa up to Tanzania. It is not known if it will have cross-efficacy against other HIV subtypes.

Like RV144, the HVTN 100 vaccine consisted of 2 different kinds of shot; a "prime" vaccine, ALVAC, consisting of HIV subtype C components contained inside a vector, the shell of another virus, canarypox, that gets into cells but is harmless to humans; and a "boost" shot of naked gp120 envelope protein from HIV, coupled with an adjuvant or chemical booster called MF59.

The HVTN 100 vaccine was given in 5 doses; there are 2 initial shots of ALVAC a month apart, then shots of both components at months 3, 6, and 12. A total of 210 people were given the actual vaccine and 42 got a placebo. The trial was conducted at 5 centers in South Africa.

The HVTN 100 study is still going on; the immunogenicity results presented here come from only 6.5 months into the study, with the 12-month booster not yet given, and primary results remain blinded. However, HVTN has met its secondary objective of passing the immunogenicity criteria that would lead to the vaccine being carried forward into HVTN 702.

These 4 criteria, with the actual responses, are as follows:

Criterion: The vaccine produces an antibody response to the HIV env protein in 75% of subjects.

Response: It produced an antibody response in 100% of subjects.

Criterion: The vaccine produced an antibody response to the HIV env protein that was at least 1.5 times greater than that seen in RV144.

Response: The antibody response was in fact 3.6 to 8.8 times larger than that seen in RV144, depending on the specific HIV antigen responded to.

Criterion: The vaccine produced a CD4 response to the vaccine in at least 36% of subjects’ CD4 cells, and non-inferior to RV144.

Response: In fact, a CD4 response was seen in 58% of subjects, 16% more than in RV144.

Criterion: At least 63% of subjects given vaccine show an antibody response to the V1 and V2 regions of the HIV envelope protein. This criterion is particularly important as it was this response that correlated with efficacy in RV144. The 63% was chosen as the degree of response that would predict a 50% efficacious vaccine that sustained its efficacy for at least 2 years.

Response: In fact there was a cumulative response to the V1 and V2 regions in over 80% of subjects.

Bekker showed evidence of other immunogenicity that was not included in these original criteria, including the fact that the HVTN 100 vaccine produced nearly twice as many CD4 cells displaying "polyfunctionality," a versatile immune response to HIV that predicts significant efficacy.

In short, the HVTN 100 vaccine comfortably out-performed RV144, at least in terms of immune indicators that are regarded as correlates of efficacy. However, there is no substitute in vaccine trials for actually giving it to large numbers of at-risk people and measuring how many, if any, infections it prevents. There have been disappointments before, as when the human response in the STEP trial, which closed due to lack of efficacy in 2007, did not match that predicted by animal models and did not correlate with efficacy.

We can say, therefore, that the signs are very promising that the HVTN 702 trial may show significant efficacy, but we have been unpleasantly surprised before, and may not know the full results for 4 years.

7/22/16

Reference

L-G Bekker, F Laher, Z Moodie, et al. Meeting the “Go” criteria: immunogenicity from HVTN100, a phase 1-2 randomized, double-blind, placebo-controlled trial of clade C ALVAC (vCP2438) and bivalent subtype C gp120/MF59 in HIV-uninfected South African adults. 21st International AIDS Conference. Durban, July 18-22, 2016. Abstract TUAX0102LB.