In 2009, a slight but statistically significant level of protective efficacy was reported from a large HIV vaccine trial conducted in Thailand. The trial, named RV144, involved a combination of an ALVAC canarypox vector encoding HIV antigens and a gp120 protein boost (AIDSVAX). Receipt of the vaccines was associated with a 31.2% reduction in the risk of HIV acquisition in a community sample of 16,402 adults aged between 18 and 30; the results were published in the New England Journal of Medicine. Ever since that time, plans have been afoot to assess whether the results can be duplicated or improved upon in other settings, and today the National Institute of Allergy and Infectious Diseases (NIAID) announced that a new efficacy trial is going to be launched in South Africa later this year.
There are a number of reasons for the lengthy interlude between the trials. The company that manufactured the original AIDSVAX protein boost no longer exists, and a replacement gp120 protein vaccine—derived from HIV-1 clade C, the prevalent virus in South Africa—has had to be developed and tested in preliminary studies. Sanofi Pasteur, the manufacturer of the ALVAC vector, also created a clade C-based version of their vaccine.
The final hurdle that the new ALVAC + gp120 protein combination had to surmount was an assessment of vaccine-induced immune responses in a trial conducted in South Africa by the NIAID-sponsored HIV Vaccine Trials Network (HVTN), dubbed HVTN 100. Researchers developed several criteria to be met in order to justify launching an efficacy trial, based on immune responses that were associated with reduced risk of HIV acquisition in RV144. These criteria were described by Glenda Gray on a webinar hosted by AVAC around this time last year (slides and audio from the call are available on the AVAC website) and involved comparing antibody and CD4 T cell responses to vaccine antigens in HVTN 100 and RV144 in order to ensure they were similar. The immune responses were also required to reach a level that, based on data from RV144, would be predictive of a 50% reduction in HIV risk for at least two years.
Today’s NIAID announcement states that these criteria were met in HVTN 100, giving the green light for a 5,400-person efficacy trial (HVTN 702), which is slated to begin in November. Participants will be randomized 50:50 to receive either active vaccines or placebo. Immunizations with the ALVAC vector are scheduled at months 0 and 1, with both ALVAC and the gp120 protein boost given at months 3, 6 and 12. The immunization at month 12 represents an addition compared to the schedule used in RV144, due to evidence that protective efficacy may have been as high as 60% at one year of follow up before waning to the final result of 31.2%. Three interim analyses of HVTN 702 are planned, two in 2018 and another in 2019, which will assess whether the trial should continue or be stopped (due to either evidence of efficacy or lack of efficacy). If the trial proceeds, the final efficacy analysis will take place in 2020.
While it is critically important to understand whether the promising results of RV144 can be duplicated or improved in other populations, there are reasons to be cautious about expectations for HVTN 702. Most RV144 participants were at a relatively low risk of HIV infection, and there was evidence that the vaccine regimen did not perform as well in those at highest risk. Furthermore, studies indicate that background levels of immune activation and inflammation are elevated on the African continent and likely contribute to higher rates of HIV transmission; for example, mucosal inflammation emerged as a significant correlate of HIV acquisition risk in a microbicide trial conducted in South Africa. It is not known if inflammation or other factors (such as co-infections) could act as countervailing forces and undermine potentially protective vaccine-induced immune responses, but this is the type of question that HVTN 702 should be able to shed light on.
An area of possible controversy related to HVTN 702, or any new trial of HIV prevention strategies, is the provision of pre-exposure prophylaxis (PrEP) to participants. The antiretroviral drug combination pill Truvada received approval as PrEP in South Africa in November 2015. The NIAID Q&A about the HVTN 702 trial issued today states:
“study participants will be referred to available local programs where they may obtain the oral medication Truvada to take daily for HIV prevention, a highly effective practice called pre-exposure prophylaxis (PrEP). HVTN 702 has been designed so investigators will be able to discern a preventive effect from the vaccine regimen even if some participants are taking PrEP.”
This is the same approach taken by recently launched prevention trials involving infusions of the anti-HIV broadly neutralizing antibody VRC01. It could be argued that Truvada should be offered through the trial itself, but it is a difficult issue to wrestle with, and it appears that the Institutional Review Boards responsible for reviewing and approving the study protocols have found the compromise of referring participants to external sources of PrEP to be acceptable, at least at the current time.
A recent slide presentation by Glenda Gray describing HVTN 702 can be found on the World Health Organization website. AVAC is hosting a webinar to discuss the launch of the trial on May 31st at 10am EST/4pm South Africa time (register at this link).