In early February, we reported on the early termination of the HVTN 702 HIV vaccine trial in southern Africa for lack of efficacy. On March 8 at the Conference on Retroviruses and Opportunistic Infections (CROI), two investigators explained why researchers thought the vaccine might work and why it didn’t do so, after all.
HVTN 702 was built on the only randomized, controlled trial of an HIV vaccine that has shown at least some efficacy, the RV 144 trial in Thailand, Lawrence Corey, M.D., of the Fred Hutchinson Cancer Research Center explained. During that trial’s first year, efficacy was 50%, but it waned thereafter. If the vaccine’s durability and coverage were improved, it just might prevent enough seroconversions to be worth rolling out, researchers thought. They tweaked its components for the HIV subtype most common in southern Africa and added a sixth shot 18 months after the initial “prime” vaccination.
Two smaller studies evaluated that modified vaccine’s pharmacological properties. The latter of these, HVTN 100, showed it to be more immunogenic than the version used in Thailand. Other parameters, including functional antibody and other responses, were also better. Thus, a decision was made to move forward with a large-scale trial of the tweaked version in southern Africa—HVTN 702.
So why didn’t it work? Researchers are still trying to figure out the details, but one possible explanation stems from the greater genetic diversity of the clade C virus common in southern Africa compared to the clade B common in Thailand. This might make the “real world” HIV strains that HVTN 702 participants encountered too far removed genetically from the strains against which the RV 144–based vaccine works. The Thai trial had also shown a difference in protection levels between women at high and low risk for seroconversion. “The force of HIV is much greater in South Africa than in Thailand,” explained Corey. Thus, vaccine immunogenicity may still have been too low for the more frequent exposure to the virus at higher viral titer levels experienced by participants in southern Africa compared to those in Thailand.
HVTN 702 trial chair Glenda E. Gray, MBBCH, FCPaed (SA) , from the University of the Witwatersrand in Johannesburg , South Africa, provided more detailed data on that trial. It enrolled 5,404 participants, with 5,383 in the modified intent to treat cohort. Trial design capped the number of women at 70% of total enrollment. Ultimately, 3786 women were enrolled, 141 of whom became pregnant during the study, evenly split between the two arms. Half of them had used oral hormonal contraceptives, and 25 reported using male condoms, most often together with another contraceptive method.
By the January 2020 interim analysis that caused the trial termination, 62% of participants had been in the study until after their final vaccination, at 18 months after their initial prime shot. HIV prevention care for both arms included risk-reduction counseling, referral to medical male circumcision, provision of condoms, free pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), and treatment for sexually transmitted infections. However, participants infrequently used PrEP or PEP, and half of the men were already circumcised at study entry.
HIV incidence rates at 24 and 36 months after initial enrollment were 3.3/100 person years in both arms. However, almost 50% of all seroconversions occurred during the trial’s rollout, Gray pointed out, with 113 of the 267 seroconversions happening between shots 1 and 3 . Fifteen percent of those who acquired HIV had received all six vaccinations (two prime and four booster shots), and most who seroconverted were up to date with their HIV vaccination at the time of HIV acquisition. Thus, the low rate of completing the vaccination series is mainly due to seroconversions, rather than lack of adherence to the regimen, Gray explained.
Although the frequency of seroconversions didn’t differ by arm, it did differ by sex at birth: the HIV incidence rate among women was around 4%, compared to 1.2% among men, reflecting the reality of the epidemic in sub-Saharan Africa. “The HIV incidence in RSA [Republic of South Africa] especially amongst young women remains unacceptably high and is catastrophic for epidemic control,” Gray commented.
Other vaccine trials are ongoing. The first set of these, collectively called Antibody Mediated Prevention (AMP) trials, will end in August of this year. Two other studies, Imbokodo and Mosaico, use a “mosaic” approach that works against a variety of HIV strains. Imbokodo is fully enrolled, and Mosaico is still enrolling participants. Results are expected in 2021 and 2023, respectively. Other attempts at a vaccine are even further down the pipeline, with one trial, PrEPVac, expected to start soon and other approaches still in laboratory development.
“The bottom line from Dr. Corey’s and Dr. Gray’s presentations is that we must not be discouraged, but remain firm in our commitment to develop a vaccine,” session moderator Susan P. Buchbinder, M.D., of the San Francisco Department of Public Health, concluded.