The early termination of the Mosaico HIV vaccine trial due to lack of efficacy was announced a little over a month ago, on January 18. Yesterday at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, preliminary details of the results were disclosed in a short presentation by Susan Buchbinder.
As outlined at the time of the original announcement, the Mosaico trial enrolled cisgender men and transgender people who have sex with cisgender men and/or transgender people at sites in Argentina, Brazil, Italy, Mexico, Peru, Poland, Puerto Rico, Spain, and the USA. Most participants (91.5%) identified as male, but the researchers were able to enroll a high proportion of transgender women (5%) in addition to transgender men, gender queer, and gender variant or non-conforming participants. The breakdown by race showed that white (44.5%), multiple races (41.8%), Black or African American (7.7%), and American Indian or Alaska Native (3.1%) were most frequently represented with the majority (86.6%) of participants of Hispanic or Latino ethnicity.
The Mosaico study employed a novel design that enrolled people at high risk for HIV infection who'd chosen not to use oral pre-exposure prophylaxis (PrEP). Counseling about PrEP continued throughout the trial, and participants could change their minds and initiate PrEP without being disenrolled. Buchbinder showed that PrEP uptake increased over time, from 1.8% during months 1-3 to 10% by months 18-21.
The vaccine regimen administered in Mosaico proved safe, with the most common side effect being the typical local and systemic reactogenicity that accompanies the mounting of an immune response. There were no thrombotic events with concurrent thrombocytopenia, which have been reported for a COVID-19 vaccine that uses a similar adenovirus serotype 26 vector. There were eight deaths unrelated to trial participation (five in the placebo and three in the vaccine arm) which may be an indication of the vulnerability of the study population. Causes were not provided so it’s not known yet if COVID-19 was a contributor (the pandemic emerged around the same time as Mosaico opened, causing some delays to enrollment).
The incidence of HIV infection among vaccine and placebo recipients was indistinguishable: there were 113 cases of HIV acquisition in each group, which included 1938 and 1940 evaluable participants, respectively. This equated to an HIV incidence of 4.1 per 100 person-years in both arms of the trial.
The highest rates of HIV acquisition were in the 411 participants aged between 18 and 20; the incidence in this group was over 5 per 100 person-years. Most enrollees were in Latin America (3218 out of 3887 participants in total), which had the highest geographic HIV incidence of 4.7 per 100 person-years in the placebo arm and 4.8 per 100 person-years in the vaccinees (214 HIV seroconversions in total). Buchbinder noted that these are interim results, and the final numbers may change somewhat.
The countries with the largest number of participants were Peru (1615, 41.5% of the total) and Brazil (852, 21.9%). A country-by-country breakdown of HIV acquisition events wasn’t provided but the results may echo a recently published report from the ImPrEP implementation study, which stated that: “Participants from Peru, transgender women, younger participants (aged 18–24 years), and individuals who were not White had greater HIV incidence, as well as increased odds of early loss to follow-up and lower odds of PrEP adherence and long-term PrEP engagement.” Taken together, both sets of results emphasize the urgent need to improve support for locally tailored HIV risk reduction approaches including PrEP access, in addition to advocating to ensure that long-acting injectable PrEP is rapidly made available. The most recent oral PrEP uptake figures on AVAC’s PrEPWatch website are 2,931 in Peru and 89,410 in Brazil.
Buchbinder’s presentation was followed by a talk from Larry Corey, Co-Principal Investigator of the HIV Vaccine Trials Network (HVTN), who emphasized the unique challenges HIV poses for vaccine development. The vaccine regimen in Mosaico was considered the most promising approach for inducing potentially protective non-neutralizing immune responses based on animal models, but the preponderance of evidence now indicates that it’s unlikely that this type of response can achieve efficacy.
As explained in our previous Mosaico post, the HIV vaccine field is now working to solve the complex challenge of inducing broadly neutralizing antibodies (bNAbs), which have demonstrated protective efficacy in a subset of participants in the Antibody-Mediated Prevention (AMP) studies (which delivered the bNAb VRC01 directly via infusion). There have been signs of progress and several trials are now underway to assess if it’s possible to nudge human B cells down the tricky pathway toward bNAb production. Corey noted that the proteins being delivered in these studies are best described as “reagents” rather than vaccines because the necessary components for a complete bNAb-inducing vaccine regimen have yet to be identified. Vaccines that induce other types of immunity, particularly T cell responses, are still under investigation, but Corey suggested they will almost certainly need to be part of a combination approach that includes bNAbs.
*Disclosure: Treatment Action Group receives funding from the HIV Vaccine Trials Network to support community engagement efforts related to biomedical HIV prevention research.
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