Phase 3 Mosaico HIV vaccine efficacy trial stopped early due to lack of benefit

Richard Jefferys, TAG

On 18 January 2023, disappointing news was announced about the only ongoing phase 3 HIV vaccine efficacy trial, Mosaico (HVTN 706/HPX3002). [1]

A scheduled interim analysis of the results by the Data Safety Monitoring Board (DSMB) found that the vaccines were safe but there was no prospect of demonstrating protective efficacy against acquisition of HIV infection in the study population, prompting discontinuation.

No details are yet available but press releases were issued by AVAC, the HIV Vaccine Trials Network (HVTN), and the vaccine manufacturer Janssen. [2, 3, 4]

HVTN and AVAC will host a global webinar on January 25, to provide additional information. [5]

Mosaico had successfully recruited around 3,900 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. There has been widespread praise for the scale and diligence of consultations with participating communities, which contributed significantly to the design and conduct of the study.

Of particular importance, Mosaico pioneered a new approach to HIV vaccine trials by recruiting people at risk of HIV acquisition who’d chosen not to use pre-exposure prophylaxis (PrEP). Flexibility was built into the design to ensure any participants who later decided to start PrEP were provided access and allowed to continue in the study. This represents one potential strategy for addressing the ethical conundrum of recruiting people into efficacy trials of novel biomedical preventions when highly effective PrEP is increasingly available (e.g. Truvada daily pills and more recently the long-acting injectable drug cabotegravir).

The lack of efficacy is somewhat bleak news for HIV vaccine research, at least in the near term. The vaccine regimen tested in Mosaico is a prime-boost combination of viral vectors (adenovirus serotype 26) and proteins designed to induce immune responses to diverse HIV variants. The trial’s name derived from the components included in the vaccines, which were mosaics mimicking elements of HIV from multiple different global clades of the virus.

The vaccine was generally considered to represent the most promising candidate that could be created with available technology. Studies in the macaque model of infection with SIV (HIV’s simian counterpart) had demonstrated efficacy, which suggests that the relevance of such models will need to be reevaluated. [6]

Today’s news was not entirely surprising given that a very similar vaccine regimen made by Janssen also failed to demonstrate significant efficacy in Imbokodo, a smaller trial conducted among cisgender women on the African continent (see TAG’s report from September 2021). [7]

For both trials, the lack of efficacy does not preclude the possibility of important information emerging from analyses of the data that have been collected; as such, the research cannot be considered a failure. The contributions of the volunteers and the many people involved in executing these logistically daunting studies weren’t for naught, because it’s crucial to know what doesn’t work even though the hope is always for success.

While there may understandably be some frustration regarding how long and difficult the road to an effective HIV vaccine is proving to be, it’s important to appreciate that this reflects the novel challenges posed by the virus.

Two features in particular stand out: one is the fact that HIV infects and disrupts CD4 T cells, which would normally serve the function of coordinating the immune system’s response to a virus or other pathogen. In other words, once HIV enters the body it immediately starts to directly undermine the immune mechanisms that might otherwise be able to clear or control it. Secondly, HIV’s outer envelope has evolved a cloud of sugary decoy molecules that serve to block inhibition by most antibodies.

The potentially good news is that in recent years, an increasing number of unusual antibodies have been identified that can strongly inhibit many different HIV variants. Work is now well underway to design HIV vaccine candidates that may be able to induce this type of broadly neutralizing antibody (bNAb).

Challenges remain however, because tricky and complex vaccine approaches will be needed to induce the immune system to make antibodies with the unusual structural features of bNAbs that convey strong anti-HIV effects. It appears unlikely that an HIV vaccine candidate capable of inducing bNAbs will be developed and ready for efficacy testing within the next few years.

In the interim, scientists are testing options for delivering bNAbs directly into the body (the scientific term is passive immunisation). The first trials assessing the efficacy a bNAb delivered by intravenous infusion did not show a reduction in HIV acquisition overall, however there was evidence of a protective effect in a subset of participants. The bNAb used in the trials, VRC01, was among the first to be discovered and there are hopes that combinations of more recently discovered bNAbs with increased potency can do better. [8]

While it’s unclear whether passive immunisation with bNAbs can become a practical and accessible HIV prevention option, these studies can also provide important information to guide the development of bNAb-inducing HIV vaccines.

As articulated very clearly in AVAC’s statement today, the uncertain timeline for an HIV vaccine underscores the importance of ensuring that currently available biomedical prevention options are made affordable and accessible for everyone in the world who needs them. Furthermore, an effective HIV vaccine remains a vital goal and continued investment is essential despite the challenges and setbacks.

TAG will provide a more detailed update on the current state of HIV vaccine and passive immunisation research in our annual Pipeline Report in July 2023. [9]

comment

It was unusual that none of the press releases linked to Mosaico included any study results, not even the top-line data used by the DSMB to recommend stopping the study. This minimal data was also withheld at the community and press briefing held a week later.

The reasons given were to be able to further check the data – a little late for that – and to comply with an embargo linked to the submitted abstract for CROI – also not justified. Avoiding the top-line results forces media to issue different reports after the headline and mainstream media interest has already passed.

At least in part due to these community concerns, the study group issued the following additional information.

There was no efficacy seen – the HIV infection rates were 4.1/100 person-years in both the vaccine and the placebo arms at the time the data were censored (23.7 months after follow-up). This was in the modified intent-to-treat analysis that includes all participants who received at least one dose of vaccine or placebo and were HIV negative at enrollment. There were also no safety concerns. 

Questions were raised about whether PrEP could have influenced the results of the trial. By month 24, only 10% reported being on PrEP, so this could not have affected the trial results. We will post answers to other questions next week.

Source

Jefferys R. Interim analysis of Mosaico HIV vaccine efficacy trial results prompts discontinuation. TAG basic science blog. (18 January 2023).
tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2023/01/interim-analysis-of-mosaico-hiv-vaccine-efficacy-trial-results-prompts-discontinuation.html

References

1. Clinicaltrials.gov. MOSAICO study.
   clinicaltrials.gov/ct2/show/study/NCT03964415
2. AVAC press release. (18 January 2023).
   www.avac.org/press-release/hiv-vaccine-research-must-continue-following-disappointing-result-mosaico-trial
3. HVTN press release. (18 January 2023).
   www.hvtn.org/news/news-releases/2023/01/phase-3-mosaic-based-investigational-hiv-vaccine-study-discontinued-following-disappointing-results-planned-data-review.html
4. Janssen press release. (18 January 2023).
   www.jnj.com/janssen-and-global-partners-to-discontinue-phase-3-mosaico-hiv-vaccine-clinical-trial
5. Link to HVTN webinar. (25 January 2023).
   www.hvtn.org/news/hvtn-news/2023/01/where-are-we-now-and-whats-next.html
6. Barouch DH et al. Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 2 Jul 2015 349(6245):320–324. DOI: 10.1126/science.aab3886.
   www.science.org/doi/10.1126/science.aab3886
7. TAG basic science blog. (September 2019).
   tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2021/09/imbokodo-trial-results-highlight-challenge-of-developing-an-hiv-vaccine-and-urgent-need-for-access-t.html
8. Corey L et al. N Engl J Med 2021; 384:1003-1014 DOI: 10.1056/NEJMoa2031738.
   www.nejm.org/doi/full/10.1056/NEJMoa2031738

This report was first published on 27 January 2023.