In a session titled 'Will mRNA lead to a long-awaited HIV vaccine?' co-chaired by Susan Buchbinder, US, and Georgia Tomaras, US, experts discussed the similarities and differences between HIV and SARS-CoV-2 mRNA vaccine development and how the renewed interest in exploiting the technology for the former—owing to its success in combatting COVID-19—can be evidenced in the form of a battery of clinical trials currently underway.

Challenges and prospects (Lynn Morris, South Africa)

With scientists worldwide pinning their hopes on mRNA technology for a vaccine against HIV, one must not overlook that unlike SARS-CoV-2, which has a relatively stable genome and triggers the development of neutralising antibodies (NAbs) within a few weeks, HIV has a highly mutable genome and takes years to evoke broad NAb (bNAb) responses. Further complications are posed by the choice of the immunogen, with the HIV envelope glycoprotein being a heavily glycosylated complex that elicits a composite response compared with that of the SARS-CoV-2 spike protein. However, owing to its unique properties such as (a) endogenous expression of native envelope glycoproteins, (b) immune stimulation for up to a week, (c) nanoparticle-based delivery to relevant immune cells, thus eliciting T follicular helper cell and humoral responses, (d) easy development and modification, and (e) superior safety profile, mRNA may not fall short of our expectations. Undertaking parallel processes and extensive industry involvement as in the COVID-19 vaccine, research would accelerate the development of an HIV vaccine.

IAVI/Moderna trials offer hope (Bill Schief, US)

Dr Schief gives an overview of HIV vaccine antigens in clinical development led by a partnership between the International AIDS Vaccine Initiative (IAVI) and Moderna. The phase 1 IAVI G001 trial is the first-in-human test in the attempt to develop a multi-step vaccine regimen that provides protection against HIV by stimulating different types of bNAbs by 'germline targeting.' The immunogen eOD-GT8 60mer plus AS01_B (a strong adjuvant) was safe and well tolerated and, after 1-2 shots, elicited the desired B-cell response (VRC01-class antibodies) in 97% of recipients. Moreover, the second vaccination increased mutation levels and affinities. IAVI G002 advances the concept: it will determine whether an additional mRNA-encoded immunogen boost (Core-g28v2 60mer) following mRNA-encoded GT8 induces further maturation of B cells. Another phase 1 trial, IAVI G003, was launched recently in South Africa and Rwanda to assess whether mRNA-encoded GT8 being evaluated in IAVI G002 in the US population leads to similar responses in the African population.

When questioned about having a plan B in place, Dr Schief sounded optimistic in that mRNA being a non-static technology, tweaking the mRNA formulas may result in even better responses in the future.

Testing native trimers (Sharon Riddler, US)

Dr Riddler sheds light on the design of the multicentre, phase 1 HVTN 302 study currently ongoing to assess whether BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO HIV trimer mRNA vaccines, in soluble or membrane-bound forms, are safe and well-tolerated among individuals uninfected with HIV and will elicit autologous NAbs. A total of 108 healthy adult participants, assigned to 6 groups of 18 participants each, will receive 100 or 250 mcg of either of the 3 vaccines, with the first 12 participants in each group evaluated for safety after 2 weeks of first vaccination. Implementation of a dose escalation plan will involve enrolment for high-dose groups after safety criteria are met in the low-dose groups. Although the primary analysis results are expected by early 2023, preliminary immunogenicity data may be available sooner.

COVID-19 success an inspiration (Georgia Tomaras, US)

Dr Tomaras begins by discussing the general strategies driving HIV-1 vaccine development: induction of CD8⁺ T cells that kill HIV-1-infected cells, non-NAbs that protect from HIV-1 transmission, and bNAbs. Despite the induction of bNAbs being the ultimate aim because of their proven inverse correlation with HIV risk, this has not yet been achieved by vaccination and is rarely elicited in infection. In contrast, SARS-CoV-2 infection and vaccination can easily elicit effective NAbs. The ongoing mRNA HIV vaccine studies attempt to boost NAb potency and breadth to first mediate autologous followed by heterologous neutralisation and maximise on-target and minimise off-target epitope specificity.

Moving ahead, she reiterates the other noteworthy differences discussed by Dr Morris: the markedly higher HIV-1 diversity and epitope complexity than SARS-CoV-2. Overriding these differences, the lessons learnt from successful HIV candidate vaccine efficacy trials have been applied to advance SARS-CoV-2 vaccine development, finally resulting in their deployment within a year. Future clinical trials may yield rewarding results for HIV.

AIDS 2022 — Will mRNA technology be able to deliver an HIV vaccine?

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