In 1987, the National Institutes of Health (NIH) began its first ever clinical trial of a vaccine against human immunodeficiency virus (HIV) (1). While that particular vaccine candidate showed no serious safety concerns in the trial participants, it eventually failed, as did most other HIV vaccine candidates that cropped up within the next two decades (1).
This trend has unfortunately persisted. Earlier this year, Janssen Pharmaceuticals ended a late-stage clinical trial of its HIV vaccine candidate because it was ineffective, marking the end of the vaccine furthest along in the clinical trial pipeline (2).
With the advent of mRNA vaccines, scientists hope that this narrative of vaccine failure may be changing. Scientists at multiple universities, the NIH, and Moderna are developing several mRNA-based HIV vaccine candidates that they hope will prove effective in preventing HIV infection. While these candidates are all currently in early-stage clinical trials, their existence marks a shift in vaccine development after the COVID-19 pandemic.
A tricky, genetically diverse virus
HIV is an extraordinarily tricky virus. “They say that there’s as much genetic diversity of HIV within a chronically infected individual as there is genetic diversity of influenza in the entire world,” said Aaron Seese, a biologist at the Fred Hutchinson Cancer Center. Because of this genetic diversity, finding a shared viral component that a single vaccine can target is difficult.
HIV replicates inside the lymph nodes to spread throughout the body. Here, an uninfected lymph node is shown with B cells (yellow) and CD4 T cells (blue).
Credit: National Institute of Allergy and Infectious Disease
Adding onto the genetic diversity, HIV also infects critical cells of the immune system: CD4 helper T cells. “CD4 cells are essential for developing a protective immune response against infections,” said Brett Leav, who directs the infection disease clinical development group at Moderna. “So, the virus is ingenious in that it infects the very target that is essential for prevention.”
These two factors, among others, create the perfect storm for HIV to be sneakily adept at infecting human cells. Once the virus enters the body, it spreads via the lymph nodes — exponentially replicating across the body’s immune cells (3). After approximately a month, a “set point” occurs where viral replication reaches a steady rate (3). If untreated, HIV causes massive loss of those important CD4 helper T cells, chronic inflammation, and over the course of several years, acquired immunodeficiency syndrome (AIDS) (3).
Currently, therapies for HIV include strong cocktails of antiviral drugs that stop the virus from replicating once it has infected the body. Individuals can also take pre-exposure prophylaxis (PrEP) regularly, which protects the body from being infected by the virus (4). The goal of the HIV vaccine, then, would be to protect everyone against HIV in one fell swoop.
Making new vaccines
From prior vaccine trials, the scientists realized that a certain type of antibody was immensely useful in the body’s fight against HIV. Known as broadly neutralizing antibodies (bnAbs), these antibodies neutralize many different strains of HIV. Some bnAbs can bind to a specific site on the viruses’ spiky protein envelope called the CD4 binding site. Because HIV needs the CD4 binding site to enter a cell, that site is well conserved between different variants. “If we can find an antibody that is going to attack the CD4 binding site of HIV, then we can block the infection,” Seese explained.
A team at the Scripps Institute of Research discovered that by arranging many copies of an HIV glycoprotein critical for viral cell entry on the surface of a nanoparticle, they could induce the production of these bnAbs (5). By injecting the vaccine into human participants in a Phase 1 clinical trial, the researchers introduced the participants’ naïve B cell precursors to this protein-conjugated nanoparticle (called the eOD-GT8 60mer immunogen) (6). As those B cells matured, they spawned more antibody-producing cells, leading to a vast array of immune cells producing bnAbs (6). This process is known as “germline-targeting.” Lamar Fleming, a biologist at the Fred Hutchinson Cancer Center, characterized this as a sort of “polishing and fine-tuning of the antibodies that are being generated” to maximize the amount of bnAbs produced.
What we’re doing is trying to show that with an mRNA version of the immunogen, we can generate the same results, or perhaps even better than what we saw in the initial study.
– Brett Leav, Moderna
These bnAbs are critical to mounting an effective immune response against HIV. “We’ve found out that a single bnAb is probably not going to provide enough protection,” Fleming said. “We’re probably going to have to come up with a way to elicit multiple bnAbs.”
When scientists tested the eOD-GT8 60mer immunogen as a protein-based vaccine in a Phase 1 clinical trial, they found that bnAb precursors were indeed generated in almost all vaccine recipients (6). There were no adverse effects, indicating that the vaccine was relatively safe.
The next steps, said Leav, are to transform the eOD-GT8 60mer immunogen into an mRNA vaccine. “What we’re doing is trying to show that with an mRNA version of the immunogen, we can generate the same results, or perhaps even better than what we saw in the initial study,” Leav said. This Phase 1 clinical trial is ongoing (7).
Besides the eOD-GT8 60mer mRNA vaccine candidate, three other mRNA HIV vaccine candidates developed by the same teams at Scripps Research Institute and Moderna are also racing through a Phase 1 clinical trial sponsored by the NIH. These candidates, like eOD-GT8 60mer, also generate pieces of the HIV spike protein critical for entry into cells, but are genetically modified (8). “We’re testing a version that is secreted, a version that is membrane bound, and one that has a genetic deletion where the binding site to CD4 is,” said Leav. The team hopes that through the clinical trial, they will figure out which of these candidates can produce the most potent bnAb response and if these bnAbs can successfully neutralize different strains of HIV in the laboratory.
Moving to mRNA
While these four vaccine candidates present slightly different versions of HIV envelope proteins, they are all mRNA-based. According to Leav, some of the advantages to mRNA vaccines are that they are easily customizable and faster to produce than protein-based vaccines. With an mRNA-based vaccine, researchers only need the genetic sequence. “Like we demonstrated in the response to COVID-19, we can go from sequence to a safe product for use in humans in a matter of months,” he said. Researchers can synthesize and test different mRNA vaccine candidates and “rapidly iterate and refine our ideas,” Leav added.
The speed by which researchers develop these vaccines means sifting through massive amounts of biological material and long days in the laboratory. Seese recalled the controlled chaos required to process and understand all of the immunological data generated from the clinical trial. “We had 17 different thermocyclers going all at once, just trying to get everything running and finished,” he said. “That sense of accomplishment you feel after everything’s finished — that was a good memory.”
The scientists hope that at least one of the candidates can prove effective in preventing HIV, although many more studies and clinical trials are needed. Until then, they will keep pushing forward, both in developing more vaccine candidates and understanding how the virus works.
References
- NIH: National Institute of Allergy and Infectious Diseases. History of HIV Vaccine Research. (2018). https://www.niaid.nih.gov/diseases-conditions/hiv-vaccine-research-history
- Johnson & Johnson. Janssen and Global Partners to Discontinue Phase 3 Mosaico HIV Vaccine Clinical Trial. https://www.jnj.com/janssen-and-global-partners-to-discontinue-phase-3-mosaico-hiv-vaccine-clinical-trial
- Deeks, S. G., Overbaugh, J., Phillips, A. & Buchbinder, S. HIV infection. Nat Rev Dis Primers 1, 1–22 (2015). https://www.nature.com/articles/nrdp201535
- Blumenthal, J. & Haubrich, R. Pre-exposure Prophylaxis (PrEP) for HIV Infection: How Antiretroviral Pharmacology helps to Monitor and Improve Adherence. Expert Opin Pharmacother 14, 1777–1785 (2013). https://www.tandfonline.com/doi/abs/10.1517/14656566.2013.812072
- Jardine, J. et al. Rational HIV immunogen design to target specific germline B cell receptors. Science 340, 711–716 (2013). https://www.science.org/doi/abs/10.1126/science.1234150
- Leggat, D. J. et al. Vaccination induces HIV broadly neutralizing antibody precursors in humans. Science 378, eadd6502 (2022). https://www.science.org/doi/abs/10.1126/science.add6502
- International AIDS Vaccine Initiative. A Phase 1, Randomized, First-in-human, Open-label Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) in HIV-1 Uninfected Adults in Good General Health. https://clinicaltrials.gov/ct2/show/NCT05001373
- National Institute of Allergy and Infectious Diseases (NIAID). A Phase 1, Randomized, Open-label Clinical Trial to Evaluate the Safety and Immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO HIV Trimer mRNA Vaccines in Healthy, HIV-uninfected Adult Participants. https://clinicaltrials.gov/ct2/show/NCT05217641
