Investigators at Stanford University and Emory University have developed an adjuvant that induced long-lasting antibody responses to the HIV Env protein, they reported in the June 19, 2020, issue of Science Immunology.

For many people, the first issue that comes to mind with respect to an HIV vaccine is the mutation rate of the virus, which makes it extremely challenging to identify an antigen that will provide broad protection.

But another problem is that immunity can wane.

In the first successful large-scale HIV vaccine trial, the RV144 trial, vaccine efficacy was around 60% during the first year after vaccination, but declined to about half that by 42 months.

At the 2019 International AIDS Society (IAS) Conference on HIV Science, NIAID director Tony Fauci said that 50-60% efficacy was a realistic goal for an HIV vaccine.

Maintaining a strong immune response after vaccination is not just a challenge for HIV vaccines.

Influenza vaccines, too, provoke only a short-lived immune response. In studies reported in the August 14, 2020, issue of Science, researchers at Emory University sampled antibody-producing plasma cells in the bone marrow of trial participants 1 month and 1 year after flu vaccination. They showed that influenza-specific bone marrow plasma cells (BMPCs) rose after vaccination, but declined to baseline levels by a year after vaccination, suggesting that the cells were either not able to reach an appropriate survival niche in the bone marrow, or not able to successfully engraft there.

And although the COVID-19 pandemic, at 8 months, is too young for definitive answers about the durability of the immune response to SARS-CoV-2, the question of such durability is a major one for the vaccines that are currently being developed.

Thanks for the memories

However, the immune system is clearly capable of developing long-lasting memory to infections and vaccines alike.

Diseases like measles and yellow fever, as well as the vaccines against them, "can enter the body and stimulate the immune system, and the immune system can remember that encounter for decades," Bali Pulendran told BioWorld Science. "That's the gold standard for what any vaccine could and should do."

Pulendran is professor of pathology and of microbiology and immunology at Stanford University and co-corresponding author, with Emory University Vaccine Center director Rafi Ahmed, of the Science Immunology paper. Ahmed is also the senior author of the Science paper reporting a rapid decline in BMPCs after flu vaccination.

The Science Immunology paper is a follow-up to a 2011 paper in Nature describing the induction of a long-lasting immune response by a vaccine that activated Toll-like receptors (TLRs). When used as an adjuvant to the flu vaccine, the TLR-stimulating synthetic nanoparticle vaccine developed by Pulendran and his colleagues induced an immune response to the flu that lasted for the lifespan of the mouse.

In the new Science Immunology paper, Pulendran, Rafii and their colleagues tested a different TLR-activating adjuvant, the TLR7/8-targeting small molecule 3M-052 (telratolimod), in combination with antigens to HIV Env protein, in rhesus macaques.

The team showed that compared with other adjuvants, combining 3M-052 with Env protein was able to induce both longer and stronger immune responses.

Interestingly, although adjuvants are meant to stimulate the innate immune system and so, prime the adaptive immune system for a greater antibody response, the work published in Nature in 2011 did not show greater activation of the innate immune system. Instead, it appeared to prime the adaptive immune response to become longer-lived.

In their newest paper, the authors suggested that the TLR7 agonist might be acting directly on B cells, at least in part.

3M-052 is currently being compared to alum as an adjuvant for an HIV vaccine in a phase I trial led by researchers at the Seattle Vaccine Trials Unit and Emory University (Kasturi, S.P. et al. Sci Immunol 2020, 5: eabb1025; Davis, C.W. et al. Science 2020, Advanced publication).

Telratolimod