In the long struggle to create an effective vaccine against HIV, scientists have taken a significant step forward. New research shows that a series of vaccines can stimulate the immune system to produce powerful antibodies capable of blocking a wide range of HIV strains, including those that are usually the most difficult to stop.
The study, published in the journal Immunity, is the result of a collaboration between scientists at Scripps Research and Sweden’s Karolinska Institute. Their findings provide compelling evidence that broadly neutralizing antibodies (bNAbs), long considered a key target for HIV vaccination, can be successfully induced in nonhuman primates. It also points to a new target on the HIV spike protein to which future antibodies can successfully bind to block the virus.
“What’s unique about this work is that we didn’t just see the first signs of a promising response, we actually isolated functional broadly neutralizing antibodies and pinpointed where they bind on the surface of the virus,” said senior author Richard Wyatt, professor in the Department of Immunology and Microbiology at Scripps Research. “This not only shows that the approach works, but also why it works.”
Because HIV mutates rapidly and there are literally millions of different strains circulating among humans worldwide, scientists have focused their research efforts on creating vaccines that can stimulate the body to produce bNAbs that recognize multiple strains simultaneously. Although some people spontaneously produce bNAbs after exposure to HIV, creating a vaccine that reliably induces bNAbs in non-human primates or humans is a challenging task.
In their new work, Wyatt and his team first developed a mimic of the HIV spike protein, a key part of the HIV mechanism that antibodies target to block infection. Unlike previous designs, the new “spike mimics” do not disintegrate after injection and closely resemble the structure of the HIV spike protein.
The group then moved on to a two-step vaccination strategy. First, they primed the immune system with a version of the spike mimetic that lacked key sugar molecules that normally coat the protein and make it difficult to recognize. This helped identify a critical, conserved region of the spike: the CD4 binding site, where the spike protein attaches to human immune cells.
After two consecutive doses of the vaccine, five boosters were administered at approximately twelve-week intervals. This series of boosters of spike proteins from different HIV strains — now with intact sugar coating — retrained the immune system to recognize the same region, even when it was partially hidden.
According to the researchers, the key to success was the carefully designed sequence of vaccines. “We didn’t just vaccinate at random,” says Javier Guenaga, senior research scientist at Scripps Research and co-author of the new paper. “It was a rational, structure-based approach aimed at getting the right types of antibodies.”
The approach proved successful. Several vaccinated animal models produced antibodies capable of neutralizing “level 2” HIV strains, which are among the most difficult to block. From one animal model, the researchers isolated a family of antibodies called LJF-0034, which neutralized nearly 70% of the 84 HIV strains that exist worldwide.
“It’s incredibly exciting to see the vaccine generate such a broad spectrum of activity in non-human primates,” says senior researcher Shridhar Bale, co-author of the paper. “And this is not an isolated case. We have observed responses targeting this region in many animals.”
The team then showed that antibodies such as LJF-0034 bind to a previously undescribed region of the virus, connecting two parts of the spike protein. Future research may help in the development of additional vaccines targeting this promising new site. Wyatt says his team would like to optimize the vaccine so that it can reliably elicit responses similar to LJF-0034 in most recipients.
Ultimately, an effective HIV vaccination regimen will likely involve a combination of vaccines that deliver different bNAbs working together.
“This is far from a final vaccine,” says Wayatt. “But having a new, highly effective target is extremely exciting and will help shape our future efforts.”
One of the vaccine candidates used in this study is already in phase 1 clinical trials, with initial results expected soon. In this study, participants receive the same spike protein (without sugar molecules) that was used as the priming vaccine in this study.
Incidentally, team of researchers from the University of Virginia has shed light on one of the key mechanisms that allows HIV to persist in the human body for decades, remaining out of reach of drugs. In a new study, scientists have shown that even small changes in a specific element of the virus’s genome — the Rev-RRE axis — can significantly affect its ability to “hide” in a latent state.