Nearly 40 years after the discovery of HIV, it has killed 36.3 million people, but so far there is still no effective vaccine available. In a new study, however, researchers from the Wesda Institute in the United States have taken a promising step in the direction of developing a HIV vaccine. They confirmed for the first time in mice that the prospect of using a unique sample env trimer (native-like trimer, a trimer similar to natural env trimer) to produce Tier-2 neutralizing antibodies, a critical player in the fight against HIV. The results of the study were published in the journal Nature Communications on February 4, 2022, under the title “Induction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer”.
In the past, the use of candidate vaccines to induce these types of antibodies required long and expensive experiments in large animal models, which posed a major bottleneck in the development of HIV-1 vaccines. “With our new findings, we have opened the door to rapid, iterative vaccinology in a model that produces Tier-2 neutralizing antibodies, making it possible to develop more advanced HIV vaccine concepts,” said Dr. Daniel Kulp, the paper’s corresponding author and associate professor at the Center for Vaccine and Immunotherapy at the Wesda Institute.
The researchers encoded the natural sample env trimer into DNA for delivery to mice. There is a practical benefit of turning the host body into an “antigen factory” rather than requiring a complex vaccine manufacturing process. They then compared the results of mice immunized with a native-like env trimer encoded by DNA and those immunized with a standard protein. Only those mice that received the native-like env trimer encoded by DNA produced Tier-2 neutralizing antibodies.
“We can generate a strong immune response on both platforms, but this DNA platform uniquely promotes this neutralization response,” Kulp said.
Once they had verified that their immunization program produced Tier-2-neutralizing antibodies, Kulp and his colleagues isolated monoclonal antibodies from these mice and used cryogenic electron microscopy to determine the atomic structure of a Tier-2-neutralizing monoclonal antibody. They found that the antibody binds to an epitope called C3V5. In the standard HIV vaccine model (non-human primates), previous studies have shown that antibodies binding to C3V5 can protect these animals from SHIV infection, a close relative of HIV that infects only non-human primates.
“This structure gives us an incredible understanding of how this antibody can neutralize the virus,” Kulp said. “For the first time, we can develop strategies on how to design a new vaccine that produces a wide range of neutralizing antibody responses to C3V5 epitopes. “
Dr. David B. Weiner, co-author and director of the Center for Vaccine and Immunotherapy at the Wesda Institute, stressed the usefulness of their findings. “What we do is to allow structurally designed immunogens to self-assemble directly in the body, which are designed and delivered to animals using nucleic acid technology. Our data show that induced autologous Tier 2 neutralization illustrates the value of this approach as a tool to counter the vulnerable sites of a pathogen that is difficult to eradicate, such as HIV. “