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Development of tier-2 antibodies- A milestone in HIV vaccine Research

HIV has killed 36.3 million people nearly four decades after its discovery, with no vaccine in sight. Researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, have published a new study that takes a promising step toward producing an HIV vaccine.

The findings, which were published in Nature Communications, show for the first time in mice that utilising a unique native-like trimer can lead to the development of Tier-2 neutralising antibodies, which are crucial in the fight against HIV.

Previously, evoking these types of antibodies with candidate vaccines necessitated lengthy and costly trials in big animal models, posing a severe bottleneck in HIV-1 vaccine development. "With our new discovery, we've opened the door to rapid, iterative vaccinology in a model that can produce Tier-2 neutralising antibodies, allowing for the development of more advanced HIV vaccine concepts," said Daniel Kulp, Ph.D., associate professor in The Wistar Institute's Vaccine & Immunotherapy Center and the paper's corresponding author.

For distribution to the mice, the researchers encoded the native-like trimer into DNA. This has the practical advantage of converting the host bodies into "antigen factories" rather than requiring a complicated vaccine manufacturing process. The researchers next compared the outcomes of mice given the DNA-encoded native-like trimer to those of mice given a normal protein vaccination. Tier-2 neutralising antibodies were only generated in mice who received the DNA-encoded native-like trimer.

"We were able to create significant immune responses with both systems," Kulp said, "but the DNA platform drove this neutralising response in a way that the others didn't."

Kulp and his colleagues recovered monoclonal antibodies from mice and utilised cryo-electron microscopy to examine the atomic structure of one Tier-2 neutralising monoclonal antibody after confirming their immunisation regime was producing Tier-2 antibodies. They discovered that the antibody attaches to a C3V5 epitope (a region of a protein that protrudes from the antigen and triggers an immune response). In the gold standard HIV vaccination model (non-human primates), prior research has shown that antibodies binding to C3V5 protect animals from a SHIV infection, which is a close relative of HIV that infects non-human primates.

"The structure reveals a lot about how this antibody is able to eliminate the virus," Kulp added. "We can now strategize about how to create new vaccines that can produce widely neutralising antibody responses to the C3V5 epitope for the first time."

The W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, David B. Weiner, Ph.D., executive vice president and director of the Vaccine & Immunotherapy Center, and coauthor David B. Weiner, Ph.D., stressed the importance of their discoveries.

"Inside the vaccinated animal, we've enabled direct in vivo self-assembly of structurally specified immunogens, which are manufactured and supplied utilising nucleic acid technology. Our findings demonstrating the induction of autologous Tier 2 neutralisation highlight the utility of this method for creating surgically tailored immunity against a problematic pathogen's susceptible spots, in this case HIV."


Ziyang Xu, Susanne Walker, Megan C. Wise, Neethu Chokkalingam, Mansi Purwar, Alan Moore, Edgar Tello-Ruiz, Yuanhan Wu, Sonali Majumdar, Kylie M. Konrath, Abhijeet Kulkarni, Nicholas J. Tursi, Faraz I. Zaidi, Emma L. Reuschel, Ishaan Patel, April Obeirne, Jianqiu Du, Katherine Schultheis, Lauren Gites, Trevor Smith, Janess Mendoza, Kate E. Broderick, Laurent Humeau, Jesper Pallesen, David B. Weiner, Daniel W. Kulp. Induction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer. Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-28363-z

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