Scientists move HIV vaccine research forward by developing an immunogen
that produces tier-2 antibodies
The vaccine delivery system uses DNA to encode genetic instruction in
vivo, producing a more efficacious immune response

Date:
February 4, 2022
Source:
The Wistar Institute
Summary:
Scientists take a promising step in the direction of developing
an HIV vaccine using a unique native-like trimer to develop Tier-2
neutralizing antibodies -- the kind that matter for combating HIV --
in mice.



FULL STORY ========================================================================== Nearly four decades after its discovery, HIV has killed 36.3 million
people, with no vaccine in sight. However, a new study by researchers
at The Wistar Institute, an international biomedical research leader
in cancer, immunology, infectious disease, and vaccine development,
takes a promising step in the direction of developing an HIV vaccine.


==========================================================================
The findings, published in Nature Communications, demonstrate the promise
of using a unique native-like trimer to develop Tier-2 neutralizing
antibodies - - the kind that matter for combating HIV -- in mice for
the first time.

Previously, eliciting these types of antibodies using candidate vaccines required long and expensive experiments in large animal models creating
a significant bottleneck on HIV-1 vaccine development. "With our new
finding, we have opened the door to rapid, iterative vaccinology in
a model that can produce Tier-2 neutralizing antibodies, enabling
development of more advanced HIV vaccine concepts," said Daniel Kulp,
Ph.D., associate professor in the Vaccine & Immunotherapy Center at The
Wistar Institute and corresponding author on the paper.

The researchers encoded the native-like trimer into DNA for delivery into
the mice. This has the practical advantage of turning the host bodies
into "antigen factories" instead of requiring what would otherwise be a
complex vaccine manufacturing process. The researchers then compared the results from the mice who received the DNA-encoded native-like trimer
to results from mice who received a standard protein immunization. Only
those mice that received the DNA-encoded native-like trimer developed
Tier-2 neutralizing antibodies.

"We were able to generate strong immune responses with both platforms, but
the DNA platform uniquely drove this neutralizing response," said Kulp.

Once they'd verified their immunization regime was producing Tier-2
antibodies, Kulp and his colleagues isolated monoclonal antibodies
from the mice and used cryo-electron microscopy to determine the atomic structure of one Tier- 2 neutralizing monoclonal antibody. They found that
the antibody binds to an epitope (a segment of a protein that sticks out
of the antigen, which prompts an immune response) called C3V5. In the gold standard HIV vaccine 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 gives us incredible insight into how this antibody is
able to neutralize the virus," said Kulp. "For the first time, we can strategize about how to design new vaccines that can generate broadly neutralizing antibody responses to the C3V5 epitope." Coauthor David
B. Weiner, Ph.D., executive vice president and director of the Vaccine
& Immunotherapy Center and the W.W. Smith Charitable Trust Professor
in Cancer Research at The Wistar Institute, emphasized the utility of
their findings.

"What we've done is enable direct in vivo self-assembly of structurally designed immunogens, which are engineered and delivered using nucleic acid technology, inside the vaccinated animal. Our data demonstrating induction
of autologous Tier 2 neutralization illustrate the value of this approach
as a tool to create surgically tailored immunity against a difficult
pathogen's vulnerable sites, in this case for HIV." Work supported
by: National Health Institutes (NIH) IPCAVD Grant U19 Al109646- 04;
W. W. Smith Charitable Trust; and Wistar Monica H.M. Shander Memorial Fellowship.

========================================================================== Story Source: Materials provided by The_Wistar_Institute. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220204085437.htm

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