For the first time, investigators from the Wistar Institute created a DNA-based vaccine that successfully produced tier-2 antibodies capable of neutralizing HIV in mice.
Tier-2 neutralizing antibodies are required to treat the most common HIV strain. Now, the Wistar Institute reports successfully eliciting the antibody response in mice for the first time.
In the study, published in Nature Communications, investigators from the Wistar Institute used a native-like trimer to develop tier-2 neutralizing antibodies in mice. Previously, HIV vaccine candidates only induced these antibodies in large animals, such as nonhuman primates.
“With our new finding, we have opened the door to rapid, iterative vaccinology in a model that can produce titer-2 neutralizing antibodies, enabling development of more advanced HIV vaccine concepts,” said Daniel Kulp, PhD, a corresponding coauthor of the study and an associate professor in the Vaccine & Immunotherapy Center at the Wistar Institute.
The investigators encoded their native-like trimer into DNA to deliver into the mice, essentially turning the host body into an “antigen factory.” The proteins mimicked the structure of the spike target for antibodies. Using a DNA vaccine allows for in vivo folding of structured antigens, providing cost and speed advantages.
In another set of mice, the investigators tested a standard protein immunization. Both groups of mice had strong immune responses, but only the mice given the DNA-encoded trimer formed the sought-after tier-2 neutralizing antibodies. “We were able to generate strong immune responses with both platforms, but the DNA platform uniquely drove this neutralizing response,” Kulp explained.
After confirming the immunization technique elicited tier-2 antibodies, the investigators isolated monoclonal antibodies from the mice, utilizing cryo-electron microscopy to determine their atomic structure. They found that the antibody binds to the epitope C3V5, which prior studies have shown to protect nonhuman primates from SHIV infection, a virus similar to HIV that infects nonhuman primates.
“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,” said study coauthor David B. Weiner, PhD, executive vice presidents and director at Wistar’s Vaccine & Immunotherapy Center. “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.”
Wistar Institute is an international biomedical research center, specializing in infectious disease, cancer, immunology, and vaccine development. Wistar was first independent nonprofit biomedical research institute in the US at the time of its founding in 1892.