Shan Lu, MD, PhD, professor emeritus of medicine, co-authored a pair of studies related to the Phase I clinical trial of a novel vaccine to prevent HIV, marking the latest step in a decades-long quest to harness the power of DNA vaccines to address a major global health need.
“This is an important milestone and the most robust immunogenicity results ever from a human HIV vaccine study run by the National Institutes of Health’s HIV Vaccine Trial Network,” said Dr. Lu. “In order to stem the global tide of AIDS, finding an effective preventive HIV vaccine is our best hope of breaking the transmission cycle. The safety and immunological results from the trial is encouraging progress in this development.”
Resulting from discoveries by Lu over three decades of research is the polyvalent DNA/prime-protein boost vaccine, called PDPHV. The DNA component is used to prime the immune system to receive a boost of HIV proteins, which stimulate the body to produce potent antibodies and CD4+ T cells (a type of white blood cell that helps the body fight infection by stimulating other immune cells) against HIV with the hope of preventing infection.
In 2018, UMass Chan licensed Lu’s novel vaccine technology to Worcester HIV Vaccine, whose product employs a polyvalent DNA-prime/protein-boost technology to target multiple subtypes of HIV-1.
Results from the trial published in The Lancet HIV show that PDPHV elicited strong and cross-reactive immune responses against several HIV subtypes by several immune parameters.
Led by protocol chair Ian Frank, MD, professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, the clinical study enrolled 60 participants at six U.S. sites from 2018 to 2019. Overall, the PDPHV formulation was well tolerated and found to be safe. More significantly, the immunogenicity of the PDPHV vaccine strategy was found to be superior to many previous HIV vaccines.
All volunteers in the prime-boost group achieved 100 percent CD4+ T cell responses, which has not been universally observed in previous human HIV vaccine studies.
“Given the challenge of developing an effective HIV vaccine, it has always been a major objective to develop a vaccine which can elicit a wide spectrum of immune responses. The HVTN124 study demonstrates that PDPHV is moving us in that direction,” Lu said.
Researchers isolate novel human monoclonal antibody from clinical trial participant
In a separate study, published in Nature Communications, Lu and his collaborators identified a novel human monoclonal antibody (HmAb64) able to neutralize HIV isolates across subtypes in a healthy trial participant who received PDPHV.
Human monoclonal antibodies have been isolated from HIV infected patients in the past, but not from any healthy HIV vaccine volunteers. These antibodies have provided critical information on the interactions between the host’s immune system and the invading virus and have revealed key areas of the virus that a protective HIV vaccine would need to target. However, it has been very difficult to develop vaccines that can induce antibodies targeting such key areas.
HmAb64, though, targets the CD4 binding site that HIV uses to invade human CD4+ T cells. HIV enters CD4+ T cells through this binding site and destroys the cells, causing a host of clinical diseases after infection.
The CD4 binding site has been a challenging target as the antigen’s structure is very hard to produce by traditional antigen design approach. Priming the immune system with the DNA component of PDPHV ensures that the antigens are produced inside the body and thus mimic the virus’ antigen structure.
Once primed, HmAb64 can neutralize primary HIV isolates across various subtypes—a major objective for HIV vaccine development. Several tier-2 resistant unrelated to the antigens used in the vaccines were also neutralized which further highlights the significance not only for this new human monoclonal antibody but also for the field of HIV vaccine development.
Using immunology, biochemistry, biophysics and cry-EM analyses, Lu and colleagues were able to confirm the CD4bs specificity and structural features of HmAb64.
“This is the first isolation of a neutralizing CD4 binding site for a human monoclonal antibody with exciting breadth against HIV,” said Lu. “Taken from a participant who received our HIV vaccine, this has been an objective for nearly 30 years.”
