An
experimental vaccine
regimen based on the structure of a vulnerable site on HIV elicited antibodies
in mice, guinea pigs and monkeys that neutralize dozens of HIV strains from
around the world. The findings were reported today in the journal Nature
Medicine by researchers at the National Institute of Allergy and
Infectious Diseases (NIAID), part of the National Institutes of Health, and
their colleagues.
Peter
D. Kwong, Ph.D., and John R. Mascola, M.D., led the study. Dr. Kwong is chief
of the Structural Biology Section at the NIAID Vaccine Research Center, and Dr.
Mascola is the center director.
“NIH
scientists have used their detailed knowledge of the structure of HIV to find
an unusual site of vulnerability on the virus and design a novel and potentially
powerful vaccine,” said NIAID Director Anthony S. Fauci, M.D. “This elegant
study is a potentially important step forward in the ongoing quest to develop a
safe and effective HIV
vaccine.”
A
preliminary human trial of the new vaccine regimen is anticipated to begin in
the second half of 2019.
Today’s
report reflects one of two broad, complementary approaches NIAID is pursuing to
develop an HIV vaccine. In one approach, scientists first identify powerful HIV
antibodies that can neutralize many strains of the virus, and then try to
elicit those antibodies with a vaccine based on the structure of the HIV
surface protein where the antibodies bind. In other words, scientists start
with the most promising part of the immune response and work to develop a vaccine
that will induce it. This method was used to design the vaccine described
today.
The
other, empiric approach to HIV
vaccine development begins by evaluating the most encouraging vaccine
candidates for efficacy in people through clinical trials. Then scientists try
to build on successful trial results by, for example, examining blood and other
clinical specimens from study participants who received the vaccine to identify
the most promising parts of the immune response. Researchers subsequently use this
information to improve vaccination approaches for future trials. This method
was used to develop the HIV vaccine regimen tested in the RV144 clinical
trial and the HIV
vaccine regimens currently under study in the HVTN
702 and Imbokodo clinical trials.
Over
the past several years, HIV researchers have discovered many powerful,
naturally occurring antibodies that can prevent multiple HIV strains from
infecting human cells in the laboratory. About half of people living with HIV make these
so-called “broadly neutralizing” antibodies but usually only after several
years of infection — long after the virus has established a foothold in the
body. Scientists have identified and characterized the sites, or epitopes, on HIV where
each known broadly neutralizing antibody binds. Many laboratories around the
world are developing HIV vaccine candidates based on the structure of these
epitopes with the goal of coaxing the immune
systems of HIV-negative people to make protective antibodies after
vaccination.
The
experimental vaccine described in today’s report is based on an epitope called
the HIV fusion peptide, identified by NIAID scientists in 2016. The fusion
peptide, a short string of amino acids, is part of the spike on the surface of HIV that the virus uses to
enter human cells. According to the scientists, the fusion peptide epitope is
particularly promising for use as a vaccine because its structure is the same
across most strains of HIV, and because the immune
system clearly “sees” it and makes a strong immune response to it. The
fusion peptide lacks sugars that obscure the immune system’s view of other HIV
epitopes.
To
make the vaccine, the researchers engineered many different immunogens
— proteins designed to activate an immune response. These were designed using
the known structure of the fusion peptide. The scientists first assessed the
immunogens using a collection of antibodies that target the fusion peptide
epitope, and then tested in mice which immunogens most effectively elicited HIV-neutralizing
antibodies to the fusion peptide. The best immunogen consisted of eight
amino acids of the fusion peptide bonded to a carrier that evoked a strong
immune response. To improve their results, the scientists paired this immunogen
with a replica of the HIV spike.
The
researchers then tested different combinations of injections of the protein
plus HIV spike in mice and analyzed the antibodies that the vaccine regimens
generated. The antibodies attached to the HIV fusion peptide and neutralized up
to 31 percent of viruses from a globally representative panel of 208 HIV
strains.
Based
on their analyses, the scientists adjusted the vaccine regimen and tested it in
guinea pigs and monkeys. These tests also yielded antibodies that neutralized a
substantial fraction of HIV strains,
providing initial evidence that the vaccine regimen may work in multiple
species.
The
scientists are now working to improve the vaccine
regimen, including making it more potent and able to achieve more consistent
outcomes with fewer injections. The researchers also are isolating additional
broadly neutralizing antibodies generated by the vaccine in monkeys, and they
will assess these antibodies for their ability to protect the animals from a
monkey version of HIV.
The NIAID scientists will use their findings to optimize the vaccine and then
manufacture a version of it suitable for safety testing in human volunteers in
a carefully designed and monitored clinical trial.
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