New
Vaccination Strategies Successfully
Coach Immune System to Make Powerful
HIV-Neutralizing Antibodies
Do better than nature
Coach Immune System to Make Powerful
HIV-Neutralizing Antibodies
International AIDS Vaccine Initiative -- September 8, 2016 -- New
approaches that could spur the human body to produce HIV-blocking antibodies
have been successful in mice mimicking the human immune system, according to
five studies published today in the research journals Cell, Immunity and Science.
The results were produced by scientists affiliated with the
International AIDS Vaccine Initiative (IAVI); The Scripps Research Institute
(TSRI); U.S National Institute of Health’s National Institute of Allergy and
Infectious Diseases (NIAID); Howard Hughes Medical Institute (HHMI); The
Rockefeller University; Ragon Institute of Massachusetts General Hospital, MIT
and Harvard; Boston Children’s Hospital; Massachusetts Institute of Technology
(MIT); Harvard Medical School (HMS); Vanderbilt University; Columbia
University; Fred Hutchinson Cancer Research Center (FHCRC); Duke University
School of Medicine and Kymab Ltd.
“It’s early work, but we’re trying to rewrite some rules of vaccine
development to overcome the extraordinary challenges of HIV,” says William
Schief, TSRI Professor and Director of Vaccine Design for IAVI’s Neutralizing
Antibody Center (NAC) at TSRI. “In a collaborative effort we have reached
critical milestones, including the first proof ever that immunization with
designer proteins can produce broadly neutralizing antibodies against HIV. The
new results strongly support further developing these approaches toward testing
in clinical studies.”
HIV circulates in a person’s body in many variants that mutate rapidly and
escape defensive immune responses. Since the virus attacks the very immune
cells that are supposed to fight it, and it hides in persistently infected
cells, capable of re-emerging and striking at any time, traditional vaccine
strategies have failed to work against HIV. New approaches are needed to
develop a broadly effective AIDS vaccine.
In laboratory and animal testing, broadly neutralizing antibodies
(bNAbs) have been shown to prevent or control infection from a wide range of
HIV variants. Many researchers believe bNAbs are a critical component of future
broadly effective AIDS vaccination. However, developing these vaccines will
require scientists to do better than nature as only 10% to 20% of people living
with HIV develop bNAbs, and such a process can take years to happen. Expanding
on earlier work, the new studies have taken further critical steps to show that
it could be possible to actually coax the human immune system to create bNAbs
against HIV.
Innovative immune system training
The researchers tested the efficacy of immune system training that combines a
prime shot with an immunogen (the active ingredient of a vaccine) to activate
bNAb precursor cells (germline B cells) with booster shots of other immunogens
that trigger mutations in the antibodies until they mature into bNAbs. They did
this in mice whose immune systems mimicked components of the human immune
system, testing for different challenges that immunogens would have to
overcome. They aimed at generating two classes of bNAbs (VRC01 and PGT121) as
it is believed that neutralizing a wide range of HIV variants will require more
than one type of bNAb.
A study published in Science expanded earlier results achieved with a
promising prime immunogen (eOD-GT8 60mer, a nanoparticle composed of 60 units
of an engineered version of the HIV envelope protein’s outer domain) in a more
human-like and challenging mouse model. Dennis Burton, Scientific Director of
IAVI’s NAC at TSRI and Chair of TSRI’s Department of Immunology and Microbial
Science, Schief and colleagues at TSRI, Ragon Institute, MIT, HMS and Kymab Ltd,
administered the immunogen to mice (Kymouse™) engineered to express human
antibodies, but to express precursor B cells for the VRC01 bNAB in a much lower
concentration than found in humans. Nonetheless, the mice were successfully
primed to have the type of immune response a vaccine should induce in humans,
demonstrating the immunogen’s strong priming effectiveness.
In
another study, published in Cell, and conducted by Schief, Burton , TSRI Professor David Nemazee and
their colleagues at IAVI’s NAC, TSRI, Ragon Institute, MIT and HMS, mice
engineered to make precursors of VRC01 bNAbs were primed with the eOD-GT8 60mer
and boosted with two other immunogens. The elicited antibodies shared many
genetic features with mature bnAbs and had the ability to neutralize one native
HIV isolate as well as multiple slightly modified HIV isolates. The boosters
seem to have guided the antibody-producing B cells to mutate in the right
direction. The researchers now think that additional boosters are needed to
complete the bNAb maturation.
A second study published in Cell succeeded with a
similar approach. They showed that a series of priming with the eOD-GT6 60mer
immunogen (an earlier version of the eOD-GT8 60mer) and boosting with different
modified HIV envelope proteins could induce antibodies with properties of
partially mature bNAbs in mouse models with immune systems that can create an
even wider range of antibodies. This study was conducted by John Mascola at the
NIAID’s Vaccine Research
Center and Frederick Alt, a HHMI
researcher at Boston Children’s Hospital and Harvard Medical
School , along with
colleagues at IAVI’s NAC at TSRI, TSRI, Vanderbilt University, Columbia
University, Ragon Institute, FHCRC and Duke University School of Medicine.
With a third study published in Cell and another
published in Immunity, Schief, Michel Nussenzweig and teams at IAVI’s NAC,
TSRI, HHMI, The Rockefeller University and Ragon Institute demonstrated the
ability of different prime and booster immunogens to induce the generation and
full maturation of a PGT121 bNAb that neutralized diverse HIV isolates in
another mouse model. This is the first proof ever that immunization with a
series of prime and booster shots using designer proteins can produce bNAbs
against HIV. This work is also novel in that it suggests a way to induce bNAbs
that bind sugar molecules that shield HIV from antibody attack. Many bNAbs that
develop during natural infection bind at least in part to the sugar coating,
but it has not been known until now how to develop immunogens to induce this
kind of response through vaccination.
Taken together, these results offer encouraging insights and proof
points for a planned Phase I clinical trial by IAVI to test the eOD-GT8 60mer
prime and to further develop booster immunogens and test their ability to
elicit bNAbs in humans in future trials. And, the work on PGT121 vaccine
development and testing in a mouse model has encouraged the researchers to
further develop their approach to get it ready for clinical studies.
Earlier ground work
In
June 2015, scientists from TSRI, IAVI and The Rockefeller University
described in Cell and Science the design of the eOD-GT8 60mer and reported that
the immunogen induced antibody responses in mice that showed some of the traits
necessary to neutralize HIV. Studies published in Science by IAVI and TSRI
researchers in
March 2016 showed that the precursor B cells for one kind of HIV bNAb seem
to be present in most people. In August
2016, the researchers described in PLOS Pathogens the minimal set of
mutations needed for one type of antibody to develop into a bNAb and proposed
the structures of priming and boosting immunogens needed in a vaccine to induce
those mutations.
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