Darrell Irvine - Evaluating strategies for HIV vaccination
Study yields insight into generating antibodies that target different strains of HIV.
Anne Trafton | MIT News Office
February 6, 2015
an investigation of a fundamental process that guides the maturation of
immune cells, researchers have revealed new insights into possible ways
to vaccinate people to generate potent antibodies of the type that are
predicted to offer protection against diverse strains of the highly
The findings, described this week in the journal Cell,
suggest that sequentially administering several different forms of a
potential HIV vaccine could stimulate a stronger immune response than
delivering a cocktail of these variants all at once. The study also
sheds new light on a fundamental process of immune-cell development
known as “affinity maturation.”
“Our work describes how affinity maturation works when there are
variant strains of the virus to contend with, and why cross-reactive
antibodies that can protect against diverse strains of the virus usually
do not arise during natural infection. But it does offer hope that a
properly designed vaccination scheme that can manipulate affinity
maturation appropriately might be able to more efficiently produce such
antibodies against the virus,” says Arup K. Chakraborty, the Robert T.
Haslam Professor in Chemical Engineering and a professor of chemistry,
physics, and biological engineering, director of MIT’s Institute for
Medical Engineering and Science, and a member of the Ragon Institute of
Massachusetts General Hospital, MIT, and Harvard University.
Such a vaccine, which has not yet been developed, would require
sequential administration of a few variants of the HIV proteins that
make up the spikes on the surface of the virus, which mutate frequently.
This would help the immune system arm itself against a wide range of
possible strains of the virus.
Other senior authors of the paper are Dane Wittrup, the Carbon P.
Dubbs Professor in Chemical Engineering at MIT; Mehran Kardar, the
Francis L. Friedman Professor of Physics at MIT; and Dennis R. Burton, a
professor of immunology and microbial science at the Scripps Research
Institute. The paper’s lead author is MIT postdoc Shenshen Wang, and
other authors are former MIT graduate student Jordi Mata-Fink; recent
MIT graduates Barry Kriegsman and Melissa Hanson; Darrell Irvine, an MIT
professor of biological engineering and materials science and
engineering; and the late Herman Eisen, a professor emeritus of biology.
Optimized immune response
Despite more than 30 years of intense effort, scientists have not yet
come up with a reliably effective HIV vaccine — in part, because the
virus mutates so frequently that it evades the body’s immune response.
This challenge could be overcome with a vaccine that generates a
population of B cells that produce antibodies that can target diverse
mutant strains of specific viral proteins.
Such antibodies, known as “broadly neutralizing antibodies,” can
arise in HIV-infected patients, but this rarely happens, and usually
takes at least a couple of years — too long to offer any natural
resistance to infection.
Antibodies, which detect foreign pathogens and alert the immune
system to take action, develop through affinity maturation. The body has
millions of antibody-producing B cells, each of which has receptors on
its surface that target different pathogenic proteins, called antigens.
When a B cell receptor binds to an antigen, usually in the lymph
nodes, it starts to reproduce itself; the resulting cells go through
several rounds of mutation and re-exposure to the antigen. B cells that
bind more strongly to the antigen survive each round of this selection.
This affinity-maturation process ensures that the resulting B cell
population, and the antibodies that they produce, will bind increasingly
strongly to the invader as time ensues. However, because the HIV virus
mutates so rapidly, HIV-specific antibodies eventually lose their
The MIT and Ragon Institute researchers used computer modeling to
carry out the first investigation of how affinity maturation happens
when multiple variant antigens, rather than just one, are present. They
found that in many circumstances, affinity maturation is “frustrated” by
the differing selection forces imposed by the variant antigens. They
also explored possible vaccination strategies for manipulating affinity
maturation to overcome this problem and produce cross-reactive
Their results suggested that sequential administration of different
variants of an antigen — in this case, the protein “spike” that allows
the virus to latch onto human T cells — offers the best hope for
generating broadly neutralizing antibodies. This strategy allows the
antibodies to gradually evolve to focus on the conserved elements shared
by diverse HIV strains — elements that are essential for virus
function. This approach was much more successful than exposing the cells
to all the antigen variants at once.
Researchers in Wittrup’s lab then tested this prediction in model
experiments with mice. “We developed a strategy for leading the immune
system to focus on such a restricted site by exposing it to a programmed
series of immunogens with variation at all the sites that we don’t want
antibodies to bind to, while the desired target patch is kept constant
throughout the series,” says Wittrup, who is the associate director of
MIT’s Koch Institute for Integrative Cancer Research. Scientists had not
yet been able to generate variants of the HIV protein spike, which
consists of three proteins joined together, so they used four variants
of a single protein that is part of the spike.
In mice that received all four variants at once, the resulting
antibodies were different and responded to only some of the variants.
However, in mice vaccinated sequentially, the antibodies generated by
affinity maturation were focused on the target patch of conserved
elements and were able to respond to all of the protein variants, just
as the computer model predicted.
Potential vaccine strategy
The researchers are careful to point out that their animal
experiments did not generate broadly neutralizing antibodies — they only
showed that it is possible to stimulate cross-reactive antibodies that
react to multiple variants of a component of the protein spike. However,
they are now working on developing variants of the full spike in hopes
of testing them as vaccines.
“These modeling studies provide us with some very concrete
suggestions as to the types of vaccine regimens that might work best to
induce broadly neutralizing antibodies, which we think are key to
protecting against HIV infection. We plan to test the models in nonhuman
primates very soon,” Burton says.
“All attempts at HIV-1 vaccination have failed for the last 30 years.
This new analysis of affinity maturation provides some important novel
insights into how immune responses to complex antigens develop and clues
about how one might go about to creating a vaccine in the future,” says
Michel Nussenzweig, a professor of molecular immunology at Rockefeller
University who was not involved in the research.
This approach may also be beneficial in developing vaccines against
other viruses that mutate rapidly, such as the influenza virus,
Chakraborty says. “Because this is a fundamental study, it is relevant
to thinking about broadly neutralizing antibodies to other pathogens
that are highly mutable,” he says.
The research was funded by the Ragon Institute, the International
AIDS Vaccine Initiative, the National Institutes of Health, and the
Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery.