|New Details on How the Immune System Recognizes
Drawing upon a massive database established with funds from the
National Institute of Allergy and Infectious Diseases (NIAID),
one of the National Institutes of Health (NIH), scientists have
completed the most comprehensive analysis to date of published
influenza A virus epitopes--the critical sites on the virus that
are recognized by the immune system. The findings, reported by
researchers at the La Jolla Institute for Allergy and Immunology
(LIAI), are being published online this week by the journal Proceedings
of the National Academy of Sciences.
The study should help scientists who are designing new vaccines,
diagnostics and immune-based therapies against seasonal and pandemic
influenza because it reveals in molecular detail exactly where
the immune system focuses on the viruses. Although the complete
molecular structures of essentially all major strains of influenza
viruses are known, immune responses concentrate on limited regions
of certain parts of the virus, and these regions must be identified
as immune epitopes by research studies. The LIAI team found that
while there were hundreds of shared epitopes among different virus
strains, including the avian H5N1 virus, only one has been published
that appears ideal for multi-strain vaccines. Information on shared
protective epitopes is important for developing influenza vaccines
that can provide broad protection against multiple strains of the
“This study is interesting for what it shows we know and do not
know,” says NIAID Director Anthony S. Fauci, M.D. “It reveals many
gaps in our knowledge of influenza viruses and indicates where
we need to focus our attention.”
The analysis drew upon a much larger effort called the Immune
Epitope Database and Analysis Resources Program, which began in
2004 after NIAID awarded LIAI a $25 million contract to create
a single repository of immune epitopes from critical disease-causing
microbes, including agents that might be used in a bioterrorist
attack. Influenza epitopes comprise only a portion of the extensive
database, which has become the largest single collection of such
information anywhere in the world. It includes data from thousands
of separate articles published over several decades, providing
extensive dossiers on dozens of pathogens.
“The purpose of the database is to provide a catalog of molecules
and structures that scientists around the world can quickly access
and use to understand the immune response to a variety of epitopes,
or methodically predict responses to as-yet untested targets,” says
Alessandro Sette, Ph.D., who heads the Vaccine Discovery division
at LIAI and is the lead investigator on the project.
For the current study, Dr. Sette and his colleagues examined 600
different epitopes from 58 different strains of influenza A virus.
One of their main goals was to determine how conserved, or similar,
epitopes are between different strains of bird and human influenza
viruses. Knowing this is important because the virus rapidly mutates
and can swap gene segments between strains, which could increase
the ability of an avian virus to be transmissible to humans.
In addition, only a handful of the epitopes are known to be associated
with protective immunity. Most of the influenza virus epitopes
in the database are those recognized by a type of immune cell known
as a T cell; far fewer are recognized by B cells, a type of white
blood cell that produces infection-fighting antibodies. Antibodies
induced by seasonal and pandemic flu viruses or vaccines are a
major component of immunity that protects against these viruses.
Strains of influenza virus can vary enough in their neutralizing
B cell epitopes that a vaccine against one strain may not protect
against another strain. But if epitopes are conserved between virus
strains, the immunity a person has developed towards one strain
might provide at least some protection against the other strain.
Using a software tool they developed, the LIAI team found hundreds
of conserved influenza virus epitopes in the database, including
those between avian H5N1 and strains of human influenza viruses.
But what is less clear from the analysis is how cross-reactive
an immune response would be to most of these conserved epitopes.
Further analyses may assist scientists in identifying vaccine targets
that might offer broader protection and in predicting how effective
a new vaccine will be.
Other analyses revealed major gaps in scientists’ knowledge about
influenza viruses. Of the 600 epitopes in the database, for instance,
very few were from strains of H5N1 avian influenza. And even though
the database contains epitopes from all the influenza virus’ proteins,
the vast majority of the data relates to just two influenza proteins,
the hemagglutinin (HA) and nucleoprotein (NP).
Most of the influenza virus data comes from analyses of immune
responses obtained with mice; some comes from rabbits, ferrets
and monkeys, and very little comes from humans or birds. In fact,
only one antibody epitope came from a human. The LIAI researchers
say more studies should be focused on identifying human T and B
cell epitopes from human and avian strains of influenza virus — especially
those associated with protective immunity.
“The bottom line is that this study shows us where we need to
go,” says project director Stephen Wilson, Ph.D., chief technology
officer at LIAI. “Hundreds of flu epitopes have already been published
and are now in the database, but critical gaps become apparent
when one looks for human antibody targets.”
Plans for the future include adding data on epitopes that are
involved in autoimmune diseases and epitopes that trigger allergic
and asthmatic reactions. Dr. Sette and his colleagues have also
built numerous tools for analyzing and visualizing the data and
for predicting immunity against different pathogens — all
of which is publicly accessible on their website (see http://immuneepitope.org).
For more information on influenza see http://www3.niaid.nih.gov/news/focuson/flu.
Also visit http://www.PandemicFlu.gov for
one-stop access to U.S. Government information on avian and pandemic.
NIAID is a component of the National Institutes of Health.
NIAID supports basic and applied research to prevent, diagnose
and treat infectious diseases such as HIV/AIDS and other sexually
transmitted infections, influenza, tuberculosis, malaria and
illness from potential agents of bioterrorism. NIAID also supports
research on basic immunology, transplantation and immune-related
disorders, including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.