Intranasal SARS Vaccine Protects Monkeys from Infection
A single dose of a test vaccine sprayed into the nose protects
monkeys against the SARS virus, according to Alexander Bukreyev,
Ph.D., Peter Collins, Ph.D., and coworkers at the National Institute
of Allergy and Infectious Diseases (NIAID), part of the National
Institutes of Health (NIH).
The study, published in the June 26 issue of the British journal
The Lancet, is the third recently issued by NIAID that describes
a promising candidate vaccine against SARS. This vaccine differs
from the previous two in that it is delivered directly into the
respiratory tract, the primary site of SARS infection; it is the
first U.S. vaccine to be tested in monkeys; and only one dose is
needed for protection. The previous two vaccines were tested in
rodents, and each required two doses for protection.
"We now have three technologically unique approaches to restricting
SARS replication in animals," says Anthony S. Fauci, M.D.,
director of NIAID. "These important studies of SARS vaccines
demonstrate the outstanding progress we have made against this newly
recognized and deadly disease."
The newest vaccine targets the SARS spike (SARS-S) protein, a compound
that protrudes from the surface of the SARS virus, enabling it to
attach to and infect human cells. Investigators developed the vaccine
by inserting the gene that encodes the SARS-S protein into a weakened
version of human parainfluenza virus 3 (HPIV3), called BHPIV3, that
is being developed as an experimental vaccine against HPIV3. In
its natural form, HPIV3 is among the most common causes of respiratory
diseases, such as pneumonia, in young children. Using BHPIV3 as
a vector allowed researchers to introduce the SARS-S protein directly
into the respiratory tract.
Investigators sprayed vaccine into the nasal passages of two groups
of African green monkeys one group received BHPIV3/SARS-S, and the
other group received a control BHPIV3 that contained a harmless
gene in place of SARS-S. Animals that received the BHPIV3/SARS-S
vaccine developed neutralizing antibodies against the SARS virus,
whereas the control group did not. Twenty-eight days after immunization,
both groups of monkeys were administered the SARS virus through
the nose to test the protectiveness of the vaccine. Investigators found that monkeys
vaccinated with a single dose of BHPIV3/SARS-S did not replicate
the virus. In contrast, the monkeys in the control group showed
evidence of SARS virus replication after exposure.
"This study shows that delivering the vaccine directly to the
respiratory tract can effectively protect primates from SARS,"
says Brian R. Murphy, M.D., co-chief of the NIAID Laboratory of
Infectious Diseases and one of the authors of the study. "With
more research, we hope to develop a vaccine based on this approach
that could be used to rapidly immunize first responders and other
medical personnel, helping them control a potential outbreak."
Dr. Murphy says that the vaccine in its current form would be most
effective in young children. Most adults have some level of immunity
to HPIV3 from childhood infections that likely would inhibit an
effective immune response to an HPIV3-based SARS vaccine. However,
Dr. Murphy and his colleagues are planning to conduct clinical studies
of BHPIV3 and other potential intranasal vaccine delivery systems,
including ones that should efficiently immunize adults. "In
the long run, we want to establish a weakened respiratory virus
vector that all people are susceptible to," he says. "That
way, we can quickly develop vaccines for numerous diseases by simply
inserting the protective genes of those viruses into our generalized
In another advance from Dr. Murphy's and Dr. Collins's lab, Ursula
Buchholz, Ph.D., and coworkers showed that no other known SARS virus
structural proteins besides SARS-S are involved in prompting a protective
immune response. Reported online in this week's issue of the Proceedings
of the National Academy of Sciences, Dr. Buchholz and her colleagues
constructed vaccines containing SARS-S as well as one or more other
SARS virus structural proteins. They also made vaccines that contained
one or more SARS virus structural proteins, but did not contain
the SARS-S protein. When given nasally to hamsters, only vaccines
containing SARS-S elicited a protective immune response; adding
other proteins to the mix did not boost the response. The magnitude
of SARS virus replication in hamsters is much higher than is detected
in monkeys, so the protective value of a candidate vaccine can be
readily measured when tested in the hamster model, explains Dr.
Buchholz. This finding will simplify the development of a SARS vaccine.
NIAID is a component of the National Institutes of Health, an agency
of the U.S. Department of Health and Human Services. 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 transplantation
and immune-related illnesses, including autoimmune disorders, asthma
Press releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at http://www.niaid.nih.gov.
References: A Bukreyev et al. Mucosal immunisation of African green
monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the
SARS coronavirus spike protein for the prevention of SARS. The Lancet
363 (9427):2122-27 (2004).
UJ Buchholz et al. Contributions of the structural proteins
of severe acute respiratory syndrome coronavirus to protective immunity.
Proceedings of the National Academy of Sciences. Published
online June 2004. DOI: www.pnas.org/cgi/doi/10.1073/pnas.0403492101.