A single dose of a test vaccine sprayed into the nose protects monkeys against the SARS virus, according to Alexander Bukreyev, PhD, Peter Collins, PhD, 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, 2004 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, MD, 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, MD, 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."
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, 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 vector."
In another advance from Murphy's and Collins's lab, Ursula Buchholz, PhD, 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, 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 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 and allergies.
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.