NIAID Vaccine Protects Against SARS Virus Infection in Mice

An experimental vaccine prevents the SARS virus from replicating in laboratory mice, according to a new report in the April 1, 2004 issue of Nature. Scientists at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health, developed the vaccine. The vaccine was tested in a mouse model of SARS infection recently validated by other NIAID investigators.

The VRC scientists are preparing further experiments to evaluate the vaccine's safety and potential to induce similar immune responses in humans. The vaccine contains a small piece of SARS virus DNA, insufficient to reproduce the SARS virus, yet able to stimulate a protective immune response.

"This research was done in a remarkably short period of time, a testament to the serious attention and great cooperation the public health community has displayed in response to SARS. It has been just one year from identification of the SARS coronavirus to the development of this vaccine that has now proven effective against SARS in a laboratory animal," says Anthony S. Fauci, MD, director of NIAID.

The DNA vaccine is made from a small piece of DNA that codes for a coat protein normally found on the outer surface of the SARS virus. This protein helps the SARS virus gain access to living cells, where it can cause infection. Because the DNA in the vaccine codes only for the protein, by itself it is unable to cause infection. NIAID scientists also modified the DNA so that it does not match the virus' genetic sequence to minimize the risk of it combining with the genetic material of SARS or other coronaviruses.

Most existing vaccines use killed or weakened forms of a whole virus or bacteria to protect against disease. This DNA vaccine works by directing the body's cells to make proteins very similar to those on the surface of the SARS virus. These proteins trigger the immune system to mount a defense effective enough to recognize and neutralize any subsequent encounters with the actual SARS virus.

"This vaccine dramatically reduced the level of virus in the lungs of infected mice, more than a million-fold," says Gary J. Nabel, MD, PhD, VRC director. "It represents a critical first step towards developing an effective human SARS vaccine." Nabel worked with Kanta Subbarao, MD, in the NIAID Laboratory of Infectious Diseases, who recently established the mouse model of SARS infection.

Testing the vaccine in mice demonstrated its effectiveness and also helped scientists learn more about different mechanisms the immune system uses to tackle the SARS virus. The immune system typically responds to foreign invaders by producing antibodies that bind them, cells that digest them or both.

Scientists found that their experimental DNA vaccine caused the immune system to produce both antibodies and cells designed specifically to defend against the SARS virus. They also determined, however, that the antibodies alone were responsible for the dramatic reduction in virus particles in mice that received the vaccine.

Scientists tested two versions of the vaccine in mice. The two versions of the vaccine differed in how much genetic material scientists removed from the original piece of SARS DNA. They gave five mice three doses of one version of the vaccine over a 6-week period. Another group of five mice received three doses of the other version of the vaccine. They also included a control group of five mice that received an inactive or blank vaccine.

Thirty days later, the scientists exposed all the mice to the SARS virus. After two days, the mice in the control group had very high levels of SARS virus in their lungs. The vaccinated mice had nearly negligible levels of SARS virus in their lungs. The mice that received either version of the modified DNA vaccine had 1 million times fewer virus particles than the unvaccinated mice.

In preparation for human trials, Nabel says, Vical Inc., San Diego, under contract to NIAID, is manufacturing a highly purified vaccine suitable for human clinical trials, pending Food and Drug Administration approval.

The SARS virus infected 8,098 people and killed 774 worldwide between Nov. 1, 2002, and July 31, 2003, according to the World Health Organization. For more information on SARS research, see NIAID's updated fact sheet online at http://www.niaid.nih.gov/factsheets/sars.htm.

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.

References:

Z Yang et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature 428:561-4 (2004). DOI: 10.1038/nature02463.

K Subbarao et al. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. Journal of Virology 78:10-16 (2004). DOI: 10.1128/JVI.78.7