ATLANTA -- September 5, 2000 -- Scientists at the Vaccine Research Center of Emory University have successfully engineered and tested a single-dose, DNA-based influenza vaccine in mice that could serve as a template for more effective vaccines against a variety of viral illnesses, including HIV. Results of the study appear in the August edition (Vol. 1, No. 2) of Nature Immunology.
The research team fused DNA from an immune system component of complement called C3d to the hemagglutinin (HA) glycoprotein of the influenza virus. For purposes of comparison, two other DNA vaccines were also constructed based on a secreted form of HA (sHA) and a transmembrane (tmHA) version.
Mice were inoculated with the vaccines and then challenged with a lethal dose of influenza virus. All three vaccines generated a neutralizing antibody response. The C3d form of the vaccine, however, produced 10 to 20 times higher levels of neutralizing antibody than the sHA and tmHA vaccines. Protective immunity was also generated at a much faster rate and at a dose ten times lower than with the non-fused forms of HA.
Previous studies have determined that combining two or three copies of C3d to a model antigen increased the efficacy of immunizations by more than 1000-fold compared to protein-based vaccines. The VRC study is the first to demonstrate the effectiveness of the C3d-fusion with a DNA vaccine and in a viral model.
Influenza virus uses the HA glycoprotein to attach and gain entry into cells. In developing vaccines, researchers target HA because raising anti-HA antibodies provide protection against the virus.
The use of the C3d subunit of complement combined with HA to prime the immune system against influenza constitutes a novel approach to immunization. When the vaccine is introduced into the body, the immune system recognizes HA and is stimulated by the C3d. The C3d stimulation increases the magnitude of the antibody response and accelerates the maturation of the raised antibody.
"This novel approach to vaccination primes the immune system on multiple fronts," said Dr. Harriet Robinson, who helped to develop the vaccine. "A protective response is mounted both in recognition of HA as an antigen and by the stimulatory effects of C3d."
DNA vaccines have several distinct advantages over conventional protein or attenuated virus vaccines. They can be manufactured inexpensively in a relatively short period of time and do not need to be refrigerated. Influenza is the only disease that has caused an actual dip in the human population in the 20th century. Outbreaks of influenza occur when the HA glycoprotein mutates (antigenic drift) or changes to a new subtype (antigenic shift).
Because of the virus's penchant for mutation, scientists must anticipate the next strain that will emerge when developing vaccines against influenza. Sometimes, of course, their predictions are inaccurate. To control emerging influenza pandemics, DNA vaccines, in contrast to conventional vaccines, could be rapidly deployed after the HA subtype of the particular influenza strain had been identified.
DNA vaccines are still in the experimental stages. Data from this latest study will enable VRC researchers to continue refining the DNA model in designing vaccines against influenza as well as other viruses, most notably HIV.
Drs. Ted Ross and Harriet Robinson, research specialist Yan Xu, and graduate student Rick Bright led the influenza vaccine study. It was funded by grants from the National Institutes of Health.
Journal
Nature Immunology