New method for designing artificial proteins capable of stimulating an immune response against RSV
Vanderbilt University scientists have contributed to a major finding, reported in the journal Nature, which could lead to the first effective vaccine against respiratory syncytial virus (RSV), a significant cause of infant mortality.
The Vanderbilt scientists and others analyzed in an animal model a new method developed at The Scripps Research Institute (TSRI) in La Jolla, Calif., for designing artificial proteins capable of stimulating an immune response against RSV.
The virus, which worldwide causes nearly 7 percent of all deaths among children ages 1 month to 1 year and is the leading cause of hospitalizations among children under 2, has been notoriously resistant to vaccine-design strategies.
"This project is the first work in which a protein that was designed on a computer has been shown to work as a vaccine candidate for a human pathogen," said Vanderbilt's James Crowe, M.D., Ann Scott Carell Professor and a leading RSV researcher.
"We believe this will be one of the principal ways that vaccines are designed and made in the future," said Crowe, also professor of Pediatrics and Pathology, Microbiology and Immunology.
TSRI scientists, led by senior author William Schief, Ph.D., used a "rational design" approach that focused on specific binding areas (epitopes) on the virus.
Virtually all existing viral vaccines use whole (killed or weakened) virus particles or entire viral proteins to stimulate antibody reactions. These vaccines display virtually the same large set of viral epitopes that the immune system would encounter during a natural infection. Yet some viruses, including RSV, conceal their vulnerable epitopes.
Scientists can sift through blood samples of virus-exposed patients to find the rare, "broadly neutralizing" antibodies that hit those vulnerable epitopes. They also know how to map the precise atomic structures of these antibodies and their corresponding epitopes using X-ray crystallography.
"What we haven't been able to do is to take that information about broadly neutralizing antibodies and their epitopes and translate it into effective, epitope-focused vaccines," lead author Bruno Correia, Ph.D., a member of the Schief laboratory at the time of the study, said in a news release.
The TSRI scientists developed a new software app, "Fold from Loops," to design proteins that folded around their functional fragments more naturally in a way that mimicked the viral epitope and which could serve as a key component of an effective vaccine.
In rhesus macaque monkeys, whose immune systems are quite similar to humans,' the designer "immunogen" proteins showed great promise. After five immunizations, 12 of 16 monkeys were producing robust amounts of antibodies that could neutralize RSV in the lab dish.
Analyses of the animals' immune responses were performed in the laboratories of Philip Johnson, M.D., at Children's Hospital in Philadelphia, and by Crowe and postdoctoral fellow John T. Bates, Ph.D., in the Vanderbilt Vaccine Center, which Crowe directs.
Former Vanderbilt faculty member Barney Graham, M.D., Ph.D., chief of the Viral Pathogenesis Laboratory at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, also participated in the analyses.
Having proven the principle of epitope-specific design, Schief and his colleagues now hope to produce a working RSV vaccine. "We're also trying to improve this protein design method further and apply it to other vaccine projects, including HIV and influenza vaccines," he said in a news release.