Only malaria kills more babies between the ages of 1 month and 1 year than respiratory syncytial virus (RSV). Now, a new experimental vaccine to protect against RSV has passed the first hurdle of animal testing. According to a report published in Science from the Vaccine Research Center (VRC) and National Institute of Allergy and Infectious Diseases (NIAID), the researchers have begun to plan human clinical trials.

“Many common diseases of childhood are now vaccine-preventable, but a vaccine against RSV infection has eluded us for decades,” Anthony S. Fauci, M.D., director of the NIAID, stated in a press release. “This work marks a major step forward.”

Respiratory Syncytial Virus

Generally, most people develop RSV infections in the U.S. between the months of November and April. Along with babies, those at risk for developing severe disease following an RSV infection include adults over age 65 and those with compromised immune systems. Symptoms of an RSV infection include coughing, sneezing, runny nose, fever, and a decrease in appetite. Sometimes people with the infection also wheeze. Very young infants may show signs of irritability, greater passivity, and breathing difficulties.

Although nearly all children become infected with RSV by their second birthday, very few develop severe disease. In fact, otherwise healthy infants generally do not need to be hospitalized and most cases usually last only a few days. Even those who are hospitalized — annually between 75,000 to 125,000 children under 1 — usually recover in about one to two weeks. In the U.S., the virus is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia in this same age group.

Worldwide, it is estimated that RSV is responsible for nearly seven percent of deaths in babies between the ages of 1 month and 1 year.

How to Build a New Vaccine

To design the experimental vaccine for RSV, the team of scientists built on their previous research into the structure of a crucial viral protein.

The interaction between any virus and the molecules within the immune system of your body begins on an atomic level and within nanoseconds and then continues to evolve. For the very first time earlier this year, the team obtained a view of an initial interaction when they detected through an electron microscope the structure of a neutralizing human antibody bound to a protein on the surface of the virus. The scientists, then, had their first look at the F glycoprotein as it appears before it fuses with a human cell.

In this pre-fusion shape, the F glycoprotein contains a region vulnerable to attack by broadly neutralizing antibodies — antibodies that can block infection from the common strains of RSV. Knowledge of the structure of this protein-antibody ‘complex,’ then, guided the scientists as they designed the new vaccine. Although this vulnerable area — the researchers named it ‘antigenic site zero’ — is no longer present on the rearranged F protein after RSV fuses with a cell, the scientists understood it was a weak moment that might be exploited. So they chose to aim their vaccine in this direction.

“Here is a case in which information gained from structural biology has provided the insight needed to solve an immunological puzzle and apply the findings to address a real-world public health problem,” Barney S. Graham, M.D., Ph.D, co-leader of the team, stated in a press release.

Targeting a Weakness

In a natural RSV infection, a person’s immune system produces antibodies against both the pre-fusion and post-fusion forms of F glycoprotein. The antibodies produced by the immune system to fight antigenic site zero — which only exists in the pre-fusion form — have much stronger neutralizing activity. Therefore, the scientists understood a vaccine against RSV would have greater chance of success if it were directed at F glycoprotein in its pre-fusion configuration.

Armed with this knowledge, the team designed and engineered F glycoprotein variants that retained antigenic site zero even when no antibody was bound to it. Using X-ray crystallography, they searched for the variants with the most stable structures believing these would elicit the most powerful antibody response. To this end, the researchers designed more than 100 variants. Of these, three retained the desired and necessary stable structure.

Finally, the team tested the three engineered variants as vaccines in a series of experiments performed on mice and rhesus macaques. In both animals, the researchers found that the more stable the protein, the higher the levels of neutralizing antibodies elicited by vaccination. The levels of antibody made in response to one of their newly engineered variants were more than 10 times higher than those produced following a vaccine based on post-fusion proteins. They were also well above levels needed to protect against RSV infection.

“Previously, structure-based vaccine design held promise at a conceptual level,” Peter D. Kwong, Ph.D., co-leader of the study, stated in a press release. “This advance delivers on that promise and sets the stage for similar applications of structure-guided design to effective vaccines against other pathogens.”

The scientists are continuing to refine their work and hope to launch early-stage human clinical trials of a candidate RSV vaccine within the next two years.

 

Source: Kwong PD, Graham BS, McClellan JS, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science. 2013.