In the Journals: Progress toward RSV Vaccine Design

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease and death in infants and the elderly. Since the virus was first discovered in 1956, researchers have worked hard to make a successful vaccine — with little success. Indeed, a whole-virus, aluminum-adjuvanted RSV vaccine in the 1960s actually enhanced clinical disease upon natural challenge.

Since that ill-fated, inactivated, whole RSV experience, researchers have turned their attention to the fusion (F) protein of the virus. Researchers have shown that antibodies directed against F protein neutralize virus infectivity. Although pre-clinical and early clinical trials have shown that immunizing experimental animals or children with the RSV F protein induces high levels of binding antibodies, it’s been difficult to elicit high levels of neutralizing antibodies. In other words, antibodies haven’t been successfully targeted to the “business end” of the F protein.

We now know that the RSV F protein exists in two conformational states: pre-fusion and post-fusion. We also know that the pre-fusion conformational state is far better at inducing neutralizing antibodies than the post-fusion state. The trick has been creating stable, pre-fusion F protein.

In August 2019, researchers at the National Institutes of Health, George Washington University, and the University of Texas at Austin found that they could produce a stabilized subunit pre-fusion RSV protein (Crank ME, et al. A proof of concept for structure-based vaccine design targeting RSV in humans. Science. 2019 Aug. 2;365(6452):505-509). Inoculation of people in phase I clinical trials showed a 10-fold boost in neutralizing antibodies directed at the pre-fusion F protein. This level of neutralizing antibodies is significantly greater than trials in which people have been inoculated with either a post-fusion or structurally undefined F protein. The authors concluded, “These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.”