In a phase 2b trial of 5,782 older adults, an adenovirus serotype 26 respiratory syncytial virus (RSV) vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) protein vaccine was immunogenic and prevented RSV-mediated lower respiratory tract disease.
The primary end point of the proof-of-concept CYPRESS trial was the first occurrence of RSV-mediated lower respiratory tract disease that met 1 of these definitions: 3 or more symptoms of lower respiratory tract infection (definition 1), 2 or more symptoms of lower respiratory tract infection (definition 2), and either 2 or more symptoms of lower respiratory tract infection or 1 or more symptoms of lower respiratory tract infection plus at least 1 systemic symptom (definition 3).
The results for older adults aged 65 years or older and in stable health showed the following: “RSV-mediated lower respiratory tract disease meeting case definitions 1, 2, and 3 occurred in 6, 10, and 13 vaccine recipients and in 30, 40, and 43 placebo recipients, respectively. Vaccine efficacy was 80.0% (94.2% confidence interval [CI], 52.2 to 92.9), 75.0% (94.2% CI, 50.1 to 88.5), and 69.8% (94.2% CI, 43.7 to 84.7) for case definitions 1, 2, and 3, respectively. After vaccination, RSV A2 neutralizing antibody titers increased by a factor of 12.1 from baseline to day 15, a finding consistent with other immunogenicity measures. Percentages of participants with solicited local and systemic adverse events were higher in the vaccine group than in the placebo group (local, 37.9% vs. 8.4%; systemic, 41.4% vs. 16.4%); most adverse events were mild to moderate in severity. The frequency of serious adverse events was similar in the vaccine group and the placebo group (4.6% and 4.7%, respectively).”
Editorial: Reflecting on this and another RSV vaccine study in this issue of NEJM, an editorialist writes: “Notably, the success of structure-based vaccine design for RSV informed the rapid response to Covid-19. Outbreaks of Middle East respiratory syndrome coronavirus were occurring while the RSV preF structure was being analyzed. At that time, we did not know the atomic-level structure of any coronavirus protein, but over the next few years, spike protein structures were solved, and ultimately stabilizing mutations were identified to maintain the prefusion spike conformation and improve protein expression levels. These studies were the basis for coronavirus pandemic preparedness planning that included public–private and academic collaborations that were operative in 2019. Because of the technical advances in biomedical science and the RSV blueprint, work that had taken decades in RSV research was compressed into just a few weeks for SARS-CoV-2, providing sequences, structures, and reagents needed to rapidly develop safe and effective vaccines and therapeutic [monoclonal antibodies].
“With Covid-19 vaccines now approved for clinical use and RSV vaccines shown to be effective and awaiting approval, we have entered an era of precision antigen design based on protein engineering guided by atomic-level structure. I hope these advances will lead to future successes in addressing unmet needs and combating threats from emerging pathogens.”