Live-attenuated Respiratory Syncytial Virus Vaccines: Time for the Next Step.

Dr. Karron and colleagues have previously made several attempts to develop a live-attenuated vaccine against respiratory syncytial virus (RSV) to protect children against one of the most common severe diseases during childhood (1). They have performed as many as seven phase I trials with different intranasal vaccine candidates. In this issue of the Journal, the study by Karron and colleagues (pp. 594–603) describes a pooled analysis of these early stage trials among 241 children aged 6–24 months (1). The authors took advantage of the postvaccination surveillance of acute respiratory infection used to monitor the occurrence of enhanced RSV disease in vaccine recipients to assess the overall vaccine efficacy and key immunogenicity endpoints. While analyzing these trials, they distinguished these vaccines into more and less immunogenic vaccines based on induced serum-neutralizing antibodies. Four vaccines that induced at least a fourfold increase in neutralization in ≥80% of the vaccine recipients were referred to as “more promising” vaccines, in opposition to “less promising” ones. Pooling data from trials with these more immunogenic vaccines, vaccine efficacy against RSV-associated medically attended respiratory infection was 67%, which suggests these vaccines might indeed hold a promise for RSV-naive children.

How does this study fall within the current landscape of RSV immunization? The field is moving rapidly with products moving forward rapidly in clinical development. The front runner appears to be nirsevimab (previously MEDI8897), an extended half-life antibody targeting the prefusion RSV F protein, showing excellent safety and efficacy data in a recent trial in prematurely born children (2). This antibody has now moved into a phase 3 trial in healthy term children. A nanoparticle-based RSV F vaccine showed excellent safety and good but mixed efficacy after administration to pregnant women during their third trimester (3). The vaccine missed its primary endpoint by a fraction. Although efficacy in the United States could not be demonstrated, it showed impressive efficacy against most severe RSV infection in South Africa, leaving us with an ethical dilemma that this vaccine might have life-saving potential in developing countries. A chimpanzee adenovector-based vaccine nicely increased serum-neutralizing activity in older adults against some modest local adverse reactions (4). Finally, there are two late-stage trials investigating a prefusion RSV F subunit vaccine in pregnant women (5).

Most live-attenuated vaccines are administered intranasally and have been attenuated by deleting one or more genes, including M2-2, NS2, SH, and G (6, 7). Intranasal live-attenuated RSV vaccines may have advantages over other approaches to prevent severe RSV infection. First, these vaccines are considered safe in general. Vaccine-enhanced disease, such as that encountered using formalin-inactivated RSV, has not been described with any live-attenuated RSV vaccine. In the case of insufficient attenuation, the vaccine may cause some respiratory symptoms, such as those observed with live-attenuated influenza vaccines (8). Second, needle-free vaccination has a clear advantage for preschool children. Third, the virus replicates in the airway, resulting in a broad immune response, including both a variety of specific antibodies as well as T-cell immunity, which may not be elicited by any other vaccine. Fourth, and this may be quite important for public health impact, live-attenuated RSV vaccines may induce herd immunity when administered to seronegative 6- to 24-month-old children (9).

The time seems right for live-attenuated RSV vaccines. Some of the candidate vaccines are the interesting and fruitful coproduction of a public–private partnership between the NIH and Sanofi pharmaceuticals (5). If live-attenuated RSV vaccines are indeed safe and effective, it is time that more candidate vaccines move forward in clinical development. There are nine active early stage trials with live-attenuated RSV vaccines, with only one in phase 2 registered on ClinicalTrials.gov. Has the bar so far been set too high to progress further into clinical development? Based on the paper by Karron and colleagues, we can conclude that the safety and efficacy profile of the group of live-attenuated RSV vaccines as well as their unique benefits over other approaches deserve a strong place in the turbulent future of RSV vaccine development.