Made available in September 2023, nirsevimab, an antibody targeting the respiratory syncytial virus (RSV) is indicated in newborns and infants for the prevention of bronchiolitis. Its wide distribution is likely to lead to resistance mutations. Published in the Lancet Infectious Disease this October 14, the French study POLYRES prospective monitoring of nirsevimab shows that at this stage, these are very rare [1].
“The low prevalence of nirsevimab resistance mutations in treated patients is reassuring. However, a few RSV-B from treated patients analyzed to date presented escape mutations, which calls for caution and highlights the importance of active molecular surveillance in the context of future use of nirsevimab. on a global scale,” commented the Pr Slim Fouratihead of the virology unit, CHU Henri Mondor, Inserm U955 and first author of the article, in an ANRS press release [2].
Theoretical risk of emergence of RSV variants
The 2023/2024 season was marked by the first preventive immunization campaign against respiratory syncytial virus (RSV) with the monoclonal antibody nirsevimab (Beyfortus®) which showed its positive impact on the prevention of bronchiolitis in infants.
This monoclonal antibody targets a specific epitope on a protein located on the surface of RSV involved in viral multiplication, the F fusion protein, and thus blocks the virus. As RSV is a variable virus, there is a theoretical risk of emergence of RSV variants carrying resistance mutations to neutralization by nirsevimab, even in the absence of selection pressure by the antibody.
Observational, multicenter study
During phase IIb/III clinical trials, only 48 RSVs that infected children receiving treatment with nirsevimab could be studied, and escape mutations were found in two of them.
But the risk could increase with the widespread preventative use of nirsevimab, now available to all infants.
Hence the development of the POLYRES study, which aimed to evaluate the risk of virological escape from nirsevimab on a larger sample thanks to a large-scale, multicenter, observational study taking place in real life during of the 2023-2024 winter season.
“This study is the largest concerning virological analyzes of nirsevimab failures to date. It was possible to achieve this thanks to synergistic and collaborative work with the consortium of ANRS MIE virologists, and constitutes a national-scale project which makes it possible to identify resistance phenomena linked to the diffusion of the drug. This type of study is essential to analyze the dynamics of evolution of viruses, in light of existing medical solutions, considered the Pre Marie-Anne Rameix-Weltihead of the National Reference Center for Respiratory Infection Viruses at the Institut Pasteur, and head of the M3P unit (Institut Pasteur, Inserm U1173), and last author of the article, in a press release from the ANRS [2].
The study included 695 infants with RSV infection, of whom 349 received nirsevimab prophylaxis. RSV-A was in the majority this season and was found in 86.6% of infected children. The teams analyzed the characteristics of RSV-A and RSV-B present in nasopharyngeal samples taken as part of the usual care of children.
The complete sequence of the viral genome was determined to look in particular for mutations in the nirsevimab binding site (genotypic analysis).
The ability of nirsevimab to inhibit the multiplication of viruses in cell culture was also studied (phenotypic analysis).
Analysis of 472 RSV-A patients (half of which were from treated children) revealed no nirsevimab resistance mutations in the F protein epitope site.
Among the 73 children infected with RSV-B, 24 had received nirsevimab for prophylaxis. In these 24 children, two RSV-B isolates presented resistance mutations to the antibody, one already known, the other unknown and described for the first time. For the authors, “the results of the POLYRES study support the continued use of nirsevimab for prophylaxis for all newborns worldwide” [1] .
This work was funded by the ANRS Emerging Infectious Diseases and the French Ministry of Health.
