Independent Analysis of the Results of the First Infant Immunization Campaign with Beyfortus® (Nirsevimab, Monoclonal Antibody Against RSV Bronchiolitis Virus): Mixed Results, Identification of Biases, and Possible Role and Mechanisms of ADE (Antibody Dependent Enhancement)

Abstract

Respiratory infections with RSV account for ¼ of hospital admissions for acute respiratory infections. Nirsevimab has been developed to reduce the hospital burden of these infections: Since it has a long shelf life thanks to its high affinity for FcRn (neonatal receptor for the Fc fragment of IgG), it requires only a single injection and can be administered to all children under 2 years of age, unlike palivizumab, which is reserved for at-risk children and requires several injections. With the reservation of a large or unknown number of excluded treated subjects in both clinical trials and post-marketing observational studies, nirsevimab has been shown to be highly effective in reducing hospitalization rates for RSV infections. In rare cases, however, RSV infections were more severe in the treated group than in the placebo group. The 2023-2024 immunization campaign involved 4 countries (USA, France, Spain, Luxembourg). Analysis of the results of the 2023 immunization campaign does not allow us to conclude on the efficacy of nirsevimab in the USA (coverage being too low at around 20%); in the 3 other countries coverage is ≥ 80%. Neither clinical trials nor observational studies point to a reduction in all-cause hospitalizations in the immunized age group in this same season compared with previous seasons. The rate of hospitalization for RSV in the treated age bracket is significantly reduced compared with previous seasons in France, Spain and Luxembourg, but biases (exclusion of a large or unknown number of subjects, and changes in diagnostic criteria in France) may moderate this reduction. In France, there is a significant signal of an increase in newborn deaths between 2 and 6 days of age during the 2023-2024 immunization campaign. This signal could be attributable to ADE (antibody-dependent-enhancement). ADE has been observed with RSV F-protein antibodies in inactivated vaccine trials. The theoretical risk of ADE with an anti-RSV F-protein antibody such as nirsevimab has been eliminated by the EMA following clinical trials. In vitro evaluation of nirsevimab's effector functions on FcγR (cellular IgG Fc receptors) and the properties of FcRn cannot exclude the possibility of an ADE. This risk has been incompletely assessed in preclinical in vivo trials. In clinical trials, pharmacokinetic studies show the possibility in rare individuals of sub-neutralizing circulating levels of nirsevimab in the blood and pulmonary mucosa, in the days following injection and at longer distances. This could explain the rare cases of aggravated RSV infections in treated subjects. ADE by disruption of the immune system has not been studied, and could explain why the all-cause hospitalization rate has not fallen in treated age groups: mAbs are indeed capable of promoting infections by binding to FcRn. Given the high price of nirsevimab, the cost-effectiveness of mass immunization campaigns may therefore be debated from an economic as well as a scientific point of view.