ABSTRACT
Respiratory syncytial virus (RSV) infection remains a major public health problem, especially in younger children and the elderly. But several monoclonal antibodies, antivirals and vaccines, either recently launched or in development, offer new hope for RSV prevention and treatment.Copyright © 2023 Wiley Interface Ltd.
ABSTRACT
BACKGROUND: Nirsevimab is an extended half-life monoclonal antibody to the respiratory syncytial virus (RSV) fusion protein that has been developed to protect infants for an entire RSV season. Previous studies have shown that the nirsevimab binding site is highly conserved. However, investigations of the geotemporal evolution of potential escape variants in recent (ie, 2015-2021) RSV seasons have been minimal. Here, we examine prospective RSV surveillance data to assess the geotemporal prevalence of RSV A and B, and functionally characterise the effect of the nirsevimab binding-site substitutions identified between 2015 and 2021. METHOD(S): We assessed the geotemporal prevalence of RSV A and B and nirsevimab binding-site conservation between 2015 and 2021 from three prospective RSV molecular surveillance studies (the US-based OUTSMART-RSV, the global INFORM-RSV, and a pilot study in South Africa). Nirsevimab binding-site substitutions were assessed in an RSV microneutralisation susceptibility assay. We contextualised our findings by assessing fusion-protein sequence diversity from 1956 to 2021 relative to other respiratory-virus envelope glycoproteins using RSV fusion protein sequences published in NCBI GenBank. FINDINGS: We identified 5675 RSV A and RSV B fusion protein sequences (2875 RSV A and 2800 RSV B) from the three surveillance studies (2015-2021). Nearly all (25 [100%] of 25 positions of RSV A fusion proteins and 22 [88%] of 25 positions of RSV B fusion proteins) amino acids within the nirsevimab binding site remained highly conserved between 2015 and 2021. A highly prevalent (ie, >40.0% of all sequences) nirsevimab binding-site Ile206Met:Gln209Arg RSV B polymorphism arose between 2016 and 2021. Nirsevimab neutralised a diverse set of recombinant RSV viruses, including new variants containing binding-site substitutions. RSV B variants with reduced susceptibility to nirsevimab neutralisation were detected at low frequencies (ie, prevalence <1.0%) between 2015 and 2021. We used 3626 RSV fusion-protein sequences published in NCBI GenBank between 1956 and 2021 (2024 RSV and 1602 RSV B) to show that the RSV fusion protein had lower genetic diversity than influenza haemagglutinin and SARS-CoV-2 spike proteins. INTERPRETATION: The nirsevimab binding site was highly conserved between 1956 and 2021. Nirsevimab escape variants were rare and have not increased over time. FUNDING: AstraZeneca and Sanofi.Copyright © 2023 Elsevier Ltd. All rights reserved.
ABSTRACT
Objective: To inform policies about possible immunization, this literature-based model sought to estimate the adverse effects burden of administering nirsevimab, a passive protection against RSV in infants. Methods: If licensed, nirsevimab could be administered during the birth hospitalization for infants born during the RSV season (October-February). Infants born outside that season would require a separate outpatient visit. The product related adverse effects were calculated by pooling nirsevimab safety data from phases 2 and 3 trials to obtain rates of each non-target adverse event (AE). Each infant and family faced non-product related AEs: a 3.17% increased risk of influenza and 6.82% added COVID-19 risks from each additional well-child visit needed by some infants born outside the RSV season. Data came from Simmering et al, 2014, CDC surveillance data, and the Global Burden of Disease (GBD) Study (burden per consequence). Results: Nirsevimab immunization resulted in adverse effects disability rate of 6.8 DALYs per 100,000 in-season birth infants and 178.2 DALYs per 100,000 out-of-season birth infants. This shows a 26-fold higher burden to out-of-season infants. These burdens are comparable to the DALY burden per 100,000 population for infant thalassemias trait (5) and infant meningitis (201), respectively. The out-of-season birth infant burden rate was mainly driven by COVID-19 and influenza cases. This is the result of additional well-child visits for infant immunization with appreciable estimated risks–6,816 COVID-19 and 3,170 influenza cases per 100,000 out-of-season infants immunized. The distribution of factors contributing to AE the DALY burden per 100,000 infants were COVID-19 (120, 67%), influenza (51.7, 29%) and nirsevimab (6.8, 4%). Conclusion: Due to possible infant and family exposure to influenza and COVID-19 from added health care visits, adverse effects of nirsevimab immunization to out-of-season low-risk births are substantial. Policy makers will need to weigh risks and benefits carefully for this group of infants.
ABSTRACT
Background. Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) in infants. Nirsevimab is a single-dose monoclonal antibody with extended half-life that was shown to protect preterm infants 29 to < 35 weeks gestation against RSV LRTI. However, most medically attended (MA) cases occur in otherwise healthy, term infants for whom there is currently no effective RSV prevention strategy. We report the primary analysis of efficacy and safety, along with the impact of nirsevimab in late preterm and term infants (≥ 35 weeks gestation) in the phase 3 MELODY study (NCT03979313). Methods. Infants were randomized 2:1 to receive one intramuscular injection of nirsevimab (50 mg if < 5 kg;100 mg if ≥ 5 kg at dosing) or placebo entering their first RSV season. The primary endpoint was the incidence of MA RSV LRTI over 150 days postdose. Cases met predefined clinical criteria of disease severity and were confirmed by real-time reverse-transcriptase PCR. Safety was evaluated through 360 days postdose. Enrollment started on 23 July 2019 and was suspended following the declaration of the COVID-19 pandemic by the WHO on 11 March 2020. Results. Overall, 1490 infants were randomized and included in the intent-totreat population;1465 (98%) completed the 150-day efficacy follow-up, and 1367 (92%) completed the 360-day safety follow-up. The incidence of MA RSV LRTI was 1.2% (n=12/994) in the nirsevimab group and 5.0% (n=25/496) in the placebo group, giving nirsevimab an efficacy of 74.5% (95% confidence interval [CI]: 49.6, 87.1;p< 0.0001). Nirsevimab averted 93.6 (95% CI 63.0, 124.0) MA LRTIs per 1000 infants dosed. Nirsevimab was well tolerated, with similar rates of adverse events (87.4% nirsevimab;86.8% placebo) and serious adverse events (6.8% nirsevimab;7.3% placebo) between groups. Conclusion. In this phase 3 study, a single dose of nirsevimab protected late preterm and term infants against MA RSV LRTI over an RSV season with a favorable safety profile. Approximately 11 infants need to be immunized to prevent 1 case of LRTI;nirsevimab has the potential to be an important intervention to reduce the burden of RSV LRTI in healthy infants.