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Randomized Controlled Trial
. 2023 Jul 19;14(1):4347.
doi: 10.1038/s41467-023-40057-8.

Molecular and phenotypic characteristics of RSV infections in infants during two nirsevimab randomized clinical trials

Bahar Ahani #  1 , Kevin M Tuffy #  2 , Anastasia A Aksyuk  2 , Deidre Wilkins  2 , Michael E Abram  2 , Ron Dagan  3 , Joseph B Domachowske  4 , Johnathan D Guest  5 , Hong Ji  2 , Anna Kushnir  2 , Amanda Leach  6 , Shabir A Madhi  7 , Vaishali S Mankad  8 , Eric A F Simões  9 , Benjamin Sparklin  1 , Scott D Speer  2 , Ann Marie Stanley  2 , David E Tabor  2 , Ulrika Wählby Hamrén  10 , Elizabeth J Kelly  11 , Tonya Villafana  6
Affiliations
Randomized Controlled Trial

Molecular and phenotypic characteristics of RSV infections in infants during two nirsevimab randomized clinical trials

Bahar Ahani et al. Nat Commun. .

Erratum in

Abstract

Nirsevimab is a monoclonal antibody that binds to the respiratory syncytial virus (RSV) fusion protein. During the Phase 2b (NCT02878330) and MELODY (NCT03979313) clinical trials, infants received one dose of nirsevimab or placebo before their first RSV season. In this pre-specified analysis, isolates from RSV infections were subtyped, sequenced and analyzed for nirsevimab binding site substitutions; subsequently, recombinant RSVs were engineered for microneutralization susceptibility testing. Here we show that the frequency of infections caused by subtypes A and B is similar across and within the two trials. In addition, RSV A had one and RSV B had 10 fusion protein substitutions occurring at >5% frequency. Notably, RSV B binding site substitutions were rare, except for the highly prevalent I206M:Q209R, which increases nirsevimab susceptibility; RSV B isolates from two participants had binding site substitutions that reduce nirsevimab susceptibility. Overall, >99% of isolates from the Phase 2b and MELODY trials retained susceptibility to nirsevimab.

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Conflict of interest statement

R.D. has received grants from AstraZeneca, Merck, and Pfizer; consulting fees from Merck and Pfizer; and honoraria from GSK, Merck, Pfizer, and Sanofi Pasteur. J.B.D. has received consulting fees from Sanofi; payment or honoraria from Sanofi; and has participated in data safety monitoring boards or advisory boards for AstraZeneca. S.A.M. has received grants or contracts from BMGF, GSK, Minervax, Pfizer, and the South African Medical Research Council; payments or honoraria from BMGF; and has participated in data safety monitoring boards or advisory boards for CAPRISA and PATH. E.A.S. has received grants or contracts from AstraZeneca, Johnson and Johnson, Merck, Pfizer, and Roche; consulting fees from Adiago Therapeutics, Cidara Therapeutics, Merck, Nuance Pharmaceuticals, Pfizer, and Sanofi; payment or honoraria from AstraZeneca and Pfizer; support for meeting attendance and/or travel from AstraZeneca; and has participated in data safety monitoring boards or advisory boards for Abbvie, Bill and Melinda Gates Foundation, and GSK. B.A., K.M.T., A.A.A., D.W., J.D.G., H.J., B.S., A.K., A.M.S., V.S.M., A.L., U.W.H., E.J.K., and T.V. are current employees of AstraZeneca and may hold stock or stock options. S.D.S., D.E.T., and M.E.A. are former employees of AstraZeneca.

Figures

Fig. 1
Fig. 1. Incidence of RSV A and RSV B subtypes in the Phase 2b and MELODY trials (full cohort).
A MA RSV LRTI and B hospitalization due to MA RSV LRTI. Cases shown are those with evaluable next-generation sequencing data. Two-sided Fisher’s exact tests comparing cases of RSV A and RSV B found no statistical difference by endpoint or timepoint. LRTI lower respiratory tract infection, MA medically attended, RSV respiratory syncytial virus.
Fig. 2
Fig. 2. Major observed pre-F substitutions in the Phase 2b and MELODY trials (full cohort).
A Location and B frequency. RSV A residues S25, S99, A102, and A103 with substitutions frequencies ≥1–<5% from Phase 2b; S24, S105, and A518 with substitutions frequencies >0–<1% from MELODY; and A103, A107 with substitutions frequencies ≥1–<5% from MELODY are not depicted due to absence or density in PDB ID: 5UDC. RSV B residues A103 with substitutions frequency ≥50% from Phase 2b; T518 with substitutions frequency ≥1–<5% from Phase 2b; N99, and T522 with substitutions frequencies >0–<1% from MELODY; and A103V with substitutions frequency ≥25– < 50% from MELODY are not depicted due to absence or density in PDB ID: 5UDD. F fusion protein, PDB Protein Data Bank, RSV respiratory syncytial virus.
Fig. 3
Fig. 3. Frequency of major variant substitutions in the nirsevimab binding site in the Phase 2b and MELODY trials (full cohort).
A RSV A and B RSV B. Weblogos (i.e., Sequence Logos) were generated in Seq2Logo-2.0 (https://services.healthtech.dtu.dk/service.php?Seq2Logo-2.0). Amino acids are differentiated by color: green, polar; purple, neutral; blue, basic; and red, acidic. RSV respiratory syncytial virus.
Fig. 4
Fig. 4. Change in nirsevimab IC50 for major RSV F protein variants evaluated in the Phase 2b and MELODY trials (full cohort).
Individual major variant substitutions from Phase 2b and MELODY trials were evaluated in a validated RSV neutralization susceptibility assay (Viroclinics Biosciences BV, Rotterdam, NLD) and compared with RSV A and B reference viruses. Both I206M and Q209R were identified in RSV B. Green, yellow and red banding represents a low, medium, and high degree of IC50 fold change, respectively. IC50 half-maximal inhibitory concentration, RSV respiratory syncytial virus.
Fig. 5
Fig. 5. Nirsevimab serum concentrations versus time after dose.
The blue and red lines/dots represent the nirsevimab serum concentrations from two participants with resistance-associated substitutions N208S and I64T:K68E who both weighed ≥5 kg and received the 50 mg dose in the Phase 2b trial. The gray lines/dots denote individual serum concentration-time profiles from participants in the Phase 2b trial <5 kg and MELODY (primary cohort) who had received weight-banded dosing; the broken lines are the 5th and 95th percentiles of the data. Samples below the limit of quantification (0.5 µg/mL) are shown as 0.5 µg/mL.
Fig. 6
Fig. 6. Susceptibility of RSV B strains with and without prevalent nirsevimab binding site substitutions I206M + Q209R.
F, fusion protein; IC50 half-maximal inhibitory concentration, LOD limit of detection, RSV respiratory syncytial virus.
Fig. 7
Fig. 7. Proposed mechanism of increased RSV B neutralization potency with nirsevimab binding site substitution Q209R.
Red indicates the electrostatics of the negatively charged pocket on nirsevimab, created by glutamic and aspartic acids (E55 and D101). Green dashed lines indicate polar contacts. F fusion protein, RSV respiratory syncytial virus.
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