Durability of neutralizing RSV antibodies following nirsevimab administration and elicitation of the natural immune response to RSV infection in infants

Abstract

Nirsevimab is an extended half-life monoclonal antibody specific for the prefusion conformation of the respiratory syncytial virus (RSV) F protein, which has been studied in preterm and full-term infants in the phase 2b and phase 3 MELODY trials. We analyzed serum samples collected from 2,143 infants during these studies to characterize baseline levels of RSV-specific immunoglobulin G antibodies and neutralizing antibodies (NAbs), duration of RSV NAb levels following nirsevimab administration, the risk of RSV exposure during the first year of life and the infant's adaptive immune response to RSV following nirsevimab administration. Baseline RSV antibody levels varied widely; consistent with reports that maternal antibodies are transferred late in the third trimester, preterm infants had lower baseline RSV antibody levels than full-term infants. Nirsevimab recipients had RSV NAb levels >140-fold higher than baseline at day 31 and remained >50-fold higher at day 151 and >7-fold higher at day 361. Similar seroresponse rates to the postfusion form of RSV F protein in nirsevimab recipients (68-69%) compared with placebo recipients (63-70%; not statistically significant) suggest that while nirsevimab protects from RSV disease, it still allows an active immune response. In summary, nirsevimab provided sustained, high levels of NAb throughout an infant's first RSV season and prevented RSV disease while allowing the development of an immune response to RSV.

Fig. 1. Baseline RSV NAb and antibody levels by hemisphere, sex and treatment.

a, GMC of RSV NAb. b, GMCs of IgG antibodies pre-F and post-F (AU ml⁻¹). *P < 0.05, ***P < 0.001. Data are presented as GMCs ± 95% CIs, which were calculated assuming log normal distribution. Two-sided P values were calculated based on the F statistic from analysis of variance (ANOVA), without adjustment. GMCs of NAb, pre-F and post-F were significantly higher in MELODY than in the phase 2b study (all P < 0.001); however, only the differences in GMC between hemispheres in MELODY were statistically significant (NAb, P = 0.0486; pre-F, P = 0.0292; post-F, P < 0.0001). n, number of infants; NH, Northern Hemisphere; SH, Southern Hemisphere.

Fig. 2. Baseline RSV-specific NAb levels.

a, GMC of NAb by gestational age. b, GMC of RSV pre-F, post-F, Ga, Gb and N IgG antibodies by gestational age. c, GMC of NAb by infant age. d, GMC of pre-F, post-F, Ga, Gb and N IgG antibodies by infant age. *P < 0.05, ***P < 0.001. Data are presented as GMCs ± 95% CIs, which were calculated assuming log normal distribution. Two-sided P values were calculated based on the F statistic from ANOVA, without adjustment. In a, P = 0.0005 and P = 0.0274 for the phase 2b study and MELODY, respectively. In b, differences between groups within the phase 2b study were statistically significant (all P < 0.0001); for MELODY, only Gb was statistically different (P = 0.0406). In c, P < 0.0001 for both the phase 2b study and MELODY. In d, differences between groups within the phase 2b study and MELODY were statistically significant (all P < 0.0001).

Fig. 3. Half-life of RSV NAbs based on infant age at randomization.

a, Phase 2b study NAbs. b, Phase 2b study pre-F IgG antibodies. c, Phase 2b study post-F IgG antibodies. d, MELODY NAbs. e, MELODY pre-F IgG antibodies. f, MELODY post-F IgG antibodies. Blue circles denote data included in the analysis; gray circles denote data that were excluded (as described in Methods section). The gray band surrounding each line represents the 95% CI. t_½, half-life.

Fig. 4. RSV NAb GMC through day 361 by treatment and medically attended, diagnostic-confirmed RSV infection.

a, Phase 2b study NAbs. b, MELODY study NAbs. ***P < 0.001, nirsevimab versus placebo with diagnostic-confirmed RSV; ^†††P < 0.001, nirsevimab versus placebo without diagnostic-confirmed RSV. n denotes number of infants who had a serum sample available at baseline. Data are presented as GMCs ± 95% CIs, which were calculated assuming log normal distribution. Two-sided P values were calculated based on the F statistic from ANOVA, without adjustment. In a, all were P < 0.0001, except for day 361 with diagnostic-confirmed RSV, which was P = 0.0005. In b, all were P < 0.0001. BL, baseline.

Fig. 5. RSV post-F antibody GMC through day 361 by treatment and medically attended, diagnostic-confirmed RSV infection.

a, Phase 2b study post-F IgG antibodies. b, MELODY study post-F IgG antibodies. *P < 0.05, nirsevimab versus placebo with diagnostic-confirmed RSV; ^†P < 0.05, ^†††P < 0.001, nirsevimab versus placebo without diagnostic-confirmed RSV. n denotes number of infants who had a sample available at baseline. Data are presented as GMCs ± 95% CIs, which were calculated assuming log normal distribution. Two-sided P values were calculated from the F statistic from ANOVA, without adjustment. a, At day 91 without diagnostic-confirmed RSV, P = 0.0227, and at day 361 with diagnostic-confirmed RSV, P = 0.0458. b, At day 31 without diagnostic-confirmed RSV, P < 0.0001, and at day 361 with diagnostic-confirmed RSV, P = 0.0391.

Fig. 6. RSV seroresponse by treatment and medically attended, diagnostic-confirmed RSV LRTI.

a, Proportion of participants with a seroresponse. b, RSV post-F antibody levels at day 361. c, RSV NAb level at day 361. The graphs show the subpopulation of participants with available data, for example, those who had a baseline sample and a day 151 and/or day 361 sample. Infants were defined as having a seroresponse if the RSV post-F antibody fold-change from baseline was above the respective cut point (>0.07 at day 151 or >0.02 at day 361; Supplementary Information Section 1). The box is bounded by the 25th and 75th percentiles; the line within the box represents the median. The whiskers represent 1.5 × interquartile range. MA, medically attended; n, number of infants who had a baseline sample and a day 151 and/or day 361 sample.

Extended Data Fig. 1. Disposition of infants who provided serum samples during the study.

n denotes population with ≥1 sample available for testing at any time point for NAb. n, number of infants; NAb, neutralizing antibody.

Extended Data Fig. 2. Baseline RSV NAb and antibody levels by hemisphere, sex, and treatment (AU ml^-1).

a, GMC of RSV NAb. b, GMC of pre-F. c, GMC of post-F. The box is bounded by the 25th and 75th percentiles; the line within the box represents the median. The whiskers represent 1.5 x IQR. No statistically significant differences between groups within the phase 2b study and MELODY were observed. AU ml^-1, arbitrary units per milliliter; CI, confidence interval; F, fusion protein; GMC, geometric mean concentration; IgG, immunoglobulin G; IQR, interquartile range; IU ml^-1, International Units per milliliter; LLOQ, lower limit of quantification; n, number of infants; NAb, neutralizing antibody; NH, Northern Hemisphere; RSV, respiratory syncytial virus; SH, Southern Hemisphere.

Extended Data Fig. 3. Baseline RSV-specific NAb and antibody levels by gestational age.

a, GMC of NAb. b, GMC of pre-F. c, GMC of post-F. d, GMC of Ga. e, GMC of Gb. f, GMC of N. The box is bounded by the 25th and 75th percentiles; the line within the box represents the median. The whiskers represent 1.5 x IQR. AU ml^-1, arbitrary units per milliliter; CI, confidence interval; F, fusion protein; Ga, attachment protein G RSV subtype A; Gb, attachment protein G subtype B; GMC, geometric mean concentration; IgG, immunoglobulin G; IQR, interquartile range; IU ml^-1, International Units per milliliter; LLOQ, lower limit of quantification; n, number of infants; N, nucleocapsid N; NAb, neutralizing antibodies; RSV, respiratory syncytial virus.

Extended Data Fig. 4. Baseline RSV-specific NAb and antibody levels by infant age.

a, GMC of NAb. b, GMC of pre-F. c, GMC of post-F. d, GMC of Ga. e, GMC of Gb. f, GMC of N. The box is bounded by the 25th and 75th percentiles; the line within the box represents the median. The whiskers represent 1.5 x IQR. AU ml^-1, arbitrary units per milliliter; CI, confidence interval; F, fusion protein; Ga, attachment protein G RSV subtype A; Gb, attachment protein G subtype B; GMC, geometric mean concentration; IgG, immunoglobulin G; IU ml^-1, International Units per milliliter; IQR, interquartile range; LLOQ, lower limit of quantification; n, number of infants; N, nucleocapsid N; NAb, neutralizing antibodies; RSV, respiratory syncytial virus.

Extended Data Fig. 5. RSV pre-F IgG antibody GMC and GMFR through day 361 by treatment and medically attended diagnostic-confirmed infection.

a, Phase 2b study pre-F antibodies. b, MELODY study pre-F antibodies. n denotes the number of infants at day 361. *P < 0.05, ***P < 0.001, nirsevimab vs placebo with diagnostic confirmed RSV; ^†††P < 0.001 nirsevimab vs placebo without diagnostic confirmed RSV. Two-sided p-values were calculated based on the F statistic from ANOVA, without adjustment. AU ml^-1, arbitrary units per milliliter; BL, baseline; CI, confidence interval; F, fusion protein; GMC, geometric mean concentration; GMFR, geometric mean fold rise; IgG, immunoglobulin G; LLOQ, lower limit of quantification; n, number of infants; RSV, respiratory syncytial virus.

Extended Data Fig. 6. RSV GMC of IgG antibody levels through day 361 by treatment and medically attended diagnostic-confirmed infection.

a, Ga. b, Gb. c, N. *P < 0.05, nirsevimab vs placebo with diagnostic-confirmed RSV; ^†P < 0.05, ^††P < 0.01, ^†††P < 0.001 nirsevimab vs placebo without diagnostic-confirmed RSV. Data were unavailable for Gb for MELODY. The CIs for GMC were calculated assuming log normal distribution. Two-sided P values were calculated based on the F statistic from ANOVA, without adjustment. AU ml^-1, arbitrary units per milliliter; CI, confidence interval; F, fusion protein; Ga, attachment protein G RSV subtype A; Gb, attachment protein G subtype B; GMC, geometric mean concentration; IgG, immunoglobulin G; LLOQ, lower limit of quantification; n, number of infants; N, nucleocapsid N; NAb, neutralizing antibodies; RSV, respiratory syncytial virus.

Extended Data Fig. 7. Viral load by RSV subtype based on central RT-PCR testing (ITT population).

a, Phase 2b study. b, MELODY study. The box is bounded by the 25th and 75th percentiles; the line within the box represents the median. The whiskers represent 1.5 x IQR. CT, cycle threshold; IQR, interquartile range; ITT, intent-to-treat; n, number of infants; RSV, respiratory syncytial virus; RT-PCR reverse transcriptase polymerase chain reaction.