Correlates of risk of respiratory syncytial virus disease: a prospective cohort study

Abstract

Few population-based studies have evaluated the importance of pre-existing respiratory syncytial virus (RSV) antibody on RSV susceptibility among children and adults. We conducted a prospective, community-based cohort study among individuals aged 6 months-50 years in Oregon and Washington State, USA (June 2022-May 2023), with weekly symptom surveys and swab collection regardless of symptoms. Swabs were tested for RSV using RT-qPCR. Enrollment sera were tested for RSV prefusion F IgG binding (all participants) and neutralizing antibodies (pediatric participants). We detected 305 RSV illnesses among 3237 participants from 1188 households. Using proportional hazards regression, higher RSV binding antibody titers were associated with a lower estimated hazard of RSV among pediatric participants (hazard ratio=0.66 per 1-unit difference in log₁₀-RSV antibody titer; 95% CI: 0.56, 0.78). In a post-pandemic period, pre-existing RSV antibody titers were associated with a lower risk of RSV illness in children aged 6 months-17 years, which could inform vaccine development for this age group.

Fig. 1. Baseline RSV antibody titers stratified by age group and RSV A/B illness status.

Plots show participant-level antibody titers represented by the dots, which are overlaid by box plots and violin plots to illustrate the distribution and density of the antibody data. Box-plot elements are defined as follows: center line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range. Baseline antibody titers are stratified by age group only for (A) binding antibody titers (log₁₀-AU/mL) (n = 2996) and (B) neutralizing antibody titers (log₁₀-IU/mL) (n = 1373). These plots are further stratified by RSV A/B illness status for (C) binding antibody titers (log₁₀-AU/mL) (n = 2996) and (D) neutralizing antibody titers (log₁₀-IU/mL) (n = 1373). Abbreviations: log₁₀-AU/mL log₁₀-transformed arbitrary units per milliliter, log₁₀-IU/mL log₁₀-transformed international units per milliliter, RSV respiratory syncytial virus, SD standard deviation.

Fig. 2. Nonparametric coefficient of determination (R²) between baseline RSV pre-F binding antibody titers and neutralizing antibody titers among pediatric participants.

Correlation between binding and neutralizing antibody titers measured at baseline among (A) all pediatric participants 6 months–17 years (n = 1355) and (B) pediatric participants 6 months–4 years (n = 323). Data are presented as a scatter plot of individual participants’ binding and neutralizing antibody titer measurements overlaid with a blue correlation trendline ± the standard error of the smooth as a 95% confidence interval shown in gray. Abbreviations: log₁₀-AU/mL log₁₀-transformed arbitrary units per milliliter, log₁₀-IU/mL log₁₀-transformed international units per milliliter, RSV respiratory syncytial virus, R² nonparametric coefficient of determination.

Fig. 3. Hazard ratios of the association between categorical baseline antibody titers and RSV A/B illness by antibody type.

The x-axis shows the low, moderate, high, and very high antibody titer categories for neutralizing and binding antibody. The y-axis shows the hazard ratio of the association between categorical baseline antibody titers and RSV A/B illness for the low, moderate, high, and very high antibody titer categories using the very low antibody category as the reference group. Data are presented as the hazard ratio (measure of center) ± the upper and lower bound of the 95% Wald-type confidence interval for the hazard ratio estimate using robust standard errors. The proportional hazards analysis was conducted among pediatric participants in whom both antibodies were measured (n = 1355). Abbreviations: CI confidence interval, log₁₀-AU/mL log₁₀-transformed arbitrary units per milliliter, log₁₀-IU/mL log₁₀-transformed international units per milliliter, RSV respiratory syncytial virus.

Fig. 4. Covariate-adjusted RSV illness cumulative incidence.

Cumulative incidence curves by 180 days since the baseline blood draw for A binding and B neutralizing antibody among pediatric participants in whom both antibodies were measured. The x-axis shows days since a participant’s baseline blood draw and the y-axis shows the cumulative incidence. Cumulative incidence curves are averaged over covariates and stratified by low, moderate, high, and very high antibody titer categories. The curves for the lowest antibody titer category where titers were below the lower limit of quantitative are not shown. The cumulative incidence estimates were obtained from the proportional hazards regression analysis. Abbreviation: RSV respiratory syncytial virus.

Fig. 5. Area under the receiver operating curve variable importance for baseline antibody titers relative to covariates.

Among pediatric participants, in whom both antibodies were measured (n = 1355), estimated gain in achievable AUC is shown on the y-axis for time to RSV illness by 180 days from enrollment based on adding each RSV antibody to a prediction model containing only baseline covariates (age; school/daycare attendance; immunocompromised status). The AUC is measured on a scale of 0-1 with the y-axis starting at 0.50 to represent the ability to predict RSV illness beyond random chance (AUC = 0.50). The measure of center of the error bars represents the estimated difference in AUC comparing the model with the baseline covariates only to the model with the baseline covariates and the RSV antibody. The error bars represent the 2.5 and 97.5 percentile of the bootstrap replicate estimates for this AUC difference. The AUC estimates are the average of all the bootstrap replicate estimates, which are themselves averages within bootstrap datasets of sample splitting over 10 different seeds. Confidence intervals for the variable importance estimates were constructed using 500 bootstrap replicates with sampling accounting for within-household correlation. Abbreviations: AUC area under the receiver operating curve, RSV respiratory syncytial virus.