Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection (LRTI) in early childhood [1]. RSV-LRTI in young children is associated with subsequent recurrent wheezing illnesses, including asthma, though it is not known whether the relationship is causal [1,2]. In 2018, a WHO working group estimated the impact early childhood RSV-LRTI prevention might have on recurrent wheeze of early childhood (“recurrent wheeze”) and calculated sample sizes for trials with these endpoints [3]. The calculations relied on assumptions for which there were limited data, including product efficacy and the risk of developing recurrent wheeze after RSV-LRTI [3]. Recently, RSV-LRTI prevention trials for a long-acting, monoclonal antibody (mAb) and a maternal RSV F protein (RSV-F) vaccine were published [4,5], as was a systematic review and meta-analysis assessing the risk of recurrent wheeze given early childhood RSV-LRTI [2]. We created an open domain tool to update the calculations (https://corinne-riddell.shinyapps.io/WHO-app/) [3].
Using previous methods [3], we calculated the sample sizes required for trials (1:1 vaccine to placebo allocation) to demonstrate efficacy against recurrent wheeze at three years of age and the number needed to treat (NNT). For product efficacy, we used 70.1% for the long-acting mAb and 44.4% for the RSV-F vaccine (which were measured against medically-attended RSV-LRTI and inpatient medically-attended RSV-LRTI, respectively) [4,5]. For the RSV-LRTI attack rate, we used 9.5%, the higher of the control arm values from the two randomized controlled trials [4]. For relative risk of recurrent wheeze given early childhood RSV-LRTI, we used 2.45 from the meta-analysis adjusting for genetic influences [2]. For baseline risk of recurrent childhood wheezing, we used inputs from the original analysis: 4.9% (global rate), 9.5% (highest region), and 20.0% (highest country) [1,3].
Trials of RSV-LRTI prevention against recurrent wheeze would require 14,343–70,865 (mAb) or 36,172–179,353 (RSV-F vaccine) total subjects, depending on the baseline prevalence of recurrent wheeze (Table 1). The NNT would be 52–212 (mAb) or 82–334 (RSV-F vaccine). Sample sizes would increase with lower values for product efficacy, RSV-LRTI attack rates, or prevalence of recurrent wheeze. Less prevalent endpoints, such as physician-diagnosed asthma, almost certainly would require longer follow-up and larger sample sizes [3]. The sample size estimates from this analysis are higher than most of the estimates from plausible scenarios calculated previously [3], due to exclusion of the most optimistic inputs for efficacy and the relative risk of recurrent wheeze given early childhood RSV-LRTI.
Table 1.
Total sample sizes for efficacy trials of RSV-LRTI prevention to demonstrate a significant effect on recurrent childhood wheezing outcomes and number needed to treat.
| Product | Product efficacy1 |
Medically-attended, respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) attack rate2 |
Relative risk for recurrent wheeze in RSV-LRTI vs. non-RSV-LRTI children3 |
Baseline risk of recurrent childhood wheezing illness4 |
Relative risk of recurrent wheeze in intervention vs. control groups5 |
Trial sample size, both arms (1:1 randomization)5 |
Number needed to treat5 |
|---|---|---|---|---|---|---|---|
| Maternal RSV F protein vaccine | 44.4% | 9.5% | 2.45 | 4.9% | 0.95 | 179,353 | 334 |
| 44.4% | 9.5% | 2.45 | 9.5% | 0.95 | 87,526 | 172 | |
| 44.4% | 9.5% | 2.45 | 20.0% | 0.95 | 36,172 | 82 | |
| Long-acting, monoclonal antibody | 70.1% | 9.5% | 2.45 | 4.9% | 0.92 | 70,865 | 212 |
| 70.1% | 9.5% | 2.45 | 9.5% | 0.92 | 34,615 | 110 | |
| 70.1% | 9.5% | 2.45 | 20.0% | 0.92 | 14,343 | 52 |
The medically-attended RSV-LRTI attack rate is the higher of the control arm values from the two randomized controlled trials [4,5].
Relative risk of recurrent wheeze given early childhood RSV-LRTI status is from a systematic review/meta-analysis [2].
Baseline risk of recurrent childhood wheezing illness estimates are from the original sample size calculations [3].
Relative risk of recurrent wheeze in intervention vs. control groups, sample size, and number needed to treat are calculated as previously described [3].
It is unknown whether the relationship between RSV-LRTI and recurrent wheeze is causal or confounded by common causes of both diseases [1,2]. Even if there were a causal association between RSV-LRTI and recurrent wheeze, our analysis indicates that the public health impact of prevention of medically-attended RSV-LRTI, which affects a very small proportion of infants, on recurrent wheeze would likely be very small. Further, it would be extremely challenging for efficacy trials of RSV-LRTI prevention against this outcome to detect differences between groups with risk ratios between intervention and control groups greater than 0.9 for the plausible scenarios assessed. Such efficacy trials would need to be very large, require multi-year follow up, and likely have complicated case ascertainment. Observational study designs and/or pooling of clinical trial results with standardized data collection should be considered as alternatives. While public health programs for prevention of RSV-LRTI would be major accomplishments, the impact of such programs on chronic respiratory illness is unknown, but would likely be small.
Acknowledgements
There was no specific funding for this study.
Footnotes
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributor Information
Amanda J. Driscoll, University of Maryland School of Medicine, 685 W. Baltimore St, Baltimore, MD 21201, USA
Justin R. Ortiz, University of Maryland School of Medicine, 685 W. Baltimore St, Baltimore, MD 21201, USA.
Tina V. Hartert, Vanderbilt University Medical Center, 2525 West End Ave, Nashville, TN 37232, USA
Corinne A. Riddell, University of California, Berkeley, 2121 Berkeley Way West, Berkeley, CA 94720, USA
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