Informing randomized clinical trials of respiratory syncytial virus vaccination during pregnancy to prevent recurrent childhood wheezing: A sample size analysis

Abstract

Background: Early RSV illness is associated with wheeze-associated disorders in childhood. Candidate respiratory syncytial virus (RSV) vaccines may prevent acute RSV illness in infants. We investigated the feasibility of maternal RSV vaccine trials to demonstrate reductions in recurrent childhood wheezing in general paediatric populations.

Methods: We calculated vaccine trial effect sizes that depended on vaccine efficacy, allocation ratio, rate of early severe RSV illness, risk of recurrent wheezing at age 3, and increased risk of RSV infection on recurrent wheezing. Model inputs came from systematic reviews and meta-analyses. For each combination of inputs, we estimated the sample size required to detect the effect of vaccination on recurrent wheezing.

Results: There were 81 scenarios with 1:1 allocation ratio. Risk ratios between vaccination and recurrent wheezing ranged from 0.9 to 1.0 for 70% of the scenarios. Among the 57 more plausible scenarios, the lowest sample size required to detect significant reductions in recurrent wheezing was 6196 mother-infant pairs per trial arm; however, 75% and 47% of plausible scenarios required >31,060 and >100,000 mother-infant pairs per trial arm, respectively. Studies with asthma endpoints at age 5 will likely need to be larger.

Discussion: Clinical efficacy trials of candidate maternal RSV vaccines undertaken for licensure are unlikely to demonstrate an effect on recurrent wheezing illness due to the large sample sizes likely needed to demonstrate a significant effect. Further efforts are needed to plan for alternative study designs to estimate the impact of maternal RSV vaccine programs on recurrent childhood wheezing in general populations.

Keywords: Asthma; Global health; Pregnant; Respiratory syncytial virus; Vaccine; Wheeze.

Fig. 1

Theoretical causal diagram for the relationships between maternal RSV vaccination, severe early infant RSV- lower respiratory infections, and later recurrent childhood wheezing. The diagram illustrates how maternal vaccination against RSV may prevent the development of recurrent childhood wheezing (the endpoint) through preventing an early severe RSV-related lower respiratory infection (LRI) during infancy (the mediator). Links between elements in the diagram and parameters in the sample size study are described in the blue caption boxes. The sign labelling each arrow indicates the direction of association as positive (+) or negative (−) between the connecting nodes. If the relationship between early severe RSV-LRI and recurrent childhood wheezing is confounded by a predisposition to respiratory infections, then observational studies estimating the increased risk of recurrent childhood wheezing due to early RSV-LRI may be overestimated.

Fig. 2

Illustration of the parameters used to estimate risk ratios and sample size in clinical trials of maternal RSV immunization on development of later recurrent childhood wheezing. Each filled dot in this figure represents a mother-infant pair, with the colour representing their RSV infection status and black outline indicating infants who go on to develop recurrent childhood wheezing. There are 100 rows of 10 dots, to represent 1000 mother-infant pairs randomized each to placebo and vaccination. Following the in-text example, 20% of placebo (200 mother-infant pairs; purple dots) acquire early and severe infant RSV vs. 10% in the immunized arm (100 mother infant pairs; purple dots), for a vaccine efficacy of 50%. If early RSV illness increases the later development of recurrent childhood wheezing, then the proportion of children who develop recurrent wheezing will be higher among those with early RSV. This is shown by the higher density of recurrent wheezing cases (black outline) among those with RSV illness (purple dots) vs. those without (blue dots). Summing the wheezing cases, there are 60 cases among the 300 infants who acquired RSV (for a 20% risk) vs. 85 wheezing cases among the 1700 infants who did not acquire RSV (for a 5% risk) giving rise to four-fold increased risk of wheezing in children exposed vs. unexposed to early and severe infant RSV. This example shows 80 cases of childhood recurrent wheezing among the placebo arm vs. 65 among the immunized arm for a risk ratio between vaccination and childhood recurrent wheezing (RR_VW) of 0·81.

Fig. 3

Minimal sample size required (per trial arm) to detect a difference in recurrent childhood wheezing for mother-infant pairs vaccinated against RSV under a 1:1 allocation scheme across several scenarios. This figure illustrates the estimated risk ratio between vaccination and recurrent wheezing (RR_VW, on the x-axis) that results from the parameters that define each scenario, indicated by the size, colour, line type, and panel. The corresponding sample size to detect the risk ratio is shown on the y-axis, which is plotted on a log scale. Scenarios classified less likely are indicated with a cross (+), and those classified least likely are denoted with an asterisk (∗).

Fig. 4

Number needed to vaccinate to prevent one case of recurrent childhood wheezing under a 1:1 allocation scheme across several scenarios. This figure illustrates the estimated risk ratio between vaccination and recurrent wheezing (RR_VW, on the x-axis) that results from the parameters that define each scenario, as indicated by the size, colour, line type, and panel. The corresponding number of pregnant women requiring vaccination to prevent one case of recurrent childhood wheezing is shown on the y-axis, which is plotted on a log scale. Scenarios classified less likely are indicated with a cross (+), and those classified least likely are denoted with an asterisk (∗).