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Vaccine. 2018 Dec 18;36(52):8100-8109. doi: 10.1016/j.vaccine.2018.10.041. Epub 2018 Nov 22.

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

Author information

1
Division of Epidemiology & Biostatistics, University of California, Berkeley, 2121 Berkeley Way, Suite 5404, Berkeley, CA, USA.
2
Center for Vaccine Innovation and Access, PATH, 2201 Westlake Ave, Seattle, WA, USA.
3
Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Lundlaan 6, Utrecht, the Netherlands; The ReSViNET Foundation, Zeist, the Netherlands.
4
Department of Biostatistics, Vanderbilt University School of Medicine, Suite 1100, Room 11119, 2525 West End Ave., Nashville, TN 37203-1741, USA.
5
Initiative for Vaccine Research, World Health Organization, 20 Avenue Appia, Geneva, Switzerland.
6
School of Epidemiology and Public Health, University of Ottawa, Children's Hospital of Eastern Ontario (CHEO) Research Institute, 401 Smyth Road, CPCR, Room L-1154, Ottawa, Ontario K1H 8L1, Canada.
7
Center for Asthma Research, Vanderbilt University School of Medicine, Department of Biostatistics, 2525 West End Ave, Suite 11000, Nashville, TN 37203, USA.
8
Center for Asthma Research, Allergy, Pulmonary & Critical Care Medicine, Vanderbilt University School of Medicine, 2525 West End Ave, Suite 450, Nashville, TN 37203, USA.
9
Department of Obstetrics & Gynaecology, University of British Columbia, Shaughnessy C408A, British Columbia Children's & Women's Hospital, 4500 Oak Street, Vancouver, British Columbia V6H 3N1, Canada.
10
Center for Immunization Research, Johns Hopkins University, 624 N. Broadway, Suite 217, Baltimore, MD, 21205, USA.
11
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland, United Kingdom.
12
Department of Global Health, University of Washington, 2301 5th Ave, Suite 600, Seattle, WA 98102, USA.
13
Child Health Research Centre, University of Queensland, 62 Graham St., South Brisbane, QLD 4101, Australia.
14
Pediatric Pulmonary Unit, Pontificia Univeridade Católica RS, Av. Ipiranga, 6690/420 Porto Alegre, Brazil.
15
Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, 2525 West End Ave, Suite 1130, Nashville, TN, USA.
16
Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, Cape Town, South Africa; SA-Medical Research Council Unit on Child and Adolescent Health, University of Cape Town, 5th Floor ICH Building, Klipfontein Road, Cape Town, South Africa.
17
Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore St, Suite 480, Baltimore, MD, USA. Electronic address: jortiz@som.umaryland.edu.

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

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