lancet-header

Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com.

Minimal Transmission in an Influenza A (H3N2) Human Challenge-Transmission Model with Exposure Events in a Controlled Environment

57 Pages Posted: 27 Sep 2019

See all articles by Jonathan S. Nguyen-Van-Tam

Jonathan S. Nguyen-Van-Tam

University of Nottingham - School of Medicine

Ben Killingley

University of Nottingham - Health Protection and Influenza Research Group

Joanne Enstone

University of Nottingham - Health Protection and Influenza Research Group

Michael Hewitt

University of Nottingham - Health Protection and Influenza Research Group

Jovan Pantelic

University of Maryland - School of Public Health

Michael Grantham

University of Maryland - School of Public Health

P. Jacob Bueno de Mesquita

University of Maryland - School of Public Health

Robert Lambkin-Williams

hVIVO

Anthony Gilbert

hVIVO

Alexander Mann

hVIVO

John Forni

hVIVO

Catherine J. Noakes

University of Leeds - School of Civil Engineering

Min Z. Levine

Centers for Disease Control and Prevention - Division of Influenza

LaShondra Berman

Centers for Disease Control and Prevention - Division of Influenza

Stephen Lindstrom

Centers for Disease Control and Prevention - Division of Influenza

Simon Cauchemez

Imperial College London - MRC Centre for Outbreak Analysis and Modelling

Werner Bischoff

Wake Forest University - School of Medicine

Raymond Tellier

University of Calgary - Cumming School of Medicine

Donald K. Milton

University of Maryland - School of Public Health

EMIT Consortium Group

Independent

More...

Abstract

Background: Uncertainty about the relative importance of modes of influenza transmission, particularly airborne droplet nuclei (aerosols), fuels controversy concerning recommendations for healthcare worker protection during pandemics. In-depth review by an expert panel, a proof-of-concept study, and an international workshop concluded that human challenge-transmission studies in well-controlled environments would be the most promising approach to fill this critical knowledge gap.

Methods: Healthy, seronegative volunteer 'Donors' (N=52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). Seronegative 'Recipients' randomised to Intervention (IR, N=40) or Control (CR, N=35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitised frequently to limit large droplet and contact transmission. Numbers of Donors and days of Recipient exposure were increased compared to proof-of-concept to increase secondary attack rate (SAR). Symptoms were monitored and viral shedding in nasopharyngeal swabs and exhaled breath viral aerosols were quantified by reverse-transcriptase PCR (qRT-PCR). Serological specimens were analysed for evidence of seroconversion.

Findings: Intranasal inoculation produced an infection rate of 81% (42/52); 60% (25/42) of infected Donors had influenza-like illness, 14% (6/42) had fever, and 26% (11/42) had mild or no symptoms. Viral aerosol shedding was observed from 26% (11/42) of the infected Donors. One transmitted infection was confirmed by serology in a CR, yielding a SAR of 2·9% among CR, 0% in IR (p = 0·47 for group difference), and 1·3% overall.

Interpretation: The SAR observed was significantly less than 16% (p<0·001) expected based on the proof-of-concept study SAR considering that there were twice as many Donors and days of exposure to Recipients. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols. The low SAR limits this study's ability to provide definitive evidence regarding modes of transmission.

Trial Registration: (ClinicalTrials.gov number NCT01710111).

Funding Statement: U.S. CDC, Cooperative Agreement: Grant Number 1U01P000497-01. The views expressed in this paper are those of the authors and do not necessarily represent the official position of the funding agency.

Declaration of Interests: JSN-V-T and BK declare previous consultancy fees from H-Vivo plc, unrelated to the current work. JSN-V-T is currently seconded to the Department of Health and Social Care (DHSC), England; the views expressed in this paper are not necessarily those of DHSC. RLW, AG and AM are employees of H-Vivo plc each of whom hold shares and /or share options in the company. All other authors declare no conflicts of interest.

Ethics Approval Statement: This trial includes written informed consent from healthy volunteers in accordance with the principles of the Declaration of Helsinki, in compliance with UK regulatory and ethical (IRB) requirements, and registered with ClinicalTrials.gov (number NCT01710111).

Suggested Citation

Nguyen-Van-Tam, Jonathan S. and Killingley, Ben and Enstone, Joanne and Hewitt, Michael and Pantelic, Jovan and Grantham, Michael and Bueno de Mesquita, P. Jacob and Lambkin-Williams, Robert and Gilbert, Anthony and Mann, Alexander and Forni, John and Noakes, Catherine J. and Levine, Min Z. and Berman, LaShondra and Lindstrom, Stephen and Cauchemez, Simon and Bischoff, Werner and Tellier, Raymond and Milton, Donald K. and Group, EMIT Consortium, Minimal Transmission in an Influenza A (H3N2) Human Challenge-Transmission Model with Exposure Events in a Controlled Environment (09/19/2019 23:58:00). Available at SSRN: https://ssrn.com/abstract=3457429 or http://dx.doi.org/10.2139/ssrn.3457429

Jonathan S. Nguyen-Van-Tam

University of Nottingham - School of Medicine

Nottingham, NG7 2UH
United Kingdom

Ben Killingley (Contact Author)

University of Nottingham - Health Protection and Influenza Research Group ( email )

United Kingdom

Joanne Enstone

University of Nottingham - Health Protection and Influenza Research Group

United Kingdom

Michael Hewitt

University of Nottingham - Health Protection and Influenza Research Group

United Kingdom

Jovan Pantelic

University of Maryland - School of Public Health

4200 Valley Drive
College Park, MD 20742
United States

Michael Grantham

University of Maryland - School of Public Health

4200 Valley Drive
College Park, MD 20742
United States

P. Jacob Bueno de Mesquita

University of Maryland - School of Public Health

4200 Valley Drive
College Park, MD 20742
United States

Robert Lambkin-Williams

hVIVO

United Kingdom

Anthony Gilbert

hVIVO

United Kingdom

Alexander Mann

hVIVO

United Kingdom

John Forni

hVIVO

United Kingdom

Catherine J. Noakes

University of Leeds - School of Civil Engineering

Leeds, LS2 9JT
United Kingdom

Min Z. Levine

Centers for Disease Control and Prevention - Division of Influenza

Atlanta, GA
United States

LaShondra Berman

Centers for Disease Control and Prevention - Division of Influenza

Atlanta, GA
United States

Stephen Lindstrom

Centers for Disease Control and Prevention - Division of Influenza

Atlanta, GA
United States

Simon Cauchemez

Imperial College London - MRC Centre for Outbreak Analysis and Modelling

London
United Kingdom

Werner Bischoff

Wake Forest University - School of Medicine

Medical Center Boulevard
Winston-Salem, NC 27157-1063
United States

Raymond Tellier

University of Calgary - Cumming School of Medicine

3330 Hospital Drive NW
Calgary, Alberta T2N 4N1
Canada

Donald K. Milton

University of Maryland - School of Public Health

4200 Valley Drive
College Park, MD 20742
United States

EMIT Consortium Group

Independent