NOROPATROL: Why do Norovirus pandemics occur & how can we control them?

In the UK, norovirus outbreaks, particularly in winter months, are the most common reason for hospital ward closures, as well as affecting schools, care homes and even cruise ships. Although new vaccines are being developed, the worldwide spread every two to five years of a new ‘pandemic’ norovirus strain may reduce their effectiveness.

In this five-year multi-disciplinary study, we propose to analyse noroviruses collected over the last 20 years to work out how many different strains a vaccine would need to protect against. Using information on where and when each norovirus was collected will help us understand the time and place of origin for each new pandemic strain. By measuring antibodies to norovirus in stored blood samples from the same time period, we will work out how quickly new norovirus pandemics spread and whether children are the first to be infected.

We will analyse all the data together to work out who should be vaccinated, how often and whether we can predict which strains are more likely to cause problems.

Next generation sequencing of norovirus will be carried out using the automated high throughput pipeline within the UCL Pathogen Genomics Unit facility.

Sample collections

The study will use samples and associated data from current UK archives and is grateful to all providers of these samples:

Public Health England - National Outbreak strain collection

This unique archive will provide norovirus-positive stool specimen collected annually in England and Wales from 1997-2016 through national surveillance. Most are from hospital/healthcare-associated outbreaks and will be sequenced to determine the norovirus strains causing outbreaks during this time span.

Infectious Intestinal Disease (IID) Studies and the Liverpool Wellcome Trust/ Health Innovation Challenge Fund prospective study of GI infections in the community (Integrate)

This project will sequence norovirus-positive samples collected by these studies to determine the norovirus strains circulating within the community.  The IID studies were carried out in 1996-1998 and 2008-2009 while the Integrate study collected samples during 2015-2017.

Health Survey for England (HSE)

The HSE is an annual population health survey which has been running since 1995. Each year, HSE recruits 3000-6000 individuals from households in England providing a unique collection of highly representative sera from the general adult population.  The HSE will supply sera from 2008 – 2014 which will be used to determine population level immunity across the general adult population.

Public Health England Serum Epidemiology Unit

This collection of over 12,000 residual diagnostic sera from children aged 0-15 years spanning 1987-2016 will provide sera from 2008-2014 to this study to allow monitoring of population level immunity across childhood.

Patient and public engagement (PPI)

Chronic norovirus is a major problem for immunocompromised children, leading to malabsorption, requirement for artificial feeding and prolonged stays. No treatment exists, however, experimental repurposed drugs have been shown to be effective in some. To aid this we are using deep sequencing to determine whether clinical improvements are accompanied by drug induced changes in the virus (Ruis et al NEJM 2019).

To gauge parental and patient views on the burden of norovirus and their attitude to experimental treatments for this non-fatal but debilitating condition, we are establishing a focus group funded by Noropatrol. The results will inform our efforts to find and evaluate new treatments for norovirus. 

Our work in pictures

Study partners

Publications

2019

• Harris JP, Iturriza-Gomara M, O'Brien SJ. Estimating Disability-Adjusted Life Years (DALYs) in Community Cases of Norovirus in England. Viruses. 2019;11(2). pii: E184. doi: 10.3390/v11020184
• Harris JP, Iturriza-Gomara M, Allen DJ, Kelly S, O'Brien SJ. Norovirus strain types found within the second infectious intestinal diseases (IID2) study an analysis of norovirus circulating in the community. BMC Infect Dis. 2019;19(1):87. doi: 10.1186/s12879-019-3706-z
• Lindesmith LC, Brewer-Jensen PD, Mallory ML, Yount B, Collins MH, Debbink K, Graham RL, Baric RS. Human Norovirus Epitope D Plasticity Allows Escape from Antibody Immunity without Loss of Capacity for Binding Cellular Ligands. J Virol. 2019;93(2). pii: e01813-18. doi: 10.1128/JVI.01813-18
• Mallory ML, Lindesmith LC, Graham RL, Baric RS. GII.4 Human Norovirus: Surveying the Antigenic Landscape. Viruses. 2019;11(2). pii: E177. doi: 10.3390/v11020177
• Lindesmith LC, McDaniel JR, Changela A, Verardi R, Kerr SA, Costantini V, Brewer-Jensen PD, Mallory ML, Voss WN, Boutz DR, Blazeck JJ, Ippolito GC, Vinje J, Kwong PD, Georgiou G, and Baric RS. Sera Antibody Repertoire Analyses RevealMechanisms of Broad and Pandemic Strain Neutralizing Responses after Human Norovirus Vaccination. Immunity 2019;50 1530-1541. doi: 10.1016/j.immuni.2019.05.007

2018

• Agnihothram S, Menachery VD, Yount BL Jr., Lindesmith LC, Scobey T, Whitmore A, Schäfer A, Heise MT, Baric RS. Development of a Broadly Accessible Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Platform. J Virol. 2018;92(11). pii: e00027-18. doi: 10.1128/JVI.00027-18
• Kocher JF, Lindesmith LC, Debbink K, Beall A, Mallory ML, Yount BL, Graham RL, Huynh J, Gates JE, Donaldson EF, Baric RS. Bat Caliciviruses and Human Noroviruses Are Antigenically Similar and Have Overlapping Histo-Blood Group Antigen Binding Profiles. MBio. 2018;9(3). pii: e00869-18. doi: 10.1128/mBio.00869-18
• Lindesmith LC, Brewer-Jensen PD, Mallory ML, Debbink K, Swann EW, Vinjé J, Baric RS. Antigenic Characterization of a Novel Recombinant GII.P16-GII.4 Sydney Norovirus Strain with Minor Sequence Variation Leading to Antibody Escape. J Infect Dis. 2018;217(7):1145-1152. doi: 10.1093/infdis/jix651
• Lindesmith LC, Mallory ML, Debbink K, Donaldson EF, Brewer-Jensen PD, Swann EW, Sheahan TP, Graham RL, Beltramello M, Corti D, Lanzavecchia A, Baric RS. Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion. mSphere. 2018;3(1). pii: e00518-17. doi: 10.1128/mSphere.00518-17
• Mallory ML, Lindesmith LC, Baric RS. Vaccination-induced herd immunity: Successes and challenges. J Allergy Clin Immunol. 2018;142(1):64-66. doi: 10.1016/j.jaci.2018.05.007

2017

• Lindesmith LC, Kocher JF, Donaldson EF, Debbink K, Mallory ML, Swann EW, Brewer-Jensen PD, Baric RS. Emergence of Novel Human Norovirus GII.17 Strains Correlates with Changes in Blockade Antibody Epitopes. J Infect Dis.  2017;216(10):1227-1234. doi: 10.1093/infdis/jix385

• Main image: '3D graphical representation of Norovirus virions', CDC/Illustrator: Alissa Eckert, MS [Public domain]
• Sample collections image: Electron micrograph of human norovirus virus-like particles.