Transmission, pathogenesis and immunogenicity of SARS-CoV-2 in frontline healthcare workers: a national longitudinal cohort of 1320 participants
Lead Research Organisation:
University of Nottingham
Department Name: School of Medicine
Abstract
We want to know how many and which doctors and nurses have been infected with the virus (SARS-Cov2) that causes COVID-19 with or without symptoms. We have been collecting blood from 1320 healthcare workers on a weekly basis during the pandemic. We are analysing blood for antibodies against the virus. We will continue to measure their blood 10 times up to 6 months after the lockdown is lifted.
This study will also allow us to know how the levels of antibodies in blood change over time and which of the antibodies are able to fight the virus. We will investigate whether individual characteristics, including genetics, age, sex, ethnicity, affect the length of time for which antibodies remain in blood at high enough levels to fight the virus.
Among the doctors and nurses in our study we have people who have had a severe infection, others who have had mild symptoms and many with no symptoms. We will put all this information together to work out how healthcare workers develop antibodies against the virus and if this is affected by the severity of the symptoms is important. We will measure proteins and gene expression to identify how to effectively vaccinate and treat healthcare workers.
This study will also allow us to know how the levels of antibodies in blood change over time and which of the antibodies are able to fight the virus. We will investigate whether individual characteristics, including genetics, age, sex, ethnicity, affect the length of time for which antibodies remain in blood at high enough levels to fight the virus.
Among the doctors and nurses in our study we have people who have had a severe infection, others who have had mild symptoms and many with no symptoms. We will put all this information together to work out how healthcare workers develop antibodies against the virus and if this is affected by the severity of the symptoms is important. We will measure proteins and gene expression to identify how to effectively vaccinate and treat healthcare workers.
Technical Summary
This multi-disciplinary national consortium seeks to maximise the research impact of a unique resource of 26,000 serial serum samples (16,000 collected) from 1320 healthcare workers (HCWs). Comprising sequential (weekly) serum, and DNA/RNA. This unique cohort provides a rare opportunity for analysis of the genetics and immunology of SARS-Cov2 seroconversion.
The study objectives are to assess:
1) Baseline prior coronavirus exposure, immunity and cross reactivity of antibody assays to other strains
2) Incidence of HCWs seroconversion over time, across sites and the relationship to hospital exposures, and community transmission rates
3) Proportion of seroconverters achieve neutralizing antibodies (Nabs) responses, dual lab validation of Nabs assays, and Nabs potency and durability
4) Effect of HLA haplotypes, severity of symptoms of COVID-19 and levels of T-cell and B-cell activation cytokines to antibody titres and NAbs
5) Antibody titers correlate with severity of illness of SARS-Cov2 infection, baseline antibodies to other human coronavirus types and other demographic factors,
These data answer prioritized research questions surrounding mechanism and severity of disease in high risk cohorts. The results will be used in spatial population modelling work to inform public health policy and vaccination strategies for this and future pandemics. Mechanistic work will characterise anti-spike protein, anti-nucleocapsid, Nabs, Vitamin D, HLA haplotype and immune cell function relationships to symptoms, demographic characteristics and COVID burden in hospitals.
The data generated will provide information to understand the mechanistic basis underpinning the development of lasting humoral immunity to SARS-Cov2 and relationships to known high risk groups.
The study objectives are to assess:
1) Baseline prior coronavirus exposure, immunity and cross reactivity of antibody assays to other strains
2) Incidence of HCWs seroconversion over time, across sites and the relationship to hospital exposures, and community transmission rates
3) Proportion of seroconverters achieve neutralizing antibodies (Nabs) responses, dual lab validation of Nabs assays, and Nabs potency and durability
4) Effect of HLA haplotypes, severity of symptoms of COVID-19 and levels of T-cell and B-cell activation cytokines to antibody titres and NAbs
5) Antibody titers correlate with severity of illness of SARS-Cov2 infection, baseline antibodies to other human coronavirus types and other demographic factors,
These data answer prioritized research questions surrounding mechanism and severity of disease in high risk cohorts. The results will be used in spatial population modelling work to inform public health policy and vaccination strategies for this and future pandemics. Mechanistic work will characterise anti-spike protein, anti-nucleocapsid, Nabs, Vitamin D, HLA haplotype and immune cell function relationships to symptoms, demographic characteristics and COVID burden in hospitals.
The data generated will provide information to understand the mechanistic basis underpinning the development of lasting humoral immunity to SARS-Cov2 and relationships to known high risk groups.
Publications
Astbury S
(2022)
HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19.
in Immunology
Kifer D
(2020)
Effects of Environmental Factors on Severity and Mortality of COVID-19.
in Frontiers in medicine
Kifer D
(2021)
N-glycosylation of immunoglobulin G predicts incident hypertension.
in Journal of hypertension
Louca P
(2022)
Body mass index mediates the effect of the DASH diet on hypertension: Common metabolites underlying the association.
in Journal of human nutrition and dietetics : the official journal of the British Dietetic Association
Louca P
(2021)
Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app.
in BMJ nutrition, prevention & health
Manisty C
(2021)
Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals.
in Lancet (London, England)
Menni C
(2022)
COVID-19 vaccine waning and effectiveness and side-effects of boosters: a prospective community study from the ZOE COVID Study.
in The Lancet. Infectious diseases
Menni C
(2021)
Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study.
in The Lancet. Infectious diseases
Petrovic T
(2022)
IgG N-glycome changes during the course of severe COVID-19: An observational study.
in EBioMedicine
Reynolds CJ
(2021)
Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose.
in Science (New York, N.Y.)
Swadling L
(2022)
Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2.
in Nature
Urbanowicz RA
(2021)
Two doses of the SARS-CoV-2 BNT162b2 vaccine enhance antibody responses to variants in individuals with prior SARS-CoV-2 infection.
in Science translational medicine
Vijay A
(2021)
The anti-inflammatory effect of bacterial short chain fatty acids is partially mediated by endocannabinoids.
in Gut microbes
Yan H
(2021)
Serum glucose, lactate dehydrogenase and hypertension are mediators of the effect of body mass index on severity of COVID-19.
in Endocrinology, diabetes & metabolism
Yan H
(2020)
Role of Drugs Used for Chronic Disease Management on Susceptibility and Severity of COVID-19: A Large Case-Control Study.
in Clinical pharmacology and therapeutics
Description | This award contributed to increased understanding on antibody responses to Covid-19 infection and to Covid-19 vaccinations |
Exploitation Route | Some of the findings generated in collaboration with the groups in UCL suggest that there may be T-cell related immunization strategies that would result in individuals being infection resistant |
Sectors | Healthcare |
URL | http://www.pantherstudy.org.uk |
Description | Influence on policy |
Geographic Reach | North America |
Policy Influence Type | Citation in other policy documents |
URL | https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-v... |
Description | Multi-centre randomised controlled trial examining the effects of interrupting low-dose methotrexate treatment for two weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions and nested mechanistic study |
Amount | £914,561 (GBP) |
Funding ID | NIHR134607 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 09/2021 |
End | 08/2023 |
Description | University of Virginia |
Organisation | University of Virginia (UVa) |
Department | Biocomplexity Institute |
Country | United States |
Sector | Academic/University |
PI Contribution | We have set up a collaboration with the University of Virginia Biocomplexity institute to analyse some of the complex temporal and spatial data related to Covid-19 transmission and seropositivity we have collected |
Collaborator Contribution | Given the higher infection prevalence in HCWs (18% serological in our cohort) it provides high enough event rates to effectively study disease biology and also transmission dynamics. We have already carried out antibody tests (IgGs) during the first and second wave and responses to vaccination. The group in UVA has extensive experienc in modelling and are working with the group in Nottingham to model interactions between gene expression at baseline and transmission into the household (available for a subset) and responses to first and second doses of the vaccine. RNAseq is ongoling |
Impact | The collaboration is multidisciplinary including modellers, experts in machine learning, biologists and clinicians |
Start Year | 2020 |
Description | COVID-19: Evidence and limitations of genetics in relation to BAME groups |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Prof Aithal presented the work on Covid among ethnic minorities at a webinar organised by the Royal Society of Medicine https://www.rsm.ac.uk/events/medical-genetics/2019-20/mgn53/ |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.rsm.ac.uk/events/medical-genetics/2019-20/mgn53/ |
Description | Dissemination article |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A dissemination article on genetic influences in South Asian populations involved in higher risk of severity of COVID-19 |
Year(s) Of Engagement Activity | 2021 |
URL | https://theconversation.com/gene-commonly-found-in-south-asian-people-affects-covid-severity-new-stu... |
Description | Dissemination articles in The Conversation |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Dissemination articles for The Conversation https://theconversation.com/gut-bacteria-could-help-protect-against-covid-and-even-lead-to-a-new-drug-new-research-175173 https://theconversation.com/gene-commonly-found-in-south-asian-people-affects-covid-severity-new-study-171334 https://theconversation.com/covid-vaccine-boosters-are-likely-to-increase-protection-against-variants-new-research-165981 the number of reads achieved by these three articles has been over 115,000 readers |
Year(s) Of Engagement Activity | 2021,2022 |
URL | http://theconversation.com/profiles/ana-valdes-345983/articles |
Description | Dissemination articles in The Conversation in 2022 |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Dissemination article read by 48,000 people relating how gut microbial metabolites and influence COVID-19 severity |
Year(s) Of Engagement Activity | 2022 |
URL | https://theconversation.com/gut-bacteria-could-help-protect-against-covid-and-even-lead-to-a-new-dru... |
Description | interview with Nature journalist |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | An interview with a journalist of the journal Nature on using healthcare worker cohorts to assess transmission and efficacy of vaccines |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.nature.com/articles/d41586-021-00450-z |