Investigation of proven vaccine breakthrough by SARS-CoV-2 variants in established UK healthcare worker cohorts: SIREN consortium & PITCH Plus Pathway

Lead Research Organisation: Public Health England
Department Name: National Infection Service


This project builds on the established PHE SIREN and associated cohorts (PITCH and HICC) working with leading immunologists and scientists to improve understanding of the immune response to infection and vaccines and study in detail those individuals who have proven vaccine breakthrough. These studies are following more than 45,000 healthcare workers, 94% of whom have received two doses of vaccine, and will assess their immune system response to COVID-19 infections and vaccinations.

Understanding the immune response is essential to determine who is most at risk of infections after vaccination, and also for vaccine developers who can target key components of the immune response effectively for future boost vaccines. The adaptive immune system has two major components - B-cells and T-cells. The B-cells produce antibodies that can be detected after previous infection or vaccination. We will be studying two that are expressed against proteins from the virus - the Spike (S) and Nucleocapsid (N) proteins that are measured using assays that can give us the quantity of each present and also a measurement of neutralising or "sterilising" immunity - assessing how well an individual's blood can kill or neutralise either a live SARS-CoV-2 virus or a lab created replica. The T-cells directly kill virus infected cells by releasing proteins known as cytokines, which can signal to other cells and provide instructions to the immune system on its strength and range of response.

The research is focused on key areas:
1. Why do some people get reinfections or infections after vaccination?
2. In individuals who get infections after vaccination, can we identify which parts of their immune system are not working to provide immune protection?
3. How long does this immunity from vaccinations last and how does it differ with different vaccines?
4. How does the immune system respond to booster doses of vaccination?
5. How do changes in the SARS-CoV-2 virus genetic make-up cause evasion of the immune response?
6. What are the differences that can be detected in the human genetic code that are associated with different immune responses to the virus and vaccination?

We will assess these questions using blood from key groups of individuals recruited into our cohort studies to assess the immune response. We will study:
a) individuals who have a re-infection (a second infection after having a previous confirmed infection) and one or two doses of vaccination and
b) individuals who develop an infection after two doses of vaccine.

We can do this effectively because all individuals who are in the study have PCR tests every two weeks and regular blood tests for antibodies that are stored for future analysis. In addition, for individuals who develop infections after vaccination, we will discuss with them in more detail to determine whether they could have a functional problem with their immune system, take specific medications that could prevent their immune system from responding and seek their consent to take additional blood tests to perform detailed analysis of their immune response to COVID. This will involve analysis of their blood tests before and after the infection episode and we will ask if they would like to participate in genetic analysis of their DNA code to see if there are particular mutations in their DNA code that might predict a poor response to vaccination.

We will seek to do this scientifically using specific study designs that will compare individuals who acquire an infection after vaccination to others who do not get infections, matched to age, sex, ethnicity, and co-morbidities. The T and B-cell immune responses will be compared to determine if there are key detectable differences between these groups.

Technical Summary

The SIREN Consortium aims to investigate the correlates of immunity against SARS-CoV-2 post-vaccination, including the durability of the immune response in healthcare workers (HCW).
The study uses the strengths of the largest global cohort study (N~45,000) with regular serological and alternate weekly SARS-CoV-2 PCR testing.
This additional funding enables detailed immunological nested case-control studies where cases are infections post-vaccination and compared to appropriately matched controls. 75 proven vaccine breakthrough cases have already been identified and daily alerts for new infections are in place.

It will assess host and pathogen factors related to infections post-vaccination with the PITCH Plus pathway
1. Anti-S and anti-N neutralising antibodies against the current SARS-CoV-2 variants of concern, using validated pseudovirus microneutralisation (pMN) assay and live virus MN & Tcell memory responses, by IFNG Elispot and T cell proliferation assay
2. The durability of binding and quantification S and N antibody, neutralising antibody and T-cell responses in recipients of different vaccines and vaccination schedules
3. Genotype to phenotype mapping including centralised genomic surveillance for all cases, analysis and exploratory assessment to better define the correlates of humoral and cellular immunity for novel mutations/ emerging variants.
4. Clinical immunology consultation: individuals with post-vaccine infections will be invited to a telephone consultation to review their medical history, have bloods undertaken to assess underlying health conditions, associated immunodeficiency and the humoral and cellular immune system.
5. Human genotyping with consent we will obtain and store genetic material from vaccine breakthrough cases to enable future assessment of known single nucleotide polymorphisms and where necessary whole genome sequencing for associations with suboptimal vaccine response and immunodeficiency.



Susan Hopkins (Principal Investigator) orcid
Eleanor Barnes (Co-Investigator)
Christopher James Duncan (Co-Investigator) orcid
Jasmin Islam (Co-Investigator)
Helen Elizabeth Baxendale (Co-Investigator)
Meera Chand (Co-Investigator)
Massimo Palmarini (Co-Investigator)
Victoria Jane Hall (Co-Investigator) orcid
Dan Wootton (Co-Investigator) orcid
Paul Klenerman (Co-Investigator)
Brian James Willett (Co-Investigator)
Thushan De Silva (Co-Investigator)
Wendy Barclay (Co-Investigator)
Jonathan Luke Heeney (Co-Investigator)
Amanda Semper (Co-Investigator) orcid
Lance Turtle (Co-Investigator) orcid
Timothy John Brooks (Co-Investigator)
Maria Zambon (Co-Investigator)
Rupert Beale (Co-Investigator) orcid
John Kenneth Baillie (Co-Investigator) orcid
André Charlett (Co-Investigator)
Alex Gisela Richter (Co-Investigator)
Colin Stewart Brown (Co-Investigator) orcid
Susanna Jane Dunachie (Co-Investigator) orcid
Rebecca Payne (Researcher)
Erola Pairo Castineira (Researcher Co-Investigator) orcid
Edward Carr (Researcher Co-Investigator) orcid
Javier Castillo-Olivares (Researcher Co-Investigator) orcid
Iain Milligan (Researcher Co-Investigator) orcid
Ashley Otter (Researcher Co-Investigator) orcid
Ana Carolina Atti (Researcher Co-Investigator)