Publication highlights

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Explore a selection of research case studies from the past five years.

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Intro

Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Highlights

Covid viruses floating

Third exposure to COVID-19 infection or vaccination initiates a different immune response

COVID-19 restrictions including social distancing were lifted in the UK in 2021 after the majority of the population had two doses of vaccine. Researchers at the Crick analysed data from the Legacy study to find out if either infection or vaccine as a third exposure generated different immunity. We found overall that both antibody-mediated and cellular immunity was similar, but when T cells were exposed to spike protein challenge in vitro, infection exposure drove production of more innate immune cytokines from T cells and expansion of mucosal-homing T cells, whereas vaccine-only exposed cells led to expansion of the T cell memory population that produced more inflammatory cytokines.

Third exposure to COVID-19 infection or vaccination differentially impacts T cell responses

Published in Journal of Infection

Published

Structure of V1H

Researchers discover how cells raise the alarm when damaged or infected

Our cells need acidic compartments for digestion and recycling of nutrients. Acid is pumped in by a complex assembly of proteins called the V-ATPase. But what happens when our cells get damaged? The acid leaks out and the cell has to respond. Researchers at the Crick discovered how the V-ATPase proton pump itself sounds the alarm: one protein in the complex recruits a crucial part of the self-eating (autophagy) machinery. They think this is especially important during infection since some bacteria target this pathway, and many viruses like influenza trigger it.

The V-ATPase/ATG16L1 axis is controlled by the V1H subunit

Published in Molecular Cell

Published

A vial of COVID-19 vaccine in a blue gloved hand.

Vaccine monitoring crucial as SARS-CoV-2 variants continue to evolve

Researchers at the Francis Crick Institute and the National Institute for Health and Care Research Biomedical Research Centre at UCLH have highlighted the importance of continued surveillance of emerging SARS-CoV-2 variants and vaccine performance as the virus continues to evolve. The research, part of the Legacy study, compared the newer monovalent COVID vaccine with older bivalent vaccines used in the Autumn 2023 booster campaign, finding that both vaccines generated neutralising antibodies against the most recent strain of Omicron, BA.2.86. However the new monovalent vaccine generated higher levels of antibodies against a range of other Omicron variants. This highlights the importance of careful vaccine updates and continuing to complement a vaccination programme with the development of antibody drugs that work against all variants, as some more vulnerable people don’t respond well to vaccines.

Divergent performance of vaccines in the UK autumn 2023 COVID-19 booster campaign

Published in The Lancet

Published

PCR testing at the Crick.

Will mucosal vaccines work against SARS-CoV-2?

Does infection or vaccination induce nasal neutralising antibodies to SARS-CoV-2 variants? The Covid Surveillance Unit has developed a fast, easy method to test if antibodies in nasal mucosa stop SARS-CoV-2 replicating in cells in swabs from participants in the UCLH-Crick Legacy study. Both vaccination and infection boosted antibody levels in nasal mucus, and repeated vaccinations could enhance this. Importantly, the range of nasal antibodies differs from that in blood, which means current vaccines may not stop infections with new antigenically different variants. The methodology used in the study will make it easy to evaluate next generation vaccines, including mucosal vaccines.

SARS-CoV-2 mucosal neutralising immunity after vaccination

Published in The Lancet Infectious Diseases

Published

Three-dimensional model of the retroviral intasome and chemical structures of some of the clinical HIV-1 integrase inhibitors studied in the lab

TMEM106B: SARS-CoV-2’s secret entrance to the cell

SARS-CoV-2 is known to enter cells using the ACE2 receptor, but the virus can also infect cells that lack ACE2. The Cherepanov lab, together with Crick and international colleagues, have shown that a second protein, TMEM106B, can act as an alternative entry port for the SARS-CoV-2 virus. The E484D mutation in the virus spike enhances TMEM106B use, and antibodies against TMEM106B can stop viral entry, suggesting their potential as therapeutics. Structural studies looking at how TMEM106B and the virus interact showed that TMEM106B engages the spike precisely at its receptor binding motif. The results may explain how SARS-CoV-2 can spread to tissues outside of the respiratory tract and highlight the ability of the virus to switch to an alternative receptor.

TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry

Published in Cell

Published

A plot on a computer screen.

Asymptomatic testing key to pandemic preparedness

Asymptomatic PCR testing for NHS staff, provided by the Francis Crick Institute and University College London Hospitals (UCLH) NHS Foundation Trust and its diagnostic partner Health Services Laboratories, effectively detected COVID-19 infections that would have otherwise been missed. The researchers examined test positivity rates across different NHS trusts, observing that from the 680,000 tests run through the testing pipeline, 40.8% of all positive tests were from UCLH and The Royal Marsden NHS Foundation Trust. This high incidence suggests a significant number of additional infections were being detected by this strategy.

Independent SARS-CoV-2 staff testing protected academic and health-care institutions in northwest London

Published in The Lancet

Published

A plot on a computer screen.

Why the UK didn't experience the predicted severe COVID wave from Omicron "escape variants"

In the UCLH-Crick Legacy study, the team asked why the UK didn't experience the predicted severe COVID wave from Omicron “escape variants” XBB and B.Q.1.1 (variants which arise from weaker immune responses to the vaccine) in winter 2022, unlike Singapore and the US. They used serum collected from Legacy study volunteers and tested for neutralising antibodies against these “escape variants” before and after the bilvalent vaccine - a type of vaccine which targets the original strain and Omicron strain.

Using data from the COVID Surveillance Unit’s specialist antibody tests against variants XBB, XBB.1.5 and BQ.1.1, they found that neutralising antibodies against these variants were boosted 3-4-fold in all participants after the bivalent vaccine. They also found any prior infection was a major contributor to high levels of neutralising antibodies against these new variants, but participants who hadn’t been infected still had neutralising antibodies against XBB after vaccination. Any 4th “encounter” with another Omicron variant, Spike, in 2022, boosted antibodies against these variants in patients who had had three vaccines. People who had been infected with the BA.1/2/5 variant had similar levels of antibodies as those who had been given the 4th vaccine. In summary, the UK’s targeted 4th dose vaccine policy by JCVI complemented widespread existing hybrid immunity in the wider UK population, protecting against the predicted severe wave of COVID-19 in UK winter 2022-3.

Neutralising immunity to omicron sublineages BQ.1.1, XBB, and XBB.1.5 in healthy adults is boosted by bivalent BA.1-containing mRNA vaccination and previous Omicron infection

Published in The Lancet Infectious Diseases

Published

Structural insights into influenza infection

Hemagglutinin (HA), the receptor binding and membrane fusion glycoprotein of influenza virus, is synthesised as a precursor (HA0) that requires cleavage and exposure to low pH for fusion activity during virus entry. Researchers in the Rosenthal and Gamblin labs have used cryo-EM to image an extensive conformational change in the HA0 protein at low pH that may mimic an intermediate in the structural transitions by which HA mediates membrane fusion. Unlike the case with HA, however, the change is reversible. The results provide insight into the role of cleavage in membrane fusion activation and have implications for the action of antiviral drug candidates and cross-reactive anti-HA antibodies that can block influenza infectivity.

Reversible structural changes in the influenza hemagglutinin precursor at membrane fusion pH

Published in Proceedings of the National Academy of Sciences of the United States of America

Published

Evolution of the SARS-CoV-2 spike protein in the human host

Researchers in the Gamblin lab identified structural changes in the spike proteins of recently emerged SARS-CoV-2 variants which provide clues to how the virus is evolving to have greater levels of infectivity.

Evolution of the SARS-CoV-2 spike protein in the
human host

Published in Nature Communications

Published

COVID-19 vaccine booster provides good antibody protection against Omicron

As part of the CAPTURE study, researchers in collaboration with the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre found that antibodies generated in people who had received only two doses of either the Oxford/AstraZeneca vaccine or the Pfizer/BioNTech vaccine were less able to neutralise the Omicron variant as compared to the Alpha and Delta variants. They also found that antibody levels dropped off in the first three months following the second dose but that a third ‘booster’ dose raised levels of antibodies that effectively neutralise the Omicron variant.

Three-dose vaccination elicits neutralising antibodies against omicron

Published in The Lancet

Published

Patients with blood cancer found to have lower protection against SARS-CoV-2

As part of the largest study to comprehensively evaluate the response of patients with cancer to COVID-19 vaccines, researchers in the Turajlic lab monitored the immune response of 585 patients with different types of cancer after receiving a first and second dose of the COVID-19 vaccine.
They found that patients with blood cancer were less likely to have antibodies than individuals of a similar age without cancer or with solid cancer, and when they did have antibodies, the levels were lower against all variants.

Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study

Published in Nature Cancer

Published

Antibody levels vary according to vaccine type and previous infection with COVID-19

The Legacy study team found that two doses of the Oxford-AstraZeneca vaccine generate lower levels of antibodies able to recognise the Delta variant, in comparison with the Pfizer-BioNTech vaccine. Their results also show that antibody levels vary considerably depending on likely prior infection with SARS-CoV-2.

Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination

Published in The Lancet

Published

COVID-19 spike with biliverdin binding site.

SARS-CoV-2 can recruit a haem metabolite to evade antibody immunity

A team led by the Cherepanov lab has found a molecule that can block the binding of a subset of human antibodies to SARS-CoV-2. This could explain patients who, despite having high levels of antibodies, become ill.

View the publication

Published in Science advances

Published

Scalable and robust SARS-CoV-2 testing in an academic center

This paper decribes how we were able to successfully repurpose the Crick to increase the capacity for Sars-CoV-2 testing in unpredented times.

View the publication

Published in Nature Biotechnology

Published

COVID testing

Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers

This important paper showed very high levels of infection amongst healthcare workers in a local hospital. It has influenced government policy – asymptomatic healthcare workers are to be screened as per our recommendation (announced October 12th).

View the publication

Published in The Lancet

Published

Spike protein of SARS-CoV-2.

SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects

We have been able to apply the knowledge we have gained from our work on the infectivity of the influenza virus to the challenge presented by the recent SARS-CoV-2 virus outbreak. In this paper we present high resolution cryo EM structures of the SARS-CoV-2 and bat RaTG13 spike glycoproteins. We describe from a structural perspective the significant differences between the strains. We draw particular attention to the addition of a furin cleavage site into the human virus spike protein. We discuss its potential role in infectivity and on the evolution of this virulent strain.

View the publication

Published in Nature Structural and Molecular Biology

Published

Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion

Here we describe the conformational changes that the SARS-Cov2 spike protein undergoes in binding to the human ACE2 receptor. This represents the initial stages of the mechanism of cell invasion by the virus particle during infection. We show a series of ten cryoEM reconstructions of the spike protein binding to ACE2 through its receptor binding domain (RBD), ranging from a closed unbound spike ectodomain trimer to the fully open conformation with each RBD in the trimer bound to an ACE2 receptor. Binding to ACE2 releases the so-called fusion peptide segment and promotes membrane fusion leading to cell invasion.

View the publication

Published in Nature

Published

D614G SARS-CoV-2 variant spike protein

The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

Research from the Gamblin lab has compared the original SARS-CoV-2 spike protein with a mutated version which arose last spring. They have found structural differences that could help to explain why the mutated version remains the dominant form circulating in all recent variants of concern.

View the publication

Published in Proceedings of the National Academy of Sciences of the United States of America

Published