New data from Addenbrooke’s Hospital in Cambridge suggests that a single dose of the Pfizer BioNTech vaccine can reduce by 75% the number of asymptomatic SARS-CoV-2 infections. This implies that the vaccine could significantly reduce the risk of transmission of the virus from people who are asymptomatic, as well as protecting others from getting ill.

The study by a team at Cambridge University Hospitals NHS Foundation Trust (CUH) and the University of Cambridge analysed results from thousands of COVID-19 tests carried out each week as part its screening programmes on hospital staff who showed no signs of infection.

Vaccination for health care workers on the CUH site began on 8 December 2020, with mass vaccination from 8 January 2021. During a two-week period between 18 and 31 January 2021, the team screened similar numbers of vaccinated and unvaccinated staff using around 4,400 PCR tests per week. 

The results were then separated out to identify unvaccinated staff, and staff who had been vaccinated more than 12 days prior to testing (when protection against symptomatic infection is thought to occur). The study, which is yet to be peer-reviewed, found that 26 out of 3,252 (0·80%) tests from unvaccinated healthcare workers were positive. This compared to 13 out of 3,535 (0.37%) tests from healthcare workers less than 12 days post-vaccination and 4 out of 1,989 (0·20%) tests from healthcare workers at 12 days or more post-vaccination.

This suggests a four-fold decrease in the risk of asymptomatic COVID-19 infection amongst healthcare workers who have been vaccinated for more than 12 days (75 percent protection). The level of asymptomatic infection was also halved in those vaccinated for less than 12 days.

Dr Mike Weekes, an infectious disease specialist at CUH and the University of Cambridge’s Department of Medicine, who led the study, said:  “This is great news – the Pfizer vaccine not only provides protection against becoming ill from SARS-CoV-2 but also helps prevent infection, reducing the potential for the virus to be passed on to others.

“This will be welcome news as we begin to plot a roadmap out of the lockdown, but we have to remember that the vaccine doesn’t give complete protection for everyone. We still need social distancing, masks, hand hygiene and regular testing until the pandemic is under much better control.” 

Dr Nick Jones, first author on the study and an infectious diseases/microbiology registrar at CUH, said: “Our findings show a dramatic reduction in the rate of positive screening tests among asymptomatic healthcare workers after a single dose of the Pfizer-BioNTech vaccine. This is fantastic news for both hospital staff and patients, who can be reassured that the current mass vaccination strategy is protecting against asymptomatic carriage of the virus in addition to symptomatic disease, thereby making hospitals even safer places to be.”

Giles Wright, programme director for the CUH Vaccination Hub said:  “Throughout the pandemic so far, we have taken a systematic approach to keeping our staff safe and well. The huge efforts of all those involved in the testing, tracing and vaccination programmes at CUH are making the plan a reality. We are very encouraged by the findings of our research. It gives further hope for the near future.”

When the team included symptomatic healthcare workers, their analyses showed similar reductions. 56 out of 3,282 (1·71%) unvaccinated healthcare workers tested positive. This compared to 8 out of 1,997 (0·40%) healthcare workers at 12 or more days post-vaccination, a 4·3-fold reduction.

The researchers have released their data ahead of peer review because of the urgent need to share information relating to the pandemic.

This work was supported by Wellcome, the Medical Research Council, NHS Blood & Transplant, Addenbrooke’s Charitable Trust and the NIHR Cambridge Biomedical Research Centre.

Paper reference:
Jones, NK et al. 
Single-dose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection. 24 Feb 2020; DOI: 10.22541/au.161420511.12987747/v1

The Pfizer BioNTech vaccine BNT162b2 is likely to be effective against the B1.1.7 variant of SARS-CoV-2, even though its efficacy is modestly affected, say scientists at the University of Cambridge. However, when the E484K mutation – first seen in the South African variant – is added, it substantially increases the amount of antibody required to prevent infection.

The preliminary data, which have yet to be to peer-reviewed and relate to only a small number of patients, also suggest that a significant proportion of over-eighty olds may not be sufficiently protected against infection until they have received their second dose of the vaccine.

As the SARS-CoV-2 virus replicates and spreads, errors in its genetic code can lead to changes in the virus. Towards the end of 2020, the Cambridge-led COVID-19 Genomics UK (COG-UK) Consortium identified a variant of the virus (now known as B1.1.7) which includes important changes that change the structure of the Spike protein, including the ΔH69/ΔV70 and Δ144/145 amino acid deletions and N501Y, A570D and P681H mutations. Researchers at Cambridge/COG-UK now report seeing a number of virus sequences that also include the E484K mutation, first seen in the South African variant.

The emergence of the B1.1.7 strain has led to strict lockdown measures in the UK because of concerns over its transmissibility. There is particular concern that these changes might enable the virus to ‘escape’ the newly-developed vaccines, which typically target the Spike protein.

The UK has begun rolling out two vaccines – the Pfizer BioNTech vaccine and the Oxford AstraZeneca vaccine. The efficacy of the vaccines can be boosted by a second dose; however, in order to reach as large a number of people as possible in a short amount of time, the government has concentrated on delivering a first dose to as many individuals as possible by giving the second dose at 12 weeks, rather than three.

Researchers at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), University of Cambridge, working in collaboration with the NIHR Covid-19 BioResource, used blood samples from 26 individuals who had received their first dose of the Pfizer vaccine three weeks previously, to extract serum, which contains antibodies raised in response to the vaccine. The age range of the volunteers was 29 to 89 years.

Working under secure conditions, the team created a synthetic version of the SARS-CoV-2 virus, known as a pseudovirus. When they tested the individuals’ sera against this pseudovirus, they found that all but seven of the individuals had levels of antibodies sufficiently high to neutralise the virus – that is, to protect against infection.

When the team added all eight Spike protein mutations found in B1.1.7 to the pseudovirus, they found that the efficacy of the vaccine was affected by the B1.1.7 mutations, which required higher concentrations of antibody in the sera to neutralise the virus. Although there was a wide range of variation between individuals, on average B1.1.7 required around a two-fold increase in the concentration of serum antibody.

However, when the E484K mutation was added, substantially higher levels of antibody were required – on average this mutation required an almost ten-fold increase in the concentration of serum antibody for neutralisation when compared to the strain circulating prior to B.1.1.7.

Professor Ravi Gupta from CITIID, who led the study, said: “Our findings suggest that the Pfizer BioNTech vaccine is likely to offer similar protection against B1.1.7 as it does against the previous strain of SARS-CoV-2. Although we found a reduction in the ability of antibodies to neutralise the virus, given the number of antibodies produced following vaccination, this should still only have a relatively modest effect and people should still be protected.

“Of particular concern, though, is the emergence of the E484K mutation, which so far has only been seen in a relatively small number of individuals. Our work suggests the vaccine is likely to be less effective when dealing with this mutation.

“B1.1.7 will continue to acquire mutations seen in the other variants of concern, so we need to plan for the next generation of vaccines to have modifications to account for new variants. We also need to scale up vaccines as fast and as broadly as possible to get transmission down globally.”

The seven individuals who were unable to neutralise the virus after the first dose were all aged over 80 years old. This accounts for almost half of the 15 individuals in this age group. However, at a follow-up visit after these individuals had received their second dose (given at three weeks), they were all able to neutralise the virus.

Dr Dami Collier, the main co-investigator on the studies, added: “Our data suggest that a significant proportion of people aged over eighty may not have developed protective neutralising antibodies against infection three weeks after their first dose of the vaccine. But it’s reassuring to see that after two doses, serum from every individual was able to neutralise the virus.”

The researchers have released their data ahead of peer review because of the urgent need to share information relating to the pandemic, and particularly the new UK variant.

The research was supported by Wellcome, the Medical Research Council, the Bill and Melinda Gates Foundation and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

 

Researchers have developed a DNA test to quickly identify secondary infections in COVID-19 patients, who have double the risk of developing pneumonia while on ventilation than non-COVID-19 patients.

For patients with the most severe forms of COVID-19, mechanical ventilation is often the only way to keep them alive, as doctors use anti-inflammatory therapies to treat their inflamed lungs. However, these patients are susceptible to further infections from bacteria and fungi that they may acquire while in hospital – so called ‘ventilator-associated pneumonia’.

Now, a team of scientists and doctors at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, led by Professor Gordon Dougan, Dr Vilas Navapurkar and Dr Andrew Conway Morris, have developed a simple DNA test to quickly identify these infections and target antibiotic treatment as needed.

The test, developed at Addenbrooke’s hospital in collaboration with Public Health England, gives doctors the information they need to start treatment within hours rather than days, fine-tuning treatment as required and reducing the inappropriate use of antibiotics. This approach, based on higher throughput DNA testing, is being rolled out at Cambridge University Hospitals and offers a route towards better treatments for infection more generally. The results are reported in the journal Critical Care.

Patients who need mechanical ventilation are at significant risk of developing secondary pneumonia while they are in intensive care. These infections are often caused by antibiotic-resistant bacteria, and are hard to diagnose and need targeted treatment.

“Early on in the pandemic we noticed that COVID-19 patients appeared to be particularly at risk of developing secondary pneumonia, and started using a rapid diagnostic test that we had developed for just such a situation,” said co-author Dr Andrew Conway Morris from Cambridge’s Department of Medicine and an intensive care consultant. “Using this test, we found that patients with COVID-19 were twice as likely to develop secondary pneumonia as other patients in the same intensive care unit.”

COVID-19 patients are thought to be at increased risk of infection for several reasons. Due to the amount of lung damage, these severe COVID-19 cases tend to spend more time on a ventilator than patients without COVID-19. In addition, many of these patients also have a poorly-regulated immune system, where the immune cells damage the organs, but also have impaired anti-microbial functions, increasing the risk of infection.

Normally, confirming a pneumonia diagnosis is challenging, as bacterial samples from patients need to be cultured and grown in a lab, which is time-consuming. The Cambridge test takes an alternative approach by detecting the DNA of different pathogens, which allows for faster and more accurate testing.

The test uses multiple polymerase chain reaction (PCR) which detects the DNA of the bacteria and can be done in around four hours, meaning there is no need to wait for the bacteria to grow. “Often, patients have already started to receive antobiotics before the bacteria have had time to grow in the lab,” said Morris. “This means that results from cultures are often negative, whereas PCR doesn’t need viable bacteria to detect – making this a more accurate test.”

The test – which was developed with Dr Martin Curran, a specialist in PCR diagnostics from Public Health England’s Cambridge laboratory – runs multiple PCR reactions in parallel, and can simultaneously pick up 52 different pathogens, which often infect the lungs of patients in intensive care. At the same time, it can also test for antibiotic resistance.

“We found that although patients with COVID-19 were more likely to develop secondary pneumonia, the bacteria that caused these infections were similar to those in ICU patients without COVID-19,” said lead author Mailis Maes, also from the Department of Medicine. “This means that standard antibiotic protocols can be applied to COVID-19 patients.”

This is one of the first times that this technology has been used in routine clinical practice and has now been approved by the hospital. The researchers anticipate that similar approaches would benefit patients if used more broadly.

This study was funded by the National Institute for Health Research Cambridge Biomedical Research Centre.

Paper reference

Mailis Maes et al. Ventilator-associated pneumonia in critically ill patients with COVID-19.
Critical Care (2021). DOI: 10.1186/s13054-021-03460-5

Fourteen out of every 1,000 COVID-19 patients admitted to hospital experience a stroke, a rate that is even higher in older patients and those with severe infection and pre-existing vascular conditions, according to a report.

COVID-19 has become a global pandemic, affecting millions of people worldwide. In many cases, the symptoms include fever, persistent dry cough and breathing difficulties, and can lead to low blood oxygen. However, the infection can cause disease in other organs, including the brain, and in more severe cases can lead to stroke and brain haemorrhage.

A team of researchers at the Stroke Research Group, University of Cambridge, carried out a systematic review and meta-analysis of published research into the link between COVID-19 and stroke. This approach allows researchers to bring together existing – and often contradictory or under-powered – studies to provide more robust conclusions.

In total, the researchers analysed 61 studies, covering more than 100,000 patients admitted to hospital with COVID-19. The results of their study are published in the International Journal of Stroke.

The researchers found that stroke occurred in 14 out of every 1,000 cases. The most common manifestation was acute ischemic stroke, which occurred in just over 12 out of every 1,000 cases. Brain haemorrhage was less common, occurring in 1.6 out of every 1,000 cases. Most patients had been admitted with COVID-19 symptoms, with stroke occurring a few days later.  

Age was a risk factor, with COVID-19 patients who developed stroke being on average (median) 4.8 years older than those who did not. COVID-19 patients who experienced a stroke were on average (median) six years younger than non-COVID-19 stroke patients. There was no sex difference and no significant difference in rates of smokers versus non-smokers.

Pre-existing conditions also increased the risk of stroke. Patients with high blood pressure were more likely to experience stroke than patients with normal blood pressure, while both diabetes and coronary artery disease also increased risk. Patients who had a more severe infection with SARS­CoV­2 – the coronavirus that causes COVID-19 – were also more likely to have a stroke.

The researchers found that COVID-19-associated strokes often followed a characteristic pattern, with stroke caused by blockage of a large cerebral artery, and brain imaging showing strokes in more than one cerebral arterial territory. They argue that this pattern suggests cerebral thrombosis and/or thromboembolism are important factors in causing stroke in COVID-19.  COVID-19-associated strokes were also more severe and had a high mortality.

An important question is whether COVID-19 increases the risk of stroke or whether the association is merely a result of COVID-19 infection being widespread in the community.

“The picture is complicated,” explained Dr Stefania Nannoni from the Department of Clinical Neurosciences at the University of Cambridge, the study’s first author. “For example, a number COVID-19 patients are already likely to be at increased risk of stroke, and other factors, such as the mental stress of COVID-19, may contribute to stroke risk.

“On the other hand, we see evidence that COVID-19 may trigger – or at least be a risk factor for – stroke, in some cases. Firstly, SARS­CoV­2 more so than other coronaviruses – and significantly more so than seasonal flu – appears to be associated with stroke. Secondly, we see a particular pattern of stroke in individuals with COVID-19, which suggests a causal relationship in at least a proportion of patients.”

The researchers say there may be several possible mechanisms behind the link between COVID-19 and stroke. One mechanism might be that the virus triggers an inflammatory response that causes thickening of the blood, increasing the risk of thrombosis and stroke. Another relates to ACE2 – a protein ‘receptor’ on the surface of cells that SARS-CoV-2 uses to break into the cell. This receptor is commonly found on cells in the lungs, heart, kidneys, and in the lining of blood vessels – if the virus invades the lining of blood vessels, it could cause inflammation, constricting the blood vessels and restricting blood flow.

A third possible mechanism is the immune system over-reacting to infection, with subsequent excessive release of proteins known as cytokine. This so-called ‘cytokine storm’ could then cause brain damage.

The team say their results may have important clinical implications.

“Even though the incidence of stroke among COVID-19 patients is relatively low, the scale of the pandemic means that many thousands of people could potentially be affected worldwide,” said Professor Hugh Markus, who leads the Stroke Research Group at Cambridge.

“Clinicians will need to look out for signs and symptoms of stroke, particularly among those groups who are at particular risk, while bearing in mind that the profile of an at-risk patient is younger than might be expected.”

While the majority of strokes occurred after a few days of COVID-19 symptoms onset, neurological symptoms represented the reason for hospital admission in more than one third of people with COVID-19 and stroke.

Dr Nannoni added: “Given that patients admitted to hospital with symptoms of stroke might have mild COVID-19-related respiratory symptoms, or be completely asymptomatic, we recommend that all patients admitted with stroke be treated as potential COVID-19 cases until the results of screening in the hospital are negative.”

The research was supported by the Medical Research Council, the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the British Heart Foundation.

Paper reference

Nannoni S, de Groot R, Bell S, Markus HS. Stroke in COVID-19: a systematic review and meta-analysis. Int J Stroke; 26 Oct 2020; DOI: 10.1177/1747493020972922. Epub ahead of print. PMID: 33103610.

14 October 2020

As the COVID-19 situation develops, research staff at Cambridge University Hospitals (CUH) continue our support of COVID-19 research studies, including Urgent Public Health Studies (UPH), while maintaining safe recruitment to existing open studies and, where possible, safely restarting research studies that were paused during the initial stages of the pandemic.

To date, we have supported, and continue to support, more than 30 COVID-related research studies, including RECOVERY and the Cambridge-led TACTIC trials, as well as recruiting patient and staff participants to the NIHR COVID-19 BioResource project and participating in vaccine studies.  At the same time, we have re-opened recruitment to more than 300 paused studies and continue to work toward re-opening the remaining studies on our portfolio.

Following NIHR guidance, R&D is closely monitoring the pandemic situation, and will continue to release guidance to research teams as local and national infection levels fluctuate. We will support the provision of safe patient care within CUH while maintaining recruitment to currently open clinical trials and studies where possible. 

Subject to the approval of the COVID-19 Research Oversight board, we will also continue to accept and support new local and nationally prioritised COVID studies; new non-COVID research studies should be submitted to R&D.  All CRN funded staff have been directed to work on UPH-listed studies as their priority.

Questions regarding research restart, COVD-risk assessment, staffing, finance and new COVID- or non-COVID research should direct their enquiries to cuh.research@nhs.net in the first instance.  Enquiries regarding CRN funded staff contact Christian.sparke@addenbrookes.nhs.uk or Tel: 01223 596458