this week COVID INFLUENCERS page 87 • FRAILTY AND VACCINATION page 88 • VENTILATION page 90 VICTORIA JONES/PA VICTORIA Hancock bars extra legal cover for doctors

England’s health secretary has rejected a the same time feel vulnerable to the risk of With the threat of ICUs being call to bring in emergency legislation to prosecution for unlawful killing.” overwhelmed, doctors fear protect doctors from “inappropriate” legal NHS doctors are covered by state being subjected to criminal action amid fears that the NHS will be indemnity for clinical negligence and by an investigations if a care decision based on resources overwhelmed by the covid-19 pandemic. additional scheme that covers pandemic leads to a patient’s death Doctors are worried that not only will they responses. The GMC has also said the covid be forced to choose which patients to treat context will be taken into account when it but they could be vulnerable to a criminal considers complaints. But the groups’ letter investigation should a patient die in such said they did not address their concerns. circumstances. Their fears follow a warning Asked by The BMJ about the letter, on 6 January that hospitals were less than Hancock said intensive care capacity was a two weeks from being overwhelmed. “very serious concern.” But he added, “I am The doctors’ plea for emergency very glad to say we are not in a position that legislation came in a letter to Matt Hancock, doctors have to make these sorts of choices signed by seven organisations, including the and very much hope that we don’t get into LATEST ONLINE Medical Protection Society, BMA, Doctors’ that situation. It is not necessary at this Association UK, Hospital Consultants and point to change the law on this matter.” Spain to become Specialists Association, and the British A day later, on 19 January, the Royal the sixth country Association of Physicians of Indian Origin. London Hospital reported that all its ICU to allow euthanasia The letter said that guidance available to beds—recently expanded from 44 to 150— and assisted suicide doctors on administering and withdrawing were occupied. treatment does not provide legal protection Jane Dacre, president of the Medical What covid variants and does not consider covid-19 specifi c Protection Society, was disappointed with are emerging, and how are they being factors such as surges in demand for Hancock’s response. “Healthcare staff investigated? resources temporarily exceeding supply. It need this legal protection now. It would added that health professionals should not enable doctors to focus on doing the best Government using lateral fl ow tests “suff er from the moral injury and long-term for their patients without fear of unfair to keep children psychological damage that could result investigations,” she said. in schools against from having to make decisions on how Clare Dyer , The BMJ regulator’s advice limited resources are allocated, while at Cite this as: BMJ 2021;372:n164 the bmj | 23 January 2021 85 SEVEN DAYS IN Doctors’ leaders call for revised PPE guidance Medical leaders have urged Public Health England to strengthen its guidance on personal protective equipment to reflect the more transmissible forms of SARS-CoV-2. Current guidance says that higher grade FFP3 masks should be provided to staff who are involved in aerosol generating procedures, but other staff looking aft er patients with covid-19 are only required to wear fluid resistant surgical masks. In a letter to PHE sent on 13 January, BMA council chair Chaand Nagpaul said that, in light of the new variant of SARS-CoV-2, increased spread of the virus, and growing evidence of aerosol transmission, it should review its recommendations on PPE usage “so that a more precautionary approach is adopted to the provision of respiratory protective equipment (RPE) to ensure staff are protected from aerosol transmission.” He wrote: “There are signifi cant and growing concerns about the role of aerosol transmission of covid-19 in healthcare settings, and the need for wider use of RPE (for example, FFP3 respirators) outside of those procedures designated as aerosol generating. We are therefore calling on [PHE] to support the wider use of RPE in other high risk settings across primary and secondary care.”

NEIL HALL/PA Gareth Iacobucci , The BMJ Cite this as: BMJ 2021;372:n146

Covid-19 trials are necessary to know (https://covidskinsigns.com ) David Williams (below) of the Many ICU staff whether convalescent plasma is after finding an association Harvard School of Public Health; in England report PTSD beneficial. One such trial from between skin rashes and a Michael Marmot of the UCL Nearly half of 700 intensive care India, published in The BMJ positive swab Institute of Health Equity; Donna and anaesthetic staff surveyed in November, found that test result (odds Kinnair, chief executive of the in six English hospitals last June it did not reduce disease ratio 1.67 (95% Royal College of Nursing; Kevin and July reported symptoms progression or mortality confidence interval Fenton, London regional director consistent with a probable from all causes. 1.41 to 1.96)), from for Public Health England; and diagnosis of post-traumatic data on 336 847 UK Chaand Nagpaul, chair of council stress disorder (PTSD), severe Japan’s suicide rate users of the Covid at the BMA. depression, anxiety, or problem falls then rises Symptom Study drinking. The preprint, from Monthly suicide rates in app. Reporting in Patient safety researchers at King’s College Japan declined by 14% the British Journal Government will appoint London, also reported that 13.4% in the first five months of the of Dermatology, they also found commissioner in England of respondents had had thoughts pandemic (February to June 2020) that among 11 546 survey The government plans to appoint that they would be better off but increased by 16% in the respondents 17% of SARS-CoV-2 a patient safety commissioner to dead or of hurting themselves. second wave (July to October), positive cases reported skin oversee healthcare in England, The BMA’s mental health lead, showed a study published in rashes as the first presentation in response to the Cumberlege Andrew Molodynski, said that a Nature Human Behaviour that and 21% as the only covid-19 review into treatments that supportive workplace culture and covered Japan’s entire population clinical sign. caused avoidable harm. But high quality wellbeing support of 120 million. It found that it rejected calls to set up an were vital. suicide rates rose the most Inequalities independent redress agency among women (up 37%) and NHS Race and Health for the people harmed or to Trials needed into children and adolescents (up Observatory board named appoint a taskforce to implement convalescent plasma 49%). The authors argue that The NHS Race and Health the recommendations of the An observational study in the the results are consistent with Observatory, set up in May review, which examined pelvic New England Journal of Medicine other studies showing the crisis 2020 to investigate mesh, Primodos, and sodium found that convalescent plasma disproportionately affected the effects of race and valproate. The government seemed to be of most benefit female dominant industries ethnicity on people’s was still considering whether to patients who received and that stay-at-home orders health, appointed doctors’ financial and non- transfusions containing high magnified mothers’ burdens. some of the world’s pecuniary interests should levels of antibodies early in the leading experts be declared, but course of covid infection. Death Skin rash is present in on health Nadine Dorries, within 30 days of transfusion 17% of positive covid cases inequalities health minister, occurred in 22.3% of the high titre Researchers from King’s College to its board of indicated that group, as compared with 29.6% London compiled a catalogue non-executive this would be in the low titre group. Experts of images of the most common directors. implemented in say that results of randomised skin manifestations of covid-19 They include the future.

86 23 January 2021 | the bmj SIXTY SECONDS MEDICINE ON . . . COVID Research news INFLUENCERS Fried food links to major heart and stroke risk PARDON? An analysis from studies involving Get with the programme, Grandad. more than 1.3 million people Influencers are very . . . influential these found that the highest category of days. And they don’t just encourage people on social media to buy things they weekly fried food consumption, don’t need. when compared with the lowest, was associated with a 28% raised Consumption of fried food was REALLY? WHAT ELSE DO THEY DO? Help spearhead public health campaigns, it risk of major cardiovascular linked to raised risk to the heart events, a 22% raised risk of seems. The fact checking organisation Full coronary heart disease, and a Fact did some digging and found that the 37% raised risk of heart failure. ago by Simon Wessely, former government paid £63 000 to 42 social media With each extra 114 g weekly president of the Royal College of VACCINES influencers to promote the national NHS test and trace service last year. This equates to serving these risks substantially Psychiatrists. The Department of A survey of 11 700 increased by 3%, 2%, and 12%, Health and Social Care has said roughly £1500 per influencer on average. British adults respectively, researchers reported changes needing legislation will TOUGH GIG in the journal Heart . be in a draft Mental Health Bill for found that vaccine Indeed. Not only were they trying to promote consultation next year. hesitancy was a troublesome brand (sorry, Dido) but Parliament highest among influencing people isn’t as easy it sounds. Lords act to combat forced UK “will miss targets” black people, with Only a select few people with very large harvesting of organs without urgent action social media followings—such as Love Island The House of Lords passed an The government will miss key 72% saying contestants Shaughna Phillips (below) and Josh Denzel, and professional hockey player amendment to the Medicines and targets to improve healthy they were unlikely Medical Devices Bill that aims ageing unless it acts urgently, an Henry Weir—were deemed fi t for this task. to protect medical institutions inquiry concluded. The House of or very unlikely to be vaccinated, THIS SOUNDS MORE CARROT THAN and practitioners from becoming Lords Science and Technology (HOCKEY) STICK? unwittingly complicit in Chinese Committee said ministers followed by You could say that. As part of a coordinated state sanctioned forced organ should produce a strategy for Pakistani and advertising campaign last year, the harvesting. The amendment gives how to achieve five extra healthy Bangladeshi groups government paid the celebrities to share ministers the power to regulate years of life by 2035, reporting messages of support for the NHS and the test against the use of human tissues, progress annually, and should (42%). and trace system on their social media pages. organs, and cells from overseas set out a clear plan for reducing THAT’S ONE WAY TO WIN FRIENDS. that may have been forcibly health inequalities over the next Among white British and Irish the WHAT WAS THE RATIONALE? harvested. The bill is expected to parliament. Messages on healthy The Cabinet Offi ce told Full Fact that become law in the spring. living weren’t effective, and more likely refusal rate as part of its wider communications targeted advice and interventions strategy for raising awareness of were needed, said the report. was 16% the service and the importance of [UK Household testing for covid-19, it decided to Maternity care Longitudinal work with “key micro and macro Bedford Hospital must Study] influencers to reach young improve urgently—CQC adults in a channel they Bedford Hospital’s maternity regularly engage with,” services were served with an alongside more traditional Mental Health Act reform urgent warning notice after an methods of marketing. aims to tackle poor care unannounced inspection, sparked I FEEL OLD. IS THIS TREND Major changes were announced by 14 complaints from August to HERE TO STAY? to mental health laws in England November 2020. The CQC placed Quite possibly. With vaccinations, and Wales that aim to ensure conditions on the registration diagnostic services, and health parity with physical health of Bedfordshire Hospitals Trust checks to promote, don’t be surprised services, put patients’ views after finding the service did not if we see influenza influencers and at the centre of their care, and always have enough staff with YouTestTubers professing their love for tackle racial inequalities. The the right qualifications and the NHS before long. proposals came in a government experience to keep women safe white paper, building on reforms from avoidable harm. Gareth Iacobucci , The BMJ recommended by a review of the Cite this as: BMJ 2021;372:n151 1983 Mental Health Act two years Cite this as: BMJ 2021;372:n154

the bmj | 23 January 2021 87 Frail patient alert after Norway vaccine deaths

What we need octors in Norway have The agency has investigated 13 of Azeem Majeed, professor of primary to know is how been advised to assess the deaths so far and concluded that care and public health at Imperial the observed severely frail and common adverse reactions of mRNA College London, said, “The experience death rate . . . terminally ill patients vaccines, such as fever, nausea, and of Norway shows the importance of compares with D to determine whether diarrhoea, may have contributed to monitoring the safety and effi cacy of the expected the benefi ts of vaccination outweigh the deaths of some frail patients. the new covid-19 vaccine. They are the risks of possible side eff ects, after Although for most elderly frail now being given to millions of people death rate reports indicated that vaccine side people any vaccine side eff ects will globally, including many people Azeem Majeed eff ects may have led to deterioration be outweighed by a reduced risk of who will be older and frailer than the and death of some patients. a severe covid-19 disease, for those participants in the clinical trial.” Reports of 33 suspected adverse with the severest frailty even relatively drug reactions with fatal outcomes mild side eff ects can have serious “Evidence based information” after administration of the Pfi zer and consequences, the Norwegian Institute Majeed added, “Some older people BioNTech vaccine had been received of Public Health said. And the benefi ts would be expected to die, and what by the Norwegian Medicines Agency as of the vaccine to those with a very short we need to know is how the observed at 17 January. All the people who died life expectancy may be marginal or death rate in older vaccine participants were over 75. Around 42 000 people irrelevant, it said. The institute is now compares with the expected death rate. are believed to have received the fi rst recommending that doctors consider Without this information, it’s diffi cult dose of the vaccine so far in Norway. the benefi ts and disadvantages of to draw any conclusions and give older giving the vaccine to extremely frail people evidence based information on patients (such as those whose frailty the safety of the vaccines.” MEDICAL agency reports all is ranked 8 or 9 on the Clinical Frailty The UK was the fi rst country to roll Scale or equivalent) and terminally ill out the Pfi zer-BioNTech vaccine, but the 33 people who died were over 75 patients ahead of vaccination. the Medicines and Healthcare Products Maternal deaths gap because of ethnicity is “unacceptable”

Urgent action is needed to tackle pregnancy. We need to address She added, “It is equally systemic biases contributing this to reduce deaths of women as unacceptable for women with to unequal mortality outcomes well as their babies.” pre-existing medical conditions in ethnic minority women and The report said that pregnancy such as epilepsy to receive a women facing multiple problems remained “very safe” in the lower standard of care.” and deprivation, say experts. UK. In 2016-18, of 2.2 million The authors of an analysis of women who gave birth, 547 Death in epilepsy maternal deaths in the UK, issued died during pregnancy or up to The analysis reported a by Oxford University’s Nuffi eld who died while pregnant or up a year afterwards from causes “concerning rise”—almost Department of Population to a year later. The proportion associated with their pregnancy. doubled from the previous three Health, say the pandemic is likely known to have been experiencing In that period 34 black women, years—in maternal mortality from to have worsened the disparities. multiple disadvantages when 15 Asian women, and eight sudden unexpected death in they died rose to 8%, from 6% white women died among every epilepsy. In many instances these Four times as likely to die in the 2019 report. Such women 100 000 giving birth. deaths were linked to inadequate Black women are four times often face mental ill health or The report said that these medicine management before or as likely as white women to domestic abuse and may misuse fi gures were “fundamentally during the woman’s pregnancy. die in pregnancy or childbirth, substances. unchanged” from the 2019 report Knight said, “Systemic biases says the seventh annual report Maggie Rae, president of and that, despite encouraging prevent women with complex from MBRRACE-UK (Mothers the Faculty of Public Health, responses from the NHS and and multiple problems receiving and Babies: Reducing Risk said, “Women who live in more government agencies, sustained the care they need. This needs through Audits and Confi dential deprived areas continue to be at focus was needed. to be addressed urgently, Enquiries). Asian women face a greater risk of dying during or Marian Knight, lead author for particularly since the impacts of twofold risk, and women in the after pregnancy, and many of the MBRRACE-UK and professor of social and ethnic inequalities, most deprived areas are almost complex factors underlying this maternal and child population multiple disadvantages, and three times as likely to die as increased risk need action much health at Oxford University, epilepsy are likely to have been those in the most affl uent areas. more widely than in maternity said that disparity in maternal amplifi ed during the pandemic.” The report used surveillance services, beyond the health mortality because of a woman’s Matthew Limb, London data from 2016-18 on women sector, and often long before ethnicity was “unacceptable.” Cite this as: BMJ 2021;372:n152

88 23 January 2021 | the bmj As soon as WHO “Past i nfection protects has gained a full understanding but may not stop spread” of these events, People previously infected with SARS-CoV-2 are likely the findings and to be protected against reinfection for several months any changes to but could still carry the virus in their nose and throat and recommendations transmit it to others, finds a study that regularly tested will be immediately thousands of healthcare workers. communicated The preprint reported interim results from Public Health World Health England’s Siren study between 18 June and 24 November. Organization In that period the researchers detected 44 potential and ACTION PRESS/SHUTTERSTOCK ACTION 409 new infections, equating to an 83% rate of protection Regulatory Agency has yet to publish gather all the relevant information. from reinfection, which seemed to last for at least five any data on adverse reactions to it. Norwegian authorities have prioritised months from first becoming sick. The World Health Organization the immunisation of residents in But the research team warned that early evidence from said it had been in touch with the nursing homes, most of whom are the next stage of the study indicated that some people Norwegian authorities and the very elderly with underlying medical who were themselves protected by antibodies still carried European Medicines Agency to get conditions and some who are high numbers of the virus and could infect others. more information. “As soon as WHO terminally ill. Susan Hopkins, PHE’s senior medical adviser and Siren and partners have gained a full “NOMA confi rm the number of lead, said, “We now know that most of those who have understanding of these events, the reports so far is not alarming and in had the virus, and developed antibodies, are protected fi ndings and any changes to current line with expectations. All reported from reinfection, but this is not total and we recommendations will be immediately deaths will be thoroughly evaluated by do not yet know how long protection communicated to the public,” it said. NOMA to determine if these reports are lasts. Crucially, we believe people may In a statement Pfi zer UK said, “We related to the vaccine.” still be able to pass the virus on.” are working with the Norwegian Ingrid Torjesen , London Medicines Agency (NOMA) to Cite this as: BMJ 2021;372:n167 PCR and antibody testing NHS staff who volunteered for the study were assigned to either the Assess effects of extending Pfizer positive cohort (antibody positive or prior PCR antibody test positive) or negative cohort vaccine dosing interval, expert urges (antibody negative, not previously known to be PCR antibody positive). They attended PCR and antibody A leading statistician has written diff erent dosing intervals, with all testing every two to four weeks and completed fortnightly to England’s health secretary, Matt participants receiving their second questionnaires on symptoms and exposures. Hancock, urging him to investigate the dose 21 days after the fi rst. Results In the study period 20 787 staff were included in the eff ects of extending the gap between published in the New England Journal analysis, of whom 6614 (32%) were assigned to the the fi rst and second dose of the Pfi zer of Medicine reported that effi cacy positive cohort and 14 173 (68%) to the negative. By BioNTech vaccine. between the fi rst and second doses 24 November 409 new infections were detected in the Sheila Bird, former programme was 52%, though Pfi zer has said that negative cohort, of whom 249 (79%) were symptomatic. leader at the MRC Biostatistics Unit at there is no evidence of effi cacy for the The researchers detected 44 potential reinfections in Cambridge University and a member fi rst dose after the 21 days. the positive cohort, 15 (34%) of which were symptomatic. of the Royal Statistical Society’s Some 42 were defined as possible, and two were covid-19 taskforce, said that, while “Precise pattern” defined as probable. This compared with 318 new PCR deviating from the recommended In her letter, Bird said, “As noted by positive infections (249 symptomatic) and 94 antibody dosing interval of three weeks could the British Society for Immunology, seroconversions in the negative cohort. be the right decision that saves more we do not know the precise pattern for The study team said that the results gave no insight into lives, ministers should be sure of the how eff ectiveness for Pfi zer BioNTech’s the effects of vaccines or the more transmissible variant, consequences. mRNA vaccine wanes after the fi rst but these factors will be considered in future analysis. In a 30 December letter, NHS dose if the second is not administered Elisabeth Mahase, The BMJ England told healthcare staff to as in Pfi zer’s trial.” Cite this as: BMJ 2021;372:n124 prioritise giving the fi rst doses of She said the UK’s rapid rollout of vaccine (either Pfi zer-BioNTech or the Pfi zer vaccine meant that 800 000 20 787 staff ( female, white, median Oxford-AstraZeneca) to as many people could be randomised in just 84% 88% age 45.9) were included in the analysis, of whom 6614 people as possible on the priority list. two weeks, enabling researchers to Second doses should then be given up ascertain outcomes such as covid (32%) were assigned to the positive cohort and to 12 weeks after the fi rst. diagnoses and related hospitalisations. 14 173 (68%) to the negative cohort. By 24 November Unlike the Oxford vaccine trials, Elisabeth Mahase, The BMJ 409 new infections were detected in the negative cohort however, the Pfi zer trial did not test Cite this as: BMJ 2021;372:n162 the bmj | 23 Janaury 2021 89 NEWS ANALYSIS When to start invasive ventilation is the “million dollar question” in covid care

Options for ventilating covid-19 patients have expanded since the fi rst wave of the pandemic, but doctors are unsure of the best management pathway, because evidence is lacking. Ingrid Torjesen reports

uring the fi rst wave of TRENDS IN CRITICAL CARE IN ENGLAND, WALES, AND NORTHERN IRELAND the covid-19 pandemic Second wave First wave almost three quarters (patients admitted 1 Sep (patients admitted to 31 of patients who were to 31 Dec 2020) Aug 2020) D admitted to critical care Total covid hospital admissions* 142 553 129 459 received invasive ventilation, and Covid patients admitted to critical care 10 149 (7.1%) 10 935 (8.4%) one in two received it within 24 hours Discharged 4927 (48.5%) 6623 (60.6%) of admission. Now the numbers are Died 2994 (29.5%) 4311 (39.4%) around half that. Most receive non- Still receiving care 2228 (22.0%) 1 (0.0%) invasive respiratory support instead, Percentage of patients receiving invasive 24.9% (2216/9563)** 54.3% (5866/10 935) such as high fl ow nasal oxygen or ventilation within first 24 hours continuous positive airway pressure Advanced respiratory support at any point 3427 (43.7%) 7878 (72.1%) (CPAP) by machine. Basic respiratory support only 4073 (51.9%) 2790 (25.5%) No respiratory support 343 (4.4%) 264 (2.4%) The pace of the move away from Mean age of critical care patients (years) 60.4 58.8 invasive ventilation varies among Mean length of hospital stay before intensive 3.0 2.5 hospitals and has been driven by care admission (days) greater clinical experience of treating Patients requiring renal support 1107 (14.1%) 2926 (26.8%) covid patients, by data associating Duration of critical care among survivors 612 invasive ventilation with higher (median days) mortality, and by the ventilation Duration of critical care among non-survivors 10 9 options available. (median days) When to move patients from Advanced respiratory support: invasive ventilation, bilevel positive airway pressure (BPAP) by trans-laryngeal tube or tracheostomy, continuous facemask CPAP to a ventilator “is positive airway pressure (CPAP) by trans-laryngeal tube, extracorporeal respiratory support. Basic respiratory support: >50% oxygen by facemask, close observation because of potential for acute deterioration, physiotherapy and suction really the million dollar question,” to clear secretions at least two hourly, recently extubated after a period of mechanical ventilation, mask or hood CPAP/BPAP, non-invasive said an intensive care consultant ventilation, CPAP by tracheostomy, intubated to protect airway. from Surrey, who asked to remain Adapted from Intensive Care National Audit and Research Centre report on covid-19 in critical care: England, Wales, and Northern Ireland, anonymous. “We’ve had people who 31 December 2020. have had CPAP for weeks, maybe *Total number of patients from https:/ /coronavirus.data.gov.uk/details/healthcare . even a month, but they prefer to carry **Data not available for all patients. on with it than go on a ventilator. We haven’t really had good data to be moving earlier towards intubating We haven’t had consultant in intensive care medicine tell us what the right thing to do is. I them, I think.” good data to at King’s College London. “The hope that’s coming through quickly, Mervyn Singer, professor of tell us what the RECOVERY-RS trial will address that because then I would be more intensive care medicine at University right thing to do partly,” he said. This trial compares confi dent in my approach.” College London, said, “The argument is. I hope that’s high fl ow nasal oxygen and CPAP with Annemarie Docherty, honorary is that if you persist for a long time, just coming through standard care (normal oxygen through consultant in critical care and the heavy breathing might cause lung a mask or nasal cannula), and patients researcher at the University of damage of its own. There are one or quickly, will be given invasive ventilation if Edinburgh, agreed. “We’ve all adopted two hospitals that still adamantly say because then I clinically required. CPAP and non-invasive ventilation that you need to invasively ventilate would be more But Singer said, “The question I on no evidence, maybe an anecdote, everybody and that you shouldn’t be confident in my would have loved RECOVERY-RS to which is the fi rst time that we’ve ever non-invasively ventilating.” approach ask is when the right time is to start done anything sort of on Twitter, and Surrey consultant invasive ventilation, because in it’s not innocuous,” she said. Trial under way our practice we start relatively late “We’re seeing lots of patients No good evidence exists from clinical because of resource limitations.” with injuries to their lungs just from trials on the use of non-invasive The danger in providing such non- the non-invasive mask—so there’s respiratory support such as high fl ow invasive forms of respiratory support defi nitely a group of patients to whom nasal oxygen outside critical care on a medical ward is that, eventually, we are doing harm, and we should settings, said Manu Shankar-Hari, a when patients don’t respond or

90 23 January 2021 | the bmj We’re seeing lots of patients with you’re giving positive pressure Surrey seeking the million dollar injuries to their lungs from the ventilation, which also has a negative answer. “In the fi rst wave everyone non-invasive mask—so there eff ect on the kidney through an was understandably panicked until are patients to whom we are increase in renal venous pressure and we knew what the best thing to doing harm Annemarie Docherty congestion. There is also a tendency to do was, so they were doing lots of keep patients on ventilators quite dry unusual things, which made me very There are hospitals that still to ‘protect the lungs,’ and that too can stressed,” said the consultant. “I say you need to invasively compromise renal perfusion.” didn’t like it. People were desperate, ventilate everybody and you perhaps just keen to help, but they shouldn’t be non-invasively Oxygen supplies were doing odd things which were High fl ow respiratory support such as potentially harmful.” ventilating Mervyn Singer CPAP also requires more oxygen than The danger of non-invasive invasive ventilation or a facemask, New variant support on a medical ward is and supplying oxygen for patients The recent large rise in the number that when patients require more with covid-19 is causing problems of covid cases has been attributed to for some hospitals. Already this year the greater transmissibility of a new invasive support they are much St Helier Hospital in Sutton, south variant of SARS-CoV-2 that was fi rst more unwell Manu Shankar-Hari London, has had to transfer some identifi ed spreading across London patients to other hospitals because and the south east of England. So they deteriorate and require a more its ageing infrastructure could not far no evidence has shown that this invasive form of respiratory support, provide suffi cient quantities. variant is more virulent or pathogenic they are much more unwell, said A spokeswoman for Epsom and St or that it leads to a greater proportion Shankar-Hari. And he pointed out Helier University Hospitals Trust said of patients needing intensive care, and that it’s often younger patients who that a new vaporiser had now been the Intensive Care National Audit and initially receive respiratory support on installed at the hospital that would Research Centre hopes to be able to medical wards, because they’re more treble the supply of piped oxygen confi rm this. able to cope with the symptoms when available to patients. Its director, Kathy Rowan, said, admitted to hospital, at least initially. While more patients are in “We may be able to look by region and If the strain on hospitals continues hospital now than in the fi rst wave, time period, to see if there were any to increase it will be these patients on in some ways working conditions diff erences in patient characteristics medical wards who are at particular are less stressful, as there is no and outcomes in London and the risk, Docherty warned. “Probably longer a shortage of personal south east creeping in at the point the biggest [additional] mortality will protective equipment, and doctors where we felt the new variant became come among patients who can’t get have some evidence and experience dominant.” into intensive care because they are to inform their decisions, said the Ingrid Torjesen , London not fl agged as deteriorating, because intensive care consultant from Cite this as: BMJ 2021;372:n121 there’s not enough people to review them,” she said. “When patients are intubated, they’re a bit more stable.”

Renal support The reduction in the proportion of patients receiving invasive ventilation has been accompanied by a fall in the proportion requiring renal support. This may be because invasive ventilation can aff ect the kidneys in a number of ways, said Singer. Patients with covid-19 require heavy sedation for invasive ventilation, and these drugs often cause a dramatic drop in blood pressure. Vasopressor catecholamines, such as norepinephrine, are then given to elevate the blood pressure and can have an adverse impact on the kidneys by aff ecting intrarenal perfusion. Furthermore, said Singer, “When you put somebody on a ventilator NEIL HALL/PA the bmj | 23 January 2021 91 THE BIG PICTURE Gothic sanctuary gives hope for the future

To the sound of organ music, hundreds of people aged over 80 receive their Pfi zer-BioNTech covid- 19 vaccination inside the grandeur of Salisbury Cathedral transept. On Saturday 16 January the cathedral was turned into a pop-up vaccination hub by Sarum South Primary Care Network. Its co-clinical director Dan Henderson said around 1000 patients and staff were vaccinated in one day. Nicholas Papadopulos, the dean of Salisbury, told the Guardian, “This place has stood here for 800 years to give glory to God, and to serve the city and the region. What better way could there be to do that than hosting Salisbury’s stage in the vaccination programme. It is absolutely wonderful.” Lichfi eld and Blackburn cathedrals have also opened their doors to help the vaccination drive, along with race courses, sports halls, and other venues closed because of the current lockdown. From the start of this week, across the UK people aged 70 and over and the clinically extremely vulnerable also began to be invited to join the 3.8 million people who have so far received their fi rst vaccine dose. The government has pledged to off er a vaccine to everyone over the age 70, all health and social care workers, and clinically extremely vulnerable people by mid-February. Alison Shepherd, The BMJ Cite this as: BMJ 2021;372:n155

92 23 January 2021 | the bmj the bmj

| 23 January 2021 93

STEVE PARSONS/PA EDITORIAL Covid-19 and moral distress in medicine Simply working harder cannot resolve the confl icts caused by responsibility without autonomy

octors are accustomed The slow tightening of the garotte to diffi culty, to long of underfunding has created ideal hours, high stress, conditions for moral distress, heavy responsibility. sapping the joy from the doctor- D The job involves patient relationship, depleting helping people navigate life’s the rewards of clinical medicine, gravest challenges: death and dying, swapping pleasure for grinding suff ering, loss, and grief. For as long distress. Plenty of anecdotal evidence as there have been healers though, suggests it contributes to early this has been part of the territory. retirement and to a general crisis of But as the profession draws deeply retention in medicine more broadly. on its resources to respond to covid- 19, a new concept is entering the Ethical conflict mainstream: moral distress.1 2 And The NHS needs to be properly it is shining a light on the deepening resourced. We must not allow structural affl ictions of medicine in permanent underfunding to place the UK, problems that predated covid health professionals in unending and, unless they are resolved, will ethical confl ict. In the meantime, endure long beyond it. JONES/PA VICTORIA doctors must learn to recognise Moral distress is a psychological Situations If moral distress is sustained it can their own moral distress, identify its harm arising when people are forced strongly lead to moral injury—a deeper or sources, and understand that they are to make, or witness, decisions or linked to more enduring harm that can lead to not at fault. Open discussion and peer actions that contradict their core moral distress burnout and psychological trauma. support are essential, acknowledging moral values. While exposure to include the The term moral distress is that simply working harder cannot the suff ering of others can lead to increasingly used to describe the resolve the confl icts born from distress, it is not necessarily moral rationing cumulative unease experienced responsibility without autonomy. distress. But if serious and sustained or triaging by doctors struggling to fulfi l their Schwartz rounds 6 can play a vital resource constraints mean doctors of scarce primary professional obligations in role here, but only if doctors have cannot meet patients’ needs, it can resources such once highly resourced medical settings. time to attend. Doctors must also be open the door to moral distress. If you as ventilatory During the covid pandemic, supported when making challenging know that delays to treatment will support situations strongly linked to moral ethical decisions, including ensuring likely lead to serious harms, consider distress include the rationing or access to ethical and legal expertise. the eff ect of repeatedly being forced triaging of scarce resources such Doctors must be psychologically—and to place patients on ever lengthening as ventilatory support, intensive contractually—permitted to make waiting lists. Moral distress arises in care beds, or protective equipment; time for refl ection and self-care. They the gap between what professional de-prioritising patients who have cannot run on fumes indefi nitely. judgment dictates should be done and substantial non-covid related health Revolutions are said to eat their what healthcare systems permit. It is needs and who are likely to be children. Tragically, the same is also associated with powerlessness— harmed by treatment delays; being true of dysfunctional organisations. the impossibility of altering the barred from work by covid rules when They force virtuous employees into situation so that professional acts colleagues and patients desperately intolerable positions as professional can accord with professional values. need help; making harrowing ethical codes collide with institutional choices without appropriate support; diktat often rooted in resource Guilt, shame, anger Julian Sheather , and denying patients access to vital constraints. Covid has highlighted The term entered health through specialist adviser social and emotional support because how essential the NHS is to our on ethics and nursing ethics 4 and found traction of infection control requirements. The collective wellbeing. It is beyond human rights among health professionals working list goes on. time to fund it eff ectively. Until then, JSheather@ in humanitarian crises, where bma.org.uk It will be said that covid is all health professionals need support professional norms have at times Helen Fidler, exceptional. That every health in managing moral distress—before been profoundly challenged. Typical deputy chair of system in the world is struggling. its eff ects become too toxic. emotional responses to moral distress UK Consultants That there will be a reset. But covid Cite this as: BMJ 2021;372:n28 include feelings of guilt, shame, Committee, BMA, is exacerbating existing pressures 5 Find the full version with references at anger, and, in extreme form, disgust. London rather than creating new ones. http://dx.doi.org/10.1136/bmj..n28

94 23 January 2021 | the bmj EDITORIAL Vaccinating people who report allergies Most patients can be reassured and vaccinated

or its components. Only one of the se of the Pfi zer- excipients in the Pfi zer-BioNTech BioNTech covid-19 vaccine is a known potential allergen, vaccine in people polyethylene glycol (PEG 2000), and with a history of this is an inactive ingredient in more U severe allergies than 1000 medications. The Oxford- was temporarily stopped in the AstraZeneca vaccine does not contain UK after two healthcare workers PEG 2000 so remains an alternative experienced anaphylactic for people with a history of allergy reactions in early December. The to this ingredient. 2 However, there is Medicines and Healthcare Products some cross-reactivity between PEG Regulatory Agency (MHRA) stated and polysorbate 80, an ingredient in that “any person with a history of the Oxford-AstraZeneca vaccine, so anaphylaxis to a vaccine, medicine, evaluation by an allergy specialist may or food should not receive the be advisable before vaccination in Pfi zer/BioNTech vaccine.”1 anyone with a suspected PEG allergy However, MHRA revised its history. 14 Allergy is antigen specifi c, position on 30 December after careful although people with one drug allergy consideration based on enhanced TESSON/ANDBZ/ABACA/PA may be more susceptible to other drug surveillance of over one million doses and immunologically mediated History allergies than the general population.15 of the vaccine in the UK and North adverse eff ects of medicines. 6 of severe America—including in jurisdictions Before the Pfi zer-BioNTech vaccine allergy does Lines of communication where people with serious allergies contraindication was announced, not preclude The best approaches to vaccine were never barred from receiving surveys reported that the public’s vaccination hesitancy include “science, the vaccine.2 It found no evidence of willingness to be vaccinated with one education, access, civil discourse, and an increased risk of anaphylaxis to of the covid vaccines ranged from unless that debate,”16 not coercion or censorship. the Pfi zer-BioNTech vaccine among 67% to 90%.10 That estimate has been allergy is to the Vaccinators should be prepared to people with serious but unrelated fl uctuating, however. In one study vaccine or its provide information, explain the allergy histories and advised that only conducted from April to May 2020, components diff erence between severe, moderate, people who had an allergic reaction 90% of parents and guardians of and mild allergies, and clarify MHRA’s to the fi rst dose of this vaccine, or who young children said they would accept decision making. People’s views previously had reactions to any of its a vaccine,11 while in June, a similar about covid vaccines may transfer components, should not receive it. questionnaire reported potential to other vaccines, so maintain open 12 uptake to be roughly 70%. By July, Rebecca E Glover, lines of communication, and if Risks to UK rollout another UK study found that 64% head of economic, vaccination is declined, then reassure This is welcome news for people of participants were “very likely” to social, and political people that they can return. with severe allergies, but risks to accept a vaccine, with 27% unsure.13 sciences, London It may still be possible to safely the UK rollout of covid-19 vaccines Vaccine hesitancy seems to be highest School of Hygiene vaccinate people with allergies to remain because of the widespread in ethnic minority populations.10 and Tropical vaccine components.17 Allergists can dissemination of the allergy Given that allergies are commonly Medicine assess patients who report allergy to contraindication in the media. reported, and public acceptance for a rebecca.glover@ a vaccine, injectable medication, or The reporting of allergy as covid-19 vaccine seems to be waning, lshtm.ac.uk PEG and triage them into those able synonymous with anaphylaxis is uptake of the Pfi zer-BioNTech vaccine Robert Urquhart, to be vaccinated with the routine chief pharmacist concerning, since in the UK and may be lower than hoped. Healthcare 15 minutes of observation, those US 20-40% of the population has workers may also be reluctant to Joanna Lukawska, requiring 30 minutes of observation, consultant allergist, at least one allergic disease,6 - 9 vaccinate people with any history of and those who require skin testing University College an umbrella term for multiple allergies. It is therefore essential that to PEG and polysorbate before London Hospitals clinical syndromes (allergic those planning and administering vaccination. Our hospitals have Kimberly G rhinitis, anaphylaxis, allergic covid-19 vaccine programmes Blumenthal, already launched such services and asthma, conjunctivitis, eczema and understand the evidence. allergy specialist, evaluation is ongoing. contact dermatitis, food allergy, Importantly, history of severe Harvard Medical Cite this as: BMJ 2021;372:n120 and urticaria) caused by food, allergy does not preclude vaccination School, Boston, Find the full version with references at aeroallergens (including pollen), unless that allergy is to the vaccine Massachusetts http://dx.doi.org/10.1136/bmj..n120 the bmj | 23 January 2021 95 Pandemic action Biden has been regularly briefed on the pandemic by respected scientists, including Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, who had been sidelined by Donald Trump’s administration. Biden has set up a scientifi c advisory board, and reportedly he demands regular updates from his staff on how vaccination planning is going, although staff ers have complained that Trump’s offi cials have been slow to provide data. Biden will ask all Americans to

CHIP SOMODEVILLA/GETTY IMAGES wear masks for his fi rst 100 days in US HEALTH offi ce, a major change from Trump, who rarely wore one and refused to endorse the practice. But the How Joe Biden plans to heal president has limited authority over mask wearing. It is the states that healthcare in America bear most of the responsibility for public health measures, and mask mandates vary across the country. The world’s highest number of covid deaths, a broken system, and a mess Biden has said he’ll urge local and of unhelpful regulations imposed by his predecessor—Joanne Silberner state governments to enact their own examines what the new president can do to meet the challenges ahead mandates and will require mask wearing on federal property and on interstate transport. uring his presidential some Democrats lean towards the The Trump With vaccines, his administration campaign the conservative side, and some types of administration is grappling with an uneven rollout Democratic candidate legislation require a “supermajority.” has left “bird that the Trump administration had Joe Biden laid out some Health experts are divided on the droppings” basically left up to individual states, D clear goals: expand fate of two of the president’s more that must be which are getting free vaccines but access to health insurance, simplify ambitious plans: allowing an little funding for distribution. dealt with to the notoriously complex healthcare insurance plan run by government to Biden has promised 100 million system, cut the costs of prescription compete against private insurers in have a clean vaccinations in his fi rst 100 days. drugs, and expand access to abortion. the Aff ordable Care Act (also known slate Politico reports that the president has Then covid cast a shadow on the as Obamacare, introduced under Chris Jennings, serious concerns about delivering whole race for the White House. Barack Obama who Biden served Biden adviser on this, given the lack of structure As Biden prepared to take the as vice president) and lowering the and resources offi cials encountered oath of offi ce on 20 January he faced age of eligibility for Medicare, the in the transition period. He has also the immediate challenge of dealing government insurance programme said he’ll push to get fi rst doses with the pandemic buff eting the US for people aged at least 65. administered as soon as they can be and reversing years of undercooked But the Senate majority does made and distributed, rather than protection and prevention measures. give Biden free rein to pick his holding back stocks for second doses. But he does have one thing on his own people for top posts without Five days before his inauguration, side that he might not have expected having to compromise with the Biden warned Americans that things at the beginning of the campaign: Republicans. He may be able to would get worse before getting better. control of the US Senate, which the open up and make some changes He said he’ll be asking Congress for Democrats won in a closely fought to Obamacare that will nullify a another $20bn to speed up federal 5 January run-off election in Georgia. pending Supreme Court decision vaccination eff orts, and is looking to With his party now in control of the that could otherwise threaten its extend insurance subsidies to more of White House, Senate, and House of viability. the middle class. Representatives, Biden has a good There are also several dozen chance of getting at least some of his more health related policy changes Abortion rights agenda approved. that Biden has the power to make Three days after his inauguration in Still, the Democratic majorities in without Senate approval. But fi rst he 2017 Trump announced the revival the House and Senate are slim, and has to confront covid-19. of the “Mexico City plan,” sometimes

96 23 January 2021 | the bmj known as the global gag rule. In its be dealt with to have a clean slate. usual form this plan blocks family One of the most worrisome for planning clinics anywhere from the scientifi c community is a rule receiving federal family planning that prohibits the Environmental funding if they provide abortion or Protection Agency from considering abortion counselling. the results of studies on pollution and Trump’s announcement continued other environmental issues unless a game of see saw that has lasted more the raw data are available. And since than 30 years. First implemented by most of the relevant research relies Ronald Reagan in 1984, Democratic on confi dential patient information, presidents cancel it the fi rst chance the need for privacy and anonymity they get. Republican incumbents would mean many of the most reinstitute it. Trump’s version—the conclusive studies would be off limits. harshest yet—banned not just family Another recently fi nalised rule

planning funding to any clinic that requires the agency to ignore the ALEX WONG/GETTYIMAGES even mentioned abortion to its economic costs of illnesses and Joe Biden receives his second covid vaccination on 11 January patients but also funds earmarked deaths when totting up the total for treating HIV, malaria, and other costs of air pollution. Which brings Biden has He expects to see a renewed drive infectious diseases. The policy us to climate change. Citing his promised 100 to fi ght the opioid epidemic, which quickly led to reduced access to family “America First” policy, Trump started million covid has been overlooked during the planning services in low income the process of withdrawing the US pandemic. vaccinations countries. Biden has promised to from the Paris Agreement early in in his first On 8 January the Trump cancel it early in his presidency. his presidency. The withdrawal was administration permitted the state He has also promised to strengthen fi nalised on 4 November, the day after 100 days of Tennessee to fundamentally the Aff ordable Care Act, Obama’s voting for the presidential election change the fi nancing for Medicaid. expansion of health insurance, closed. Biden has promised to rejoin The new programme gives the state which Trump vowed to repeal and on the fi rst day of his presidency. more power over how federal funds replace. Throughout his presidency are spent, while putting a cap on Trump repeatedly promised a new Fixing the healthcare “system” total funding, regardless of need. and better plan but never introduced The Department of Health and Such an approach could destroy the one. He was, however, able to Human Services (HSS) runs the programme. The New York Times weaken Obamacare in several ways, Food and Drug Administration, the reported that the current head of including cutting funding for public Centers for Disease Control, various Medicaid has been pressing states information about the insurance government health insurance to sign contracts that would make it programmes, allowing people to programmes, drug treatment diffi cult for them to alter any special buy insurance that didn’t off er all agencies, and more. During his deals they’ve made with the Trump the benefi ts covered by the act, and tenure Trump often second guessed government, which could make the allowing insurance policies that did or ignored advice from the agencies, Tennessee plan diffi cult to cancel. not cover pre-existing conditions. and morale throughout HHS is low. One of Trump’s rare bipartisan Don Berwick, a senior fellow actions, taken just before the end of Back on the world stage at the Institute for Healthcare his presidency, was to sign legislation The Trump presidency had seen Improvement and former acting that eliminates “surprise billing,” the US step back from global head of Medicare and Medicaid (the as of 2022. This is where a patient health leadership like never healthcare programme for people goes to a hospital that is part of before, epitomised by last July’s on low incomes or with disabilities), their insurance plan but where announcement that he was pulling thinks the way to get things moving the individual anaesthetist or the the US out of the World Health again is to start with morale. “From surgeon, say, may not be covered by Organization. what I’m hearing, there’s a level of that plan. Patients in the US regularly But the withdrawal process takes demoralisation among people who’ve wake up from surgery to bills of a year, and Biden promised to cancel spent their careers trying to make thousands or tens of thousands of the pullout on his fi rst day in offi ce. good federal programmes that is dollars for care that would have He will also put back in place a job profound,” he says. entailed only a small copayment had eliminated by Trump, a high level HHS will need to create new the doctor been in the plan. appointment for global health programmes, bolster old ones, and Now Biden’s people get to write the security and biodefence. reverse some Trump changes, rules for one of the few health laws Chris Jennings, a long time says Berwick, who was to come out of the Trump years health adviser to Democratic also an adviser that benefi ts patients. administrations, told Kaiser Health to the Biden Joanne Silberner, US coronavirus News that the Trump administration presidential news editor, The BMJ has left “bird droppings” that must campaign. Cite this as: BMJ 2021;372:n142 the bmj | 23 January 2021 97 THE BMJ INTERVIEW Andrew Pollard: How the Oxford- AstraZeneca covid-19 vaccine was made

The leader of the clinical trials in the UK, Brazil, and South Africa tells Elisabeth Mahase how the vaccine came to be, how dosing was worked out, and whether it will stand up to the new variants

ndrew Pollard was in In light of the emerging new variants, that’s why surveillance is going to a French taxi when how much would the virus need to be critical in the year ahead to make he realised what was mutate to make a vaccine ineffective? sure that we’re not in a position coming. On his way to The vaccines that are currently in where, at the point of population A a meeting to present late stage development, or that immunity, the virus escapes. And if it his group’s research on typhoid, are authorised for use, use a large does, we need to know that, so that he happened to share a ride to the part of the spike protein, which is we can redesign the vaccines. airport with John Edmunds of the a very big protein. So, the immune I realised UK Scientifi c Advisory Group for response is against lots of diff erent How easy would it be to redesign a that our lives Emergencies, and they discussed a bits of that protein. This means that, vaccine to counter mutations? new virus emerging in China. to completely escape, the virus has For the RNA vaccines and the viral were going “He had a fairly catastrophic view to mutate quite a lot—so this may vectors it’s relatively straightforward, to change of what was likely to happen to the give some advantages against escape because you just have to synthesise a completely. world from that point,” says Pollard. happening in the short term. new bit of DNA in our case—or RNA Straight away “That was an incredibly chilling Mutants can arise that escape in [the Pfi zer and Moderna] cases— I was thinking moment because I realised that our from the vaccine when there’s a lot and then insert that into the new that we needed lives were going to change completely of pressure on the virus to change. vaccine. Then there’s a bit of work to a vaccine during 2020. Straight away I was At this moment hardly anyone in do to manufacture the new vaccine, thinking that we needed a vaccine.” the world has been vaccinated and which is a reasonably heavy lift. But A multi-award winner, Pollard hardly anyone in the world has had the same processes would be used. has become one of the faces of the disease, even though it feels like a And there will almost certainly world’s pandemic vaccine eff ort. As huge impact. Most people have not need to be some testing, whether it’s chair of the UK’s Joint Committee on had an infection yet. And so, the virus in animals or humans, to show you Vaccination and Immunisation and is not under huge immune selection. can still generate immune responses, the European Medicines Agency’s When lots of people have had and then the regulator would have to scientifi c advisory group on vaccines, disease or been vaccinated, the approve that new product. he knew better than anyone the virus is going to come under a lot of size of the task ahead. But, as an pressure, and when that happens SARS-CoV-2 is new to us, but it’s from experienced climber (he was deputy some viruses just can’t compete a known family of viruses. Was this leader of the successful 1994 British against that immunity. helpful in getting the vaccine effort off Mount Everest Medical Expedition), Will it mutate instead? With this the ground? he knows that mountains are there to coronavirus we don’t know the This has been the great thing about be conquered. answer to that question yet, and this being a coronavirus, because we

WHAT HAS IT BEEN LIKE TO HAVE BEEN IN THE INTERNATIONAL SPOTLIGHT?

To be honest, the year has been in many ways not exceptional . . . we’ve been doing the mundane stuff we normally do—it’s the day job. And yet you step into the outside world, and suddenly you realise that everyone’s watching you and wants to know exactly what you’re going to do next and why you did what you did yesterday. I think in many ways it’s been a completely normal year in vaccine development. What’s been different about it has been much longer hours and then immense pressure on the team, because of that external spotlight on us and the urgency of a pandemic.

98 23 January 2021 | the bmj STEVE PARSONS/PA STEVE The Duke of Cambridge meets Pollard last June during a visit to the Oxford Vaccine Group’s facility at the Churchill Hospital in Oxford

know so much about the biology of planned a one dose strategy, and Absolutely some people who were vaccinated these viruses and particularly how to that was really going back to those fascinatingly a month after the fi rst dose and make vaccines against them. discussions with the modellers back those who some people, because they’d been Over the past 20 years we’ve had in February, where it looked as if the had a longer vaccinated before the manufacturing two huge outbreaks of coronaviruses: UK would be struck by a huge fi rst dose interval happened, who had to wait almost one back in 2002, which was the wave of disease that was devastating. three months for their second dose. SARS coronavirus with about an My thinking then was that, if you actually make So, we’ve got this spectrum 11% mortality, and then about eight waited for two doses, we’d have much better of people between four and 12 years ago the MERS coronavirus, enormous numbers of inpatients immune weeks who were vaccinated, and which had a 35% mortality. Because and deaths—whereas, if you got one responses the regulator has approved that those were so horrifi c and there were dose, we might be in a much better after the interval because there’s a lot of around a thousand cases on each position to manage. second dose data. Absolutely fascinatingly, and occasion, lots of eff orts went into So, the original strategy when we perhaps predictably, those who making vaccines, which were mostly set out in our trials was just a single had a longer interval actually make tested in animals. dose. But we had a subgroup where much better immune responses We found out from those studies we gave two doses, and we found in after the second dose. We see that that making immune responses that group that we ended up with with other vaccines, such as the against spike protein could result much better immune responses. cervical cancer vaccine. in protection. My colleague Sarah We went back to the regulators and The half dose has an advantage of Gilbert was already working on agreed that we’d move to a two dose dose sparing, but the vast majority of a MERS coronavirus vaccine just strategy, with the idea that you the data that we have is around two before the [current] pandemic. It hopefully get some protection from full doses. For the regulator, that’s was essentially switching the spike the fi rst dose but that the second the compelling data package. The protein from the MERS coronavirus to dose would give better and perhaps downside [to a half dose strategy] the spike protein of SARS-CoV-2. more sustained protection. is that it’s a bit more complicated to As a result, we had to then deliver for a practitioner who has to All the current vaccines are two dose manufacture enough doses to give decide whether this is a half dose regimens, and the dose interval has the second dose, and that inevitably person or a full dose person. been intensely debated. Is there a led to a delay in having the second case for a one dose strategy or two dose available. That’s given us this Why does a longer dose interval seem half doses? really interesting phenomenon in to provide a better immune response? The two dose strategy for our vaccine our trial, which wasn’t intended at It’s almost certainly because the is actually a change. We originally the beginning, where we [now] have immune response matures after you

the bmj | 23 January 2021 99 give a fi rst dose, and, if you give it long enough to mature, you get a very good memory booster response to the second dose. If you have the second dose too early the immune response hasn’t matured fully: there’s a bit of negative feedback so it doesn’t overshoot the mark, and you get a much smaller response to the second dose.

Are more data being collected on these dosing regimens? The analysis that has led to the BLATCHFORD/SHUTTERSTOCK GREG The Oxford /AstraZeneca vaccine was developed at the the Jenner Institute (above) UK authorisation of the [Oxford- AstraZeneca] vaccine was an interim analysis, and so we still and actually, for our studies, We still just the scale of what we’ve been have 23 000 people being observed we’ve got fi ve publications on the have 23 000 doing as a small university research in my trials in the UK, Brazil, and clinical trials. All of the data are people being group: we just couldn’t do everything South Africa. We’re accumulating out there for people to see. And it’s observed that maybe the big pharmaceutical more data, and that may be very a bit perplexing that there’s this in my trials companies could. important because we’ll have data constant accusation of a lack of in the UK, on the new variant and hopefully transparency. It’s actually something What can the UK learn from the covid-19 effi cacy against the new variants, that, as a university, we’re absolutely Brazil, and vaccine development? both here and in South Africa. committed to and have been doing South Africa We could be better set up in the UK We don’t have any new trials all the way through. than we are, and we’re one of the best planned to look at diff erent regimens What we normally do with our countries in terms of being able to here in the UK, but we’re moving on research projects is write a protocol stand up multiple trial sites. In the to new trials to evaluate diff erent age paper, and BMJ Open is one of the UK we have 19 trial sites helping run groups—for example, children. places we usually launch those. I the trials, and they were set up in have to say that, in this pandemic, about three weeks. They’ve done an Why did your group wait longer than we’ve just been a bit busy. We didn’t amazing job in setting up, but they the other trials to release its phase III focus on publishing a protocol paper didn’t have a dedicated infrastructure protocol? as we’ve gone along; we just said already in place. It required a lot of All the way through I think we’ve that we’ll put it in the publications work to get that up and running. followed the normal processes, when we get there. But I think it’s There are multiple vaccine centres already established in the US, where they’re doing vaccine development, vaccine research and evaluation, and laboratory work on testing immune responses. We have very little of that in the UK, so [one thing is] having more of this established, well funded, and running so that capacity is there on the research side. And then there’s the clinical delivery side. I think that one of the real stresses for everyone was being able to fi nd the staff , to fi nd the space and the training required to stand up a large scale study. If we were doing more of this day to day, I think we could do even more than we were able to do—and more quickly. Elisabeth Mahase, clinical reporter, The BMJ [email protected] Andrew Pollard has recused himself from the JCVI’s meetings and discussions on covid-19 to prevent any conflict of interest STEVE PARSONS/PA STEVE Pollard receives his own covid-19 vaccine from Sam Foster at the Churchill Hospital in Oxford on 4 January Cite this as: BMJ 2021;372:n86

100 23 January 2018 | the bmj