Covid3

A YouGov poll in December showed that 85% of Britons thought they had insufficient information about Covid-19 vaccines, their safety, and so on. Welcome to Coronavirus – Part 3. It's big, but then so are the issues surrounding Covid-19.

V-day finally arrived
At 06:30 GMT on Tuesday 8 December 2020 at University Hospital, Coventry, a 90-year-old woman originally from Enniskillen, Northern Ireland, became the first person in the world to receive the Pfizer-BioNTech Covid-19 vaccine outside of clinical trial conditions. Three weeks later, on Tuesday 29 December, she received her second vaccination.

Margaret Keenan, whose name is forever destined to be the answer in various quizzes, turned 91 the following week. The jolly grandmother turned up for her jab and global photocall in a natty Christmas penguin T-shirt and said it was, ‘… the best early birthday present I could wish for.’ She urged everyone, ‘Go for it because it’s free.’ The second recipient was an 81-year-old man with the improbable name of William Shakespeare from – I kid you not – Warwickshire. Journalists insisted the jab was ‘much ado about nothing.’ Everybody wanted their say on this extraordinary occasion. The UK’s ever-optimistic Health Secretary, Matt Hancock, wanted all to know that he had already booked his 2021 holiday – in Cornwall. It was left to the ever-realistic Sir Patrick Vallance, the Chief Scientific Adviser to the UK government, to caution, ‘It may be that next winter, even with vaccination, we need measures like masks in place. We don’t know yet how good all the vaccines are going to be at preventing the transmission of the virus.’ Thus, this historic, triumphant and even jocular day marked the official start of the UK's largest ever mass vaccination programme.

The Big three vaccines
On 4 January, Brian Pinker, an 82-year-old dialysis patient, became the first person to receive the Oxford-AstraZeneca vaccine. Then on 8 January, the Pfizer and Oxford vaccines were joined by one developed by the US company Moderna after the UK regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), also gave it emergency MHRA Regulation 174 approval. The UK has ordered an extra 10 million doses of this vaccine, taking its total order to 17 million, but Moderna supplies are not expected to arrive here until the spring.

Will the Big three soon become the Big four? On 28 January, Novavax, the US biotech company, reported that, in a UK-supported trial with over 15,000 people, its new vaccine was 89.3% effective against the Covid-19 virus. In addition, it had an efficacy of 85.6% against the UK mutant and 60.0% against the South African. The vaccine must now be assessed and approved by the MHRA before being rolled-out later this year. The UK government has already secured 60 million doses. This 2-shot vaccine, to be made in Stockton-on-Tees, is stable for up to 3 months in a domestic refrigerator. It is looking good.

Or could it even be the Big five? On 29 January, Johnson & Johnson, the US pharmaceutical giant, announced that its new vaccine was 66% effective at preventing moderate to severe Covid-19, 28 days after vaccination. However, it was less effective against the South African variant. Like the vaccine from Oxford-AstraZeneca, the Janssen jab is an adenoviral vaccine, as opposed to the mRNA vaccines produced by Pfizer and Moderna. It has advantages - it can be stored at 2 to 8⁰C for up to 3 months, and it requires just one dose. Trials are currently being conducted to test the efficacy of a two-dose regimen. The UK government has already ordered 30 million doses even though it has yet to be approved by the MHRA.

Vaccine dosing differences
The vaccines of the Big three require two doses per person – a primer and a booster. Their manufacturers recommend that these are given 3 to 4 weeks apart. At the end of December, the UK’s Joint Committee on Vaccination and Immunisation (JCVI), made the controversial decision, endorsed by the four UK Chief Medical Officers, to increase that gap to approximately 12 weeks. Why? Because they considered it was more important to give the primer jab to a greater number of at-risk people – in fact, to double the number – in the shortest possible time. Moreover, the JCVI considered that this primer dose of either the Pfizer-BioNTech or Oxford-AstraZeneca vaccine provides substantial and sufficient protection against Covid-19 by the third week after vaccination. However, a late-January report from Israel suggested that the first dose of the Pfizer-BioNTech vaccine led to only a 33% reduction in Covid-19 cases compared with at least 52% reported in the Pfizer-BioNTech clinical trials. A few days later another Israeli report raised that earlier datum to 50%. Preliminary results can be so tentative and misleading.

Another reason for this shift in UK policy was vaccine supply. This is a major barrier that will likely persist for several months, particularly during the critical winter period and amid reported production problems at both the Pfizer-BioNTech and Oxford-AstraZeneca manufacturing plants. As a result, late in January, Oxford-AstraZeneca warned that it was planning to reduce supplies to the EU. The EU responded by warning it will tighten export procedures of the Belgian-produced Pfizer-BioNTech vaccine to the UK. Oh dear – Covid-Brexit politics! Oh dear – ‘vaccine nationalism’!

Nevertheless, this new pragmatic UK policy raises several questions. Six are considered here. First, is it backed by good scientific evidence? Not really. During the early vaccine clinical trials the issues of one versus two doses and dose spacing were not rigorously examined. For example, the Pfizer-BioNTech manufacturers reported testing its vaccine's efficacy only when the two doses were given up to 21 days apart. The limited available data suggest that while two doses are optimal, their spacing may not be particularly crucial. In other words, it may well be a better policy to vaccinate more people with less efficacy than a greater efficacy in only half a population. It should reduce severe disease, hospitalisations and deaths. Moreover, such extended vaccination gaps are not new. For example, the gap for HPV vaccine for girls is a year and it provides a better immune response than a gap of a month. Could the same be true for Covid-19 vaccines?

Second, so, should the gap be 3 weeks or 3 months? The World Health Organization (WHO) recommends a gap of four weeks, to be extended only in exceptional circumstances to six weeks. The European Medicines Agency (EMA) has stated that the gap between the first and second doses of the Pfizer-BioNTech vaccine should not exceed 42 days. The Doctors’ Association UK (DAUK), which represents front-line doctors, has expressed serious concerns about this new vaccine schedule and the lack of guidance around the decision, warning that patients are at risk if they do not receive a timely second dose. And on 22 January, senior doctors from the British Medical Association (BMA) said the current plan was ‘difficult to justify’ and called for the gap to be cut from 12 to 6 weeks, particularly for the Pfizer-BioNTech vaccine. So, should the gap be 3, 6, or 12 weeks? The truth is, as yet, nobody really knows. Could it even be that all three gaps are OK?

Third, how effective is one dose? The statistics are complex and not easy to compare across the Big three vaccines. However, as an example, short-term (between days 15 and 21 after the first dose of the vaccine) efficacy for the Pfizer-BioNTech vaccine was estimated to be around 52%, whereas for the Oxford-AstraZeneca vaccine the figure was 70%. After the second dose, both figures rose to almost 95%. In other words, significant protection is obtained after the primer dose, but the booster is important. However, it should be born in mind that these data were obtained from trials under exacting clinical conditions, not out in the real world.

Fourth, is it important for people to receive the double dose of the same vaccine? Ideally, yes. But depending on supplies, regional differences, records and prioritisation, this may not be possible. Therefore the somewhat utilitarian thinking is, go for two of any. However, although the mode of action of the Pfizer and Oxford vaccines is the same, they are not identical, and it therefore makes sense that the second shot should be of the same vaccine as the first. The World Health Organization (WHO) and other medical authorities have stood by the manufacturers’ recommendations and have expressed uncertainty about such hybrid dosing strategies because there are no data to indicate that such dosing would be unsafe or less effective. Again, the truth is, as yet, nobody really knows because the relevant clinical trials have not been undertaken.

Fifth, how long will immunity last? Some vaccines, such as for measles, provide protection for a lifetime, whereas others, such as for flu, require annual booster jabs. Yet no vaccine is 100% effective, so a small percentage of people are not protected after vaccination and for others the protection may wane over time. For the Covid-19 vaccines, nobody knows because their current usage has been only short-term. Nevertheless, in mid-January, a UK study, led by Public Health England, demonstrated that most people who had had a Covid-19 infection would be protected against reinfection for at least five months. Immunity due to past infection was linked to an 83% lower risk of reinfection, compared with those who had never had Covid-19. But some people do catch Covid-19 again – and they can also transmit the virus to others. Therefore, those who have had the disease, as well as those who have been vaccinated, need to continue to practise those Hands, Face, Space rules.

Sixth, is this UK change of policy bureaucratically sensible? The BMA thinks not. It has called the government’s decision ‘unreasonable and totally unfair.’ For instance, it claims that rebooking patients for 12 weeks hence would ‘… cause huge logistical problems.’ And it asks, would the initial consent given for the original two doses still apply?

This vaccine roll-out is riddled with problems and questions – extra time and more clinical trials are needed to overcome these challenges and to answer these uncertainties definitively.

Other life-saving treatments
Many say that our only way to beat this pandemic is by mass vaccination. That is not strictly true. Even post-vaccinated people may spread the disease, especially in the early days after their primer. So frequent hand washing (for 20 seconds?), isolation (staying at home) and social distancing (keeping 2 metres apart) still perform keynote functions. After all, if you avoid all human contact, you will avoid Covid-19. In addition, the disease will probably never be entirely ‘beaten’ – it will likely persist somewhere in the world for ages, maybe for ever.

While vaccination remains the primary strategy, such is the seriousness of the Covid-19 pandemic that several non-antiviral agents are being studied for their potential to defeat the virus. Whereas some recommend a wild tactic of ‘try anything’, the UK’s RECOVERY trial (Randomised Evaluation of COVid-19 thERpaY), at the University of Oxford, has taken a more measured approach by examining a limited number of non-vaccine products that have shown early promise. These include tocilizumab, sarilumab, dexamethasone, convalescent plasma, colchicine, Regeneron’s antibody cocktail and aspirin.

For example, tocilizumab and sarilumab are commonly-used arthritis medications. In early January, they were reported to be effective in reducing the time that critically-ill Covid-19 patients need to spend in intensive care units by up to 10 days. And these anti-inflammatory drugs were shown to cut the death rate by about 25%. Supplies of these relatively-cheap medicines are already available across the UK and it was believed that their wider use could save hundreds of lives. Spoiler alert! A January report of a trial conducted in Brazil concluded, ‘In this trial including patients admitted to hospital with severe or critical covid-19, the use of tocilizumab plus standard care was not superior to standard care alone in improving patients’ clinical status at 15 days, and might have increased mortality.’ Yet there are other therapeutic medicines, like remdesivir, which have ostensibly been shown to shorten the time of recovery for Covid-19 patients. Similarly, dexamethasone is reported to decrease mortality and shorten the time to recuperate. It is clear that more trials, more data are needed.

And there is ‘convalescent plasma’. Plasma from people recovering from infection, particularly after severe Covid-19 illness, may contain high levels of coronavirus antibodies – these may confer passive immunity to recipients. However, though its simplicity to treat Covid-19 patients is attractive, definitive evidence of its efficacy has been elusive. Another spoiler alert! In mid-January, the RECOVERY team announced that in a trial with 10,400 participants, convalescent plasma did not reduce deaths among hospital patients and so that line of investigation has now been closed.

Interferon beta is another possible candidate. Could it help stop Covid-19 patients from developing severe illness? A trial at Hull Royal Infirmary involved inhaling interferon beta to stimulate the patient’s immune system. Preliminary findings suggest that the treatment decreased the probability of developing severe Covid-19, the sort that would require hospital ventilation, by almost 80%.

Could stem cells help treat severe Covid-19 patients? According to a small study from the University of Miami, umbilical cord mesenchymal stem cells (UC-MSCs) may dampen a hyperactive immune response, the so-called 'cytokine storm', which is a frequent complication of severe Covid-19. This double-blind trial provided evidence of significantly improved patient survival – at one month it was 91% in the stem-cell treated group versus 42% in the control group – and reduced recovery times. Such results warrant a larger study.

And there is a mechanical treatment now being trialled for the most seriously-ill Covid-19 patients, whose lung function has not responded to ventilation. It is a technique called ECMO (extracorporeal membrane oxygenation). The ECMO procedure uses an artificial membrane to oxygenate the patient’s blood. This in turn allows the patient’s lungs to rest and recover. As yet, only six NHS centres in the UK offer this treatment.

Finally, let no-one dismiss tweaking the mundane. What about extending the current social distancing measure from 2 to 3 metres? And what’s happened to that erstwhile advice from the government to ‘stay alert’ (whatever that really meant), to wash your hands not ‘regularly’, but frequently (Christmas comes ‘regularly’ namely, once a year) and to sneeze, if necessary, into your elbow? And 'to act as if you have the virus'. Such simple strategies can work well and save lives.

Covid-19 variants
The pandemic refrain of early 2021 is ‘viruses mutate’. And this Covid-19 virus has already done so. This has been achieved maybe by naturally-occurring genetic errors as it reproduces itself, or maybe by seeking to escape anti-viral drugs, or patients’ immune systems. Such mutations may be of no medical consequence, or, alarmingly, they may display resistance to coronavirus vaccines, or increase transmissibility (is that a real word?) among a population, or overcome natural immunity and create a spate of reinfections. Scientists are scrambling for answers – those previously lacklustre disciplines of genomic surveillance and genomic epidemiology have truly come of age.

A little variant history. It was at the end of December 2019 that Chinese health authorities reported investigating 27 cases of viral pneumonia in central Hubei province. Unbeknown at the time, this was the beginning of the global coronavirus pandemic. First reports suggested that the Covid-19 virus, known officially as SARS-CoV-2, originated in a so-called ‘wet market’ in Wuhan, which sold fish and other live animals for human consumption. It was there that many suggest the virus made the lethal leap from animals to humans, and thereafter from humans to humans. Others believe that pangolins were the source of the virus, or that it had been circulating undetected in Chinese bats for decades. Some even deny it started in China, pointing instead to Italy or Spain. In mid-January, a 10-member team of World Health Organization (WHO) specialists arrived in Wuhan to investigate the viral source. Their conclusion is awaited. Whatever its origin, the original Covid-19 virus spread rapidly and widely – within days and globally.

Then it mutated. In April 2020, researchers in Sweden found a novel mutant Covid-19 virus with two genetic changes in its spike protein that seemed to make it roughly twice as infectious as the original. And then in June 2020, Danish authorities reported an extensive spread of this Covid-19 variant on mink farms in Denmark. By 5 November, the Danish public health authorities confirmed that this mink-associated variant had infected 12 human patients. This led to the deliberate culling of the entire Danish farmed mink population.

Wait. Here is an exasperating conundrum – how are variants of the SARS-CoV-2 virus named? Currently, confusion reigns and no nomenclature is universally accepted. For example, in late 2020, when a fast-spreading variant was identified in the UK, Public Health England initially used a date-based system, and called it Variant Under Investigation 202012/01 (or VUI 202012/01 for short). Then after a risk assessment, which showed it to be dangerous, it was dubbed Variant of Concern 202012/01 (or VOC 202012/01). Yet there is an alternative naming scheme based on the viruses’ developmental or lineage features, so VOC 202012/01 becomes B.1.1.7, whereas yet another scheme, based on the biochemical changes in the mutant, calls it 20I/501Y.V1. To add to the labelling confusion the terms, variant, lineage and strain are often ill-defined and ambiguously applied.

It was estimated that the B.1.1.7 variant might be as much as 70% more infectious. This figure prompted the UK government to institute a third lockdown on 5 January. The task is now to determine what causes this increased transmissibility. Does, for example, the mutation allow the virus to bind to lung cells more strongly and enter cells more rapidly, thus making infection easier? At the same time, there was thought to be no evidence that this new variant made the infection more severe or more deadly. However, on 22 January, as more data, albeit tentative, became available, it was announced that there is a ‘realistic possibility’ that the new variant actually is more deadly. Be that as it may, the mere existence of increased transmissibility equals more infected people, equals more hospital admissions, equals more deaths.

The second variant in question emerged during a fast-growing Covid-19 epidemic in South Africa in early October and is known as 20C/501Y.V2, or B.1.351 lineage. It carries 9 such genetic changes which cause the E484K and N501Y mutations. Research has shown that E484K could be ‘associated with escape from neutralising antibodies’ – meaning it may be able to evade parts of the body’s natural defence memory that bestows immunity. This could be bad news in terms of vaccination efficacy.

In mid-January, the discovery of a third dangerous variant was announced. It was initially detected in four people – a man, a woman and two children – who travelled from Brazil’s Amazonas state to Tokyo on 2 January. It shares structural similarities with the highly-infectious UK and South African variants, but little is yet known about its disease properties or global spread. Japan’s National Institute of Infectious Diseases (NIID) has reported that the new variant belongs to the B.1.1.248 or P.1 lineage of the coronavirus and has 12 mutations, including N501Y and E484K, in its spike protein. It is thought to be the cause of soaring infections in some Brazilian regions. Hence, from 15 January, the UK government banned all flights from South America and Portugal.

The hot question: will the Big three vaccines work against these new variants? Vaccines train the immune system to attack several different parts of the virus, so even though part of the spike has mutated, the vaccines may still work. Public Health England has stated that there is currently no evidence to suggest these Covid-19 vaccines will not protect against these mutated virus variants. The manufacturer of the Pfizer-BioNTech vaccine has also declared that their product works against the N501Y mutation found in the English and Brazilian variants. However, research is ongoing to establish whether the South African variant, with its E484K mutation, will be effectively neutralised by the body’s immune system. This property of so-called ‘vaccine escape’ is of grave concern.

These are not going to be the last mutations we hear about. Identification and blocking strategies continue apace. For example, at the end of January, came the identification of a novel Californian strain, known as Cal.20C, in up to 50% of recently-diagnosed cases in the Los Angeles area. And in the vanguard of developing innovative strategies, Moderna has recently initiated clinical trials of a new vaccine after warning that its existing vaccine was less effective in tackling the South African strain.

Other variants are already circulating undetected throughout the world. Undoubtedly some of these will need investigating because they will generate considerable uncertainties and prompt a long list of unanswered questions.

The UK vaccination delivery plan
On 11 January, Matt Hancock, the UK Secretary of State for Health and Social Care, showed himself to be a man with a plan, at least for England. It consists of a four-fold strategy:

1] Supply – this is currently the rate-limiting step. The UK has so far ordered 367 million doses from seven vaccine manufacturers at a cost of about £3 billion. However, the logistics of supply and distribution have proved to be troublesome – as yet there are not enough vaccines available to be injected into willing UK arms.

2] Prioritisation – the top four priority groups, which have so far accounted for 88% of Covid-19 deaths, should be vaccinated by Monday 15 February. This cohort, of 15 million people, consists of residents in care homes for older adults, people aged 70 and over, front-line health and social care staff, and people who are clinically extremely vulnerable. And then another 17 million jabs for the next cohort by the spring, and every adult by September.

3] Places – where to get a jab. Vaccinations will occur at three types of location. Large vaccination centres – over 60 are expected to be operational by the end of January. Hospital hubs at NHS trusts – 206 will be established by the end of January. Local vaccination services, such as GP surgeries, pharmacies and roving mobile centres – around 1,200 local sites should be established by the end of January.

4] People – who will make the plan happen. More than 80,000 health professionals have now been mobilised and are ready to be deployed. These include military personnel, dentists, midwives, paramedics, trainee doctors and nurses, plus thousands of other general volunteers.

Questions arise. For instance, is this UK prioritisation plan, based on age and vulnerability, the right one? Would it also be sensible to divert doses of vaccines to geographical regions that display large clusters of Covid-19 cases? And should other exposed groups, such as school teachers and the police, be pushed up the timetable? Such arguments are rife.

Other Covid-19 effects
Besides the devastation caused by the virus in terms of disease, deaths, economics, and so on, there are other serious outcomes. Of course, medicine is at ground zero for both healthcare professionals and patients. For instance, during mid-January, nearly half of intensive care and anaesthetic staff were reported to be suffering symptoms of probable post-traumatic stress disorder (PTSD), severe depression, anxiety, or problem drinking. And for Covid-19 patients, four naked statistics tell the extent of the grim story. On 26 January, it was announced that over 100,000 deaths in the UK had been caused by Covid-19. It is a forbidding milestone. In addition, there has been a total of almost 4 million UK cases reported since the start of the pandemic, with currently some 40,000 people hospitalised and 4,000 on ventilators.

Other outcomes for non-Covid-19 patients, include that by mid-January, according to Professor Neil Mortensen, president of the Royal College of Surgeons of England, the pandemic was having a ‘calamitous impact … on wait times for surgery.’ At the end of November 2020, a total of 4.46 million people were waiting to start hospital treatments in England – the highest since records began. Covid-19 has caused hospitals to be full and in some cases overflowing.

Then there are the non-medical harms of unemployment, sub-standard schooling, anger, deprivation, social division and more. For example, Covid-19 has caused a massive backlog of 457,000 cases within the UK criminal system including 54,000 unheard Crown Court cases, which may not be resolved until 2022.

One year ago, on 31 January 2020, the first two cases of Covid-19 in the UK were confirmed in Newcastle upon Tyne. One year later, that miserably minute Covid virus has turned not only the UK, but also the entire world, upside down. And it has not finished yet. Of course, it is a cliché, but truly, our lives will never be the same again.

Covid-19 divides the world
The head of the World Health Organization (WHO), Tedros Adhanom Ghebreyesus, has recently warned that the world faces a ‘catastrophic moral failure’ because of unequal Covid-19 vaccine policies. He cited the recent example that over 39 million vaccine doses had been administered in 49 rich states, whereas one poor nation had been given only 25 doses. More questions arise. Is it right or fair for younger, healthy people in richer nations to get vaccinated before vulnerable people in poorer states? Should rich countries buy up supplies in what has been called ‘vaccine nationalism’, abandoning the world’s poor and serving only to prolong the pandemic? True, the UK has so far donated £548 million to the global COVAX Advance Market Commitment (AMC), the international initiative to support global equitable access to vaccines. Is that enough? Cold cash is not the same as injected vaccines. Should developed countries donate some of their massive vaccine resources to the under-developed? Why does the UK need 367 million doses for a population of just 67 million people? Are some lives more valuable than others? What does loving my neighbour actually look like? These are awkward Covid-19 related questions.

Who’s had the jab?
Apart from that unsuspecting global celebrity, Margaret Keenan, who else has been vaccinated against Covid-19? Well, top of the UK list have been the Queen and Prince Philip, though not before the world’s press and TV cameras, but privately in Windsor Castle. Similarly, the Pope in the Vatican. Yet there is a perceived need to encourage the ‘vaccine hesitant’ to join the queue for the jab. So a phalanx of celebrities has appeared on our screens with their sleeves rolled up. They include Sir David Attenborough and the Archbishop of Canterbury, as well as President Joe Biden and former Vice-President Mike Pence. Then up stepped a host of UK golden-oldie stars, such as Marty Wilde, Lionel Blair, Joan Collins and Prue Leith. A new campaign, starring Black, Asian and Minority Ethnic (BAME) celebrities, has also been launched to encourage the BAME community to overcome its high vaccine hesitancy numbers. None of these was camera shy, but will they sway the hesitant?

On your V-day
The start of the Covid-19 vaccine roll-out is a reason to be cheerful. Hold that thought. Cheerfulness, along with other positive personality traits and social interactions, can actually enhance the body’s response to vaccinations. Writing in the 13 January edition of the New Scientist, Anna Marsland, a psychologist at the University of Pittsburgh in Pennsylvania, stated, ‘There is now a large literature that shows that these sorts of psychological factors influence how people respond to vaccinations as measured by magnitude of antibody response.’ So remember, as you get your jab, smile!