Coronavirus - Part 4
(February 2021)

Coronavirus - Parts 1, 2, and 3 can be accessed here and here and here

First, some elementary biology plus a home truth.  Viruses cannot mutate unless they are replicating and they cannot replicate unless they can get into cells.  Keeping them out by vaccinating people can shut down that process.  That’s what you want.  You want to stay out of the hospital, and stay out of the morgue.

What a difference a month makes
Consider the data.  In Coronavirus – Part 3 (January 2021) I wrote, ‘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.’  Now, a month later, at the end of February 2021, the total UK deaths have slowly risen to just over 120,000 with barely more than 4 million cases and with fewer than 15,000 people hospitalised and 2,000 on ventilators.

The figures are falling steadily, but they are still too high.  The current rate of infection, at about 6,000 cases per day, is still far, far too great.  The other big numerical difference is that in January less than 6 million people had received their first coronavirus vaccination, whereas by February that figure had reached 20 million.

Are we doing well?  Yes and no.  UK domestic hospitalisation and death numbers have certainly decreased.  But, think globally about the 112 million cases and 2.5 million deaths.  And there is one striking statistic – the UK's current death rate is 1,800 deaths per million population.  We are top of that league table and therefore the worst in the world.  It is far from over.

The vaccination roll-out
This great event began, with appropriate media razzmatazz, on Tuesday 8 December 2020.  It has since made remarkable progress.  It has already been called a ‘game changer’.  Indeed, it has already been linked to a substantial reduction in hospital admissions.

The UK vaccination plan has set various targets for various groups.  The one-dose target for 15 million people in the top four priority cohorts was met by mid-February – that was no small accomplishment.  The next goal is to offer a first dose by 15 April to all those in the phase 1 priority groups, namely the 32 million people in the top nine priority groups, those aged 50 and over and those with underlying health conditions.  And finally, everyone over 18 and living in the UK will have been offered a coronavirus vaccination by 31 July.

At the end of February, the Joint Committee on Vaccination and Immunisation (JCVI) modified the phase 2 vaccination roll-out by making it simply age-based, starting with the oldest, rather than prioritising those in occupational groups, such as teachers and police officers.  The JCVI has stated that individuals who are at increased risk of severe outcomes from Covid-19 on account of their occupation, male sex, obesity or ethnic background are likely to be vaccinated most rapidly by this revised, operationally-straightforward, vaccine strategy.  In other words, since age is the biggest risk factor, this is considered to be the most effective way to minimise hospitalisations and deaths.

The road map out of lockdown
On 22 February, the prime minister of the UK, Boris Johnson, announced his long-awaited road map, the way out of lockdown, a ‘one-way road to freedom’, at least for England.  The details were set out in a 60-page document.  The other three UK nations have similar plans for monitoring the data and, when considered appropriate, unlocking activities on particular target dates.  These are wise and cautious approaches, though they have their detractors – some want faster progress, some want slower.

The English road map consists of four steps with key dates.  In brief, they are Step 1]  8 March when schools reopen, and two people are allowed to meet outdoors, plus 29 March when six people, or two households, will be able to meet outdoors.  Step 2]  12 April when non-essential retail and outdoor hospitality venues are due to open.  Step 3]  17 May when six people, or two households, can meet indoors and indoor hospitality, cinemas and hotels can open.  And finally Step 4]  21 June when all restrictions are due to end.  Health secretary, Matt Hancock, warned that everybody has to ‘play their part’ if this timetable is to be achieved.

These dates are not immutable, they are contingent on four conditions – the vaccination programme going to plan, decreasing numbers of deaths, no surge in hospitalisations, and no emergence of dangerous variants.  The road map’s four steps include 5-week gaps so that risks can be assessed before moving onto the next set of lockdown freedoms.  This makes scientific and medical sense.  It is reckoned that each step in the liberalisation of lockdown will take about 4 weeks to show positive effects.

Under the road map, international travel will not return until 17 May at the earliest, but that did not deter people planning their trips abroad.  On the day the road map was announced, travel bookings leapt.  For instance, EasyJet reported a 337% rush in flight bookings and a 630% jump in holiday bookings.

So, Monday 21 June is now circled in everyone's diary.  From then, hopefully, social distancing will no longer be legally required, weddings will have no attendance limits and we can again hug and kiss our families and friends in private and in public, with their consent, of course!

Vaccine efficacy
No vaccines are 100% effective, but we still want to know how beneficial they might be.  Previous data, published by the manufacturers, were obtained under strict clinical-trial conditions.  Now data from so-called ‘real-world’ situations are being published.

At the end of February, early results from three such trials were announced.  First, the SIREN (Sarscov2 Immunity and REinfection EvaluatioN) study focused on healthcare workers under 65, who, after 21-days post-vaccination with the Pfizer-BioNTech product, had a more than 70% reduced risk of catching Covid-19 rising to 86% after the second dose.  This corresponds with data from Israel suggesting that 75% protection occurs after a single dose of the Pfizer-BioNTech vaccine in healthcare staff.  Second, there were data from Public Health England (PHE), which showed that in the over 80 age group there was a 57% decrease in mild or severe Covid-19 after the primer dose of Pfizer-BioNTech, rising by a further 30% after the booster.  Third, there were results from the University of Edinburgh, based on 1.14 million vaccinations, which showed that both the Pfizer-BioNTech and Oxford-AstraZeneca vaccines were highly effective.  By the fourth week after receiving the initial dose, the risk of hospitalisation from Covid-19 was reduced by up to 85% and 94% respectively.

In summary, these preliminary figures show that vaccination provides a very substantial protection after the first dose while the second dose provides even greater protection, so it is important for people to roll up for their booster.

Vaccine hesitancy
It would be too optimistic to expect ardent anti-vaxxers, conspiracy theorists and maybe even misinformed sceptics to line up for their jabs.  But there are still considerable numbers of other people who are vaccine hesitant – figures suggest they account for between 11 to 15% of the adult population.  Top of the numerical list are members of BAME (black, Asian and minority ethnic) communities.

For example, by 11 February 2021, among those aged over 80 years old, 91% of white people had been vaccinated, compared with only 58% of black people and 72% of people from South Asian backgrounds.  Similarly among the 70 to 79 year olds – 66% of white people in this cohort had been vaccinated, compared with 46% of black people and 62% of people of South Asian ethnicity.  These differences are a concern and they require attention.

New vaccines and treatments
There are already some 300 Covid-19 vaccines in various stages of development – 10 are in use or approved and 70 are in clinical trials.  Small biotech businesses, as well as Big Pharma companies, are busy designing, producing and testing new Covid-19 vaccines.  Other enterprises, such as those conducted by the Oxford University-based Randomised Evaluation of COVid-19 thERapY (RECOVERY) trials, are experimenting with promising Covid-19 treatments.  Theirs are stories of hope, success and failure
here are a few examples.

Antibody therapies are being devised by several companies including Eli Lilly and Regeneron.  For instance, scientists at the University of Pennsylvania and the biotech firm Regeneron are investigating whether technology developed for gene therapy can be used to make a nasal spray that will prevent coronavirus infection.  Regeneron’s antibodies are themselves in clinical testing but have received emergency approval for patients with mild or moderate Covid-19 who are at high-risk of getting severe disease.  This regimen was notably used last November to treat President Donald Trump.  Researchers are hoping that the nasal spray could be squirted into the nostrils, enter nasal epithelial cells and then hijack their protein-making machinery so that they generate Regeneron’s antibodies.

Sorrento Therapeutics of San Diego is also working on new antibody therapeutics.  The company has recently announced a phase 1 clinical trial to test the safety and efficacy of COVI-DROPS, nose drops containing the company’s COVI-AMG neutralising antibody.  It is claimed it can boost immunity against Covid-19 by blocking the infection and spread of the virus.  This intranasal route is attractive – it is simple, avoiding both an injection and a visit to a vaccination site.

In February, Sanofi and GlaxoSmithKline announced the start of a new phase 2 study with 720 volunteers to select the most appropriate antigen dosage for phase 3 evaluation of their adjuvanted recombinant protein Covid-19 vaccine candidate – a ‘refined antigen formulation’.  This comes some two months after they disclosed lower immune responses and higher levels of adverse events than expected for their first vaccine.  Even if these trials are successful, the vaccine will not be available until the end of 2021 – a significant setback of six and more months for a programme funded by $2.1 billion from the US government.

And looking ahead, the team behind the original Oxford-AstraZeneca vaccine has been devising a new product that could be effective against all Covid-19 variants.  Instead of targeting the spike protein, as all current vaccines do, it would target the core of the virus.  It could be ready for use in as little as a year.

In addition, several non-antiviral agents are being studied.  The World Health Organization (WHO) already strongly recommends that corticosteroids, such as dexamethasone, hydrocortisone and prednisone, be given orally or intravenously for the treatment of patients with severe and critical Covid-19.

And there is, tocilizumab, a monoclonal antibody, commonly used as an anti-inflammatory drug in the treatment of rheumatoid arthritis.  Preliminary results from the RECOVERY trial conducted by Oxford University showed that tocilizumab significantly reduced deaths in patients hospitalised with Covid-19 – for every 25 patients treated with tocilizumab, one additional life can be saved.  And for Covid-19 patients who were not on invasive mechanical ventilation, tocilizumab also significantly reduced the likelihood of their progression to either invasive mechanical ventilation or death by 38% and 33% respectively.

And there is azithromycin, an antibiotic medication.  However, when almost 8,000 patients were enrolled in a RECOVERY trial to assess its effects in patients admitted to hospital with Covid-19, it did not improve survival or other pre-specified clinical outcomes.  In other words, azithromycin had no meaningful clinical benefit for patients hospitalised with severe forms of the disease.

The first Covid-19 challenge study
The first of its kind, a Covid-19 human challenge study, has begun in the UK by recruiting up to 90 healthy volunteers, aged between 18 and 30.  They will be deliberately exposed to the Covid-19 virus in a safe and controlled environment, closely monitored by doctors and scientists.  Later, a test vaccine will be given to see if it is successful in preventing the coronavirus infection, as well as identifying any adverse side effects.  According to Clive Dix, of the Vaccines Taskforce, ‘We expect these studies to offer unique insights into how the virus works and help us understand which promising vaccines offer the best chance of preventing the infection.’

However, such challenge studies are controversial and not without risks to the volunteers, who will in this particular investigation, be compensated up to the tune of £4,500.  Professor Julian Savulescu, the provocative bioethicist from Oxford University, has stated (The Lancet, 2020, 30 December), ‘Despite their ethical justifiability, it is quite possible that the backlash against a death of a healthy volunteer might shut down or significantly retard the use of challenge studies, and perhaps vaccines in general.’  Nevertheless, he added that in this worldwide pandemic emergency, time lost means lives lost, and thus there is a moral imperative to develop a safe and effective vaccine as soon as possible.  He continued, ‘The chance of someone aged 20 to 30 years dying of Covid-19 is about the same as the annual risk of dying in a car accident.  That is a reasonable risk to take, especially to save hundreds of thousands of lives.  It is surprising challenge studies were not done sooner.  Given the stakes, it is unethical not to do challenge studies.’  The results from this study will be eagerly awaited.

Vaccination passports or immunity certificates
These are prickly topics surrounded by complex legal, ethical and logistical paraphernalia.  Should a government make it a legal requirement to prove that a person has been vaccinated, whether for employment, or travel, or whatever?  Is ‘no jab, no job, no journey’ the best way forward?  For instance, should such a passport be compulsory for healthcare workers in hospitals or care homes?  What about those attending schools or football matches?  The ideological shift has already begun.  For example, from 2021, the Australian airline Qantas will demand passengers provide proof that they have had a Covid-19 vaccination if they want to fly into or out of that country.

Again, Julian Savulescu comments that, ‘Smallpox was eradicated by 1979 through vaccination, which was mandatory in many countries (parents were fined in the UK if they did not vaccinate their baby in time).  In the face of that kind of emergency, research and control are moral imperatives, even involving compulsory vaccination.  There is a moral imperative to prevent and treat any disease that causes suffering and death.’

UK governments have long been opposed to issuing identification cards, with exceptions, such as travel passports and driving licences.  And so it was with this current administration.  After all, who wrote in 2004, ‘Ask to see my ID card and I'll eat it’?  Why, Boris Johnson, of course.  Nevertheless, the UK appears, in line with many other countries, to be capitulating.  Michael Gove, Chancellor of the Duchy of Lancaster, who in December 2020 announced there were no plans to introduce such passports, has recently been appointed to lead a review into the need and style of such documentation.  It will not be easy.

In February, the SET-C (Science in Emergencies Tasking – COVID) responded to a government request by proposing 12 criteria that should be satisfied by a Covid-19 vaccination passport.  They are, a passport should 1] meet benchmarks for Covid-19 immunity, 2] accommodate differences between vaccines in their efficacy, and changes in vaccine efficacy against emerging SARS CoV-2 variants.  It should be 3] internationally standardised with 4] verifiable credentials for 5] defined uses, and based on 6] a platform of interoperable technologies, 7] secure for personal data, 8] portable and 9] affordable for individuals and governments.  It should meet 10] legal and 11] ethical (equity and non-discrimination) standards, and 12] the conditions of use should be understood and accepted by passport holders.  Complex, eh?

Fertility and vaccinations
The internet has been buzzing with vaccination misinformation including that Covid-19 jabs can adversely affect fertility, so making some men and women vaccine hesitant.  The Association of Reproductive and Clinical Scientists and the British Fertility Society have recently published a 2-page joint-document entitled, ‘Covid-19 vaccines and fertility’.

In answer to the key question, ‘Can any of the Covid-19 vaccines affect fertility?’ it states, ‘No.  There is absolutely no evidence, and no theoretical reason, that any of the vaccines can affect the fertility of women or men.’

Pregnancy and vaccinations
Are pregnant women at risk of severe complications from Covid-19?  Uncertain healthcare professionals have often advised them to get vaccinated even though vaccine trials have not included pregnant women.

In mid-February, Pfizer-BioNTech started a clinical trial with pregnant women to evaluate the safety, tolerability and immune response of its vaccine.  The company is recruiting 4,000 women, over 18 years old, who are between 24 and 34 weeks into their pregnancies.  After her baby is born, if the mother was given the placebo, she will be offered the vaccine.  In addition, the babies will be monitored for six months to see if they have protective antibodies, transferred from their mothers.  That is all well and good, but vaccines also need to be tested with women much earlier in their pregnancies to determine risks of birth defects and miscarriage.

Children and vaccinations
The University of Oxford has launched the first study to assess the safety and immune responses in children and young adults of its Oxford-AstraZeneca vaccine.  When given to adults this vaccine has proven to be safe and effective in producing strong immune responses with a high efficacy.  The new trial will assess if children and young adults, aged 6 to 17 years, respond similarly.

From February, this single-blind, randomised phase 2 trial, will enrol 300 volunteers, with up to 240 of these volunteers receiving the vaccine and the remainder given a safe meningitis vaccine as an active control.  Though most children are relatively unaffected by the coronavirus, it is important to establish the vaccine’s safety and immune response as some children may benefit from inclusion in vaccination programmes in the near future.

Employment and Covid-19
Besides the devastating medical outcomes of Covid-19 infections, the subsequent lockdowns have created a battered UK economy, with many enterprises in the hospitality, retail and entertainment industries forced to close their doors.  Owners of such businesses are still required to pay rent, rates and so on, but with no hope of any trading income.  Theirs are dire situations.

So far, unemployment has been somewhat protected with about six million people currently on furlough schemes, but job losses are expected to rise during 2021.  According to the Office for National Statistics (ONS), the UK unemployment rate from October to December 2020 was 5.1% – the highest for five years and disproportionately affecting the under 25 year olds.  And according to the Bank of England’s latest forecast unemployment will peak at 7.75% by mid-2021, especially if job support schemes are not extended.  On the other hand, the vaccine roll-out and the easing of lockdown restrictions may help to keep job losses down.  It is proving to be a turbulent time for both employers and employees.

And what of the future?
In January, the journal Nature surveyed more than 100 immunologists, infectious disease researchers and virologists asking their views on the future of the Covid-19 pandemic.  The results of the survey have been published as, ‘The coronavirus is here to stay – here’s what that means’ by Phillips N., in Nature (2021, 590: 382-384).

Almost 90% of respondents expected that the coronavirus will not be eradicated, but will become endemic, continuing to circulate in pockets of the global population for years to come and causing outbreaks in regions where it had been previously eliminated.  Nevertheless, the future impact of the virus on the world, in terms of deaths, illness and the need for social isolation, will probably lessen as more of the population acquires some immunity to it through either exposure to the virus or from vaccination.  That’s quite heartening.  Roll on the roll-out!

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