5 February 2022

Coronavirus update – Part 15

Dr John Ling continues to provide us with a monthly review of all things Covid. This, his latest offering, was published a few days ago on his personal website, which is well worth a look for many other resources and information. Thank you John!

Covid-19 numbers

Welcome to the third year of the Covid-19 plague. At last, there is some cautious optimism about – the virus is perhaps beginning to become endemic, at least in the UK. It also looks as though those harsh lockdowns and other severe restrictions are no longer likely to be introduced and enforced. Yet just another variant, or stupid behaviour could trigger a further pandemic.

Meanwhile, Omicron is still whizzing through the population. That key metric, case numbers, are reportedly falling, but that is debatable. Are those apparent falls an artefact of a struggling testing system? Are fewer people self-testing and are they now less inclined to report positive results? After all, on 4 January, the highest ever UK figure of a whopping 218,724 cases was reported. But that included a backlog of data from the four home nations delayed over the New Year holiday period. Cases have since declined, plateaued and even increased to approximately 90,000 per day during the second half of January.

Covid-19 deaths, namely those reported within 28 days of a positive test, and though erratically relayed at weekends, they increased in early January and then plateaued at about 300 each day. Patients in hospital currently number 17,000 with around 550 on ventilators. Hospitalisations remain well below the peak of nearly 40,000 in January last year. Since the start of the pandemic, the UK’s death toll has reached a sad 155,000. The only other European country with a higher death toll is Russia with a total of 320,000.

Vaccination roll-outs continue but their media campaigns have started to wind down – they are no longer particularly newsworthy. However, the total numbers of first, second and third jabbed people are reported as 52.3, 48.4 and 37.3 million respectively. Overall, 77% of the UK population have received at least one dose, including 61% of children aged 12 to 15 years. Even so, there are still some 5 million people in the UK who remain unvaccinated.

Globally, many countries are resolutely stuck in a pandemic crisis. Total global cases are approaching 400 million with 6 million deaths. The USA still tops the daily infection table with an average of 800,000 cases, followed by France with 400,000, India with 300,000 and the UK in eighth place with 90,000. The USA also still dominates the total death table at 885,000, followed by Brazil (630,000) and India (500,000) with the UK in seventh place at 155,000.

What to conclude? Speaking in Geneva on 24 January, Tedros Adhanom Ghebreyesus, the Director-General of the World Health Organization (WHO), declared that, ‘The world must accept that Covid-19 is with us for the foreseeable future, even if it is possible to end the acute phase of the pandemic this year.’ He noted that 100 cases were now reported every three seconds, and someone lost a life to Covid-19 every 12 seconds. He added, ‘It is still dangerous to assume that Omicron will be the last variant, or that we are in the endgame of the pandemic. On the contrary, globally, the conditions are ideal for more variants to emerge.’

Nota bene, neither the pandemic nor the endemic is over – far, far from it.

From Plan B to Plan A

Reducing the required self-isolation period after a Covid-19 infection has been a useful indicator of the government’s strategy and its determination to press towards a return to some sort of normality. From 22 December, the isolation period for infected people was cut from 10 to 7 days as long as (lateral flow tests (LFTs) were negative on days 6 and 7. Then from 17 January, the self-isolation period was cut from 7 to 5 days.

The justifications for these changes have depended on a combination of scientific facts and computer modelling. For example, research by the UK Health Security Agency (UKHSA) had shown that 6.2% of people would still be infectious after two negative LFTs by day 7, which was nearly the same as the 5% of infectious cases if released from isolation after 10 days with no testing. However, testing after 5 days of isolation resulted in 31.4% of people still being infectious. Or as the health secretary, Sajid Javid, put it more positively, ‘around two-thirds of positive cases are no longer infectious by the end of day five.’ In addition, people without Covid-19 symptoms who have a positive LFT no longer need to take a confirmatory PCR test.

However, because of the continuing pressure to alleviate the staffing crisis in the NHS and other workplaces caused by high numbers self-isolating, the government reckoned that the risk of viral spreading after day 5 was proportionate and responsible. So, from 17 January, people could leave self-isolation 5 full days after experiencing symptoms or receiving a positive test result, whichever was first, provided they had negative Covid-19 tests on days 5 and 6. Nevertheless, they should remain cautious around others and avoid those who are vulnerable.

This was a pragmatic move, which has been largely welcomed, as long as more workers can safely return and it does not significantly add to the risk of viral transmission. Governments sometimes resort to such pragmatism and to knee-jerk policies. An example of the latter occurred in early January. At that time, there were apparently serious LFT kit shortages. They were simply unavailable via the NHS website or from many chemists or other regular outlets. On 9 January, The Sunday Times ran a feature suggesting that free LFTs would soon no longer be available. Up went the maroon. Talk about hyped journalism!

It was all something and nothing. Yet the government felt under pressure to act decisively. So early in January, it announced a new initiative affecting some 100,000 critical workers to include those employed in the national infrastructure, national security, transport, food distribution and processing. Police and fire and rescue services’ control rooms, electricity generation, test kit warehouses and test surge laboratories were also included. These employees would start to receive free, daily LFTs in an effort to reduce the spread of Covid-19 within this essential workforce. Supply and delivery of LFTs had suffered a major, albeit temporary, glitch over the Christmas and New Year holidays and so this knee-jerk initiative was more style over substance. Supplies were soon restored. Indeed, it truly was something and nothing.

However, on 26 January, something far more weighty was announced, namely, that the restrictions of Plan B had expired and those of Plan A were to be restored, at least in England. The four home nations have different Covid-19 rules, but these are gradually aligning. The move to Plan A involved lifting some principal curbs, such as working from home, wearing masks for indoor settings and the need for vaccine passports at large events. Other restrictions were also relaxed. For example, from 31 January, care home residents have been able to receive unlimited visitors rather than the three-person limit brought in under Plan B.

As well as pragmatism and knee-jerk initiatives, governments sometimes resort to policy U-turns. In December, it was announced that front-line NHS workers in England must be fully vaccinated by 1 April, meaning they would need a first jab by 3 February. On 31 January, the health secretary, Sajid Javid, announced in the Commons that the mandatory vaccination strategy for NHS and social care workers was to be reconsidered with a view to axing it. The anticipated exodus from among the 77,000 or so unvaccinated NHS workforce would apparently create a major staffing shortage crisis. And he added that because Covid-19 immunity was rising and Omicron was intrinsically less severe, the mandatory policy was no longer proportionate. This U-turn shift will be subject to a consultation.

Herein lies the hope of the government, industry and the public for a return to something ‘much closer to normality’. But are these radical moves too slow or too fast? Or are they basically a shambles? Surprise, surprise, opinions differ. Time will tell. For the moment, it certainly seems as though the dreaded Plan C has been ditched.

From pandemic to endemic?

The Covid-19 question of January has been, ‘Are we there yet?’ No, not that children’s chorus from the back seat of the car, but the genuine request from a world weary of Covid-19. The straightforward answer, if you mean, ‘Are we now virus free?’ is, ‘No.’ Overall, the world is still in pandemic mode, and for some, the worst is definitely yet to come. For others, the future looks somewhat brighter, that is, ‘It could be … very soon.’ In fact, a rather different question in now beginning to be asked, namely, ‘How are we to live with Covid-19 in 2022 and beyond?’ At least in the UK, there are growing calls for an alternative future approach to Covid-19, one that stresses living with it rather than constantly fighting it. Indeed, Michael Gove, the levelling-up secretary, declared on 10 January that ‘the UK had to learn to live with Covid-19.’

But there will be no overnight viral vanishing like a morning mist. Instead we will move slowly from pandemic to endemic. In other words, Covid-19 is here to stay, but its influence will be less malicious, more benign. Endemic means that the virus will constantly continue to circulate in a region, but with a relatively low spread of infection among the population so that social isolation, illness and death will continue, but at much reduced, and at a mostly static, rates. Infection case numbers will be more consistent and predictable. Communication care is needed. Misuse of the word endemic in relation to Covid-19 may encourage a misplaced complacency. Endemic does not necessarily mean local and mild. Endemic diseases can be both widespread and deadly. For example, malaria is an endemic disease that killed more than 600,000 people worldwide during 2020. Policymakers, scientists, citizens take note. We need to continually tackle this virus head-on, effectively and globally.

The two big unknowns are first, how immunity, derived from either infection or vaccination or both, will play out, and second, how the virus will evolve into other variants. Influenza is a useful template – immunity and vaccines keep it largely endemic with no official requirement for masks, social distancing or lockdowns. Moreover, this move from pandemic to endemic will not occur all at once across the globe, but rather nationally or regionally – inequity of vaccine distribution will make sure of that.

Incidentally, in epidemiological parlance there is an in-between state known as an epidemic, whereby a sudden increase in cases spreads through a large population. It is a term rarely used. In truth, the world will probably never be Covid-19-free, there will always be the distinct possibility of sudden increases or local outbreaks. That is not necessarily scary – we already live with a host of endemic diseases such as, common colds, measles, malaria, tuberculosis, and expectantly around the corner, Covid-19.

Listen to some experts. Professor Julian Hiscox, Chair in Infection and Global Health at the University of Liverpool, said in mid-December 2021, ‘I think life in 2022 will be almost back to before the pandemic.’ And Professor David Heymann of the London School of Hygiene and Tropical Medicine, who again stated in mid-December that, ‘the UK is the closest to any country in being out of the pandemic if it isn’t already out of the pandemic and having the disease as endemic.’ Such boffins could, of course, be entirely mistaken. But the optimists’ ace card is immunity – it will be THE game-changer. Just two years ago an unknown virus flew out of Wuhan and zipped around the world. None of humankind’s 7 billion individual immune systems had ever seen anything like it. And there were no Covid-19 vaccines or drugs in our armamentaria. We were vulnerable. Now in 2022, we have effective ways and means of making us all immune, so now we are far less vulnerable. The major obstacle would be a new variant that could outcompete others, in particular Omicron, and cause significantly more severe disease, hospitalisations and deaths.

So what about the UK – are we there yet? We have already paid a terrible price with severe illness and over 155,000 Covid-19 deaths, though all such numbers are likely to be significant underestimates. Yet paradoxically, these infections and associated vaccinations have left a legacy of high immunity. But that immunity will wane. So, with Omicron as the principal transmissible variant, we are still likely to catch endemic Covid-19, though as a less severe disease. Nevertheless, deaths will still occur, especially among the old and vulnerable. Fewer deaths could occur if harsh lockdowns were again enforced. But society will probably not stand for a return to such restrictions. Thus a balance has to be struck. How many deaths are tolerable? During a bad winter flu season some 200 to 300 people die each day. Is that where the line should be drawn? Will lockdowns, restrictions on large gatherings and mass testing disappear this year? And the compulsory wearing of face masks too? Many think so, though even more hope so. More certain is the use of booster vaccines, especially among the vulnerable, in order to maximise those antibodies before winter 2022 sets in. Autumn 2022 is going to be a time of double jabbing for Covid-19 plus influenza. Maybe autumn 2022 will look more like autumn 2019.

Those are some predictions for an endemic UK. What about the rest of the world? According to the World Health Organization (WHO), a different long-term policy is needed. Giving repeated booster doses of existing Covid-19 vaccines, as already happening in some rich, developed countries, is not a sustainable global strategy for tackling the pandemic. Instead, the WHO argues that the focus should shift towards producing new vaccines that work better against transmission of emerging variants.

Make no mistake, the poor and undeveloped world is still in a pandemic, far, far from an endemic. These countries are also vaccine poor. For many, including the vulnerable and front-line healthcare workers, have yet even to see a vaccine syringe. For countries that have locked down and closed their borders and successfully minimised deaths now have less immunity across their populations as they seek to re-join the rest of the infected world. The WHO has concluded that the world is a long way off describing Covid-19 as an endemic. Without doubt it is still in a pandemic and an acute medical emergency. Some even predict that the darkest days are yet to come. May they be proved wrong.

LFT and PCR testing

Millions upon millions of us have been through the rigours, discomfort and inconvenience of Covid-19 testing using LFTs (lateral flow tests). We have dutifully stuffed little sticks down our throats and up our noses for a good reason, or so we thought. Fewer of us have been through a PCR (polymerase chain reaction) test, yet again we thought it must be a useful exercise. But do we know how they work? An excellent question! Are we sure we know what they tell us? Another excellent question! And beyond the how and what of testing there is THE fundamental rationale of testing. It is not how well Covid-19 molecular fragments can be detected in a single sample, but how effectively infections can be detected in a population by the repeated use of such tests as part of an overall testing strategy – ultimately it is about the sensitivity of the entire testing and subsequent treatment regime that counts.

These two tests obviously measure different parameters. LFTs are rapid antigen diagnostic tests that use immunoassay technologies to produce results, in a similar way to pregnancy tests. The LFTs contain antibodies designed to recognise and bind to the Covid-19 antigens produced on the outer surface of the virus. As the sample moves along the nitrocellulose strip by capillary action, it encounters coloured nanoparticles and it reacts with other reagents. If a coloured band appears, the person being tested has been infected by Covid-19. And these LFTs have been ingeniously developed so testing can be done in the kitchen, at the bedside, or in the field. In other words, they do not need sophisticated laboratory settings to conduct them. They are not as accurate as PCR testing, but they are a simple and fast way to test people who do not have symptoms of Covid-19, but who may still be spreading the virus. As such, they are an important tool in the control of the Covid-19 pandemic.

By contrast, PCR testing screens directly for the presence of viral RNA, which is detectable before antibodies form or symptoms of the disease are present. PCRs can tell whether or not someone has the virus very early on in their illness. The tests are quite sophisticated and therefore need to be carried out in a laboratory, hence the delay and typical turnaround time of several days.

Even if you have been triple-jabbed, a positive LFT means you are infectious because viral protein is present in your throat or nose – the virus is still multiplying inside your body. By contrast, a PCR test can be positive for days or weeks after an infection because it detects small amounts of the viral RNA that are not necessarily infectious.

Here is a typical comparative timeline. Start with the time (day 1) when our patient, Scott Dive, an anagrammatical imaginary friend, is exposed to the Covid-19 virus. His viral load, the amount of virus in his body, begins to increase on that day. And the higher the viral load the more infectious he is likely to be. A PCR test is able to detect that upsurge of antibodies by day 2, before Mr Dive becomes infectious. It is only by day 3 that the LFT would be positive. Mr Dive is infectious from day 3 to day 8. LFTs would return test positives throughout this 5-day phase. By contrast, PCR tests would be positive from day 2 through to day 13, that is, not only one day before, but also five days after Scott is no longer infectious.

T cells

This is not the place for a tutorial on this wonderful, but complex, piece of bodily equipment we all carry around – the human immune system. First, a general observation. With respect to Covid-19, antibodies have been regarded as our main line of defence against its upper respiratory tract symptoms. Antibodies have stolen the limelight. But the immune system has numerous other components including T cells.

T cells, also called T lymphocytes, are a type of white blood cell and an essential constituent of the human immune system. T cells originate in bone marrow and migrate and mature in the thymus – hence they are called thymus-dependent (T) lymphocytes, or T cells. They then multiply and differentiate into various types of T cells, such as helper, regulatory, or cytotoxic T cells, until required by the immune system. Fascinating and complex.

However, during the Covid-19 pandemic T cells have been the poor cousins of neutralising antibodies, the unsung members of the immune system. T cells are now making a comeback. It is well-known that neutralising antibodies can bind to sites on the Covid-19 spike protein – these features have been used as templates for several Covid-19 vaccines. But if those sites mutate then antibody protection can wane. Yet T cells are more resilient. Among their immune functions, they can act as cytotoxic, or ‘killer’, T cells that seek out and destroy virus-infected cells. So, by annihilating infected cells, T cells can limit the spread of infection and potentially reduce the possibility of serious illness.

Moreover, T-cell levels tend not to decline as quickly as antibodies do after either infection or vaccination. And because T cells can recognise more sites along the spike protein than antibodies can, they should be better able to recognise mutated variants.

And that is the case with Covid-19. Recently, it has become clear that T cells can recognise Covid-19 variants, including Omicron, even when antibodies cannot. So here is a fundamental question. Have those researchers, who have been assessing the efficacy of Covid-19 vaccines, mistakenly concentrated on measuring antibody responses while ignoring important T-cell responses? True, antibodies are easier to study, making them simple parameters to measure in those large, international, Phase 3-type clinical trials. But Covid-19 variants remain highly susceptible to T-cell attacks. Surely they too should be assessed. Moreover, while antibody efficacy can fade, that of T cells can last for years providing long-term immunity.

In this war against Covid-19, T cells have perhaps come of age. Maybe. Whatever, don’t diss T cells!

R numbers

The R, or reproduction, number is a way of estimating how a viral disease is spreading within a population. The government has said that R numbers for Covid-19 are one of the most important factors in its policy-making decisions to control the pandemic.

In statistical theory, R numbers are estimated by independent computer modelling groups based in UK universities and the UK Health Security Agency (UKHSA). They typically use a variety of data sources. For example, some groups will use epidemiological figures, such as testing data, hospital admissions, ICU admissions and deaths. This is a backward-looking approach that typically takes up to 3 weeks to assess changes because of the time delays between initial infections and the need for hospital care. Other groups use data from contact pattern surveys that gather information from participants. These can be rapid, but because these rely on self-reporting, they are susceptible to bias. And there are household infection surveys where swab testing is performed by individuals and reported for collation. They are direct, but again dependent on patient collaboration.

Whatever the method used all these sources have inherent uncertainties, so estimates can vary between the different models. Moreover, estimates of R values are usually shown as a range because of statistical unevenness across a region caused, for example, by local outbreaks. A single value would not necessarily reflect the variations of infection rates within that particular area.

In statistical practice, the R value represents the average number of people a Covid-19-infected person will pass the disease onto. If R is below 1, then the number of people contracting the disease will fall and the pandemic will be shrinking. If R is above 1, the number of infected people will be growing. So, an R value between 1.2 and 1.5 means that, on average, every 10 people infected will infect between 12 and 15 other people.

In the early days of the Covid-19 pandemic, the government would regularly publish R numbers for the whole of the UK. However, nowadays, because of the increasingly-localised approach to managing the pandemic, values are published for each of the four home nations. The latest R values (released on 27 January) for England were between 0.8 and 1.1, for Scotland they were 0.7 to 1.1 and for Wales they were 1.1 to 1.5 and for Northern Ireland they were 0.7 to 0.9.

R values cannot be measured directly. However, they are useful estimates of the spread and intensity of Covid-19, but they have their limitations. For instance, they convey little about geographical differences – the smaller the subsection sampled, the greater the potential variation and the less reliable they become. And they say nothing about different viral variants. Nevertheless, despite such shortcomings R numbers are valuable guides to the general developmental trends of Covid-19. In summary, with respect to R numbers, less is best.

mRNA vaccines

The Pfizer-BioNTech and Moderna vaccines are messenger RNA vaccines, also known as mRNA vaccines. These were among the first Covid-19 vaccines authorised and approved for use in the United States and elsewhere. mRNA vaccines prompt the human body to make a protein that is part of the pathogen, triggering an immune response.

The development, approval and use of mRNA vaccines have been staggeringly successful. According to a recent Commonwealth Fund study, in the absence of such vaccines there would have been approximately 1.1 million additional Covid-19 deaths in the US and 10.3 million more hospitalisations by November 2021. In other words, mRNA vaccines have saved lives and prevented severe disease with comparatively few adverse events.

Yet mRNA vaccines have suffered a bad press, especially among a vociferous minority. Anti-vaxx individuals and groups have persistently referred to mRNA vaccines as ‘experimental gene therapies’. These people are gravely mistaken. Vaccines that use mRNA technology do not alter a person’s genes, therefore their use cannot be considered as gene therapy. Nor are mRNA vaccines particularly novel, or ’experimental’. It was in 1961 that mRNA was discovered and so for decades, well before Covid-19 appeared, hundreds of scientists have rigorously studied and worked on mRNA vaccines. Its first human clinical trial as a vaccine was against rabies in 2013.

Pfizer-BioNTech and Moderna mRNA vaccines contain the genetic code for cells to produce the spike protein that the Covid-19 virus uses to enter cells, to elicit an immune response in recipients. More precisely, the Pfizer-BioNTech and Moderna vaccines use mRNA that has been chemically modified to replace the uridine nucleotide with pseudouridine. This change is thought to stop the immune system reacting to the introduced mRNA.

The Covid-19 pandemic has allowed Pfizer and BioNTech to develop a strong partnership, with Pfizer providing its antigen research and BioNTech providing its proprietary mRNA platform technology. Such has been the success of their mRNA Covid-19 vaccine that the two have agreed to develop an mRNA-based vaccine for another viral infection, shingles. This is a widespread and painful condition triggered by the same virus that causes chickenpox. Clinical trials are expected to start in the second half of 2022.

This will be the third collaborative project for the two companies – in 2018 for influenza, 2020 for Covid-19 and now 2022 for shingles. Pfizer is making an equity investment worth $150 million for this latest deal and BioNTech will receive $225m upfront. BioNTech is also currently developing an mRNA vaccine targeting malaria. And in late January, Pfizer and BioNTech announced they have begun enrolment for a clinical trial to evaluate their novel, Omicron-specific vaccine for Covid-19. A day later, rival Moderna did the same.

These mRNA vaccines – big business using startling technologies with life-enhancing and life-saving possibilities.

One new vaccine

Pfizer-BioNTech and Moderna are not the only duo in the Covid-19 vaccine trade. Recently, two other companies, the manufacturer, Bharat Biotech and Ocugen, the distributor, based in India and the US respectively, have applied for regulatory approval of their Covaxin vaccine by the US Food and Drug Administration (FDA).

Covaxin appears to have at least four advantages. First, it has already, on 3 November 2021, received authorisation for emergency use from the World Health Organization (WHO). Second, Covaxin has been shown to possess high antibody neutralising activity, similar to the mRNA vaccines, against both Delta and Omicron. Third, for those who are cautious about the newish technology of mRNA vaccines, Covaxin is an old-school, inactivated virus vaccine. Fourth, while some other vaccines have a remote link to abortion via testing on foetal cell lines, Covaxin has no such connection in production, development, or testing.

Dr Krishna Ella, the chairman and managing director of Bharat Biotech, declared in an upbeat statement that, ‘Our goals of developing a global vaccine against Covid-19 have been achieved with the use of Covaxin as a universal vaccine for adults and children.’

However, controversy has arisen. According to Bharat Biotech, the vaccine was more than 90% effective in a late-stage, Phase 3, US-based clinical trial, but this was even before the Indian regulators had approved its use. The company has since published data suggesting 78% efficacy against Covid-19 of any severity. And a real-world study, published in The Lancet (23 November 2021), gave Covaxin an even lower effectiveness against symptomatic Covid-19 at 50%.

Not all vaccine trials are the same – treatments, dosages, patients, variants and other variables make testing and comparing vaccines a thorny problem. Manufacturers and regulators would do well to confer and to increase transparency and to assist with the proper interpretation of their data.

One new Omicron variant

On 21 January, the UK Health and Security Agency (UKHSA) announced that it was investigating a sub-lineage of the Omicron coronavirus that it had formally designated as a ‘Variant Under Investigation’ (VUI). It is known as Omicron BA.2 and nicknamed by some scientists as ‘stealth Omicron’.

The UKHSA has reported that, ‘Early analyses suggest an increased growth rate compared to BA.1 [the original Omicron variant], however, growth rates have a low level of certainty early in the emergence of a variant and further analysis is needed.’ However, BA.2 appears to be outpacing other forms of the variant around the world and is raising fears of an even more transmissible strain of the virus. By 21 January, some 426 cases of BA.2 had been detected in the UK, with the earliest dating back to 6 December. According to Dr Meera Chand, Covid-19 Incident Director at UKHSA, ‘So far, there is insufficient evidence to determine whether BA.2 causes more severe illness than Omicron BA.1, but data are limited and UKHSA continues to investigate.’

Meanwhile, according to scientists in Denmark, where BA.2 is dominant, it appears to be more contagious but not more severe than the more common BA.1 sub-lineage. Moreover, the UKHSA has recently reported that BA. 2 has now been identified in 40 countries.

Three new doubtful variants

With the possible exception of BA.2, so far in 2022, there have been no reports of new variants, or at least the potentially dangerous variants of concern (VOC). However, there have been three interesting and seemingly false alarms of such variants nicknamed ‘Deltacron, ‘Flurona’ and ‘IHU’.

During the first week of January, a team of scientists from Cyprus reported the existence of ‘Deltacron’, this novel Covid-19 variant that combines characteristics of Delta and Omicron. However, the claim has been widely dismissed as being a result of contaminated laboratory samples or laboratory processing errors, though some suggest that it could be due to a genuine mutation caused by a recombination of the two viruses.

According to Leonidos Kostrikis, professor of biological sciences at the University of Cyprus, he and his colleagues identified 25 cases of the so-called ‘Deltacron’ variant, which had resulted in the hospitalisation of 11 patients and 14 with less severe Covid-19. On 7 January, the scientists submitted their data to the GISAID global surveillance database which tracks changes in viruses – a further development is awaited.

Meanwhile in Israel, a 31-year-old pregnant woman contracted Covid-19 and seasonal influenza at the same time. It has been reported as the world’s first case of ‘Flurona’, a neologism of flu and coronavirus. The patient, who was only mildly ill, was not vaccinated against either Covid-19 or influenza. She was discharged without complications. However, this incident has led to fears of a possible ‘twindemic’, but in truth, it seems like a false media story that should worry no-one.

‘Flurona’ is neither a new, nor a single, viral variant. It is two viruses acting in tandem. It is a two-viruses-at-once condition. Indeed, such infections with two or more disease-causing organisms at the same time, correctly called a co-infection, are not uncommon. Specifically, cases of flu and Covid-19 appeared together in the USA during the spring of 2020. And in the same year, a Chinese study reported that 7 out of 257 Covid-19 patients also tested positive for influenza. If viral co-infections occur, the best advice is, get both treated, get both vaccinated.

The third suspected Covid-19 variant was first detected in October 2021 and was thought to have been introduced into France by a traveller returning from the Cameroons. The World Health Organization (WHO) classified it as B.1.640.2 and on 22 November 2021 designated it as a variant under monitoring (VUM), meaning its spread and severity would be repeatedly scrutinised and assessed.

By December 2021, it was reported to have infected 12 patients in France. It was temporarily dubbed the ‘variant IHU’ because a team from the Méditerranée Infection University Hospital Institute (IHU) in Marseilles, France were the first to report the variant in a pre-print paper entitled, ‘Emergence in Southern France of a new SARS-CoV-2 variant of probably Cameroonian origin harbouring both substitutions N501Y and E484K in the spike protein’ by Philippe Colson et al., in MedRxiv on 29 December 2021. Variant ‘IHU’ apparently has 46 mutations and 37 deletions in its genetic code, many of which affect the biologically-significant spike protein, including the familiar N501Y and E484K. Further testing to assess the virological, epidemiological or clinical features of this ‘IHU’ variant are ongoing. The French researchers, rather disrespectfully, did not submit their data to GISAID, the global surveillance database.

Both ‘Deltacron’ and ‘Flurona’ are less about serious aspects of Covid-19 and influenza than about the power of social media to create hyped stories based on meagre evidence. The WHO has subsequently reported that ‘IHU’ or B.1.640.2 has been spreading more slowly than Omicron and so it was of relatively little concern, so far. This is not unusual. There are scores of new Covid-19 variants frequently being discovered, but the vast majority are of no or little consequence with respect to human health.

Whatever the eventual outcome of these three reports about ‘Deltacron’, ‘Flurona’ and ‘IHU’ so-called ‘variants’, they can all be largely avoided by getting both Covid-19 and influenza jabs – ask your doctor for details!

And another antiviral

In mid-January, Molecular Partners, a small Swiss biotech company, agreed with Novartis, the giant Swiss drug maker, to in-licence its Covid-19 antiviral drug known as Ensovibep for 150 million Swiss francs (£120 million). It is being promoted as the first antiviral to attack the coronavirus’s spike protein not in just one, but in multiple ways. This multipronged attack suggests that it might work well against future highly-mutated variants.

In mid-December, Novartis had released some preliminary Phase 2 results that showed Covid-19 patients who took the therapy achieved a statistically significant reduction in their viral load over an eight-day study period and also had a 78% lower risk of being hospitalised or dying. Novartis had already reported that its Phase 1 laboratory studies indicated that Ensovibep could neutralise variants of concern including Alpha, Beta, Gamma, Delta and Omicron.

However, while these results look encouraging, there is a lack of information on safety data and protocols for use, such as dosage and timings of administration. But perhaps the biggest downside of Ensovibep is that the therapy needs to be given via an intravenous infusion, hence only in a medical environment. Whereas the Merck and Pfizer antivirals, molnupiravir and Paxlovid, as more convenient pills, can be administered anywhere.

On the plus side, Ensovibep belongs to a new class of drugs called DARPins (Designed Ankyrin Repeat Proteins), which can be manufactured relatively simply, cheaply and in bulk. Novartis is therefore emphasising the potential of Ensovibep for large volumes at lower cost, for equitable access across Africa, Asia and Latin America.

Novartis is now preparing for a 1,700-patient clinical trial of Ensovibep around the world. And there are plans to apply for emergency use authorisation in the US and for talks with European agencies too.

And another antibody

Covid-19 treatments as alternatives to vaccines are big business. Think of the potential numbers of patients. The hunt is up and running. Antibodies seem like sensible candidates since they are dominant components of the remedial immune system.

David Veesler thought so too. He and his colleagues at the University of Washington, Seattle, have taken a pragmatic approach to finding a suitable monoclonal antibody. They searched the blood of an infected person, the so-called convalescent plasma approach, for antibodies that bind to the Covid-19 spike protein, the gateway which lets the virus enter human cells. They found one particularly potent antibody, called S2K146, which protected cells from infection by the original strain of Covid-19 as well as the Alpha, Beta, Delta and Kappa variants and more recently, in a separate study, the Omicron variant too.

This is very preliminary work. However, administering S2K146 to hamsters infected with Covid-19 greatly reduced or eliminated replication of the virus. In addition, the team found that mutations that prevented S2K146 from binding to spike protein also rendered Covid-19 much less effective at infecting cells. Maybe variants will be less likely to mutate in order to escape the effects of S2K146.

This research has been reported as ‘Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry’ by Young-Jun Park et al., published in Science, 6 January 2022.

So, here is S2K146, another monoclonal antibody treatment, maybe, along with GlaxoSmithKline’s Sotrovimab and AstraZeneca’s Evusheld, and numerous others already in early trials. S2K146 may yet prove to be effective in treating and preventing Covid-19. Time and money and commitment and enthusiasm are required to bring it to fruition, but S2K146 does appear to be an ideal candidate for clinical development.

The nocebo effect

Nobody likes having a vaccination jab. And vaccinations often come with adverse effects. Common reactions to Covid-19 jabs are headaches, short-term fatigue and arm pain. Now American scientists have reported that more than two-thirds of these side effects can be attributed to a negative version of the placebo effect rather than the vaccine itself. They call it the nocebo effect.

The scientists examined data from 12 clinical trials of Covid-19 vaccines and found that the nocebo effect accounted for about 76% of all common adverse reactions after the first dose and nearly 52% after the second dose. These reactions were evidently caused not by the vaccine per se, but by other factors including anxiety, expectation and wrongly attributing various ailments to having had the jab.

This work has been reported as, ‘Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials: A Systematic Review and Meta-analysis’ by Julia Haas et al., in JAMA Open Network (18 January 2022).

The researchers think that better public information about nocebo responses may improve Covid-19 vaccine uptake by reducing the concerns that make some people hesitant. ‘But’, they say, ‘we need more research.’

Five Covid-19 jokes

It is said that humour is an essential coping tool for surviving tough times. On the basis that shared laughter can apparently give strength in adversity, here are five Covid-19-related jokes. Sincere apologies to those who may find them gratuitous – they are included with only good intentions.

I would make a Covid-19 joke, but it would be tasteless.

Has Covid-19 forced you to wear glasses and a mask at the same time? You may be entitled to condensation.

Why did the chicken cross the road? Because the chicken behind it didn’t know how to socially distance properly.

What’s the difference between Covid-19 and Romeo and Juliet? One is the coronavirus and the other is a Verona crisis.

Day 7 isolating at home and the dog is looking at me like, ‘See? This is why I chew the furniture!’