Coronavirus update – Part 18 (April 2022)

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

Somewhat disturbingly, sources of Covid-19 information have been drying up. Until this month, most newspapers and media outlets published daily Covid-19 reports and figures. They have since mostly disappeared. Now the most consistent and readily-available source of global information is the Johns Hopkins Coronavirus Resource Center (CRC) in Baltimore, USA. Indeed, there is concern that the UK government no longer wants to talk about Covid-19. What has happened to that no-nonsense, medical double act of Chris Whitty and Patrick Vallance? Is this a case of ignoring the problem in the hope it will go away?

So is Covid-19 really on the way out? Currently, the UK key metrics – cases, hospitalisations and deaths – are mostly trending downward. In mid-April, the Office for National Statistics (ONS), perhaps the most reliable data source in the UK, reported that the number of people who currently had Covid-19 in the UK was continuing to fall, by about 15% on the previous week. Even so, in late April, around 3.76 million are still infected – about one in every 17 people – so the levels of infection are lingeringly high.

Hospitalisations are decreasing. They currently stand at about 14,000 admissions with 320 patients on ventilators, whereas in March the figures were 18,500 and 360. However, related deaths bucked the data trends and escalated to approximately 330 each day – the equivalent March figure was just 150. In Easter week it was announced that UK deaths from, or with, Covid-19 had passed the landmark figure of 170,000. It now stands at about 174,000.

Globally, the picture remains mixed. Some European countries are now seeing a slower increase in new cases, or even a decline. Nevertheless, the region is still reporting over 0.5 million cases every day. Huge infection surges are occurring elsewhere. For example, China is on the verge of serious upheaval with cities, such as Shanghai and Beijing, imposing strict lockdown rules. And by late April, the total global cases stood at 510 million, total deaths at 6.2 million and total vaccinations administered at 11.3 billion.

Germany and South Korea have taken over the top spot of the infection table with a daily average of approximately 170,000 cases, followed by France with 116,000 and Italy with 63,000. The UK has slipped to eighth position with 39,000. The USA still dominates the total death table at 992,000, followed by Brazil (662,000) and India (522,000) with the UK in seventh place at 174,000.

Is the Covid-19 pandemic outlook appearing a little rosier? Yes, but no. Yes, cases do seem to be lessening, at least, in some parts of the world. No, they are definitely increasing, at least, in other parts of the world. The refrain is unremitting – this Covid-19 pandemic is not over. Much of the world is still in its grip.

The UK Covid-19 Inquiry

Consider the response to Covid-19 in the UK – what went right, what went wrong? These hotly-debated questions began unofficially long ago in the family hub, the sports club, the local pub and elsewhere, but the start of the official UK Inquiry was announced on 12 May 2021. Its chairwoman is The Right Honourable Baroness Heather Hallett DBE. She is a lawyer, who rose to become Vice-President of the Court of Appeal Criminal Division in 2013. In 2019, she retired and was made a crossbench life peer. She has vast experience in conducting high-profile inquests, inquiries and reviews, such as acting as coroner for the July 2005 London bombings.

The Covid-19 Inquiry’s remit is, ‘to examine the UK’s preparedness and response to the Covid-19 pandemic, and to learn lessons for the future.’ It started with a four-week public consultation on its draft Terms of Reference which ended on 7 April 2022. Currently, over 20,000 responses from people and organisations are being analysed – a summary is expected to be published in May. That will shape Baroness Hallett’s recommendations to the prime minister so that the final Terms of Reference of the Inquiry can be established and the topics for the Inquiry’s investigations can be set, probably again in May. In the meantime, Baroness Hallett and her team have met with over 150 bereaved families and numerous representatives from a wide range of interested groups, including long Covid survivors, children, faith leaders, scientists, key workers and many more.

Typically, a public inquiry focusses on three major questions. First, what happened? Second, why did it happen and who was responsible? Third, what lessons can be learned? Once the Terms of Reference are finalised, this Inquiry will begin its work proper, requesting written evidence from government and other bodies. Public hearings are expected to start in 2023. However, the published outcome from the Inquiry will not appear for several years.

List of symptoms expanded

When the Covid-19 infections started some two years ago, a short list of symptoms was issued. There were just three – a high temperature or fever; a new persistent cough; and a loss of sense of smell or taste. As the pandemic developed, more symptoms became commonly observed and several groups began lobbying for an expansion to that list.

On 1 April 2022, the UK Health Security Agency published a revised list of ten extras. The full catalogue is now, a continuous cough; high temperature, fever or chills; loss of, or change in, your normal sense of taste or smell; shortness of breath; unexplained tiredness, lack of energy; muscle aches or pains that are not due to exercise; not wanting to eat or not feeling hungry; headache that is unusual or longer lasting than usual; sore throat, stuffy or runny nose; diarrhoea, feeling sick or being sick. Oh dear, who isn’t suffering from a few of these lurgies right now?

These criteria are not particularly diagnostic of Covid-19 and other respiratory infections, such as colds and flu, can exhibit very similar symptoms. Meanwhile, the official advice is, if you feel unwell with a few of these symptoms, you should rest, keep hydrated and maybe take analgesics, such as paracetamol.

These symptoms vary among patients, but a recent study has found that symptoms also vary according to which variant has been the infecting culprit. These observations were derived from a large cohort study entitled, ‘Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study.’ It was undertaken by Cristina Menni et al., and published in The Lancet (23 April, 2022, 399: 1618-1624).

Among the findings, involving 63,003 participants, were that vaccinated people infected with the Omicron variant had symptoms for 6.87 days on average, compared with 8.89 days for those with the Delta variant. Moreover, patients infected with Omicron reported a loss of smell less frequently and were more likely to have a sore throat and a hoarse voice than those infected with the Delta variant. And those infected during the Omicron wave were around half (47%) as likely to display at least one of the three ‘classic’ Covid-19 symptoms compared with people infected with Delta. And patients infected during the Omicron wave were 25% less likely to be admitted to hospital (1.9%) than patients infected during the period of high Delta prevalence (2.6%). These data suggest that infection with the Omicron variant is notably less severe than with the previous dominant variants.

Though the incidence of Covid-19 seems to be in retreat, at least in the UK, this new list of symptoms is more embracing, and although these were never intended to be diagnostic, they may encourage people to think that they may be infected with Covid-19. Counter to this, is the governmental-driven withdrawal of free lateral flow tests (LFTs) and their more accurate detection of infection. So, are you Covid-19-positive? Do you guess or test? For many, it is an unsatisfactory dilemma.

Moderna updated

As the Covid-19 pandemic has unfolded so have offensive vaccines. But their efficacies are always less than total and always subject to waning. Come on manufacturers, we want better and longer-lasting vaccines. The US-based company Moderna has responded with the announcement in mid-April of its updated Covid-19 vaccine, known as mRNA-1273.211.

This Moderna upgrade was designed as a booster against two variants, the original Wuhan strain of the virus and the Beta strain, first identified in late 2020 in South Africa. Now it appears to provide better protection against Omicron and other variants.

The initial Moderna product was an mRNA vaccine based on the Wuhan spike. This latest version is a bivalent vaccine because it includes two varieties of mRNA, derived from the spike proteins of the Wuhan and the Beta variants. In trials, volunteers inoculated with the new booster produced about twice the number of antibodies against the Beta, Delta and Omicron variants one month after their jab, compared with people who received the original Moderna vaccine. After six months, the new booster remained more effective against Beta and Omicron. These results were published as a preprint entitled, ‘Safety, Immunogenicity and Antibody Persistence of a Bivalent Beta-Containing Booster Vaccine’ by Spyros Chalkias et al., in Research Square on 15 April 2022.

This novel vaccine strategy, more tailored towards particular variants and maybe more than one at a time, may signal a new generation of vaccines and a better way of tackling Covid-19. After all, annual influenza jabs typically generate immunity against up to three different influenza strains in one vaccine dose. As the Moderna researchers conclude, ‘These results indicate that bivalent booster vaccines can induce potent and durable antibody responses providing a new tool in response to emerging variants.’ Indeed, better and longer-lasting vaccines may be on the horizon.

Valneva approved

In mid-April, the Valneva vaccine (technically known as VLA2001) became the sixth Covid-19 jab to be approved by the Medicines and Healthcare products Regulatory Agency (MRHA) for use in the UK as long as its recipients are aged 18 to 50 years, with their first and second doses taken at least 28 days apart. Back in 2020, the Pfizer-BioNTech jab was the first to be approved and this was followed by the Moderna, Oxford-AstraZeneca, Janssen and Novavax vaccines, although the latter two are not currently available in the UK. Nor, somewhat strangely, is this approved Valneva vaccine – in September, the UK government cancelled its contract to buy some 140 million doses over allegations of agreement breaches.

Valneva is manufactured by the French pharmaceutical company of the same name. Unlike the other five UK-approved Covid-19 vaccines, Valneva is an inactivated whole-virus vaccine, which means that the live Covid-19 virus is grown in a laboratory, inactivated so as to be incapable of infecting human cells, combined with two adjuvants, alum and CpG 1018, to induce higher antibody levels and then administered to patients to trigger their immune responses. There is evidence to suggest that such vaccines, based on this more traditional technology of inactivated whole viruses, and with long-term usage in vaccines against polio, hepatitis A and influenza, may result in broader immune responses than those that involve only the spike protein, and that they may also be more effective against new Covid-19 variants. Furthermore, Valneva can be stored in a standard refrigerator.

Herein, is this rather weird, even gloomy, saga. Yes, Valneva is a safe and effective vaccine, but No, you cannot have a jab of it because of some bureaucratic quarrel. Perhaps in some ways, none of this matters. The UK’s population is already fairly well vaccinated, especially among its elderly and vulnerable. And there are other suitable vaccines currently readily available. On the other hand, Valneva and its traditional manufacturing procedure may appeal to the vaccine hesitant. And Valneva may yet find a major role in low-income countries because of its ease of transport and storage.

Yes to monoclonals, no to ivermectin

‘The earlier, the better’ is a catchphrase that applies to much of human life, especially to medical treatments. And so it does to monoclonal antibodies in relation to Covid-19 remedies. A recent analysis of data from 37 relevant clinical trials, looking at timing and dosage, produced this clear message – the earlier people get this type of treatment, the better they fare. The work entitled, ‘Determinants of passive antibody effectiveness in SARS-CoV-2 infection’ was carried out by Eva Stadler and her colleagues mostly from the Kirby Institute, New South Wales, Australia, and was published as a preprint in medRxiv on 22 March. They concluded, ‘However, we find that effectiveness of passive antibody therapy in preventing clinical progression is significantly reduced with administration at later clinical stages.’ In other words, the earlier, the better.

Monoclonal antibodies are very effective at keeping people with Covid-19 out of hospital. Early treatment can reduce the risk of hospitalisation by around 70%. Stadler and co-workers also reported that such synthetic antibody therapies might function at doses lower than currently recommended. Doses up to 1,000 times lower than typically administered can still achieve high, around 90%, efficacy. Given the exorbitant costs of monoclonal antibodies, this could be good news since it should allow a more widespread usage at a lower cost.

The bad news is that of the six monoclonal antibodies the researchers studied, only two were likely to be effective against the BA.2 version of Omicron. They predicted that imdevimab and sotrovimab were only 60% and less than 20% effective against hospitalisation caused by BA.2.

In a different context, the anti-parasitic drug ivermectin has repeatedly been controversially recommended as an effective therapy for Covid-19. Several of the contentious issues have already been documented in Coronavirus – Part 12 (October 2021), yet some people, mostly vaccine opponents, still consider it to be a Covid-19 ‘miracle’ drug.

The results of a large clinical trial from Brazil should now dash all hopes that ivermectin has any benefit as a treatment for Covid-19. The trial was a gold-standard, double-blind, randomised, placebo-controlled trial with 1,358 participants. They were infected with Covid-19 and given either ivermectin (for 3 days at a dose of 400 μg per kilogram per day), or a placebo. The work was published as, ‘Effect of Early Treatment with Ivermectin among Patients with Covid-19’ by Gilmar Reis et al., in The New England Journal of Medicine on 30 March 2022.

The researchers concluded, ‘Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19.’ In other words, ivermectin had no significant effect on Covid-19 patients, specifically, it did not reduce a Covid-19 patient’s risk of ending up in hospital.

Will these results end the arguments over the effectiveness of ivermectin? Probably not. Numerous small-scale trials are still currently being carried out around the world. We await their data. Nevertheless, ivermectin has its champions no matter what.

Nasal Covid-19 vaccines

Talk about Covid-19 vaccines has focused almost entirely on the syringe-and-needle delivery method. There have been random references to nasal delivery, more in jest than reality. But since the wretched virus mostly enters the victim’s body up a human nose, perhaps a nasal-sprayed vaccine deserves more attention. After all, the virus has the spectacular ability to jump from one nose to another. Indeed, the next leap in coronavirus vaccine strategy could be nasal sprays.

Some have already taken up the challenge seriously. It is reckoned that there are a half-dozen Covid-19 nasal sprays currently in clinical trials across the world. For example, in early April, the Russian Health Ministry registered a version of its Sputnik-V vaccine as the world’s first nasal vaccine against Covid-19. It is expected to be available to ordinary Russians within the next three to four months.

The original Sputnik-V vaccine was developed by researchers at the Gamaleya National Research Centre for Epidemiology and Microbiology in Moscow. According to Alexander Gintsburg, the director of the Gamaleya Centre, ‘Laboratory tests show the Sputnik V protects against the Omicron in its ordinary injection form, and it will certainly be efficient in the nasal form.’ Maybe. Some hard experimental data will be more convincing.

Back to the UK. The following is a somewhat uncanny news story. Did you know that you can now buy a Covid-19 nasal spray from your local high-street chemist? For example, LloydsPharmacy has just begun selling its Viralize anti-viral nasal spray, online and in-store, for £15. It claims to irreversibly inactivate nearly 100% of multiple strains of the Covid-19 virus within one minute. Its active ingredient is sodium astodrimer, known primarily as a non-antibiotic treatment for bacterial vaginosis, but now with proven in vitro activity against the Covid-19 virus, though its mode of action is currently unclear and no in vivo data are available. Its efficacy, publicity and sales may therefore be regarded as premature.

And here is another. BHM anti-viral nasal spray is a joint product of Birmingham Biotech and the University of Birmingham. It is designed to help prevent the inhalation of infectious viruses, such as Covid-19. Its two main active ingredients are carrageenan and gellan gum – the former is a natural anti-viral derived from red seaweed and the latter is a polysaccharide gel. The product, a patented blend of natural ingredients named Norizite, appears to merely physically trap viral particles rather than exert any destructive neutralising action. Presumably inhaled viruses are removed with a sneeze.

The manufacturers have a rather flashy website laden with clichés. They are currently seeking Norizite distribution partners. But will customers actually pay for this nasal spray? It has no serious pharmaceutical activity and no human clinical trial data.

Omicron variants BA.4 and BA.5

Backtrack and recap. The global persistence of Covid-19 has been largely driven by the appearance of new variants of the original virus that was first reported in January 2020 at Wuhan, and technically identified as SARS-CoV-2. Like all viruses it is prone to mutate and variants, such as Alpha, Beta, Gamma and Delta, have circled and infected much of the world.

The fifth and latest variant of concern, known as B.1.1.529 or Omicron, emerged from South Africa in late November 2021. It has since mutated into an Omicron family of sub-lineages starting with BA.1 and BA.2. These are caused by small genetic changes, yet exhibit different properties, such as resistance to antibodies, and thus differences in Covid-19 severity and transmissibility. So, BA.2 is less severe but more transmissible than BA.1. BA.3 has been detected but has never posed a threat to human health.

Will there be a BA.4, BA.5 and BA.ad nauseam until a Sigma variant appears? An excellent question. And how will we know? Fewer case numbers and deaths do not necessarily mean good news of ‘lower risk’. Someone should be on watch and looking out for dangerous mutations. In the UK this task is handled by the COVID-19 Genomics UK Consortium (COG-UK). This is ‘a group of public health agencies and academic institutions in the United Kingdom created in April 2020 to collect, sequence and analyse genomes of SARS-CoV-2 [the infecting virus of Covid-19] as part of COVID-19 pandemic response.’

Another such lookout post is based at the Centre for Epidemic Response and Innovation (CERI) at Stellenbosch University in South Africa. There it runs one of the world’s strongest genomic surveillance programmes for Covid-19 mutations. It has recently recorded the appearance of the Omicron sub-variants called BA.4 and BA.5. During the last month, these have spread rapidly in South Africa and have been detected in at least nine other countries, including the UK and France. Should we be worried? Not really. Covid-19 cases and hospitalisations in South Africa have remained numerically stable, indicating that BA.4 and BA.5 pose no overwhelming threat to public health. But, of course, they could mutate and begin to evade human immunity and become a serious medical problem. For now, they are under the watch of bodies, such as the COG-UK, the CERI and the World Health Organization (WHO). As Tulio de Oliveira, head of CERI, says, ‘It’s just time to work carefully and diligently, but calmly.’

And that is how these particular mutations have been tracked. During the first week of March, the abnormal genome sequences of BA.4 and BA.5 that encode the virus’s spike proteins comprised around 5% of the 500 or so genomes sequenced in South Africa. By the first week of April, that proportion had risen to 50%. These sequences were documented as separate sub-lineages on the Omicron family tree and assigned their drab identities. A significant feature of both BA.4 and BA.5 is an amino acid mutation they share called F486V. This occurs on the spike protein in a location that operates like a door to infection – this is where antibodies from vaccines and prior infections can neutralise the virus by attachment at this location.

Such genomic sequencing information derived from novel Covid-19 variants needs to be handled carefully. The general public can be easily alarmed. Misleading news of new variants can leak out, cause shock and result in some health organisations adopting largely futile policies, such as travel bans that can cause more harm than good. ‘Watch out’ and ‘keep calm’ are the appropriate watchwords for genomic scientists and epidemiologists (and the general public).

Covid, iPhones and cars

Covid-19 has caused disrupting, even devastating, illness as well as death. Such events must not be belittled. However, not all of Covid-19’s trail of destruction has been so up-front and personal. Take two auxiliary problems that have, perhaps as yet, not been fully appreciated.

First, the Covid-19 crackdown has raised fears for the supply of iPhones. Oh no! The root of the problem is a global shortage of semiconductor parts – it’s a chip crisis. And the principal cause? As China battles its worst outbreaks of Covid-19 amid record numbers of deaths, strict rules have been imposed on the Chinese factories that account for about 50% of global smartphone production. The output of computers and other electronic gizmos have been similarly affected.

Second, are you looking to buy a car, either new or second-hand? Look away and think again. There is a pent-up, post-pandemic demand for most cars. And the cause is largely due to Covid-19. There is a huge supply-demand mismatch. Dealers have full order books but the pandemic has disrupted the manufacturer’s supply chains, primarily because of illness and absenteeism among workers. Prices of both new and used cars have increased by as much as 25% over pre-pandemic prices.

Do you really need all this new technology? Are you sure? Covid-19 may have indirectly helped you safeguard yourself from it.