Daily update Covid -19

Daily update Covid -19

Israel announced those over 60 and healthcare workers will be eligible for a 4th shot, 4 months from their 3rd. The UK said it wouldn’t change anything pre-Christmas but I note after Christmas things may change. Germany announced that from 28 December limits would return that restrict private gatherings to 10 people and nightclubs would close. Football matches from that date will also be played behind closed doors. "Coronavirus doesn't take a Christmas break," Germany's Chancellor Olaf Scholz said. Meanwhile Portugal ordered bars and nightclubs to shut from 26 December, and made working from home obligatory from that date until 9 January. Outdoor gatherings will be limited to 10 people. Bars and restaurants in Finland will have to close at 22:00 on 24 December, as the Nordic nation sees infections at a record level. For three weeks from 28 December, restaurants will have to close at 18:00 with limited seating. Travellers coming from the EU's border-free Schengen zone will have to show a negative Covid test.

The White House will distribute 500mn Covid tests for free next month. The first shipment of tests will arrive at some point in January, the White House said. Americans will be able to request that rapid tests be shipped to their home, free of charge, via a new government website. The new policy of handing out free tests mirrors that of other like Germany and the UK. Few countries, however, have taken the step of mailing tests to individual homes, instead requiring that people request the kits at a pharmacy, doctor’s office, or testing site.

In he UK, Omicron makes up 72% of cases in England for 19th December The peak total number is still for specimens from 15th December, with both Omicron and Delta now declining Omicron down from about 55k on 15th to 42k on 18th Delta from 43k on 13th to 19.4k on 18th:

There remains ongoing Omicron controversies. Median R-value across England is 1.28 for week ending 19th December Highest growth is in London, followed by East of England Highest infection rate is Lambeth (2937/100k):

https://archive.uea.ac.uk/~e130/R.html

But overall an encouraging lack of major growth in case numbers in the last 3 days (partly day-of-week effects, but one might have expected Omicron to swamp those given constant behaviour). Looking at what we might be able to deduce from the published proportions of Omicron combined with daily case counts. If the case counts are accurate (discussed below), then growth in new cases per day of Omicron in London has crashed, i.e. new cases are roughly constant:

Given the growth rate is what it is, a lower generation time would be good news, because it means R(Omicron) is lower and so changes in behaviour have a greater impact. (This is a nice explanation here for those interested:

https://plus.maths.org/content/epidemic-growth-rate

These are results of a secondary attack rate (SAR) survey from Test and Trace here:

https://www.gov.uk/government/publications/investigation-of-sars-cov-2-variants-technical-briefings

99% booster vax effectiveness vs hospitalisation; UKHSA test negative case control study for Delta:

https://www.gov.uk/guidance/monitoring-reports-of-the-effectiveness-of-covid-19-vaccination

Weekly new case numbers in the US to show concerning signs with last week’s 880,430 new cases up 17% from two weeks prior. This week regional numbers continue to reveal a mixed picture of infections throughout the United States compared to two weeks prior; new cases declined in the West (8% decrease), were flat in the Midwest (2% increase), increased by 34% in the South, and increased dramatically in the Northeast by 47%. With cases rising in much of the United States, especially in more northern states, it is now clear the United States is in another wave of COVID-19, likely driven by seasonality in colder regions, overall fatigue with nonpharmaceutical interventions, waning vaccine immunity (leading to more mild/moderate disease), and the unprecedentedly rapid spread of Omicron, although we remain uncertain of how large the wave will be. In the US, most samples are now Omicron:

Closer to home, this is UK cases confirmed using Taqpath PCR assay. S-gene target failure (SGTF) in purple is a surrogate for Omicron:

This is where the world vs SA is at re Omicron:

As expected in the US, following the recent upward inflection in new cases, hospitalizations also trended upward and increased 15% from two weeks prior to 68,801 patients. While hospitalizations are trending upward, I note that the current rate is much slower than rates observed during prior COVID-19 waves: in early August during the summer 2021 Delta-driven wave, hospitalizations were increasing by over 17,000 patients per week, significantly greater than the most recent week when hospitalizations increased by only 3,000 to 6,000 patients compared to the prior week. While still early in the wave, we believe the lower rate of new hospitalizations is an early signal that widespread vaccination is blunting a large flow-through to hospitalizations. Breaking down hospitalizations by region, compared to two weeks prior, hospitalizations trends are mixed throughout the United States: while hospitalizations declined slightly in the West by 5%, hospitalizations increased by 10%, 19%, and 19% in the Midwest, South, and Northeast, respectively. Over the week, 8,278 new deaths were recorded, up slightly (4%) from the week prior and up 7% from two weeks prior. While we will continue to track new case dynamics, which we view as a leading indicator of the COVID-19 trajectory, we believe hospitalization trends, despite being a lagging indicator, will be a more informative indicator of COVID-19 dynamics in the United States considering high rates of vaccination throughout the country, which should blunt a flow-through from new cases to hospitalized patients and make the pandemic more manageable:

With an unprecedented rapid spread, Omicron has eclipsed Delta to become the dominant COVID-19 variant within the United States, accounting for 73.2% of COVID-19 cases sequenced for the week ending December 18, increased from just 0.7% of all cases just two weeks prior, according to CDC “Nowcast Weighted Estimates”. For context, during the first week of April, the highly transmissible Delta variant accounted for just 0.1% of all sequenced COVID-19 cases in the United States (approximately 400-500 cases); eight weeks later, in early June, Delta rose to account for 14.7% of all COVID-19 cases; and by the end of June Delta had become the dominant COVID-19 variant in the United States. Given the rapid spread of the variant, moving forward we will be closely monitoring how hospitalizations flow through from new case growth in regions where Omicron becomes dominant as an indicator of the severity of disease caused by the variant, as well as vaccination rates, to ascertain the real-world evidence of the level of protection offered from available vaccines.

The combination of seasonality, waning vaccination immunity against mild/moderate disease and transmission, the still large number of unvaccinated adults and children, an understandable exhaustion with safety protocols, and rapid growth of the Omicron variant is leading to another spike in cases. However, with the rise in new cases, hospitalizations, and deaths, we reiterate that unvaccinated persons are carrying most of the risk. According to the CDC, during the month of October, unvaccinated persons had 5 times the risk of testing positive for COVID-19 and 14 times risk of dying from COVID-19; for hospitalizations, the cumulative COVID-19 associated hospitalization rate has been about 8 times higher in unvaccinated persons compared to those fully vaccinated. The risk disparity is even more striking when booster doses are included: during October, unvaccinated persons had a 10 times higher risk of testing positive for COVID-19 and a 20 times greater risk of dying from COVID-19 compared to fully vaccinated persons who also received an additional or booster dose.

As we see another wave of cases, oral antiviral therapies are quickly approaching the market. On December 16 the EMA issued advice on the use of Pfizer’s) oral SARS-CoV-2 protease inhibitor Paxlovid, which will guide use of the therapy for any country that approves the product for emergency use prior to an authorization. A rolling submission in Europe and in the United States is underway and I expect an approval early in 2022. Interestingly, the status of Merck’s oral antiviral Lagevrio (molnupiravir) is still under review by the FDA despite the 13-10 vote for approval at the November 30 Advisory Committee.

While the growth of the Omicron variant continues to be the focus, within this note we provide a full update on therapeutics and vaccines pertaining to the Omicron variant. From a therapeutics and vaccines perspective, we saw the first data on the mRNA vaccines suggesting that Omicron does indeed reduce the effectiveness of the initial two-dose series, but booster doses provide a significant increase in neutralizing ability against the variant, with in vitro data from Pfizer-BioNTech and Moderna showing their booster doses result in 25-fold and 37-fold increases in neutralizing antibodies against Omicron. Moderna also shared data from in vitro studies of its existing variant-specific vaccine candidates used as boosters, which showed similar increases in neutralizing antibodies in the sera of boosted patients against the Omicron variant. Discovery Health, the largest healthcare provider in South Africa, released an analysis of real-world data showing that two doses of the Pfizer-BioNTech vaccine provided 70% protection against being admitted to hospital with the Omicron variant, lower than the 93% protection against Delta, but still highly effective. While we note the caveat that the data was not peer reviewed, the study also showed rates of severe disease were lower in the early phase of Omicron. Beyond vaccines, we also got data on the neutralizing ability of two monoclonal antibodies—sotrovimab and Evushield—against Omicron, confirming that both retain activity against the new variant albeit with some level of diminished activity compared to the ancestral strain.

The global new case count continued to trend upward over the past two weeks, albeit at a more modest pace, with 4.5 million new cases in the week ended December 19, up 6% from the prior week and 4% from two weeks prior. The increase was largely driven by Africa (+19.7%), North America (+11.0%), and South America (+13.2%). However, while South Africa had been in the midst of a rapid surge in new cases coinciding with the emergence of the Omicron variant, new cases in the country have been sequentially lower in the most recent 4 days after peaking on December 15. Elsewhere, Europe saw only a modest increase of 4.3% over the prior week, while Asia saw modest decline of 2.1%. Given the continued growth in new cases in some regions, and the increasing prevalence of Omicron around the world, we expect several challenging weeks ahead as the spread of Omicron coincides with the holiday season.

Pfizer provided an update on its vaccine development program in children under the age of 5 years: in infants age 6-24 months, the 3 μg dose achieved non-inferiority to adults age 16-25 years on the key immunogenicity endpoint, but this endpoint was not met in children age 2-<5 years. Given these findings, and recent developments showing the importance of boosters to protect against Omicron, the companies plan to add a third dose to the trial, and expect to be ready to request an EUA in the second quarter of 2022.

Pfizer released final data from the Phase II/III EPIC-HR study of Paxlovid in high-risk adults that were consistent with the interim results, with a relative reduction in the risk of hospitalization or death for any cause of 89% compared to placebo in patients treated within 3 days of symptom onset, and by 88% in patients treated within 5 days of symptom onset. The company also released interim data from the EPIC-SR study of Paxlovid in unvaccinated adults at standard risk of severe disease (or vaccinated adults with at least one risk factor) based on data from 80% of enrolled patients, which failed to meet its endpoint of patient-reported, sustained alleviation of all symptoms for 4 consecutive days as compared to placebo, but did show a 70% reduction in the risk of hospitalization compared to placebo that was nearly statistically significant (p=0.051).

As a now triple-vaxxed person I am intent on living my life as normally as possible, which includes not unduly worrying about it or demanding others do so. And I would argue that expecting otherwise from me would make you functionally an anti-vaxxer. Your risk calculus might be different, but that’s all it is, a little back-of-the-envelope maths. Dealing with Covid is just acting as your own private actuary. That’s it. Your relationship towards Covid and the steps you take to mitigate its risks are fundamentally self-interested decisions that you should try to make as unemotionally as possible. Imagine my confusion, then, at the number of vaccinated people, almost all of them educated, liberal, and upwardly mobile, existing in a state of constant anxiety and dread over Covid, despite the fact that these feelings confer no survival advantage at all. While I have no issue with people feeling what they’re naturally feeling, I would argue that those with large platforms have a responsibility not to contribute to panic. Unfortunately, many people with huge followings are being remarkably irresponsible, openly spreading fear and engaging in baseless speculation about mass death. This despite the fact that almost all of them fall in demographic slices with low risk. The immense popularity of overstating one’s personal risk from Covid, and of structuring one’s whole life around that exaggerated risk, can’t be explained in logical terms. It can only be understood with the animal logic of the force that dictates the living conditions of our entire elite class: their competition against each other. And with this there’s this essay:

https://www.theatlantic.com/health/archive/2021/12/omicron-pandemic-giving-up/621004/

Bogost’s piece is an absolute classic, maybe the classic, in a particularly strange form of worry porn that progressives have become addicted to in the past half-decade. It’s this thing where they insist that they don’t want something to happen, but they describe it so lustily, imagine it so vividly, fixate on it so relentlessly, that it’s abundantly clear that a deep part of them wants it to happen. This was a constant experience in the Trump era: liberals would imagine that Trump was about to dissolve Congress and declare himself emperor, they’d ostensibly be opposed to such a thing, but they were so immensely invested in the seriousness and accuracy of such predictions that they’d clearly prefer for it to happen. And so, with Bogost here, that level of anxious catastrophizing always carries with it the quiet, throbbing need for the bad dream to come true. Covid is already bad, very bad. I am always so confused that so many people seem desperately to want it to be worse.

See the Vox piece linked to in the tweet above, where the headline reads: “The world as we know it is ending.” The person who wrote this wrote it on a functioning computer, passed it off to her superiors as part of a more-or-less unaltered business operation, and it was uploaded to the internet, where it can be accessed by billions of people wireless through the use of technologies that require an exquisite amount of collaboration across vast distances of geography and circumstance. In other words, the world as we know it is apparently ending in such a gentle way that the most basic economic, technological, and communicative infrastructures of our civilization are puttering along nicely. If you’re someone who is not predisposed to think that the world is ending, and people are flailing their arms and pointing at a society that seems to be functioning very similarly to how it always has, wouldn’t you just tune out all the doomsaying? You can’t keep ringing the bell over and over again:

https://www.vox.com/2021/12/16/22837830/covid-pandemic-climate-change-great-resignation-2021

Or take the casual statement, in this piece for the Ringer, that “Faced with a story about a pandemic that sweeps the globe and ends life as we know it, some will understandably balk at the prospect of reliving the last two years.” I have a, shall we say, somewhat less alarmist take on the last two years, where for the vast majority of the human species life as we know it has not ended:

https://www.theringer.com/tv/2021/12/17/22840768/station-eleven-show-book-review-hbo-virus-pandemic

Something like 5.3 million people across the world have died of Covid, which is indeed a tragedy. But the 1918 flu pandemic killed ten times that amount, when the world population was about a fourth of what it is now. Yet life went on. Institutions still functioned. There were stock markets, they held parades and fairs, people got married in grand halls. And the flu was very, very bad and it killed a lot of people. But what is the purpose of this kind of serial exaggeration of the impact on day-to-day life for the vast majority of people? At least 40% of those who catch Covid-19 never develop symptoms, a number that jumps to >60% among young adults. Maybe it’s higher with Omicron but more than 80% of symptomatic cases are mild. We have vaccines that have proven remarkably effective at preventing hospitalization and death, and though Omicron appears to spread more quickly we have no reason to believe it undermines those benefits of vaccination. The vast, vast majority of people are going to survive this pandemic, and the efficacy of Pfizer’s antiviral will fundamentally change treatment, lowering deaths, but they can’t make very much. I write all of this knowing that what I’m saying is responsible and buttressed by evidence. But the environment our media has created is so wildly sensationalistic and addicted to doomsaying that I get anxious just writing this. I’m afraid I’ll be called an antivaxxer for asserting the power of vaccines. Why do they want it to be worse?

I keep chewing on what function this disaster porn performs. It’s hard to say that it has any bearing on public health; does anyone think that the problem with the vaccine-hesitant is that they just haven’t been told loudly enough that Covid is bad? No. I do think that this worry is a performance, but I don’t think the unvaccinated are the audience. I think the audience is, as for so much of what these people do, their peers, other people in the broad world of the educated, the liberal, the upwardly mobile if not affluent, the very online. These people compete against each other relentlessly, habitually, ritualistically.

This basic observation has been made in several different context before: our striving class is made up of people who are raised to compete and who structure their emotional lives around competing with each other. They go through the grindhouse of competition, running themselves ragged for scarce seats in the kind of colleges they feel they simply must attend. When they get there, they grind out the best grades they can get and busily occupy themselves with clubs and activities that will help them assemble the best resume for jobs or grad school. They might get a masters degree, or maybe do an MSF/boy scouts role or the Peace Corps, but sooner than later they enter professional life in fields where education, attitude, and vocabulary are hugely important, sectors of the workforce where your ability to convey that you are A Certain Kind of Person is as important or more important than the quality of your professional output. And I find that, often, when they get to a certain station in life they have a kind of spiritual crisis because they now lack the structure and purpose that constant explicit competition provided. Academics, journalists, writers, researchers, non-profit bureaucrats, “consultants” of all kinds, PR reps, marketing people, professions that are filled with people who find as they ease into middle adulthood that they are materially comfortable but miss the simpler existence of trying to climb the ladder. So, they compete in less explicit arenas.

When this major international crisis arose, they felt a lot of legitimate fears and worries, which just makes them human. But when it became clear that the public health response to Covid involved denying ourselves things we wanted and enjoyed, including non-negotiably important things like in-person schooling and face-to-face human contact, they (subconsciously) saw an opening: if denial of human pleasures is virtuous, I can be more virtuous than my peers. If caution is noble, overcaution must be even nobler. Elizabeth Currid-Halkett’s book ‘The Sum of Small Things’ lays out the essential psychology brilliantly. As she demonstrates, changing norms among bourgie liberals has made conspicuous consumption crass, declassee. But the urge to compete, to win, trumps all. Thus, our striving castes have developed all manner of other signals through which they subtly assert their superior virtue, their superior lives. Covid now fills such a role. With Covid, you never need an excuse to assert your superior seriousness, never need to wait for the right moment to insist that you’re doing it better than all of your peers. You can just openly tell the world “I am more responsible than you,” and the circumstances seem to justify it, even if the behaviour is not in fact justified by The Science (like, say, by masking outdoors in regular conditions.) Currid-Halkett calls them the aspirational class. The point is not that they strive, we all strive, but that for this class of people striving is a end itself, not a means to an end. And so, something like Covid becomes more grist for the mill.

For some people, it seems, being more freaked out about Covid is quite like an I Voted sticker in their window. It’s another way to let everyone know that they have the greatest wealth of all, the wealth of superior character, of greater moral standing. They’re fond of pointing out those 5.3 million people who have died, in the midst of their self-aggrandising diatribes. I would perhaps invoke the dead in a different way: even this, even now, even them, you turn into yet another way to let the rest of us know how advanced you are.

The danger is far from over. But when we got the vaccines case rates decoupled from the rate of hospitalization and death. Therefore, if you are breathlessly reporting increases in case rates without reference to those other metrics, you are engaged in, yes, misinformation. For you normal people out there? Get vaccinated. Get boosted. Be smart.

Next, I note that the CDC recounts initial identification of Omicron in United States now: they published a paper in its MMWR reviewing providing some details on the early cases of Omicron in the United Sates. The first case of COVID-19 attributed to Omicron was identified in the United States on December 1, and as of December 8, a total of 22 states had identified at least one case of Omicron infection, including some that indicate community transmission. Among 43 cases with initial follow-up, one hospitalization and no deaths were reported. To accelerate detection of COVID-19 cases attributed to the Omicron variant until they are common enough to be reliably measured by routine genomic surveillance, enhanced surveillance was initiated through National SARS-CoV-2 Strain Surveillance on November 28 based on rapid screening for S-gene target failures (SGTFs) by PCR to flag for potential cases of Omicron. Of the 43 cases identified, 25 (58%) were in persons age 18-39 years. The earliest data of symptom onset was November 15 in a person with a history of international travel. Fourteen (33%) persons reported international travel during the 14 days preceding symptom onset or receipt of a positive test result. Thirty-four (79%) of these Omicron cases occurred in persons who completed the primary series of an FDA-authorized or approved COVID-19 vaccine ≥14 days before symptom onset or receipt of a positive SARS-CoV-2 test result, including 14 who had received an additional or booster dose; five of the 14 persons had received the additional dose less than 14 days before symptom onset. Six (14%) persons had a documented previous SARS-CoV-2 infection. The most commonly reported symptoms were cough, fatigue, and congestion or runny nose. One vaccinated patient was hospitalized for 2 days, and no deaths have been reported to date. Case investigations have identified exposures associated with international and domestic travel, large public events, and household transmission:

https://www.cdc.gov/mmwr/volumes/70/wr/mm7050e1.htm?s_cid=mm7050e1_w

Next, for more than a year now, scientists and clinicians have been trying to understand why some people develop severe COVID-19 whereas others barely show any symptoms. Risk factors such as age and underlying medical conditions, and environmental factors including socio-economic determinants of health, are known to have roles in determining disease severity. However, variations in the human genome are a less-investigated source of variability. Now the COVID host genetics initiative (www.covid19hg.org) report results of a large human genetic study of SARS-CoV-2 infection. The researchers identify 13 locations (or loci) in the human genome that affect COVID-19 susceptibility and severity.

Scientists already knew that human genetic variants can influence the severity of infectious diseases, including infection with SARS-CoV-2. The effects of genetic factors range from those of rare, high-impact mutations that can make the difference between an individual developing mild symptoms and life-threatening illness, to more-common genetic variants that only moderately affect symptom severity.

Even so, human genomic studies of infectious diseases remain scarce compared with those of other immune-mediated conditions, such as autoimmune disorders. There are several reasons for that. Chief among them is that infectious diseases are typically studied with a focus on the disease-causing microorganism, rather than the host. Moreover, human genetic variants usually have relatively small effects on infection outcomes compared with the effects of socio-demographic factors such as age or access to health care. Identifying these generally modest effects requires studies of large, well-characterized groups of people to produce sufficient statistical power to reveal the relevant genetic factors. Finally, unlike for chronic diseases, the window for characterizing the severity and outcomes of infectious diseases is often limited to a short period during which individuals are symptomatic.

The authors overcame these challenges by rapidly setting up a large, international collaboration when the pandemic started. This collaboration of around 3,000 researchers and clinicians includes data from 46 studies involving more than 49,000 individuals with COVID-19 and 2 million control individuals, with participants recruited from 6 ancestry groups and 19 countries. By acting swiftly, the authors could recruit symptomatic patients, and, by setting up international collaborations, were able to include enough participants to overcome statistical-power limitations. In addition, they tried to account for the role of socio-demographic factors by collecting data on some of the known risk factors, such as age and sex, and including this information in their statistical analyses.

To obtain comparable results across all 46 study groups, the authors defined 3 categories of analysis: infection, which included people with physician-confirmed, laboratory-confirmed or self-reported COVID-19; hospitalization, which consisted of individuals with laboratory-confirmed moderate to severe COVID-19; and critical illness, patients with laboratory-confirmed infection who were hospitalized and required respiratory support or died. To identify genetic variants associated with COVID-19 susceptibility and severity, the authors first compared the difference in the frequencies of millions of genetic variants between the people infected with COVID-19 and the control individuals in each study. They then combined the results from all 46 studies to increase the statistical power of their data.

Through this combined analysis, the authors identified 13 loci that were associated with SARS-CoV-2 infection and disease severity (Figure below), including 6 loci not reported in previous human genomics studies of COVID-19. Four loci affect general susceptibility to SARS-CoV-2, whereas nine were associated with disease severity. Two of the previously unassociated loci were discovered only when individuals with East Asian ancestry were included in the analysis, highlighting the value of including diverse populations in human genomics studies.

Figure. Identifying regions of the human genome associated with COVID-19 susceptibility and severity. The COVID-19 Host Genetics Initiative sought to identify genetic variants that account for the variability in individuals’ susceptibility to COVID-19, as well as in the severity of the disease. The authors compared the genomes of 49,562 individuals with COVID-19 (including 13,641 individuals who were hospitalized with the infection and, of those, 6,179 who were critically ill with the disease) with the genomes of around 2 million control individuals without known infection. This comparison pointed to 13 locations in the genome (loci): variants in 4 of these loci are associated with susceptibility to COVID-19, whereas variants in 9 others are associated with disease severity.

To better understand the biology of COVID-19 and the mechanisms that connect these loci to disease outcomes, the authors looked for genes that were in the proximity of each locus (that is, ‘candidate genes’). They identified more than 40 candidate genes, several of which have previously been implicated in immune function or have known functions in the lungs, suggesting that variants in the genomic regions highlighted by the authors’ findings might exert their effect on COVID-19 outcome through the respiratory system.

One such example is the gene TYK2. Variants of this gene can increase susceptibility to infections by other viruses, bacteria and fungi. In line with this, the authors reported that individuals who carry certain mutations in TYK2 are at increased risk of being hospitalized or developing critical illness from infection with SARS-CoV-2. Another example is the gene DPP9. The authors found a variant in this gene that increases the risk of becoming critically ill with COVID-19. Notably, the same variant can increase the risk of a rare pulmonary disease characterized by scarring of the lung tissue. Clearly patients can be simply divided like this:

This study by the COVID-19 Host Genetics Initiative represents a major milestone in our understanding of the role of human genetics in susceptibility to SARS-CoV-2; however, more work remains to be done. Future experiments should determine all the genes, signalling pathways and biological mechanisms that connect the genomic loci identified to COVID-19 outcomes. Moreover, despite the authors’ efforts to include genetically diverse study groups, about 80% of the participants are of European ancestry. Future studies containing a larger number of individuals from other ancestry groups are needed to ensure that the results apply to non-Europeans, and to identify other loci that might be associated with risk in people of other ancestries.

Another complex question that could not be addressed in the authors’ study is the combined effect of specific variants in the SARS-CoV-2 genome and variants in the human genome on disease outcome. Finally, as the authors mention, they could not fully control for all socio-demographic factors, such as access to health care. Although such non-genetic factors are unlikely to explain all the findings, they could bias some of the associations between genetic variants and disease outcome. Despite these limitations, the implications of the study’s results are far-reaching. This study is important not only for advancing our understanding of human susceptibility to COVID-19; it also underlines the value of global collaborations for clarifying the human genetic basis of variability in susceptibility to infectious diseases. Infections remain among the top causes of mortality in lower-income countries, and represent a growing global threat, owing to climate change, urbanization and rising population size. Human genomics can be an effective tool with which to understand the biological mechanisms that underlie immune responses to specific infections, to identify at-risk individuals and to develop new drugs and vaccines for existing or emerging infections:

https://www.nature.com/articles/d41586-021-01773-7

Now some work from the Gupta lab on the molecular biology of Omicron:

  1. Omicron Spike protein mediates deficient cell entry and is inefficiently cleaved compared to Delta spike. They tested viral entry mediated by Wild Type, Delta and Omicron spikes using a pseudotyped virus system, infecting primary 3D lung alveolar organoids:

  1. Omicron Spike protein induces relatively poor cell-cell fusion compared to WT and Delta. They expressed spike in cells stably expressing split GFP, so that Green signal could be measured over time upon cell-cell fusion and syncitia formation. The difference is significant.

  1. What does this all mean? Efficient infection of lung cells could correlate with severity of lung disease. Syncitia or fused cells are often seen in respiratory tissues taken following severe disease. Delta was very good at both, in contrast to Omicron.

 

  1. They also tested how well antibodies from vaccinated individuals neutralised Omicron v Delta. They found that Omicron was poorly neutralised after two doses of mRNA or Ad vectored vaccine compared to Delta, but that the third dose (mRNA vaccine) rescued this at an early time point:

  1. In summary, this work suggests that Omicron does appear to have become more immune evasive, but that properties associated with disease progression *may* be attenuated to some extent. The significant growth of Omicron nevertheless represents a major public health challenge:

https://twitter.com/GuptaR_lab/status/1471941645797146628

A group show that the Omicron spike confers very significant evasion of vaccine elicited neutralising antibodies that is more pronounced for ChAdOx-1 adenovirus vectored vaccine versus BNT162b2 mRNA vaccine. Indeed neutralisation of Omicron was not detectable for the majority of individuals who had received two doses of ChAdOx-1. Third dose mRNA vaccination rescues neutralisation in the short term. Despite three mutations predicted to favour spike S1/S2 cleavage, observed cleavage efficiency is lower than for wild type Wuhan-1 D614G and Delta. We demonstrate significantly lower infectivity of lung organoids and Calu-3 lung cells expressing endogenous levels of ACE2 and TMPRSS2 but similar infection as compared to Delta when using H1299 lung epithelial cells. Importantly, fusogenicity of the Omicron spike is impaired, leading to marked reduction in syncitia formation. These observations indicate that Omicron has gained immune evasion properties whilst possibly modulating properties associated with replication and pathogenicity:

https://www.biorxiv.org/content/10.1101/2021.12.17.473248v1.full.pdf

After facing setback after setback this year, the non-profit formed to make sure COVID-19 vaccines reach the poorest countries of the world may finally live up to its promise in 2022. A 14 December report shows that after scaling back its ambitions, the COVID-19 Vaccines Global Access (COVAX) Facility is close to meeting a revised target of 1.42 billion doses available this year. And today, the effort got a huge boost when the WHO gave an emergency use listing to a vaccine that COVAX is counting on for up to 1 billion doses next year.

Despite COVAX’s recent successes and its optimistic new supply forecast, delivering the prized shots to needy countries isn’t the last word in achieving global vaccine equity: many nations may still struggle to distribute their supplies and, in some cases, overcome vaccine hesitancy. “Supply still needs attention, but we have pivoted to delivery and absorption as the main issues,” says Seth Berkley, CEO of Gavi, the Vaccine Alliance.

Established by WHO, Gavi, UNICEF, and the Coalition for Epidemic Preparedness Innovations (CEPI), COVAX initially set a goal of vaccinating 20% of the population in every country—enough to cover health care workers and the people most at risk of developing severe disease. To accomplish this, COVAX said it needed to have 2 billion doses available by the end of this year. The COVAX forecasting report issued this week shows the effort will fall far short of that, with 1.38 billion doses available by year’s end:

https://www.gavi.org/sites/default/files/covid/covax/COVAX-Supply-Forecast.pdf

COVAX set out to buy vaccines in bulk and then provide them to 1.8 billion people in 92 low- and middle-income countries at little or no cost. But after COVID-19 vaccines first became available in December 2020, many wealthy countries ordered far more doses than they needed, bumping COVAX—which negotiates steep discounts—to the end of the purchasing line. COVAX also counted on the Serum Institute of India to supply up to 1.1 billion doses, but it backed out of the arrangement in March in order to protect India during its Delta variant surge. But supply steadily increased as wealthy countries began to donate excess doses and more manufacturers received emergency use listing (EUL) authorization from WHO, a COVAX requirement. Last month, Serum also began to export again. And a few days ago, WHO issued an EUL for the Novovax vaccine made by Serum, the ninth COVID-19 vaccine to receive the designation.

The current COVAX forecast projects it will have made 2.39 billion doses available by March 2022. It has options for a total of more than 6.5 billion doses by the end of next year. “I think we’re at a tipping point of the problem being demand-driven versus supply-driven,” says Nicole Lurie, the U.S. director of CEPI.

For now, the vaccine disparities between rich and poor remain stark. As of 16 December, 56.5% of the people in the world have received at least one of the 8.56 billion doses of COVID-19 vaccines that have been administered, according to OWID. But in low-income countries, that figure drops to 7.5%—and plummets to 0.2% in Burundi, the lowest of the low. And the large numbers of doses soon to be “available” may not boost those figures quickly. The supply forecast number is certainly important to track, but it is not the most important measure of how many people are actually getting access to vaccines from COVAX.

Once manufacturers offer the vials, COVAX must allocate them, based on requests from countries and their ability to “absorb” the shipments. There’s a 4- to 6-week lag between availability and delivery, which means at most, COVAX will deliver a total of 1 billion doses this year. Half of their 92 priority countries now have access to enough doses to cover more than 20% of their population. High-income countries that donate vaccines often don’t give recipient countries a timeline for delivery and sometimes provide vials that are near their expiration dates, making it difficult to administer doses in time, he says. And COVAX leadership is diffuse, with four institutions jointly coordinating different aspects and no one person running the effort. The attempt to vaccinate the world is going to run into more intractable problems than the supply issue.

Political instability afflicts countries that have the lowest COVID-19 vaccine coverage, whereas others have yet to express much demand. After leaders dismissed the pandemic for most of the year, Burundi had not even signed the paperwork to join COVAX by mid-November. There are many settings where COVID is just not the priority. Also, COVAX recipients have also become increasingly discriminating about the vaccines on offer. Now with all these different vaccines out there and countries expressing preferences for some vaccines and saying which ones they don’t want, it’s a bigger and bigger challenge: ‘We want the same vaccines used in America.’ Vaccine misinformation and the attendant scepticism and hesitancy have also become global challenges.

COVAX is now moving away from trying to do a blanket distribution of vaccines to hit the 20% mark and instead focusing on helping the 25 countries that have the lowest coverage. But now having hindsight and experience we have the opportunity to really set up a system that will work, and the question is, is the world going to come together and have the appetite to do that so we never have to go through this again?


Justin Stebbing
Managing Director

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