Christmas Joy or Christmas Panic?
I've rushed to publish this post, mainly to catch you up on Omicron but also to squeeze in some advice on safe celebration while there are still a few days to go before the holidays.
Molnupiravir: We now know in a word why the efficacy of Merck’s antiviral plummeted from 50% to 30% between the interim and final results of its major Phase 3 trial: Delta. The fairly good interim results were obtained on patients enrolled between May and early August, largely before Delta started rising in July and well before it took over the world. The lousy final results included patients enrolled in the Delta era, between August and October, in whom the drug apparently had virtually no effect. This means we can expect its current efficacy, in what are probably the last weeks of the Delta era, to be not 30% but close to nil. In the Omicron era? Nobody knows.
Paxlovid: Pfizer has announced that final results of their Phase 3 trial in high-risk unvaccinated COVID-19 outpatients are even better than the already excellent interim ones: treatment of high-risk unvaccinated patients within 3 days of symptom onset lowered hospitalization rates by 89%, treatment within 5 days by 88%. Since this trial began in mid-July, we can be sure Paxlovid, unlike molnupiravir, is effective against the Delta variant. Against Omicron? Again, nobody really knows, but Pfizer is optimistic based on laboratory studies. Interim results of a separate trial (EPIC-SR) in standard-risk unvaccinated and high-risk vaccinated outpatients seem promising, but I won’t discuss them before seeing some more definitive results. I’m eager for this excellent drug to be authorized for emergency use, but I share the concern that this could widen rather than narrow the chasm in COVID-19 outcomes between marginalized and well-off communities, due to limited access to testing and physicians – especially in the United States.
Boosters: The Israeli health system were the first to tell us that boosters 5 months after dose 2 restored full efficacy to the Pfizer vaccine in individuals over 60. Now they provide data saying the same thing for all ages. Out of nearly 5 million individuals 16 and up who had completed their primary cycle 5 months earlier, those who had a booster were 10 times less likely to be infected with SARS-CoV-2 and 18 times less likely to develop severe COVID-19, while those over 60 were 15 times less likely to die of COVID-19. Protection varied little by age, and began to rise just a few days after the shot. Another Israeli study, from a major insurance company, found death rates to drop by 90%. Both studies were during the Delta wave, so they have nothing to tell us about Omicron.
The mRNA derby: Moderna wins out yet again. In a study from the Mayo Clinic, people who had gotten two doses were 40% less likely to have breakthrough infections than those who had had Pfizer, even after age, date of vaccination, and medical history were taken into consideration.
Moderna: But in another arena Moderna’s the loser. They’ve had to drop a lawsuit against the federal government over the vaccine patent, yielding co-ownership to the National Institutes of Health. This should be good for the rest of the world, because Moderna has been particularly stingy about contributing to COVAX or otherwise getting vaccines to the developing world. Now the Biden administration can get going, provided it has the will.
Omicron: Judging from the number and type of its mutations, the Omicron variant seemed on the face of it more likely than others to escape the protection from current vaccines. Concrete evidence is arriving fast and furious. In South Africa, for example, a group of 7 young, healthy German visitors all fell ill with Omicron despite being triple vaccinated, 5 with Pfizer-Pfizer-Pfizer, one with AstraZeneca-Pfizer-Pfizer, and one with Pfizer-Pfizer-Moderna (full-dose). A good demonstration that the neutralizing antibodies an mRNA booster can induce against Omicron do not necessarily translate into protection against infection or illness.
We have particularly valuable data from a preprint performed in the UK, the country with more documented Omicron cases than any other outside South Africa (581 at the time of this study, more than 10,000 new cases every day now). Vaccine effectiveness against symptomatic Omicron illness could be estimated at 15 or more weeks after a second dose of vaccine: for AstraZeneca, protection was nil, for Pfizer, about 35%. A Pfizer booster increased it to 71% if the initial vaccine had been AstraZeneca, to 76% if it had been Pfizer. There were too few cases at that time to break down effectiveness by age group, but we can expect updates on that question soon now that the epidemic there is spiraling out of control.
I should mention that in this study Pfizer was actually very effective against Omicron in the short run – 88% during the period between 2 and 9 weeks after the second dose. This figure is a bit distorted because younger people were the ones most recently vaccinated, and the vaccine may be less effective in the elderly, but for the sake of argument let’s take that high effectiveness at face value. Since higher doses of medications generally last longer, this finding suggests in my mind the possibly crazy idea that simply hiking up Pfizer’s 30 mg dose, either to Moderna’s full-dose 100 mg or even to the 50 mg in a Moderna booster, might make its high efficacy against Omicron last much longer. That’s just my own thought, I’ve never heard or read anybody else saying it. The study also confirms what we already knew about vaccine effectiveness against Delta variant COVID-19 at 6 months after the second dose: it was 42% for AstraZeneca and 64% for Pfizer, hoisted by a booster to around 93%.
Another interesting study comes from a private insurance company in South Africa, that according to a press releasefound double vaccination with Pfizer to be 70% protective against hospitalization with Omicron disease, lower than the 93% against Delta but still respectable. But at age 70-79 protection was only 60%, and it could be even lower over age 80. Efficacy against all COVID-19 was 33%, very close to the UK figure. Few South Africans have received boosters, so this study couldn’t gauge their effect.
Are new vaccines or new versions of old vaccines necessary? As of December 15th Anthony Fauci was still saying no, because “Our booster vaccine regimens work against Omicron.” I’m not so sure of that. A 70% protection after a booster isn’t high enough to be reassuring. I do still believe that in the long run Omicron could be the variant from heaven, but I’m pretty scared of what we may have to expect in the next few months.
A particularly disgusting hoax
One can only respond to this craven headline by asking conservativebeaver, as Joseph Welch famously asked Joseph McCarthy in 1954, “Have you no sense of decency, sir?”
Here are the Bourlas together on November 11, the day after that headline:
There’s ever more confirmation that it’s highly contagious, and some interesting speculation as to some societal reasons. According to a South African government report the Rt, for COVID-19, a measure of the rate the disease is spreading in the population, rose from 0.8 late in the Delta wave – i.e. the epidemic was shrinking – to well over 2 now that Omicron is taking over. But that’s a young population with considerable prior exposure to SARS-CoV-2, so the rate of spread could be slower than elsewhere. And, in fact, confirmed Omicron cases have been doubling every 3 days in the UK, leading scientists to estimate that the Rt could be as high as 3.7, meaning every case infects about 4 others.
A laboratory study from Hong Kong has given us the first biological hints of why Omicron is so contagious. The researchers exposed surgical specimens of bronchial and lung tissue to the wild Wuhan strain and the Delta and Omicron versions of SARS-CoV-2 virus and watched what happened over 48 hours. Omicron multiplied much faster in bronchial cells, and much more slowly in the lung, which could explain both its sky-high contagiousness and its low virulence. Curiously, the Delta variant multiplied less quickly in the lung than the wild strain, even though it’s thought to cause more hospitalizations and more deaths per capita.
Denmark is up there with the UK in rates of Omicron, with the new variant already causing at least a third of new cases. As of December 12th there had been only 27 hospitalizations in Denmark due to Omicron, out of 2471 cases (about 1%). That’s encouraging, because the ratio of hospitalized patients to new cases in Denmark during this summer’s Delta wave was around 10%. But Danish scientists are concerned nonetheless, for 4 reasons:
- The new variant has spread thus far mostly in young people, who rarely get very sick
- COVID-19 patients often deteriorate a week or more after their symptoms start, and Omicron only arrived recently, so it’s early to judge
- Denmark is the most highly vaccinated country in Europe, but most Danes have had only two doses of vaccine, leaving them vulnerable to Omicron, and getting everybody boosted will be a logistical nightmare
- The variant spreads like wildfire, so even if the rate of severe disease is much lower than with Delta, the hospitals could be overwhelmed nonetheless
Imagine that wildfire burning its way through the US, where only 72% of adults have had even two doses of vaccine (the comparable figure in Denmark is 96%, in Italy 87%) and 15% of all adults – including 5% of those over 65 – have still not had a single shot.
We now have some proper severity data from a South African presentation, and they show death rates and other bad outcomes that are strikingly lower than in earlier waves of the pandemic despite climbing case numbers and hospitalizations. The graphs at the top are screenshots from the Powerpoint. Note that the denominator is always hospitalized patients, not all symptomatic COVID-19 cases or all infections. One explanation for the better outcomes could be that doctors are hospitalizing people who are not as sick; I think that’s unlikely. More relevant is that most South Africans have already been infected with SARS-CoV-2, judging from a seropositivity rate estimated at 60-70%, and that the population is particularly young (median age 28, as vs. 39 in the US and 47 in Italy), two reasons infected individuals are likely to have milder disease whatever the viral strain.
In the South African private insurer’s study, too, the disease seemed relatively mild, with a 29% lower hospitalization rate than in early 2020, and less need for ICU care (no figures provided), though it did seem Omicron might be a bit more aggressive in children than previous variants.
Yet more hints come from that cluster of German visitors to South Africa. Most had only common cold-like symptoms, and oxygen saturations remained normal, but 3 of the 7 did become short of breath despite being young and triple-vaccinated. This suggests that Omicron COVID-19 may not be trivially mild as has been hoped. Eighty-five hospitalizations and 7 deaths from Omicron, mostly in double-vaccinated individuals, have now been reported in the UK.
Predicting the future
The scary headline at the top about 75,000 deaths was only one of many. What’s the reality? If you look at the actual study they’re talking about, a collaboration between English and South African scientists, you’ll see the results are somewhat less dire. The researchers construct various models on the basis of various possible levels of vaccine efficacy and immune escape. Assuming immune escape to be high, as seems to be the case, their model estimates vaccine effectiveness against infection after an mRNA booster at 50%-60%. But on the basis of the real-world evidence from the preprint I just described, effectiveness is actually above 70%. And even more crucially, all their models assume that Omicron is just as virulent as Delta. Since all the evidence points to its being less virulent, all those dire predictions of hospitalizations and deaths will likely be adjusted downward. The authors cautiously call their report not a preprint but a work in progress, to be updated as more data become available.
However… Tedros Adhanom Ghebreyesus, the smart and non-alarmist Director-General of the World Health Organization, is warning that even if Omicron does cause less severe disease than Delta it is so contagious that it could still overwhelm health care systems if huge numbers of people get sick all at once – as I said above about Denmark.
Vast numbers of infections could wreak havoc on the economy, our healthcare systems, and our lives even if they are mild and even if countries don’t impose lockdowns, since all the swab-positives and their close contacts will be isolating or quarantining at home and unable to work. A giant pandemic of “long COVID” could also follow, since it can be caused by mild disease – perhaps even by asymptomatic infection, though I find the study that says so somewhat questionable, and it remains unpublished 9 months after being posted as a preprint.
What to do? What is obvious is that we need to vaccinate the unvaccinated like crazy, boost the vaccinated like crazy, have Pfizer and Moderna work like crazy on developing Omicron-specific vaccines, and intensify measures such as masking, ventilation, and distancing. I personally support even more drastic measures: institute Italian-style Green Passes everywhere (they are in the UK), close down restaurants and other public-facing businesses for several weeks (they are in the Netherlands), tell people to return to working from home if possible, quarantine people entering countries – or even US states – from high-risk areas, and seriously consider brief but stringent lockdowns.
Deck the halls
Plan on getting together with family on Christmas? On shaking a leg with friends on New Year’s Eve? Watch out, the coronavirus may be an uninvited guest. Holiday celebrations aren’t totally out of the question like last year, but caution is essential – Queen Elizabeth cancelled hers at the last minute. A few words to the wise I’ve assembled from here, here, and here, plus my own little grey cells:
- keep the guest list down, so seats can be spaced out at the table
- make sure everyone is vaccinated (with boosters if they’re 5 months out)
- everybody should do rapid tests that morning
- anyone with the slightest symptom should stay home
- party outdoors if weather permits
- everybody wash their hands when they come in
- leave a window at least partly open
- consider wearing masks when not actually eating or drinking
- consider investing in a portable HEPA air purifier: examples in the US and Italy
- hugs and kisses: try to resist the temptation
- separate unvaccinated kids from older adults
- no Christmas carols! (singing is the best way to spread droplets)
- be extra careful if anyone is over 65, chronically ill, immunosuppressed, or pregnant
- be extra careful if there’s high community transmission
- coming in by train, bus, or airplane? Wear KN-95 masks when travelling, grab bites quickly, open a window if you can…
- …and ideally self-isolate for 3-5 days before the event
My new favorite conspiracy theory
It's a total invention, of course.
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