Discouraging treatment news, so-so vaccine news, BA.5 triumphant, Anthony Fauci, Eric Adams, long COVID, the mirage of single-payer, and hot new conspiracy theories.
Treatment news
Whistling a happy Paxlovid tune: The FDA has now authorized American pharmacists to prescribe Paxlovid themselves, if they can’t reach a patient’s physician but the patient brings enough health records to demonstrate they can take it safely. In Italy, which claims to have one of the highest prescription rates in the world, only 28,000 coursesof treatment had been distributed as of July 5th, a mere 0.4% of the 7,822,349 COVID-19 cases reported since the drug first arrived; I can’t find US statistics, but in Israel during early months Paxlovid was prescribed in 0.8% of all adult cases, and only 2.6% of eligible cases. Also, contrary to the suspicion that vaccination might invalidate Paxlovid, it did lower hospitalization rates among older, vaccinated Israelis during the Omicron era – by 60% in one study, but only 38% in another.
Singing the Paxlovid blues: A large-scale study, available only as a preprint, reveals that post-treatment relapses are more frequent and more severe than previously thought. Nearly 6% of treated people had recurrent symptoms, as vs. 1% in Phase 3 trials, while 0.8% went on to require hospitalization. Though the FDA continues to advise against restarting Paxlovid, Anthony Fauci himself chose to take a second course when he experienced a rebound worse than his initial illness. Here’s a possible reason relapses have increased: the SARS-CoV-2 virus has been mutating to escape from Paxlovid. This is the worst COVID-19 news I’ve heard for months. Though perhaps I should emphasize that if I became ill with COVID-19 myself I would certainly take Paxlovid. If the virus becomes resistant to Paxlovid (not confirmed in one case report) then we’re left with remdesivir, whose multiple intravenous infusions can’t possibly be provided to masses of patients. There is an oral version of remdesivir, but frankly it’s not very promising. More bad news for Paxlovid: Pfizer has scrapped a study in average-risk patients, after early results were a wash.
Sabizabulin: There’s little news lately about drugs for inpatients – particularly unfortunate when hospitalizations and ICU admissions are rising in the US (more than doubling since new variants arrived, and much of Europe). Early results of a Phase 3 trial suggest this oral antiviral may be lifesaving, but there are several important caveats: 1) the results are preliminary; 2) the number of patients enrolled is small; and 3) the death rate in the placebo group was higher than expected, which could make the drug look better than it really is.
Vaccine news
Toddlers: One issue parents will face when choosing between Pfizer and Moderna vaccines is how sick the shot will make their kid. Moderna’s 25 mcg of mRNA gives, unsurprisingly, more side effects than Pfizer’s 3 mcg. Among toddlers in the Pfizer studies, more placebo recipients than vaccine recipients (5.2% vs. 4.9%) developed a fever, while for Moderna it was the other way around (10.6% vs. 18.9%). Ummmm… how come all those kids got fevers after getting shot up with salt water? In any case, the preschool vaccination campaign is fizzling. Despite endorsement from pediatric societies and pandemic pundits, only one in 5 American parents of little kids are rushing to get them vaccinated. I’m still not sure where I stand personally, but I was shocked to see a Florida pediatrician being punished for advocating the CDC’s position.
Second boosters, data: One new Israeli study documents that the first booster’s benefit is nearly gone after 3 months, contrary to hopes it would last longer than the primary series. Another, among elderly nursing home residents, found the second booster to protect well against even moderate COVID-19 and cuts mortality by 72%, with no waning over 11 weeks; this study has substantial methodological weaknesses, however. It seems the older and frailer the population the better the 4th shot works and the longer it lasts. A Swedish study among people over 80 reports that the second booster decreased total, all-cause mortality by 42%; the benefit against COVID-19 mortality was undoubtedly higher. There are some data from the CDC as well (slide 29 is above), suggesting that a second booster decreases the short-term risk of death from COVID-19 by 75% in people 50+. Italy is just about to open up eligibility to everybody over 60, and so many doses are lying around unused that they may let even younger people get a second booster if they want – as may the US.
Second boosters, upshot: Since we know that fourth dose only wards off infection for a month or so, and don’t know how long protection lasts against severe disease, I’ve been recommending people get it only if they’re facing a high-risk situation. But with cases and hospitalizations soaring over the last few weeks I'm starting to soften up. Maybe older people should in fact consider getting a booster now, anticipating yet another one in the fall. I’m still ambivalent, in part because a booster now will likely disqualify you from getting a bivalent booster soon after it arrives.
Pericarditis again: Moderna has been thought to cause about twice as much pericarditis as Pfizer in young men, with one case in about 10,000 second doses. Now a study from Ontario suggests both numbers are overoptimistic. With about 20 million vaccine doses and 300 cases of pericarditis to examine, they found Moderna’s risk to be five times higher. One in 3300 men 18 to 25 years old developed pericarditis following the second dose of Moderna, compared with one in 17,000 after Pfizer. The risk was lower if the second dose was delayed, so an 8-week interval might make sense in that demographic. A French study found slightly less dire numbers: one in 5900 second doses for Moderna, one in 21,100 for Pfizer.
Sanofi-GlaxoSmithKline: Their first stab at a protein-based vaccine flunked Phase 2, but now they’ve come up with a new two-dose one, adjuvated to be more potent. It’s bivalent, like Moderna’s latest, but mixes in the Beta rather than the Omicron variant. The companies summarize early top-line results of a Phase 3 trial as 63% efficacy against all symptomatic COVID-19 and, surprisingly, higher (72%) efficacy against Omicron. Not bad, but not as good as the similar Novavax. They don’t say how many Omicron cases were involved or, of course, how long protection lasts. I’m eager for a proper manuscript.
Valneva: I was shocked to see the European Medicines Agency authorize emergency use of this French company’s whole-virus inactivated vaccine for people between 18 and 50 without any Phase 3 trials, on the basis of “immunobridging studies” showing it stimulates more antibodies against the original Wuhan wild strain of SARS-CoV-2 than the AstraZeneca vaccine. Considering how mediocre the AstraZeneca vaccine is, that’s not saying much. And there’s no information regarding any Variant of Concern, much less Omicron. The EMA announcement mentions “limited data” but it doesn’t provide them.
Corbevax: India has given its definitive OK to a locally produced version of this famously inexpensive vegan/halal vaccine as a booster following two doses of Covishield (=AstraZeneca) or Covaxin (the vaccine developed in India). This is on the basis of Phase 2 studies, mislabled Phase 3, that show an unspecified increase in neutralizing antibodies against earlier variants and neutralizing antibodies in “most vaccinees” against Omicron. It’s a mystery to me why the American developers don’t do real Phase 3 trials – they shouldn’t be too difficult given how cases are soaring in many countries.
Omicron-busters face off: With Moderna on the verge of getting an Emergency Use Authorization for its anti-Omicron vaccine Pfizer is, predictably, on its tail. The economic stakes are high, now that both an FDA advisory panel and the World Health Organization are saying all future boosters should aim at Omicron (though one panel member has gone public with his skepticism). The FDA has even said that new boosters should directly target Omicron 4 or 5. It will be several months before those versions are available, though, so vaccines targeting the original Omicron spike protein might be rolled out first; the bivalent Moderna product actually induces a fairly good supply of antibodies against BA.4 and BA.5. Pfizer has one new vaccine in either hand: a monovalent one targeting only the Omicron BA.1 spike protein, and a bivalent one mixing in some of the original wild strain vaccine. According to Pfizer’s press release the monovalent version is better at inducing anti-Omicron antibodies, but unfortunately both are much less potent against BA.4 and BA.5. If given the chance I’ll grab whichever one comes around first, though it would be nice to see 1) some effectiveness data rather than just lab tests, 2) real manuscripts rather than press releases, and 3) a head-to-head comparison between Moderna and Pfizer.
AstraZeneca: A French group reports that the AstraZeneca vaccine was as effective as Pfizer and nearly as effective as Moderna in preventing hospitalization from the Alpha and Delta variants (91%, 91%, and 95% respectively). But we already know that AstraZeneca wears off even faster than the mRNA vaccines, particularly in older people. And, of course, Omicron is a whole new ball game.
CoronaVac: We had already had hints that Sinovac’s inactivated whole-virus vaccine loses its meagre punch quickly. That’s now confirmed by a Brazilian study: the effect wanes sharply by 3 months, especially in the elderly.
Lives saved: Imperial College London researchers have calculated that vaccines saved 20 million lives worldwide during the first year they were available. American research groups have variously estimated the number of lives saved by vaccines in the United States as 225,000 as of the end of September 2021 and 1,100,000 by the end of November – I have no idea why those figures are so different.
The Holy Grail: A British group is working on a new vaccine candidate that targets both spike and non-spike proteins and is specifically engineered to maximize T-cell immunity as well as antibodies. They don’t provide much in the way of details, and have only tested it as a booster in a handful of people previously vaccinated with AstraZeneca. According to Reuters, Pfizer-BioNTech is working on its own version of a universal anti-coronavirus vaccine, and maybe on another intended to block only serious disease, with plans to start human testing in just a few months. I looked through the Powerpoint the Reuters article seems to be referring to and couldn’t find discussion of these vaccines, but maybe I scrolled too fast through the 153 slides. In any case, hope springs eternal.
Tony the Great
If you’re curious about what Anthony Fauci has to say about on his history, the history of the pandemic, and what it was like to work with Donald Trump, click here.
Variant watch
It’s been long suspected that immunosuppressed people, in whom the virus can live on for many months, might be a breeding ground for variants. Now more evidence is piling up, including tying the Alpha variant to one specific person in England…
The hyper-contagious and hyper-immunity-escaping subvariants, BA.4-BA.5, are now officially dominant in both the United States (about 80% of new cases) and Italy (71% at last call). Even the official, lowball, Italian case count has more than quintupled in the last month. Rome hospitals are so overloaded that ambulances show up, if at all, as long as 6 hours after you call the emergency number.
Anecdotal Italian reports that rates of COVID-19 pneumonia are increasing, combined with a near doubling of ICU occupancy and deaths in the past month, suggest that Omicron 5 may be more aggressive than previous Omicrons. BA.5 certainly is even better at evading immunity, attacking many people who are triple-vaccinated and/or COVID-19 survivors.
Out of 169,233 COVID deaths in Italy since the beginning of the pandemic, 31,720 have been due to Omicron. “It's just a bad cold”???? Italy has already reinstated a mask requirement on public transport, and regions may be allowed to reimpose indoor masking. Rome’s Lazio region said 2 weeks ago it wants to, but for some reason it hasn’t yet.
Not only is Omicron good at escaping prior immunity, but it turns out that catching it after previous infections or triple vaccination leaves you with hardly any immune boost, via either antibodies or cellular (T cell) immunity. That’s one reason so many people are getting Omicron twice, and why the hope is vain that having a mild case now will protect you forever. And don’t forget about long COVID: “Not having got long Covid after a prior infection in the earlier waves offers no guarantee against getting it this time” – in fact, reinfection makes it more likely.
…Those new subvariants are coming ever faster and more furious. BA.2.75, thus far largely been confined to India, has additional mutations that make Eric Topol think it might surpass even BA.5 at infecting triple-vaccinated or recently-infected people. Then there’s BA.5.1 recombinant, detected in Europe and the US, still basically an unknown.
Worms in the Big Apple
I’ve thought for a while that New York City Mayor Eric Adams has cranial rectal uppitis when it comes to COVID-19, and now I’m sure. He already disregarded CDC advice back in May by refusing to reimpose indoor mask mandates in the face of Red Alert levels. Now city cases and swab positivity rates are soaring, hospitalizations have more than quadrupled since the end of March (rising by 61% in the last month), and all 5 boroughs are classified as High Transmission even according to the CDC’s lenient standards, which is supposed to make indoor masking imperative. So now has Adams ordered masking? Nope, he’s doubled down instead, quietly dismantling the entire color-coding alert system he himself had introduced in March, and closing down half of the city’s PCR testing centers. Astonishing!
Long COVID updates
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| Vagal stimulation via the ear |
Numbers:
According to a one recent CDC study, COVID-19 more than doubles the risk of developing a new health condition over the next year. Another even worse one found that about one in 5 Americans who has ever had COVID-19 still has symptoms to this day. In an English study of 76,155 community residents with self-reported COVID-19, 38% still had symptoms 12 weeks after their diagnosis (and 22% after 6 months).
Of 78,252 Americans who filed private insurance claims for long COVID during the first 4 months after it was recognized as a medical condition, more than 3/4 had never been hospitalized, and about 1 in 3 had previously been perfectly healthy.
In the Omicron subvariant era, when many people who survived previous bouts of COVID-19 are getting sick again, it’s particularly discouraging to learn that, as I’ve mentioned, repeat infections increase the risk of long COVID.
Hospitalized patients: In one British study, only 29% had returned to their previous state of health a year later. Half of American patients without previous cognitive difficulties had them a year later. And a frightening Chinese study of 2469 hospitalized patients found that 55% still had symptoms two years later.
Special cases:
Omicron: Everybody is itching to know whether the milder Omicron variant carries less risk of long COVID. According to the only available study, from the UK, the risk is in fact 25%-50% what it was from Delta. Oddly, they define long COVID as persistent symptoms after 4 weeks – longer follow-up is needed. Even more oddly, they included people who tested positive but were entirely asymptomatic. This makes the very low 4.5% rate after Omicron much less believable, since people without symptoms rarely develop long COVID.
Breakthrough infections: Do vaccinated patients have a lower risk of post-COVID-19 sequelae? The answer seems to be yes, but not by much. A large-scale Veterans Administration study found that fully vaccinated patients were 34% less likely to die during the months following their acute illness – sounds good – but only 15% less likely to develop long COVID. In a British systematic review 2 out of 8 studies found previous vaccination to give no benefit at all.
Patterns:
British researchers have developed a Symptom Burden Questionnaire (SBQ-LC) to assess how much various symptoms affect patients. Hopefully this will be useful in gauging progress over time, with or without treatment. I found the Appendix including the actual items and some patient reactions to them to be the most interesting part of the article.
The risk of developing Alzheimer’s disease or Parkinson’s disease has been found to double or even triple following a bout of COVID-19. Other infections can increase those risks too, but with COVID-19 being so extremely common its impact will be far greater.
American researchers who carefully assessed 60 outpatients an average of 7 months after acute COVID-19 found that 27% scored “extremely low” on tests of cognitive function, including many who didn’t complain of brain fog or memory problems.
An Australian team studying patients who had cognitive symptoms a year after COVID-19 claims to have identified a blood test (“kynurenine pathway metabolites”) that predicts brain dysfunction. They go even farther, hypothesizing that these metabolites might actually cause the thinking problems, and that treatment targeting the kynurenine pathway could be useful. I confess it’s all Greek to me.
Causes:
The three dominant theories remain: microclots clogging up small blood vessels, persistent live virus, or an immune system in overdrive. All probably contribute, though to different extents in different patients.
Microclots: one key study that I’ve mentioned but didn’t link to showed that patients with long-lived exercise intolerance have poor oxygenation of their muscle tissues, not because the lungs fail to get oxygen into the blood but because the muscles themselves fail to extract it. This was documented by performing a special stress test while patients had a catheter threaded into their hearts. And since poor circulation causes organs to shrink, the finding that the brain loses 2% of its substance following COVID-19 also supports the microclotting hypothesis.
Live virus: viral RNA has been found in the stool of 4% of COVID-19 survivors 7 months after their initial illness, indicating ongoing infection of the gastrointestinal tract. There is no reason to think that the virus doesn’t persist in other organs as well, suggesting, as I have said before, that antiviral drugs might have a role in treating long COVID. Now case reports of 3 long COVID sufferers hint at some possible benefit.
Immune system: An Australian group has shown that immune system overactivity persists for 8 months following mild-to-moderate SARS-CoV-2 infection. Another relevant study in mice, found that even mild COVID-19 infectionleads to immune hyperactivation involving the brain.
Treatment:
The STIMULATE ICP trial just now getting under way in the UK will assess 3 pharmacological approaches: the antigout and antiinflammatory drug colchicine, the anticoagulant rivaroxaban, and the paired H1- and H2-antihistamines loratidine and famotidine; those last two are more promising.
Two treatments have been proposed to help patients regain their sense of smell. One, the old-fashioned asthma drug theophylline added to saline nasal irrigations, has been tested in only a few patients. The other, an Italian package of “olfactory training” plus two dietary supplements, palmitoylethanolamide and luteolin, may actually help, though there’s no evidence yet that it impacts “brain fog,” as boasted by the Lazio medical association.
Does a dose of vaccine ease the symptoms of long COVID, as some early surveys reported? A large UK community study and a corresponding BMJ editorial basically conclude “sometimes, but don’t count on it.”
The English National Opera has come up with an intervention that supplements standard breathing exercises with singing! I love the idea, but their package seems if anything to help only psychological well-being, not exercise tolerance or shortness of breath.
Another cute one: American researchers have prepublished a pilot study claiming that 6 long COVID sufferers had fewer symptoms, especially “mental fatigue,” after 4 weeks of stimulating their vagus nerve through electrodes on the left ear.
Universal health care
Yale researchers have calculated that if the US had a single-payer healthcare system one in 3 deaths from COVID-19 would have been averted: 338,594 out of the 984,287 clocked as of the end of March 2022, with hundreds of billions of dollars in costs avoided. I and many others had hoped the pandemic would push the USA toward joining the rest of the civilized world and introducing a universal healthcare system, but, alas, it ain't happening.
In Italy, as in most other European countries,
- Nobody lost medical insurance along with their job (7.7 million Americans did in March-June 2020, along with 6.9 million of their dependents)
- Nobody paid a penny for COVID-19 testing or treatment (50 million Americans have medical debt related to COVID-19)
- Nobody had to put their coworkers at risk by going in to work sick (21% of American workers have no sick leave)
For many months paid sick leave in Italy covered not only anyone home with COVID-19 but also their contacts who quarantined for 14 days. But the money ran out at the end of 2020 and KN95 masking has unfortunately replaced quarantine.
My favorite new conspiracy theories
- COVID-19 vaccines cause monkeypox
- World Health Organization pandemic plans will steal power from governments
- Bird flu, a current problem for poultry farmers, is chicken COVID
- Bill Gates has been trying to vaccinate people against religion since 2005
- COVID-19 is actually snake venom
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