Boosters, Blues, and Battling Long COVID

 

J. Wtewael, The Battle Between the Gods and the Titans

New Paxlovid studies, the lowdown on bivalent boosters, Titanic battles, the CDC blues, more on lab leaks, vaccine hooey, and for perhaps the first time ever some good news about long COVID.

Treatment and prevention news

 

Paxlovid efficacy: New examination of old data has cast doubt on the idea that it works better if started within 3 days than on days 4-5 – and some even think that very early treatment may increase the risk of post-treatment rebound. 

Symptoms: We do not know whether Paxlovid shortens illness or makes it milder, though the manufacturer has hinted it does not. Pfizer has abandoned its trial in average-risk patients, whose main goal was symptom relief, releasing very few results. But only now have I learned that in their main trial, about preventing hospitalizations in high-risk patients, they also gathered data on symptom duration and severity, but chose not to report those data in the published paper. Not transparent, and not encouraging. And, in case you’ve wondered, we know nothing whatsoever about whether Paxlovid reduces the risk of long COVID.

The large Israeli study showing Paxlovid does little for younger COVID-19 patients has now been properly published. The drug reduced the risk of hospitalization by 73% in people over 65, but by a statistically non-significant 26% in people ages 40-64, even though all those younger patients had multiple risk factors for developing severe disease. Patients who were over 70, incompletely vaccinated, or immunosuppressed were automatically eligible.

Antivirals are still vastly underused in Italy, being given lately to 0.65% of all diagnosed cases. Let me explain: 19% of recent cases have been in people over 70, of whom approximately 20% are mildly to moderately symptomatic, so at least 3.8% of diagnosed cases were eligible for antiviral treatment – add in patients 65-69 plus younger ones with high-risk medical conditions and I’m sure you’ll reach 5%, meaning only about 1 in 8 eligible patients gets treated. (Though, as above, younger patients get little benefit from Paxlovid even if they are at high risk.)

Fluvoxamine: Is my go-to prescription for high-risk patients who can’t get their hands on Paxlovid ineffective after all? That’s what a New England Journal of Medicine study has found, looking at outpatients whose only risk factor was being overweight or obese. The study was enough to convince both a NEJM editorialist and the writers of WHO guidelines. I’m not entire sure, because in two smaller randomized trials among truly high-risk patients fluvoxamine seemed surprisingly effective at reducing hospitalizations (74%) and mortality (33%), though so few patients reached those endpoints that the results were not statistically significant. But I confess I’ll be relieved to have an excuse to stop prescribing fluvoxamine, since few people tolerate its side effects at the recommended dose.

Convalescent plasma: In a 416-patient randomized trial in the Netherlands convalescent plasma failed to meet statistical criteria for success. But there are two important caveats. One is that it did cut the hospitalization rate by a hefty 39%, which fell short of statistical significance only because so few people became very sick. Secondly, the authors admit that the antibody titer of the plasma they administered was probably far too low. So we still don’t know whether this low-tech, low-cost intervention works.

Folic acid: Here’s a strange one: according to a large observational study from the UK, people taking folic acid, a B vitamin, were 51% more likely to get sick with COVID-19, and more than twice as likely to die if they caught it. 

Exercise: Might regular exercise help keep you from getting COVID-19, and help prevent severe disease if you get it anyway? That’s what’s hinted by a study from South Korea, confirming a recent meta-analysis. 

Vitamin D: New large clinical trials from the UK and Norway have found that, as I’ve always suspected, vitamin D supplements do nothing to prevent or mitigate COVID-19. An editorialist points out some caveats, of which in my opinion the most significant is that fully half the subjects in the UK placebo group were taking vitamin D supplements on their own.

Vaccine news

 

Bivalent vaccines: They’re hot news but, as they say on Facebook, it’s complicated. Even old-fashioned monovalent boosters have some activity against the Omicron BA.4 and 5 subvariants, but the next mRNA vaccine boosters against COVID-19 used in the USA and in Europe will for the first time all include two kinds of mRNA rather than one. A half-dose of the original vaccine, which targeted the spike protein of the original Wuhan wild strain, will be combined with a half-dose targeting the spike protein of an Omicron variant. Two that take direct aim at the twin BA.4-BA.5 subvariants, from Moderna and Pfizer, have not only been approved for emergency use by the FDA, but are already available in American and UK pharmacies and will soon reach Europe. 

Some have expressed doubts because of the lack of human Phase 3 trials. I’d remind them that yearly flu shots aren’t tested that way either, but are formulated according to experts’ best guess as to the next season’s dominant influenza strains. Usually the experts do OK, but sometimes (as in the 2021-22 season) their predictions are so far off that the vaccine is practically useless.

Others wonder whether targeting Omicron 4/5 is really necessary, given evidence that retooling against the original BA.1 Omicron variant might work pretty well too. Both Moderna and Pfizer mRNA vaccines with an Omicron BA.1 component have been shown to induce neutralizing antibodies against the BA.4 and BA.5 variants. But for the vaccines now on American pharmacy shelves, whose Omicron portion comes directly from the spike sequences of BA.4-5, we won’t even have antibody data until at least mid-September, weeks before the new vaccines are likely to arrive in Italy or elsewhere in Europe. So we folks on the far side of the pond will be better poised to decide which vaccine to get, and will have a broader choice than Americans. EU regulators and Italian authorities have already approved BA.1-spiked boosters from both Moderna and Pfizer-BioNTech. My bottom-line advice for Europeans is wait until those data come in before deciding which booster to choose.

As far as I know only one group, in Israel, is studying the real-life efficacy of any of these vaccines (specifically, the Moderna version with a BA.1 component). That study began during the dreadful BA.4-5 summer spike, so it has a chance of encountering enough cases to be able to assess vaccine effectiveness. But the impact of the bivalent vaccines will mostly need to be estimated post-hoc, months after the vaccines are rolled out.

In any case, with the pandemic showing no sign of disappearing and with all boosters somewhat protecting against severe disease and death, older or medically vulnerable people should definitely get a fall booster if they’re 2 or more months after their last booster or 3 months after a breakthrough infection. That will definitely include my husband and me. We’ve managed to escape infection for 2 ½ years now, and we plan to do everything we can to maintain that record, from masking and distancing to ventilation, HEPA filters, and vaccine boosters. As Eric Topol emphasizes in a review article on long COVID, “There’s only one surefire way to prevent Long Covid: not to get Covid.”

Various experts, including one featured in the New England Journal of Medicine and the FDA itself, avoid speculating as to how well the updated boosters will ward off infection, emphasizing their ability to prevent severe outcomes. I hope that’s just a case of deliberately setting low expectations.

Should I mention that the American government is paying $26.36 for every dose of the updated Moderna booster and $30.48 for Pfizer-BioNTech, compared with $15.75 and $24 for the original versions. So it can only afford 66 million doses of Moderna and 105 million of Pfizer, enough to cover half the population, again for lack of funding. But to be honest the supply is unlikely to ever run out, given that only 40% of Americans have gotten any boosters at all (compared to 73% of Italians and 60% of Brits).

Self-boosting vaccines: This concept has generated some enthusiasm, but I don’t get it. What the technology seems designed to do is to release vaccines in dribs and drabs – perhaps allowing a vaccine that usually needs two shots 3-4 weeks apart to be given as a single dose instead. That’s not my idea of self-boosting.

Heterologous boosters: Starting with one vaccine and boosting with a different one isn’t a new idea but has been getting a bit more traction. Originally the concept was to top up mRNA vaccines with viral vector boosters, but the latter have been largely abandoned because of those pesky blood clots. Spike protein vaccines, specifically the Sanofi-GSK version, are now being tested as boosters to mRNA vaccines, with reports that they hoist neutralizing antibodies not just to wild strain and Delta variants but also to Omicron. We’ll see how this story unfolds.

Novavax: both EU regulators and the FDA have decided this vaccine must carry a warning about myocarditis and pericarditis as possible side effects. This is particularly unfortunate because it will be even less likely that no-vaxxers will flock to this vaccine because of its more traditional technology. 

School-age kids: In Singaporean children, the Pfizer vaccine was less than 40% effective for preventing Omicron infections, but more than 80% effective against hospitalizations. I wish they had tested Moderna, whose higher dose may work better.

Valneva: This whole-virus inactivated vaccine, made by a French company, has received the nod from the WHO on the basis of immunobridging studies showing it stimulates a somewhat stronger antibody response than the notoriously ineffective Astrazeneca vaccine, which isn’t saying much. Only people 18 to 50 were examined, heaven only knows why, so the vaccine is being recommended only in that age group. And the antibodies were against the original Wuhan wild strain, to boot! With no Phase 3 trials, no data on older people, and no data about any variants much less Omicron, this vaccine probably deserves a miss worldwide.

Leap or leak, redux

 

For me the lab leak theory was killed by the recent Science paper whose chief graphic I’ve pasted again here.

But now we have Columbia University economist Jeffrey Sachs to the contrary. He is not just 100% convinced the virus was created in a laboratory but thinks it’s not the Chinese but Americans who are chiefly responsible for covering up the evidence. In a Current Affairs interview laying all this out he also claims the NIH won’t release material about its bat coronavirus research. Isn’t it weird that Sachs, who is not a physician, epidemiologist, or virologist, came to be named as the head of The Lancet COVID-19 Pandemic Commission’s origins task force? For me the origin question has been settled, the NIH has been transparent, and the whole business about a furin cleavage site that’s supposedly key to the lab leak argument is less than meets the eye, but if you feel like taking a deeper dive into the whole controversy you might consider starting here.

Long COVID 

 

A hyperbaric chamber

Impact: “Long COVID-19 is keeping between 2 million to 4 million Americans out of work, according to an Aug. 24 report from the Brookings Institute.” Since about 16 million working-age Americans have long COVID and a high percentage of sufferers who are able to work have to reduce their hours, those depressing figures clearly underestimate the overall impact. Omicron probably entails a lower rate than Delta, but there have been so many cases that a long COVID epidemic may end up being its long-term legacy.

Hyperbaric oxygen therapy: I’ve already mentioned that HBOT sounded reasonable, and cited a promising pilot study. Now an excellent randomized study reports that it really does work. Patients who had been suffering for an average of 5-6 months improved in terms of brain fog, fatigue, sleep, and pain after 40 sessions of HBOT, 90 minutes each on 5 days a week, as compared with patients who received a sham procedure. Brain scans even showed improved blood flow to the brain. This is the most exciting long COVID news I’ve read for a long time if ever. Only problem for my own patients is that whereas in the US it’s not hard to get HBOT privately and off-label – for several hundred dollars per session – in Italy that’s not possible.

Autologous mesenchymal stem cell therapy: Harvested from a patient’s own fat or bone marrow and then replaced either into the nose or by intravenous infusion, stem cells are being touted as a treatment for long COVID in Russia, South Korea, and at least one, somewhat dubious-looking American center, in Colorado. Some theoretical mechanisms have been proposed, but there is zero published, preprinted, or even promised evidence in actual patients. One clinical trial promised by Sorrento Therapeutics was subsequently withdrawn and replaced by another protocol that had not started recruiting as of August 8th. Another trial is “no longer available.” A third was supposedly being planned last year by the American Cryostem Corporation, but is nowhere to be found in the Clinicaltrials.gov database. The Colorado center simply claims, “Our preliminary clinical evidence shows that our stem cell therapy has been effective for some of our long hauler patients. Those who saw benefits no longer experienced shortness of breath, heart palpitations, brain fog, or chronic fatigue.” How many is “some”? 80%? 10%? Their failure to provide even that basic number is suspicious.

Kids: I’ve ignored long COVID in children, partly because it’s so rare, but it’s worth mentioning that it seems to behave quite differently from long COVID in adults, with the most common pathology being myocarditis, inflammation of the heart muscle.

 

A depressing headline at the doctors-only website Medpage Today: “Most COVID-Related Smell, Taste Dysfunction Resolved at 2 Years.” Only most? Alas, yes. Italian researchers report that more than 1 in 10 patients who lost their sense of smell when they had mild COVID-19 hadn’t fully gotten it back two years later.

Legal battle of the Titans

 

C. van Haarlem, The Fall Of The Titans

The competition between Moderna and Pfizer/BioNTech is now adding a monetary plane to the scientific one, as the former sues the latter for patent infringement. CureVac is doing the same, while Moderna fights off similar suits in turn. The Moderna suit is apparently legally questionable because of Moderna’s pledge not to enforce its patents during the pandemic, and it looks scientifically questionable to me as well, since BioNTech claims it’s been working on mRNA vaccines for 20 years, but what do I know? Any damages assessed are considered likely to be tens of millions of dollars – an amount Pfizer can brush off as a rounding error after raking in $36.8 billion for its vaccine in 2021 alone.

CDC blues

 

The latest guidelines from the Centers for Disease Control, updated in mid-August, practically eliminate contact tracing, quarantines, workplace screening, and physical distancing, and lean more heavily than ever on the flawed COVID-19 community levels, saying that people – except those at highest risk – don’t need to wear face masks in any settings unless their local hospitals are overwhelmed. This while COVID-19 is killing around 400 Americans every day, with about 30,000 patients in the hospital for it. The CDC continues to say infected people can go out into the world after 5 days without even an antigen swab, though most patients are still swab-positive on day 6 and many until day 14, with at least half of swab-positives carrying culturable, infectious virus. Deborah Birx is among those blasting the new guidelines. 

Rochelle Walensky herself now admits that the agency she leads has done miserably in handling the pandemic and is recommending a major overhaul. Experts approve. I’ve always thought she wasn’t up to the task. 

After the ball is over?

 

Just as the FDA is telling people it’s crucial to do lots of home testing, the US government program that sends everybody 16 free tests a month is ending because Congress isn’t willing to allocate the funds.

Speaking of testing, a study finding that more than half of people who’ve had Omicron didn’t know they had COVID-19 has gotten lots of press. They supposedly thought they just had a cold. But come on already, don’t people know by now that a “cold” can be COVID-19 and that they should test whenever they get upper respiratory symptoms? Failure to test – which is often done to avoid seeing a positive result – means failure to protect others. COVID-19, even with mild symptoms that last only a few days, can be transmitted to people who may get much sicker or develop long COVID.

Was there really a period in late August when nobody in the UK was dying of COVID-19? That’s what the official stats said for a few days. Now, though, I see they’ve taken it back and admitted the numbers were far from zero. What I suspect is that the authorities were momentarily and perhaps deliberately misattributing this summer’s huge excess mortality to other causes.

Vaccine hooey

 

In April 2022 the journal Food and Chemical Toxicology – already known for publishing fake research – brought out an article by known COVID-19 misinformation-mongers with the (deliberately obfuscating?) title, “Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs.” Its conclusion? “Billions of lives are potentially at risk” from mRNA vaccines. The article, which has been shared 45,000 times on social media, is complete nonsense, as carefully documented by a group of scientists who asked in a Letter to the Editor that the article be retracted. FCT refused to publish the scientists’ letter, and the article didn’t just remain in that obscure journal but got publicized by none other than Tucker Carlson.

More: Texas state Senator Bob Hall claimed last year that “they actually started the animal tests and because the animals were dying, they stopped the tests.” Sorry I missed this pearl at the time!

Still more: According to widely-circulated conspiracy theories, between 44% and 97% of pregnant women who received the Pfizer vaccine had miscarriages. The number is actually about 10%, if anything less than what’s expected for all pregnancies.

 

Obsessive readers of this blog may remember the notorious ivermectin-mongering physician Paul Marik, whose chief research paper was withdrawn after it turned out he’d faked the statistics. Some months ago he prudently resigned from his teaching position at the East Virginia Medical School before getting the inevitable boot, and now there’s even better news: he’s no longer licensed to practice medicine.