Thursday, October 20, 2022

Alphabet Soup


Treatment and testing news

Monoclonal antibodies: It was starting to seem as though the monoclonal antibody era was over, with the WHO strongly advising against the use of both casirivimab-imdevimab (Regeneron, which we already knew was no good against Omicron) and sotrovimab (it worked against Omicron BA.1 but not against BA.2 and thus probably not against later subvariants either). But what about Lilly’s latest, bebtelovimab? It does a good job of neutralizing both BA.4/5 and BA.4.6 in the test tube. Yes, its clinical trials in humans were pre-Omicron, but if laboratory evidence is enough to spur a wide rollout of updated vaccine boosters, I’d think it could be enough for Emergency Use Authorization of bebtelovimab in Europe – it already was for the US but the drug is near-unobtainable in practice.

Evusheld: A couple of posts back I wondered why AstraZeneca’s monoclonal antibody combo given by intramuscular injection had been approved only for prevention of COVID-19 in the immunocompromised and not for treatment of high-risk outpatients, given that it was effective in the laboratory against early varieties of Omicron. Well, now the European Medicines Agency is encouraging just that, so outpatients will have another option besides Paxlovid and remdesivir, assuming AstraZeneca can produce the drug fast enough and doctors catch on about prescribing it. Furthermore, recent real-world data from San Diego say it is effective in preventing clinical COVID-19 from Omicron BA.1, but that in the BA.4/5 era it only prevents severe disease. So far Evusheld is still being underused for its preventive indication even in the US. In Italy only 8000 or so doses have been administered and in the UK it is theoretically approved but in practice unavailable to patients.

Molnupiravir: Remember the first anti-COVID-19 pill, the one from Merck? It proved ineffective against Delta, carries various major concerns, and has been entirely eclipsed by Paxlovid. Now a manuscript from the UK claims it substantially shortens the duration of symptoms, from 14.5 to 10.2 days, while doing nothing to prevent hospitalization or death. I frankly don’t believe a word of it, nor apparently do any experts other than Paul Sax. Why? Because the PANORAMIC study was open-label. People randomized to molnupiravir knew they were taking it, and people who were randomized to usual care knew they were in a drug study and weren’t getting the drug. Patients reported their symptoms themselves, guaranteeing such a powerful placebo effect that in my opinion that aspect of this study is useless.

Ivermectin: Can you believe it’s shown up again? This time in the form of a study performed in Brazil, involving the infamous Pierre Kory, published in an obscure medical journal, under a truly amazing title: “Regular Use of Ivermectin as Prophylaxis for COVID-19 Led Up to a 92% Reduction in COVID-19 Mortality Rate in a Dose-Response Manner: Results of a Prospective Observational Study of a Strictly Controlled Population of 88,012 Subjects.” If you believe that one I have a great bridge I’d like to sell you. Other articles by Kory and his coauthorshave been retracted for fake results, and hopefully this one will be too. If you feel like looking closely at its flaws, start here. And – please – don’t miss the conflict of interest disclosures. I couldn’t find them in the article itself but you can view them on Twitter.

Home tests: We’ve always thought COVID-19 tests were lousy at detecting Omicron. A Dutch study now confirms, reporting that home tests miss up to 50% of symptomatic, PCR-proven cases.


Vaccine news

Bivalent BA.1 boosters: Moderna’s human neutralizing antibody results for their first bivalent updated booster, the one called mRNA-1273.214, which targets the spike protein of the original BA.1 Omicron variant, have now been properly published. As we already knew from the preprint, it induced somewhat more antibodies against both BA.1 and BA.4/5 – 61% more in both cases – than did Moderna’s original monovalent booster, and did better against all the pre-Omicron variants as well. Please note that this is not the bivalent booster (mRNA-1273.222) being administered now in the US and soon to arrive in Europe. That one targets the spike protein of BA.4/5 directly. Both Moderna and Pfizer promised the first human data would come through in mid-September, but it ain’t happened yet. 

Bivalent BA.4/5 boosters: This one is finally available in Italy, 6 weeks after the US. Anyone who’s over 12 and 4 months after their last vaccine dose or last infection is eligible, though people at risk because of age, pathology, or occupational exposure are prioritized. I am still gritting my teeth and waiting for those damned human neutralizing antibody results on BA.4/5-targeting boosters that were due in mid-September. Promising early results for both Pfizerand Moderna were only in mice! …But now, on October 13th, Pfizer-BioNTech announced that a 30-mcg dose of their bivalent vaccine given to adult human beings yields “a substantial increase in the Omicron BA.4/BA.5 neutralizing antibody response above pre-booster levels.” Substantial increase. That’s it. No specifics. We already knew that a 30-mcg bivalent Pfizer booster with an admixture of BA.1 stimulated neutralizing antibodies at a level of 226, three times as good as the original monovalent booster. Why is Pfizer holding those data so close to its chest?

Kiddies: Data showing the Moderna vaccine produces lots of antibodies in young children but doesn’t give much concrete protection against illness (50.6% in babies and 36.8% in 2-5-year-olds) has now been published in the New England Journal of Medicine.

Symptoms: There’s good new evidence that mRNA vaccination, especially with a booster, makes for milder disease in people who get breakthrough COVID-19, especially if the latest shot was less than 5 months earlier.

Quick fade: We have 2 real-life studies coming down on opposite sides of the vaccine duration question. Down side: researchers from South Africa report that vaccine protection against hospitalization due to the BA.4/5 subvariants falls to 19.3% by 9 months after a two-dose initial series. Booster data are more limited because of the time frame, but suggest that the dropoff may be similar: effectiveness fell from an initial 68.8% to 46.8% by just 3-4 months. Remember, we’re talking about protection not against infection but against severe disease, which is commonly considered long-lasting. These data call into question the fantasy of an annual booster. 

Slow fade: Up side: a vast study of more than 10 million North Carolina residents, extending well into the Omicron era, suggests on the contrary that COVID-19 vaccines may last more than a year against severe outcomes. Protection against infection with the SARS-CoV-2 virus fell off drastically over time, reaching 17% for Pfizer and 30% for Moderna by 14 months after the first dose. This corresponds to the plunge in neutralizing antibodies against all Omicron subvariants by 6 months after any dose of the original mRNA vaccines. But efficacy was still 42% and 68% respectively against hospitalization, and  was about 68% against death for both vaccines. Interestingly, the Johnson & Johnson vaccine, whose initial efficacy is much lower, retains that efficacy better over time, still reducing deaths by 80% after 14 months. Third doses provided a further boost. I should say that this study had methodological issues that somewhat limit my optimism. 

Natural immunity: A study from Qatar confirms that having been infected by a pre-Omicron SARS-CoV-2 variant gives little protection (35%) against symptomatic BA.4/5 disease. Infection with earlier Omicron variants, though, gives much more (76%).

Supply chain: The US has a limited supply of updated boosters – at least of Moderna. Nonetheless there should be plenty to go around given that in the 7 weeks since the bivalent shots have been available they’ve drawn only 14.8 million customers (tripled in the last month). That’s out of some 105 million Pfizer and 66 million Moderna that are on order. As the Washington Post points out, this could be the last free booster, so get one while you can. People without health insurance will be particularly badly off, likely having to pay out of pocket not only for COVID-19 vaccines but for tests and treatments as well.             

Clotting issues: Rare cases of serious blood clots, Vaccine-Induced Immune Thrombocytopenia and Thrombosis, can follow Johnson & Johnson’s and AstraZeneca’s vaccines. Now a fatal case has been reported in Argentina soon after vaccination with Russia’s Sputnik V product. No surprise, since Sputnik V is similarly a viral vector vaccine, but if cases have been happening in Russia, as is likely, the authorities ain’t lettin’ on.


Variant watch

The BA.2.75 Omicron subvariant first detected in India has been randomly nicknamed “Centaurus” by some guy on Twitter who thought the name was cute. The WHO disapproves. It’s very contagious, and already accounts for about 1% of cases in the US. Fortunately, vaccines may be more effective against it than they are against BA.5, which still accounts for 85% of US cases. Even newer strains such as BA.4.6 and BF.7 (the Mongolian one) are already accounting for more than 15% of US cases. But BA.2.75 already has a daughter, BA.2.75.2, that is said to be 5 times better at escaping previous immunity than even BA.5. Now that, as Anthony Fauci has said, is “suspicious” not to say scary. 

Not to speak of BQ.1.1 and especially XBB (lately driving a nasty surge in Singapore), which  have extreme levels of immune evasion and are more able to infect people who are ultravaccinated, even with the bivalent boosters, or have had recent infections.

All the ingredients in this alphabet soup are Omicron subvariants, mostly subsubvariants of BA.5.

Then there’s a brand-new virus, Khosta-2, which has been found in Russian bats and like SARS-CoV-2 is a sarbecovirus. According to researchers at Washington State University it’s capable of infecting human cells and is resistant to all the monoclonal antibodies and vaccines we have. Should we worry?

There are multiple bad aspects of all this. One is is the rapid development of new subvariants which overlap instead of replacing each other, and the other is the failure of BA.5 to fade away the way previous variants did (as per the wastewater tracking in the picture). As evolutionary biologist T. Ryan Gregory points out, the less we do to stop transmission (dropping mask mandates…) the more these phenomena will occur. And the more likely there will be a vicious winter surge, just as masks are falling off faces and vaccine uptake is in the cellar.


Ever more CDC blues

The Centers for Disease Control have pulled another fast one. Their latest guidelines, quietly released in late September, have scrapped masking in healthcare facilities, including nursing homes. They do at least make an exception for areas with high levels of community transmission, which currently means 70% of American counties. But individual facilities can opt out if they want… No more testing before hospital admissions or medical procedures either. And, as in the next-to-last version, no more quarantines.

As usual whenever it offers more liberal policies, the CDC is getting pushback, from physicians whose hospitals are experiencing staff shortages due to COVID-19, from prominent pandemic expert Jeremy Faust, and from at least one former Surgeon General.

At least under the Biden Administration there isn’t the blatant political interference with the CDC that there was under the Former Guy, as documented in shocking detail by the third installment from the House Select Subcommittee on the Coronavirus Crisis.


Boys and girls

new study from St. Louis claims that having a low testosterone level puts men at increased risk of hospitalization for COVID-19. Men using testosterone replacement therapy had no increased risk. This seems bizarre at first glance, given that men are more likely than women to get COVID-19 or to become very sick with it. But in fact, as I have learned only now, similar findings have been reported by researchers in both Italy and Turkey.


Leap vs. leak re-re-redux

I thought the final nail in the coffin of the lab leak theory for the origin of the pandemic was hammered in months ago, but it seems another one was still needed. A world expert has described in great detail the ways the actual SARS-CoV-2 virus differs from anything that could have been designed in, and thus leaked from, a virology laboratory. He also emphatically refutes economist Jeffrey Sachs’s accusation of an NIH conspiracy to suppress the laboratory leak theory.


The state of the pandemic

President Biden said in a interview on 60 Minutes, “The pandemic is over. If you notice, no one’s wearing masks. Everybody seems to be in pretty good shape.” Directly contradicting what his own COVID-19 response coordinator, Ashish Jha, had said a week earlier. Biden did admit that “We still have a problem with Covid.” Damn right! With COVID-19 killing 400-500 Americans every day, Biden deserves the backlash he's getting from the recently bereaved, the Washington Post editorial board, and scientists from Anthony Fauci to Eric Topol to Paul Sax and onward to Michael Mina, who supposedly said “COVID is not over.” Biden has even received a pointed rebuke from the Chief Medical Officer of the European Medicines Agency. As far as I can tell Leana Wen is the only supposed expert who’s backing him up, though the dropping of mask requirements on New York’s subways suggest other support in high places. And while his foolish words have no direct policy effect, they will surely make it less likely that Congress will allocate the $22 billion needed to keep fighting the pandemic, and even less likely that vulnerable Americans will bother to get the updated boosters they need. 

Many ordinary Americans are of course ecstatic, with nearly half saying they’ve returned to their pre-pandemic life.

What Joe Biden thinks about the end of the pandemic actually means nothing. It’s the World Health Organization’s job, and WHO chief Dr. Tedros Ghebreyesus, was more circumspect in mid-September: “We are not there yet, but the end is in sight.” His reasoning was, “Last week, the number of weekly reported deaths from COVID-19 was the lowest since March 2020.” His perspective is global, not domestic, and surges in Europe can and do coincide with drops elsewhere. It’s wonderful to know that vaccination and immunity from prior infections (antivirals are not contributing) have reduced deaths so dramatically worldwide, but that doesn’t mean we’re out of the woods.


Let me point out that we’ve been here before. In Italy COVID-19 cases nearly zeroed out in July of 2020 and 2021, with dreadful surges just months later. Cases nearly tripled here this September-October, reaching an official case count 40 times higher than in July 2021, though the peak may now be passing. I – and other colleagues confirm – am now again hearing every day from friends and patients with COVID-19. Absurdly, 2 weeks into this latest surge Italy went through with removing its last remaining mask mandate, which required KN95 masks on public transport. Now, though, they may reconsider… 

The US was doing pretty well in June 2021 too, with optimists predicting the coming end of the pandemic, but it’s running triple the new cases and twice the deaths it was then. Nobody knows whether another variant is going to hit hard, or whether the current ones will soar again when people go back indoors in the chilly weather.

But even if no winter surge happens, and even if COVID-19 is in fact in the process of going from epidemic from endemic – even if, as some think, COVID-19 is now less lethal than flu – I’m still far from reassured. First, there continue to be plenty of new cases. Second, SARS-Co-V-2 is not like the flu. It’s a uniquely insidious virus, particularly capable of causing long-lasting disability itself and triggering downhill slides in chronic medical conditions from heart failure to dementia. 


The latest vaccine mishegos

This one, which came from WND News Services on October 11, is worth quoting in full:

“Pfizer executive Janine Small testifies before the European Parliament in Brussels on Monday”

Undermining the premise for mandates and "passports," a Pfizer executive admitted to the European Parliament on Monday that her company's vaccine was never tested during clinical trials for the ability to prevent transmission of COVID-19. Janine Small, Pfizer's president of international developed markets, was asked by Dutch MEP Rob Roos if the pharmaceutical giant had tested the vaccine “on stopping the transmission of the virus before it entered the market.” 

No ... you know, we had to really move at the speed of science to really understand what is happening in the market," she confessed.

Roos later posted a video on Twitter of Small's response and added his own comment.

"This is scandalous!" he said. "Millions of people worldwide felt forced to get vaccinated because of the myth that you do it for others."

That claim, he said, has “turned out to be a cheap lie.”

This is obviously total bullshit: aside from anything else, if you prevent infection, which the vaccines do, then by definition you prevent transmission. So it occurred to me to google the website where this appears. I was not entirely shocked to read the first paragraph of its Wikipedia entry:

WND (formerly WorldNetDaily) is an American far-right fake news website. It is known for promoting falsehoods and conspiracy theories, including the false claim that former President Barack Obama was not born in the United States.