|Elvis Presley getting a polio shot, 1956|
Hydroxychloroquine: I’d hoped never to have to type that word again, but my hand has been forced. Back in July, the Italian Drug Agency forbad off-label use of hydroxychloroquine in COVID-19, leading a whole flock of deluded General Practitioners to sue. Now an Italian high court has ruled in their favor, saying the drug can be prescribed legally to COVID-19 outpatients, though without National Health Service coverage. Then the good news of a plan to start up African COVID-19 trials was followed immediately by the bad news that the first drug to be tested is… you guessed it, hydroxychloroquine.
Colchicine: UK researchers have decided to add an arm to their RECOVERY trial testing this age-old gout remedy as a treatment for COVID-19. Unfortunately it’s yet another half-assed open trial, without a placebo group.
Tocilizumab (Actemra): Recently I said researchers from Imperial College London might have found the sweet spot for using this arthritis drug in COVID-19. With a new negative report from Harvard the story has turned sour again. If tocilizumab does any good, it can’t be much.
Antibodies in a nose spray? The latest effort from Regeneron is just too damn fancy. They’ve produced so little of their already-authorized intravenous antibody cocktail that hardly anybody has received it besides Donald T. and Rudy G. By the time we have human results on this nasal version, most of us will likely already have been vaccinated.
Natural protection: Finally a study proving that COVID-19 survivors are immune. Among 1246 health care workers who were antibody-positive for SARS-CoV-2 in April, none had developed COVID-19 by November, as compared with 89 of 11,052 who didn’t initially have antibodies. So despite occasional reports of reinfections – under 50 worldwide among 47 million COVID-19 survivors – exposure sufficient to raise an antibody response clearly protects you for at least 6 months. Other studies show a pattern of persistent anti-SARS-CoV-2 immune cells that suggests natural immunity may last not months but years.
|A Pfizer vaccine cool box|
Pfizer’s: The big Pfizer vaccine news is of course the US Food and Drug Administration’s green light, with doses flying around the US as I write. This was pretty much a foregone conclusion given the spectacular results we already knew: only 8 out of 170 COVID-19 cases in their Phase 3 trial had received vaccine rather than placebo, and only 1 out of 10 severe cases. But Donald Trump managed to poison even this piece of great news. Rather than gloating justifiably over having made the vaccine happen, on December 11th he menaced the head of the FDA with firing if the vaccine wasn’t approved by the end of the day. The vaccine was approved.
Two potentially deadly allergic reactions on day 1 of the UK’s vaccination campaign threatened to derail the American certification process at the last moment. British authorities were doubly stupid. First, in administering the vaccine to people with a history of anaphylactic drug reactions when such people had rightly been excluded from clinical trials. Then, having reaped the consequences, by instantly declaring that anybody who had had “severe allergic reactions” shouldn’t be vaccinated, making everybody with bad hayfever quake in their boots. Nonsense – you only need to hesitate if you’re one of the very few who have had anaphylactic drug or vaccine reactions.
Great news, though still preliminary, is that even a single dose of the Pfizer vaccine works with 82% efficacy. So people who get so turned off by the side effects of their first dose that they skip the booster will be reasonably protected against COVID-19.
It seems the challenge of distributing this vaccine at sub-Antarctic temperatures may be met largely by the manufacturer itself, rather than depending on local or national infrastructures. Pfizer will bring vaccine doses to airports in its own hyper-refrigerated trucks, fly them on specially chartered planes rigged to carry as many as a million doses each, use specially trained drivers of specially equipped trucks (from UPS and Fedex in the US, probably DHL in Europe) to carry suitcase-sized “cool boxes” containing 1000 doses from the airport to hospitals and distribution centers and oversee their transfer to local super-freezers. For my beloved but notoriously chaotic adoptive country, this is reassuring news.
But transport supervision can’t eliminate other nightmarish logistical details, such as vaccinators having to draw not a drop too much or too little from multidose vials into a syringe and then dilute the dose, instead of having prefilled syringes like most vaccines.
Moderna’s: Following a formal request to the FDA, mRNA-1273 should be approved on December 17th and reach US hospitals days later. Final data from all 30,000 Phase 3 volunteers confirm the interim results: the vaccine is 94.1% effective in preventing symptomatic COVID-19 (185 cases received placebo, 11 received vaccine), and 100% in preventing severe disease (30 cases, with one death, all in the placebo group). Moderna’s vaccine and the science behind it are better than Pfizer’s and much better than AstraZeneca’s, and it doesn’t require Pfizer’s outlandish cold chain (though it shares the multidose vial problem), so for now they get the trophy. Authorization in Europe and elsewhere should soon follow, but doses seem unlikely to arrive anywhere outside the United States before April.
|Boris John as chimp in Russian anti-AstraZeneca smear campaign|
AstraZeneca’s: The “Oxford vaccine” was already in deep doodoo because of weird results, mediocre efficacy, and lack of transparency, and its published interim report does little to boost enthusiasm or trust. The factory screw-up that led to some trial volunteers getting a half-dose of the first jab was inexcusable. As was AstraZeneca’s attempting to palm off the oddly superior performance of that accidental low-dose/high-dose schedule as its real results. As are the multiple post-hoc changes they made to their protocols, the varying gaps between first and second doses, the different methods in different countries, and the fact that almost no subjects were over 70 years old, none were obese, and few had chronic illnesses. (All of the low-dose/high-dose volunteers were under 55.) Pooling the results from wildly variable trials into a single efficacy number of 70.4% is nuts. And what about the shadow of neurological complications and their coverup? Or the ethically challenged partner the company has chosen in China? Critiques from The Lancet and The New York Times verge on the harsh, and the company is waiting before seeking regulatory approval.
(Anyway, who would take a vaccine that works 70% when others weigh in at 95%?)
More hangs on AZ’s handling of this crisis than merely the health of humanity. AZ is hoping, for example, to corner the market on the 1.3 billion inhabitants of India, where millions of doses have already been manufactured. AZ has pledged not to profit on their vaccine “as long as the pandemic lasts,” but according to inside dope they may declare the pandemic over as early as July 2021. After which, even if they make just two bucks per dose, 2 billion doses for India alone – and AZ is expected to supply most other developing countries as well – would net more than AstraZeneca’s operating profits for any of the last 3 years.
Johnson & Johnson: After vaunting a single-dose regimen, J & J have decided not to put all their eggs in that basket, starting up a new worldwide Phase 3 trial with an added booster.
Minor players: A promising Australian candidate vaccine has become the first to be officially scrapped. Errata corrige: Novavax won’t have its first interim Phase 3 results until February or March. And bad news for the French vaccine maker Sanofi, who managed to pre-peddle millions of doses before even starting Phase 3 trials. Now they’re back to the drawing board retooling their vaccine after Phase 1-2 studies showed it doesn’t stimulate the immune system of people over 50. So Sanofi is likely out of the running for 2021.
|Siberians lining up to be vaccinated|
Back East: Putin began offering Sputnik V vaccination to a skeptical Russian public the second week of December. We know virtually no details of the vaccine’s Phase 3 trial. But we do know that the vaccination campaign excludes anybody over 60 or chronically ill, suggesting that Sputnik V has been tested only in the young and healthy. Skepticism seems the most appropriate stance for what someone has called “a mixture of Polonium, Novichok and Holy Water.”
Way Back East: Several Chinese vaccines are into Phase 3 testing beside the biggies, Sinovac Biotech and CanSino. The latest, from the Anhui Zhifei Longcom Biologic Pharmacy, is new to me, as are two vaccines from Sinopharm that have apparently been administered to a million people before trial results are in.
|Vaccination center under construction in Eschwege, Germany|
In the United States: The approval of effective COVID-19 vaccines was supposed to bring a giant opening salvo – Operation Warp Speed promised 300 million doses by New Year’s – and cover the entire population by June. Hmmm… recalculating. Now the Warp Speed folks admit there will be just 40 million doses this month and 200 million by the end of March, with The New York Times calling even that “an ambitious timetable,” citing experts who say “To meet those kinds of aggressive timelines, all the stars would have to align.” Such a low number of doses are being allotted initially to some states that they’ll barely be able to cover their front-line Emergency Room and intensive care unit staff. One Philadelphia hospital had 3,000 high-risk employees but only 252 vaccination slots, all grabbed up within a day.
True to form, Trump is trying to rig later phases of the vaccination campaign to punish his perceived foes: “As soon as April, the vaccine will be available to the entire general population, with the exception of places like New York state.” Andrew Cuomo has threatened legal action, which should dissolve with the new Administration.
But the whole campaign risks dribbling to a temporary halt in late winter. Turns out the Administration arranged with Pfizer to buy 100 million doses, enough for only 50 million people, and turned down the company’s offer to option hundreds of millions more. Those additional doses have now been snapped up by the European Union, and since manufacture takes time, more doses may not reach the US until June or July. Mr. Trump signed an executive orderdemanding that Pfizer renege on its commitments to Europe, but that is unlikely to get him anywhere. The US has done better with Moderna, managing to reserve 80% of the doses to be produced by March and now ordering an additional 100 million doses to make up for the Pfizer snafu. Everybody hopes the Phase 3 results from Novavax and Johnson & Johnson, due next month, will be brilliant, but that’s not a foregone conclusion; many or most Americans will have to wait until the fall.
Success depends on beating vaccine reluctance, especially but not only in the African-American community. It should help if, say, LeBron James, Barack Obama, and Sean Hannity all line up for vaccines, emulating Elvis Presley’s famous polio shot in 1956. I’m optimistic – with sky-high 95% protection, and with millions of people leading the way, I think everybody except hard-line anti-vaxxers ought to eventually come around.
In the United Kingdom: The UK treated vaccine authorization more as a race than as a life-saver, braggingshamelessly about being the first in the West. Pfizer’s vaccine is already getting shot into British arms, with Moderna’s soon to follow. The Brits got slammed by European regulators for taking shortcuts, and even Anthony Fauci delicately blasted them, though – ever the diplomat – he unconvincingly walked back his criticism the next day. Fact is, the US Food and Drug Administration and the European Medicines Agency both insist on examining raw trial data for themselves before approving medications, whereas UK regulators went ahead on the basis of the company’s summary reports.
In Continental Europe: The European Medicines Agency is expected to authorize Pfizer’s vaccine on December 29thand Moderna’s on January 12th. A few Pfizer doses will be distributed pronto, but a substantial supply isn’t expected before March. Countries are scrambling to outfit hospitals with ultra-cold freezers and set up vaccination centers in gymnasiums, conference centers, and arenas.
Germany and France claim they’ll start their campaigns the instant approval arrives, but admit they can only vaccinate 1.5 million and 500,000 people respectively in January, out of 84 and 65 million inhabitants. Italy didn’t expect to really get going until the end of next month, but now the EU is pushing for an earlier symbolic kickoff date, simultaneous in all member countries, between January 12th and 15th – will the French and Germans have to hold off and the Italians speed up? Not yet clear.
Italy reserved 200 million vaccine doses in 2021, for a population of 60 million, and the overshoot turns out to be fortunate; 40% of the doses were supposed to come from AstraZeneca (with its Italian connection) and Sanofi, both of which are now in doubt. At the moment all we can count on is 11 million doses from Moderna and 27 million from Pfizer, enough to cover only 19 million people and trickling in over 9 months. If the single-dose Johnson & Johnson vaccine performs well that should do the trick (54 million promised doses), but if two doses turn out to be preferable Italy will have to fall back on its 30 million doses from CureVac, assuming the Phase 3 trial results pan out.
In the rest of the world: 75% of the doses of COVID-19 vaccine produced in 2021 are already spoken for by rich nations. (Vaccine priorities will be strictly regulated everywhere – except inexplicably in Australia, where you’ll be able to buy your way to the front of the line.) Despite the World Health Organization’s best efforts and the generosity of the Chinese, only 10% of people living in developing countries are likely to get vaccinated next year.
Challenge trials: I was wondering what happened to the threat to test vaccine efficacy by deliberately infecting volunteers. It vanished from the news after proponents last ran it up the flagpole 5 weeks ago. And now that splendid vaccines have emerged from ethically impeccable trials, American researchers have decided to chuck the idea. Brits, though, say they’re plunging ahead.
The placebo debate: Once a Phase 3 trial has proved a vaccine effective, should the volunteers in its placebo arm get the real thing? This is a very ticklish issue. Vaccinating everybody would make it hard to learn, for example, how long vaccine protection lasts. To me offering the vaccine to placebo recipients seems ethically imperative, and Moderna agrees, but a World Health Organization working group thinks otherwise, with both Johnson & Johnson and Pfizerequivocating. The best approach in my opinion would be to let the control group all know they received placebo and offer them the choice of being vaccinated right away or waiting two years for the sake of science. If enough people agree to hold off, we will know exactly how long the vaccine’s protection lasts. But even if they don’t, we can learn something by monitoring antibody levels and comparing early and late vaccinees. Note that by late 2021 most Westerners should have received one vaccine or another, so there will be less SARS-CoV-2 virus floating around for trial participants to catch and researchers to analyze.
The survivor debate: Should people who have had COVID-19 get vaccinated? Probably yes, but late in the game. Vaccines may give even longer protection than natural immunity, partly because they stimulate the immune system so intensely. Ideally we would pretest everybody for antibodies, and put the positives at the back of the vaccine line – something under 10% of Americans were seropositive and thus presumed immune as of September. Most countries may decide, more simply, just to vaccinate last the smaller group of known COVID-19 survivors.
The transmission debate: Will vaccines prevent transmission as well as disease? Maybe vaccinated individuals exposed to SARS-CoV-2 will grow virus in their noses and have the potential to pass it on to others, as happened in some monkey studies. The Pfizer and Moderna Phase 3 trials can’t say, because they tested for the virus only if subjects developed symptoms. AstraZeneca’s messy research did have one methodological strong point: some volunteers sent nose swabs to a lab every week for PCR testing, allowing the detection of 69 cases of asymptomatic SARS-CoV-2 infection. The small low-dose/high-dose vaccine schedule seemed fairly good (59%) at preventing nasal colonization, but at standard dosage the vaccine was useless for that purpose.
It would be useful if ongoing Phase 3 trials amended their protocols to include molecular swab tests on some volunteers and measured the amount of virus present in the noses of breakthrough cases in vaccinated people.
|A pediatric ward full of polio victims in iron lungs, 1950|
The safety debate: Several scientists have published an article whose splash sentence is “We also know all too well the tragic story of a rushed polio vaccine.” They’re referring to the flubbed inactivation of live virus in an early lot of the Salk vaccine, leading to hundreds of cases of polio and 10 deaths. But none of the major Western vaccines involve inactivated SARS-CoV-2 virus (two Chinese ones do), so there is exactly zero risk of a similar disaster.
The authors go on: “The FDA must not, as currently planned, eliminate inspections of manufacturing plants before issuing a vaccine emergency use authorization.” This is nonsense. The FDA document they link to actually says:
"Inspection assignments . . . deemed mission-critical will still be considered for inspection . . .,” mission-critical covering notably “products used to diagnose, treat, or prevent a serious disease or medical condition for which there is no other appropriate substitute.”
As I wrote in a published comment, the fear-mongering in this article is irresponsible on the part of those who wrote it and those who published it.
A rumor has reached my ears that the Vatican Pharmacy has Russian and Chinese COVID-19 vaccines in stock… No hint of this at the Pharmacy website, but all is possible.
Hackers from unknown hostile powers are said to be working on sabotaging Pfizer’s crucial cold chain transport system. Unspeakable cruelty? Or just trying to steal technology?
In Germany there's concern that vaccination centers could be targets for anti-vaxxers and followers of conspiracy theories. Good God! I guess the US should worry too.
After bolloxing up its research so far, AstraZeneca is trying out a new approach, mixing-and-matching with of all things the even more poorly tested Sputnik V. This after Russia carried out an astonishing smear campaign against the AZ vaccine. As I see it, with this little joint venture AZ only risks tarnishing its image still further.
Purveyors of bullshit bite the dust
Scott Atlas has quit as COVID-19 advisor to the lame duck President, but he went down swinging.
Sidney Powell went so far with her election conspiracy theories that even Rudy Giuliani disavowed her.
Puya Dehgani-Mobaraki has been temporarily banned from Facebook.
Sapan Desai has given up on practicing medicine.
So now the only purveyors left standing from my last post are the United States Senate (who are doubling down on their B.S.) and the notorious Dr. Didier Raoult – now lovingly immortalized in a €35 handmade creche figurine.
Is there any information on whether or not the Moderna vaccine generates anaphylactic reactions?ReplyDelete
That's a good question. Moderna's Phase 3 protocol (like Pfizer's, for that matter) specifically excluded as volunteers anyone with "Known or suspected allergy or history of anaphylaxis, urticaria, or other significant adverse reaction to the vaccine or its excipients." Its instructions for administration include observation for 30 minutes after each injection, enough time for anaphylaxis to manifest and be treated. They have not mentioned anaphylactic reactions so far, and they're unlikely if the vaccine isn't given to inappropriate people, but with millions of doses there may be a few such reactions.Delete
I've read that the Pfizer and Moderna vaccine manufacturing processes use the same reagents necessary for PCR tests, thus creating a painful competition between disease prevention and detection. I don't know if this is also true of the other vaccines. Can you comment?ReplyDelete
I'm afraid I can't, because I haven't heard anything about it. Can you give me a reference to look up?Delete
Excerpt from NYT's article on 12-18-2021:ReplyDelete
Two volunteers in Moderna’s late-stage clinical trial developed anaphylactic reactions, the company reported at the F.D.A. committee meeting on Thursday. Neither was deemed to be linked to the company’s vaccine, which also contains mRNA, because they occurred weeks or months after the participants received their shots. One of these volunteers also had a history of asthma and a shellfish allergy.
Moderna, unlike Pfizer, did not exclude people with a history of anaphylaxis from its trials.
Thanks for pointing this out, I'll include it in my next post. Anaphylactic reactions usually happen within a few minutes, maximum a half-hour, so those two Moderna incidents definitely had nothing to do with the vaccine. Severe reactions do sometimes happen in relation to vaccines...Delete
Thank you for the refreshing reality of the vaccine race. All too often, we are guided by numbers and faulty research tossed about by pundits not medical professionals. Grazie.ReplyDelete
Thank you for the kind words.Delete