Wednesday, March 3, 2021

All The Way With J & J?

 

There’s next to nothing on the treatment front since the last Stethoscope, but vaccine news more than compensates. I’m rushing this post to get it to you fast.

 

Treatment updates


Plitidepsin (Aplidina): A candidate antiviral drug, currently approved only in Australia and only for treating a blood cancer, multiple myeloma, seems to block SARS-CoV-2 in testtubes. Ummmm, so does hydroxychloroquine, and we all know how that story turned out. Plitidepsin slightly decreased the viral load of SARS-CoV-2 in mice, but has never been given to a human being with COVID-19. I love the El Pais headline – isn’t nationalism grand?

Monoclonal antibodies: The European Medicines Agency has been sitting on applications from Lilly and Regeneron for nearly a month now, declining to approve the best treatments we have for COVID-19. The anticipated €1000-€1200 price tag sounds scary but is less than one night in the cheapest intensive care unit. Italy will soon join Germany, jumping the gun and buying the drugs directly from the companies. I was surprised to learn that the Lilly cocktail is actually produced in Italy, though all the doses are currently shipped abroad. Similar antibody products are under development in Europe but none will have Phase 3 trial results for months to come.

 


Fit for the trash heap



Azithromycin and doxycycline: Both antibiotics have struck out yet again, in the British PRINCIPLE trial, for treating non-hospitalized patients. Nothing new here. I don’t understand why anyone is still studying them.

Hydroxychloroquine: One problem with Plaquenil having been proposed early on as a treatment for COVID-19, and especially its being pushed as a miracle cure by political figures who will remain unnamed, is that literally hundreds of clinical trials were set in motion. An enormous waste of resources that could have gone toward finding other cures. Now we’re dealing with the flood of research reports that this misplaced enthusiasm engendered. The latest shows that giving hydroxychloroquine to people exposed to a known case of COVID-19 does nothing to prevent SARS-CoV-2 infection or symptomatic disease, while giving lots of side effects. Can’t journals resist publishing these studies? Giving them space at this point is like beating a dead horse. Maybe now that the World Health Organization has strongly recommended against using hydroxychloroquine, at least for prevention, the flood of articles will slow down.

 


Gone with the wind 

 


Just for the heck of it, I thought I’d look through my old posts for COVID-19 nostrums that once sounded promising but then disappeared into a black hole. Here’s what I found, starting with prevention and moving up through different levels of treatment: 

-       vaccines against tuberculosis or measles or polio for a general boost to the immune system; 

-       preventatives: drinking human breast milk, gargling hydrogen peroxide, popping lactoferrin, spraying povidone-iodine up your nose;

-       llama antibodies: they went straight from the testtube to cutely packaged “AeroNabs” before fizzling; 

-       for COVID-19 outpatients: the osteoporosis drug raloxifene, the herb artemisia, “biologicals” such as infliximabsticky polysaccharides in a nasal spray, monoclonal antibodies in a nasal sprayACE-inhibitorssuch as enalapril, the oral antiviral EIDD-2801

-       Russian mystery drug never tried in humans but claimed to be “99% effective”;

-       fenofibrate, a cholesterol-buster touted as “eradicating” COVID-19 “in days”; 

-       inhaled nitric oxide, intended to improve breath-starved patients’ oxygen levels; 

-       the immune modifier Saccovid, the antacid famotidine, and inhaled interferon-beta, all of which were said to keep hospitalized patients from deteriorating; 

-       Pluristem placental stem cells, the cancer drug ruxolitinib, and the bradykinin blocker icatibant, each with its claim to have saved critically ill patients. 


Vaccine updates


Johnson & Johnson/Janssen: The big news is of course the approval of this convenient one-dose vaccine, immediately in the United States and probably on March 11th in Europe. The exhaustive documentation presented to the US Food and Drug Administration for its 45,000-subject multinational Phase 3 trial showed it to perform better than I had expected. Overall efficacy was 66% against “moderate-to-severe” COVID-19 (two symptoms in addition to a positive PCR swab), 85% against severe COVID-19, and 93% effective in preventing hospitalization; not a single vaccinated subject died. 

Furthermore, it’s a little unfair to Johnson & Johnson to compare its 66% with Pfizer and Moderna’s 95%. The latter two completed their trials earlier, so they didn’t have to contend with the vaccine-resistant variant, B.1.351, that now accounts for 94% of cases in South Africa. In the United States, against the original Wuhan strain, Johnson & Johnson’s efficacy was 72%. Even in South Africa it was 64% effective, much better than Novavax (49%) or heaven forbid AstraZeneca (10%). It prevented hospitalizations and deaths just as well in South Africa as in the US.

Protection from Johnson & Johnson begins 2 weeks after vaccination and peaks at 4 weeks. It works about as well in men and women, blacks and whites, and older and younger volunteers. It is, however, considerably less effective in older people with medical conditions such as hypertension and diabetes. The usual flu-like side effects, including hives and angioedema but no anaphylaxis. 

Importantly, the Johnson & Johnson vaccine seemed to be 74% effective in preventing asymptomatic infection with SARS-CoV-2. So like the RNA vaccines (but unlike AstraZeneca), it will help keep the pandemic from spreading silently.

I’d summarize these results as somewhat better than AstraZeneca, though not in the same league with Pfizer or Moderna.

Why do I say this vaccine performed better than I expected? Because their “moderate-to-severe COVID-19” endpoint (requiring 2 symptoms) makes it impossible to compare their results directly with other vaccines’ clinical trials, all of which used an “any COVID-19” endpoint (requiring only one symptom). I worried this might have overestimated the efficacy of Johnson & Johnson, as it did for SinoVac, and that the efficacy against “any COVID-19” could be as low as 50%. Fortunately that’s not the case. Johnson & Johnson’s FDA document included a report of efficacy against “any” COVID-19, and it was fine (66.5%). 

But the arrival of the Johnson & Johnson product will force the United States to face the ethical issues we’ve seen in Europe in relation to AstraZeneca: who gets one of the RNA vaccines (95% effective) and who gets Johnson & Johnson (72% – or AstraZeneca, 63%)? The pushback already seen in Europe will surely come to America, especially if Johnson & Johnson is prioritized, as many fear, in “marginalized,” “hard-to-reach” (read black and Latino) communities. One solution proposed by the president of a small Iowa college, which I find brilliant, is to offer the Johnson & Johnson vaccine first to the 53 million Americans between 18 and 29. They’re at low risk for serious disease but act like collective superspreaders.

AstraZeneca: Next biggest news: this vaccine does do some good for the elderly after all. We know this not yet from the long-awaited American Phase 3 trial, but from two studies of the UK’s single-dose vaccination campaign, both available only as preprints.

First from Scotland: the manuscript shows that a scheme using both Pfizer and AstraZeneca prevented COVID-19-related hospitalization at all ages. People over 80 had overwhelmingly received AstraZeneca – their foolish theme song was “I want the English one” – and that their crude hospitalization rate was decreased at all is encouraging, though only by 53%. Since sicker old folks were vaccinated first, the researchers appropriately adjusted that figure statistically to take chronic medical conditions into account, giving us an adjusted efficacy of 70%. 

Then to England, where another preprint of a very different kind of study reports that, in people over 70, AstraZeneca was about 60% effective at preventing COVID-19 and 80% effective against hospitalization.

But note: in younger people, AstraZeneca works better than that. In its second Phase 3 trial report, including 17,178 volunteers who were almost all under 55, the vaccine was 67%-76% effective at preventing COVID-19 and 100% effective against hospitalization: no vaccine recipients needed to be hospitalized for COVID-19, versus 15 controls. 

It is reassuring to know for the first time that the cheap, convenient AstraZeneca vaccine does in fact reduce COVID-19 risks in older people. It is considerably less effective in that population than the RNA vaccines, though, and it has no impact on the asymptomatic infections that help drive the pandemic.

Pfizer: The Pfizer vaccine is performing if anything better in the real world than in its   clinical trials. Among the first 600,000 two-dose vaccinees in Israel, it was 94% effective at preventing clinical COVID-19 overall, 98% effective in people over 70, and a remarkable 89% in people with 3 or more chronic medical conditions. By 2 weeks later, when the number of fully vaccinated Israelis had reached nearly 3 million, another article reported Pfizer to be 98.9% effective at preventing hospitalizations.

There are now some data testing the UK’s single dose regimen for Pfizer. The Scottish study now confirms that efficacy starts in 2 weeks and peaks in a month, but tell us that it starts to fall off immediately thereafter. Hospitalizations were reduced by only 68% at 5 weeks after a single dose, instead of the 90% to 99% efficacy against severe COVID-19 when a 21-day booster is added. 

Pfizer also figured in the English vaccination campaign study. For unclear reasons that may be related to its unusual “test negative case control design” (comparing people with COVID-19 symptoms who had a positive versus a negative SARS-CoV-2 swab), a single dose of the Pfizer vaccine never approached the high efficacy found in all other studies: only 60-70% in everyone over 70, and 59% in people over 80. Follow-up did not extend anywhere near 12 weeks, though, so we still have no idea about efficacy after the interval being used in the UK.  Few people 70 to 80 were followed for longer than 5 weeks, and few over-80’s longer than 8 weeks. In those lucky enough to have had a second shot, the vaccine’s efficacy was a more reasonable 89%. Based on the findings of these two studies, the second dose of Pfizer should not be put off for more than a couple of weeks, if at all. Anthony Fauci has fortunately come down, in his usual diplomatic way and without citing the UK data, on the right side of this debate.

Curious how much Pfizer paid in taxes on last year’s maxi profits? We now know the answer: 6.4%. Wouldn’t you love to pay your taxes at that rate? At least it was a positive number. From 2010 to 2012 they not only paid no US taxes, but got $2.2 billion in refunds from the Feds. Positively Trumpian.

CureVac: The European Union has bet on this German RNA vaccine big-time, and is now starting to examine it. CureVac was supposed to come through in the second trimester, but it probably won’t. While waiting for its Phase 3 results in Europe and Latin America, the company has run tests against the UK and South African variants in animals, and claims it works. No details yet.

ReiThera: The made-in-Italy candidate vaccine is making baby steps. Despite disappointing Phase 1 results it’s about to start Phase 2/3 trials, though they’re unlikely to get anywhere before the fall. More important is that ReiThera has offered to retool its factories near Rome to produce AstraZeneca, Johnson & Johnson, and Sputnik V, which could give a boost to the European vaccination campaign. 

Other European options: The EU’s vaccination campaign has been crippled by shortfalls of doses from Pfizer and AstraZeneca. As of February 10th the European Union was still “close to finalising talks” with Novavax, exactly where it was last November. Gamelaya hadn’t even asked for approval of Sputnik V. If Johnson & Johnson is approved on March 11th,  maybe distribution can start on schedule in April. 

One, two, buckle my shoe: Following France, Italy has decided to administer only one dose of vaccine to COVID-19 survivors, and to hold that dose until 6 months after infection. This gives some breathing space to the Italian vaccination campaign – all 2 million people who tested positive in the last 3 months alone can be skipped for now. But Italy is also considering a terrible idea: copying the UK’s one-dose policy not just for AstraZeneca but for Pfizer and Moderna. Prime Minister Mario Draghi is its main proponent, but fortunately he’s been overruled for now, at least for people over 80. 

 


Vaccine tidbits


Vaccine diplomacy: In a bizarre twist, Israel will be supplying Sputnik V vaccine to Syria, in return (it seems) for the release of a detained Israeli citizen.

Race to the top: Chile has become the unlikeliest contender in the vaccination race, with 19 doses already administered per 100 people, barely trailing the US (24) and well above the EU at 8. It’s succeeded partly by participating in numerous clinical trials but mostly, alas, from depending heavily on Sinovac’s CoronaVac, the very worst performer among COVID-19 vaccines (50% efficacy, vs. AstraZeneca’s 63% and Pfizer’s 95%).

Monkey business: Pfizer, AstraZeneca, and the rest, are lucky to have squeezed in their animal studies early last year. The researchers still working on other candidate vaccines will have a harder time, because the supply of those precious macaque monkeys has dried up.

Antivaccine antisemitesLiliana Segre, a 90-year-old Auschwitz survivor and Lifetime Senator in Italy, has been viciously attacked for supporting COVID-19 vaccines. This is weird on two fronts, because neither antisemitism or novaxx sentiment are historically big in Italy. Three, actually: why is Signora Segre such a target that she needs a bodyguard? Italians have always casually stereotyped Jews, but only in the last few years has vicious, German-style antisemitism been raising its head. I put the blame largely at the door of Donald Trump and his lackeys (especially Steve Bannon, who peddles white nationalism in Europe), for shifting the center of discourse worldwide and giving new legitimacy to the worst of the right. 

Vaccination equity: In the United States blacks are being vaccinated at much lower rates than whites, between vaccine hesitancy in the black community and inequities affecting appointment-taking (lack of internet access…) and administration (lack of cars, lack of nearby vaccination centers…). The coming of a third vaccine may only make things worse (see Johnson & Johnson news, above). But even if black Americans are only getting half to a third as many doses as whites, 8% to 12% of them have already received at least one dose of vaccine. Compare that with 8% of Italians.


Liquid LuciferCoronavirus vaccines are the mark of the beast placed by Satan to herald the end of the world. Or not?



 

Dog eat dog


Doses of the Russian vaccine arriving in Hungary


One of Italy’s strengths in the battle against the coronavirus has been its unity behind a national strategy. First the lengthy and rigorous lockdown that ended the first wave, then the weekly assignment of regions to yellow vs. orange vs. red mitigation measures that was beating the second one until a few weeks ago, and uniform, well-followed masking and distancing rules. Now, though, there are beginning to be signs of fragmentation. The Piedmont region threatens to hunt down its own vaccine supply on the international market, Lazio approaches Gamelaya about licensing a Sputnik V factory, Veneto is tempted by Sinopharm, Emilia Romagna by Croatian sources of AstraZeneca… 

…all of them risking winding up in the hands of shysters, who are roaming government halls offering back-door dose supplies and peddling fake vaccines. (Thousands of convincing-looking counterfeit Chinese vials have been seized or exported.) From La Repubblica on February 15th: “The army of fixers aiming to get rich off the coronavirus emergency is back in action…. Self-styled mediators between the Russians who developed the vaccine and the drug industries that could produce them, a series of shadowy characters moving around Lazio have already drawn the attention of the police.”

The European Union has by and large held on to a cohesive policy on COVID-19 pharmaceuticals, but Hungary has splintered off by buying Sputnik V straight from the Russkies, Denmark and Austria are striking a vaccine deal with Israel, and Germany is ordering Lilly’s and Regeneron’s monoclonal antibody products directly from the source …not to speak of snapping up extra doses of Moderna from poorer European Union countries, and Pfizer straight from the company.

It’s not too surprising that phony vaccines are being peddled on Mexican social media and in Ecuadorian pop-up clinics. But in the UK, with its well-organized free vaccination program? Charlatans have been going door to door in London, having surprising success in finding unsuspecting elders they can shoot up with salt water in return for hard cash.

European requirements for pre-travel COVID-19 swabs have inevitably spawned an industry of bogus certificates. Last year they were crude imitations, now – apparently – they’re totally convincing.

 

Random vaccine headlines



What was he supposed to do, throw them out? The criminal case against Dr. Gokal seems to have been tossed, but US physicians are campaigning to get him rehired as well.


The US couldn’t get Pfizer or Moderna to its diplomats in Russia, so the embassy workers became the only Americans thus far to have received the Sputnik V vaccine.


Cuba, which prides itself on its medical and biotech sectors, is about to start Phase 3 testing of a homegrown vaccine. Cuba had only a hint of first and second waves last spring and summer, but it’s being massacred by a third one that began in December.

4 comments:

  1. Thanks for another excellent post Susan. Im a bit disappointed in the Brazilian Study of Vit D as it seems that it takes months for Vit D3 to work ans the didnt even give that till 10 days into the illness. Califediol is the fast acting preparation. I've just had my AZO jab; not much choice here - then choice would mean a slower rollout - our vaccination centres are slick quick matters - no time to ponder! PS - Steven Bannon is no relative of mine - if he were I would have a word!! Keep up the good work!

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    1. Thanks for the vitamin D erudition, which I can't claim to have (N.B. this all refers not to this blog post but to the previous one). I did look it up, and saw that Calcifediol is the same as 25-hydroxyvitamin D3, which according to Table 3 of the article doubled after treatment in the group as a whole and nearly tripled in D-deficient patients. Congrats on your jab. Since AZ increases in efficacy over 10-12 weeks while Pfizer starts falling off after a mere 5 weeks, in the present UK setting it may be 6 of one and half-dozen of the other.

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  2. Thanks for another great post. I'm hoping you'll address some vaccine-related practicalities in the next. The variously attributed pieces of advice arriving via WhatsApp are making my head explode. Should one be tested for (a) covid and/or (b) antibodies before receiving the vaccine? any vaccine or just AstraZeneca? How much in advance? Should we be worried about AstraZeneca? I don't even know where to go to get tested. Thanks!

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    1. Great question, which I'll happily address next time. The answer is a resounding no. No need to do any tests before, or after, receiving any of the vaccines. I worry about AZ only very slightly more now (about reactions) than I did a week ago (about efficacy). I didn't realize this particular piece of misinformation was going around - if there are others you might send them to me via email. Also tell me in that email how old you are...

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