Monday, January 11, 2021

Vaccine Follies and Gifts that Keep Giving

 

Elderly Floridians camp out hoping for vaccines

Treatment update

Monoclonal antibodies 1: 80% of the distributed doses of these drugs from Regeneron and Lilly are sitting on American pharmacy shelves. The reason is largely the logistical nightmare they pose. They are only effective if given within the first 10 days of disease; sick patients who’d rather stay in bed need to be dragged out for an hour-long intravenous infusion and another hour of monitoring; patients need to be isolated in safe spaces; and precious nursing time is needed. If only the drugs could be given at home, or as a single shot in the arm…

Monoclonal antibodies 2: A new pair of monoclonal antibodies, BRII-196 and BRII-198, from a North Carolina-Beijing collaboration, has just now begun testing among outpatients with early COVID-19 in a large-scale randomized, placebo-controlled trial. The National Institutes of Health’s decision to undertake this study now underlines how long experts expect the pandemic to continue despite the vaccine rollout.

Convalescent plasma: Finally a properly-done study and – consequently – finally a positive study. It always seemed odd to me that convalescent plasma didn’t seem to work in COVID-19, and I always suspected the reason was bad research. Previous studies either enrolled patients too late enough in their illness, used plasma too weak in antibodies, lacked placebo controls, or all 3. This new trial, in Argentina, administered plasma with particularly high titers of IgG antibodies to high-risk elderly patients suffering mild symptoms, within 72 hours of a positive molecular swab. Patients who had received plasma were only half as likely to become severely ill. The same logistical issues I just set out for monoclonal antibodies dog the administration of plasma, which must similarly be given by intravenous infusion in a safe setting, but the intervention is much simpler, cheaper, and more widely available.


Tocilizumab (Actrema): The large study I said might have hit the sweet spot for this drug, and for the similar cytokine antagonist sarilumab, has now been pre-published and the results look better than I expected, deserving their newspaper headlines. Severely or critically ill patients with COVID-19 who were given these drugs were 25% less likely to die than placebo recipients, over and above the benefit from the corticosteroids nearly all of them were already receiving. Anothing study in less serious patients, now properly published, showed more equivocal results, with if anything an increase in mortality. So it’s looking like the cytokine storm hypothesis may have come through after all, and that these drugs have value in battling COVID-19, but only in the very sickest patients.

Miracles: The Russkies are promising what amounts to a magic wand for COVID-19, a drug that is “more than 99% effective.” I’ll believe that one when I see it. Maybe.

 

Vaccine updates


Moderna: The New England Journal of Medicine has now published preliminary analyses from Moderna’s Phase 3 vaccine trial in the United States, basically confirming data we had already seen. There were 11 COVID-19 cases among mRNA-1273 recipients and 185 in the placebo group, for an overall efficacy against COVID-19 of 94.1%; all 30 cases of severe disease had received placebo (efficacy 100%); the vaccine was somewhat less effective (86.4%) in people over 65; and the vaccine reduced asymptomatic infection by 60%. Nothing new, but it’s nice to see it again. If you’re a data nerd like me and happen to have noticed the apparent discrepancy with the briefing document presented to the FDA, where the vaccine was reported 100% effective in the elderly, the reason is that the NEJM article is based on longer follow-up and twice as many cases.

An anaphylactic reaction
Pfizer: We now have more data on allergic reactions during the American vaccine rollout, and it’s a bit discouraging. First, there were 21 cases of anaphylaxis after 1,893,360 first doses, 10 times as many as expected based on previous vaccines. Second, only 7 of the 21 had had any kind of anaphylactic reaction in the past. Third, 6 of the reactions happened more than 15 minutes after the injection, the standard period of observation, and three were later than the extended period of 30 minutes allotted to allergic people. Finally, 4 required hospitalization. The CDC comment that these reactions are “still exceedingly rare” is true but not entirely reassuring.

Bharat Biotech: A new vaccine from India, named Covaxin, is of interest chiefly because it has been authorized by Indian authorities for emergency use in that giant country and may thus end up being given to hundreds of thousands of people. Regulators say it’s safe (Phase 1), and a preprint posted just before Christmas said it successfully elicited antibodies and a cellular immune response (Phase 2), but Phase 3 trials of real-life efficacy have only just been started.

Curevac: This German company is working on an RNA vaccine in collaboration with Bayer, and claims promising but as yet unpublished Phase 1-2 data. Phase 3 trials began on December 22nd, so results and approval are unlikely before late spring.

Sinovac: I had already seen the tentative report of CoronaVac’s 91% efficacy from a Phase 3 trial in Turkey, but the trial was so small (1322 subjects) that I decided to ignore it. Now a much larger trial in Brazil, analyzing more than 12,000 subjects, claims efficacy rates of 78% against any COVID-19 and 100% against severe disease. Though no details are offered, much less a published manuscript, the Chinese have already made millions of doses available in Brazil, Turkey, and Indonesia, and are promising 600 million doses to developing and middle-income countries this year.

AstraZeneca

-       It somehow went past me that we have absolutely no idea how well the AstraZeneca vaccine works in the elderly. The published interim data from their Phase 3 trial included only 13,000 subjects total (Moderna had 30,000, Pfizer 43,000). All but 1428 were under age 55, only 444 were over 70, and a mere 5 of those 1428 developed COVID-19, far too few to draw any conclusions. 

-       The company claims to have come up with a secret “winning formula” (their words) that will boost their vaccine’s efficacy from 62% toward the 94-95% of Pfizer’s and Moderna’s. They’re letting nobody except UK regulators in on the details until they’re ready to publish.

-       The Serum Institute in India, the world’s largest vaccine maker, bargained with AstraZeneca to churn out a billion doses of the Oxford vaccine to distribute to the global South. They’re sticking with the billion doses, but now say that until March they’ll reserve their entire output for India.

-       There may possibly be a third neurological complication in an AstraZeneca trial volunteer. It seems pretty questionable from what I’ve seen, but if confirmed could be the product’s death knell.

 

Vaccination campaigns 




Saudi Arabia, China, Bahrain


United States: Distribution has been so chaotic that millions of doses may hit their expiration date before they can be administered. Ouch.

Italy: The campaign hasn’t done badly in its first two weeks, administering well over half the doses they’ve received and getting a first dose into 1.1% of the population – the best in Europe! Italians need to put their foot on the gas pedal, though, if their allotted 470,000 Pfizer doses are to be administered every week. At that rate they can get a first dose into all 2 million health care workers and nursing home residents/staff by mid-February, to all 4.4 million over 80’s around the end of April, and then start in on 60-79-year-olds. Italy is also due for some Moderna and Johnson & Johnson doses in the spring, enough to finish vaccinating half the population. HOLD THE PRESSES: On January 8ththe EU managed to nearly double its order for the Pfizer vaccine. Italy’s share will rise to 40 million doses, perhaps making it possible to cover everybody by September without having to fall back on the less effective AstraZeneca product.

India: The most ambitious campaign in the world. Though they haven’t started vaccinating yet, the Indians think they can cover a quarter of their 1.3 billion people by August, though they’ll probably have to double their current number of health care workers to do so. India has the lowest rate of vaccine hesitancy in the world, at 13%.

Russia: Despite their Sputnik V COVID-19 vaccine having been approved way back in August, so few people are willing to roll up their sleeves that only a million doses have been administered so far, fewer per capita than Italy.



Israel: Israeli wins the efficiency derby hands-down, serving as a model for the world: eligible citizens are assigned appointments at vaccine centers, get their shots on time, are monitored for allergic reactions, and leave. In 10 days they covered 10% of their population, and after 3 weeks they’re up to 18%, including more than 70% of Israelis over age 60. For comparison, the US vaccinated 0.5% of its population in 10 days, Germany and Italy 0.4% each. Two important notes: 1) Israel happens to have paid triple to score extra supplies from Pfizer – $62 per dose versus $19 in Europe. 2) in the occupied territories, contrary to the Geneva Convention, Palestinians are not being vaccinated, only Jewish settlers.

 

Contenders for the vaccine folly trophy


Elderly Floridians line up in cars hoping for vaccines

The French health authorities, for imposing 
a 5-day waiting period before vaccination, kind of like what some American states require before an abortion. This misguided policy foments vaccine hesitancy, by planting the suggestion that the procedure is questionable or even dangerous. A week into the campaign, a grand total of 562 people had received their first dose – after 11 days they had reached 7000, and even now they’re only at 45,500 compared to similar-sized Italy’s 600,000 plus. 


Operation Warp Speed, for considering giving half doses of the Moderna vaccine to the young and healthy, claiming that the half dose induces an “identical immune response.” Does it? In the published article a half dose was not mentioned, and a 25 µg dose was much less efficient than a 100 µg dose, inducing antibody titers of 299,751 and 782,719 respectively. A 50 µg dose was, however, administered in an unpublished Phase 2 study presented to the FDA where the immune response was not reported but was said to be “comparable in the 50-μg and 100-μg dose groups.” The 100 µg dose is the only one that has been proven to work in Phase 3 studies, though, and the FDA has thus far rightly turned thumbs down.

 

The AstraZeneca and Sputnik V vaccines

The UK health authorities, for considering the mixing and matching of vaccines, giving a person a different brand for their second dose. From official guidelines: "For individuals who started the schedule and who attend for vaccination at a site where the same vaccine is not available, or if the first product received is unknown, it is reasonable to offer one dose of the locally available product to complete the schedule." The CDC condemned that scenario, and a Cornell virologist spoke for the scientific community as a whole when he said British officials “seem to have abandoned science completely now and are just trying to guess their way out of a mess.” The Brits have backtracked slightly, but alert observers may have noticed a month ago that they were already playing with the idea of deliberately giving first one vaccine and then a different one, and are actually undertaking a trial that pairs the Sputnik V and AstraZeneca vaccines.

The UK health authorities a second time, for a terrifying phrase buried in the above: “or if the first product received is unknown.” If there’s anything crucial to vaccination, especially one that requires two doses, it’s keeping scrupulous records of exactly who got what when. 


The UK health authorities once more, for deciding to give only one dose of vaccine per person, delaying the booster dose for up to 12 weeks. All COVID-19 vaccines thus far have been proven efficacious only if a second dose is given after 3-4 weeks. This delay is not not a great idea but it’s not awful, with enough evidence in its favor to make it a venial rather than a mortal sin. There’s really no need to try it, though, unless there’s an absolute shortage of doses. For now, on the contrary, doses are mouldering in freezers everywhere. And there is unlikely to ever be a shortfall in the United States, given how many doses of home-grown Pfizer and Moderna vaccines the country has reserved for itself.

 

Steven Brandenburg

Steven Brandenburg, the apocalypse-obsessed Wisconsin pharmacist who trashed 500 doses of the Moderna vaccine for the good of humanity, because injecting it into people would “change their DNA”?

The state of Florida, which opted to offer its vaccines to everybody over 65 on a first-come-first-serve basis. Ninety-year-olds camped out overnight to be first in line, only to be turned away in droves when doses ran out. (Tennessee shares the shame here.)

And how about the Florida nursing home that sneaked doses of vaccine to donors and friends? If that had happened in New York, they might have been slapped with a $1 million fine and stripped of their license.


…or the scammers who seem to have set up fake versions of the Eventbrite ticketing platform to sell fraudulent vaccination slots?

 


…or the 60% of Ohio nursing home workers who are refusing to be vaccinated, putting the residents they care for at risk? “They see on social media that the government is putting microchips in you."

Then there’s the health commissioner of Lombardy in northern Italy, given the boot after he stopped the regional vaccination campaign dead in its tracks with “Doctors need their rest. I won’t call them back from vacation to vaccinate on holidays.” 

My personal favorite: an anonymous Instagrammer who parsed “COVID-19” as “C = Certificate, O = Of, V = Vaccine, ID = the mandatory I.D. chip which is planned to accompany the vaccine, 1= (A is first letter), 9= I is the 9th letter, 19 stands for A.I. (Artificial Intelligence).” Comments from before Instagram purged the post: “Proof you can function without a brain” and “They figured that out with their Little Orphan Annie Secret Decoder Ring.”

 

Theme and variants



London, January 2021. Count the bare noses.

Given the continued failure of the English to follow distancing and masking advice, I remain skeptical about the need to invoke hypertransmissibility of the British strain of SARS-CoV-2 – now called either B.1.1.7 or VOC, for Variant Of Concern – to explain their disastrous surge in COVID-19. At least one expert agrees with me, saying it will likely turn out to be only 10-20% more contagious, a far cry from 70% or even 56%. The CDC cautiously says only that it “seems tospread more easily and quickly than other variants.” I’m still waiting for commentary from someone better placed than myself to judge the modelling studies.

And as for concerns about the UK and South African strains that one or both might escape existing vaccines, Anthony Fauci’s reassurances have fortunately now been confirmed by research pre-published by Pfizer, which found that the sera of vaccinated subjects effectively neutralized the variants’ key mutation.

 

What, me worry?

Alfred E. Neuman

We learned early in the COVID-19 disaster that the Trump Administration had dismantled the National Security Council’s highly praised pandemic response team in 2018. But we only found out in October, from the New York Times, that a year later it also declawed the National Vaccine Program Office, which had previously been responsible for monitoring the long-term safety of vaccines. What could possibly go wrong?

The Office was not exactly shuttered, but was folded into a larger infectious disease unit with the goal of “eliminating program redundancies and decreasing program costs.” It does still have a webpage, which confuses the story, but experts say its duties have now been fragmented, without central leadership and without connection to crucial databases. One former official in the office said, “We’re behind the eight ball. We don’t even know who’s in charge.”

Joe Biden is doing a brilliant job of returning major health positions such as Surgeon General and the heads of the Health and Human Services department and Centers for Disease Control to competent hands. Hope he remembers to reinstate this lesser institution as long as he’s at it.

 

Go to the back of the herd

The Trump Administration’s COVID-19 delusions seem to have gone farther than we knew, well beyond the Scott Atlases and the Paul Alexanders. It’s been clear for a while that the White House was fiddling with scientific papers coming from Centers for Disease Control scientists, and censoring the Morbidity and Mortality Weekly Report (MMWR, the CDC’s epidemiological holy of holies). Under investigation by the House Coronavirus Crisis Subcommittee led by Jim Clyburn, what is now emerging is the possible underpinnings: a frank but secretive herd immunity strategy aiming to undermine the CDC’s professed mitigation and containment approaches in favor of having as many people as possible catch COVID-19 – and then blame the resulting case spikes on the scientists themselves to avoid hurting Trump’s reelection chances. Click here to read the rather astonishing details…


La Crosse, Wisconsin, population 50,000, has provided a perfect microcosm of the absurdity of the herd immunity strategy promoted secretly by the White House and openly by the so-called Great Barrington Declaration, which proposes we “protect the vulnerable” while allowing COVID-19 to run amok through the young and the healthy. When three local La Crosse colleges opened for business, COVID-19 ripped predictably through the young and healthy student population. But soon thereafter it spread widely, with the county’s total cases tripling between August 31st and October 20th, and deaths increasing 15-fold. Most of the deaths were in “well-protected” nursing homes, demonstrating that the Barringtonite idea of sheltering the vulnerable is pure fantasy. 

Not to mention the 12,000 Americans aged 25-44 who had died because of the pandemic as of the end of July, a figure that must have more than doubled by now along with the overall death toll.



In the meantime, the people who actually live in Great Barrington, Mass. are up in arms, campaigning to get their town’s name removed from that infamous Declaration.

I was taught in my medical training that for real herd immunity upwards of 85% of the population needs to be immune. So how come people were floating numbers such as 60% for COVID-19? In part, deliberate prevarication: Anthony Fauci, for one, admits he decided to low-ball the figures in hopes of encouraging optimism. Now that more Americans are leaning toward accepting vaccination, he’s letting his estimates creep upward toward 90%. Incidentally, by now well over 10% of the United States population has been exposed to SARS-CoV-2. That means if people were prescreened for antibodies and the positives not given vaccines, the number of adults we’d have to vaccinate might only be 70% or so.

 

Gifts that keep giving



Trump’s January 6th offering to Congress may have reverberations long after the effects of the physical havoc and psychological trauma have worn off. According to one of the Representatives evacuated in the attack, “half the people” in the safe room –Republicans, natch – refused to wear face masks. At least one of them, Jake LaTurner of Kansas, turns out to have been swab-positive for SARS-CoV-2 at the time. Given the close quarters in that hideout crowded with people “yelling at each other,” followed by the lengthy discussion and voting in the congressional chamber, Trump’s attempted coup could turn out to be a super-duper spreader event for COVID-19.



The same goes, of course, for the hundreds of invaders who milled around indoors, largely unmasked, for hours.

What can super-duper mean? Well, last February 3 participants in an international business conference in Boston came down with COVID-19, and the number ultimately grew to 99. Tracking the genetic footprint of the specific strain of SARS-CoV-2 that infected them, researchers have shown that by November that single event had seeded outbreaks involving 300,000 people, in settings from universities to homeless shelters

A homeless shelter in San Diego