The Good, The Bad, and The Ugly

 

Drugs and money, vaccine and booster news galore, virus challenge trials resurface, more on origin stories, behavior good and (mostly) bad.

Treatment news

Molnupiravir: The UK shilly-shallied for a year before approving monoclonal antibodies, but when it came to Merck’s anti-COVID-19 pill they decided to be the first on the block. They’re hoping to start giving the drug ASAP, carefully monitoring outcomes, to elderly patients with underlying health conditions that put them at risk for severe disease.

Repurposed drugs: Colchicine (a gout drug), inhaled budesonide (an asthma drug), and fluvoxamine (an antidepressant) have each been shown to decrease outpatients’ progression to severe disease by around 20% – fluvoxamine even hits 32% in a newly published trial. Merck’s much-hyped molnupiravir weighs in at only 50%. I wish somebody would take a look at whether a cocktail combining those 3 cheap old drugs, which I’ve prescribed several times, might do just as well. Adding them to molnupiravir might also be a nice idea.

Sotrovimab: Interim results from the Phase 3 trial of GSK’s monoclonal antibody product have now been published, and they are so good that the trial was stopped early. An intravenous infusion given to high-risk patients within 5 days of falling ill slashed bad outcomes by 85%. Only 3 of 291 patients given the drug, versus 21 of 292 given placebo, were hospitalized or dead by day 29, and all 3 who needed ICU care had gotten placebo. Secondary results, such as symptom duration, should be available soon, and an ongoing study is trialing the drug as a simple shot in the arm rather than an infusion. This trial predated Delta, but laboratory studies suggest that sotrovimab is particularly effective against that nasty variant. 

Regen-Cov and the bottom line: Regeneron has made a new deal with the American government, to supply another 1.4 million doses at $2100 per dose. Same price as previous batches. But when the feds made those previous orders a dose contained 2400 mg of antibody, whereas now it contains 1200 mg, so the price has actually doubled. Interestingly, at the end of August the company seemed about to set the price of the lower dose at $1250, but apparently after a millisecond they caught on to what the market would be willing to bear. (Big Pharma habitually does this, and worse. When Novo Nordisk, makers of Vagifem vaginal tablets, lowered its dose of estradiol from 25 mcg to 10 mcg, they simultaneously increased the price of each dose – at least in Italy – by about 25%.)

Injected interferon-beta: In hospitalized patients not only did it flunk out, but those who got the drug did worse. Guess we can finally cross that one off the list, though an inhaled form is still being tested.

Natural immunity: A CDC study reports that people who have recovered from COVID-19 are 5 times more likely to be hospitalized for reinfection than people who received an mRNA vaccine are to be hospitalized for a breakthrough infection (Moderna, as usual, was better than Pfizer). The CDC concludes by urging all COVID-19 survivors to get vaccinated. This study does suggest that vaccination gives stronger immunity than infection, but I have 3 caveats: 1) The researchers only examined outcomes starting 90 days after infection – survivors might have been better protected during the first 3 months; 2) They only looked at hospitalization, not at milder illness; 3) They didn’t consider the European policy of giving one rather than two doses to COVID-19 survivors. 

 

Vaccine news

Pfizer for kids: Turns out I was wrong about the vaccine being authorized for 5-to-11-year-olds solely on the basis of antibodies in the lab. There actually were (barely) enough cases of COVID-19 in the Phase 2/3 trial to suggest that the vaccine is effective in that age group: 3 in the vaccine group, and 16 in the placebo group. Given that twice as many kids got vaccine as got placebo, that equals 91% efficacy. The 1/3 strength two-dose version will start being rolled out in the United States within days. I confess that if I had school-age children I – like most American parents – wouldn’t rush to bring them in for the jab; my own hesitation concerns the myocarditis risk. 

Boosters: thumbs up: Until now the best data supporting boosters for the Pfizer vaccine came from an observational Israeli study suggesting effectiveness bounced back to its original 95% in people over 60 who received a booster. Now we have a methodologically superior and similarly positive study from Pfizer – a randomized, placebo-controlled trial that according to a press release reaches the same 95% in volunteers of all ages.

Boosters: thumbs-down: Some experts on the federal advisory councils that approved boosters are going public with doubts. Their position is that even after 6 months the vaccines are “holding steady against severe Covid-19 and death,” and that saving lives is what these vaccines were always intended to do. I disagree. We deserve to get more out of vaccines than merely staying alive, and even relatively mild COVID-19 carries a high risk of long covid. Early on the rate among survivors was pegged at 10%, but that was clearly an underestimate. Patients sick enough to require hospitalization are the worst off, but 33%, 56%, perhaps even 70% of people treated as outpatients report persistent symptoms at 6 months. 

So in my opinion the only real argument against widespread boosters can be the World Health Organization’s ethical one, that the entire globe should get vaccinated first. To be honest I don’t think that reasoning holds water either, given how many doses are lying around in wealthy countries ready to distribute in the global South – estimated at 1.2 billionby the end of this year. That would be more than enough to vaccinate the approximately half a billion Africans 15 and older who still haven’t gotten a single dose.

Johnson & Johnson: A case-negative study in Brazil found J&J to be considerably less effective than in Phase 3 trials, just 51% against symptomatic COVID-19 and 73% against hospitalization rather than about 66% and 85%. This may be related to the growing dominance of the Gamma variant.

AstraZeneca solo: Another Gamma-period study from Brazil found complete vaccination with AstraZeneca to protect about 75% against COVID-19 and 90% against death. It also confirmed that a single dose does little: 33% effective against COVID-19, 62% against death. More evidence that the common pattern of putting off the second dose by 3 months is a bad idea.

AstraZeneca mix-n-match: Good news for “heterologous” protocols. A study from Sweden, performed in the Delta era, strongly suggests that a two-dose AstraZeneca regimen protects less against symptomatic COVID-19 (50%) than a regimen giving AstraZeneca first but Pfizer (67%), or especially Moderna (79%), as the second shot. This was not a randomized blinded trial, but it is the first evidence from the real world, rather than from antibody levels, that people who’ve had one AstraZeneca shot are better off getting an mRNA second dose than a second hit of the same. The same can be expected for AstraZeneca’s cousin from Johnson & Johnson, making this study relevant in the US as well. 

Moderna: Emergency use authorization was based on early interim results from a Phase 3 trial. The final results have now been published, and they are consistent: efficacy was 93% against all COVID-19, and 98% against severe disease. All ages were equally protected, and efficacy did not wane over an observation period averaging 5.3 months. My sole caveat is that the study ended before the Delta variant appeared on the scene – but we already know Moderna is the best vaccine against Delta.

Pfizer: Pfizer too has now published what seem to be final results from the blinded phase of their chief Phase 3 trial. Efficacy started at 96% but faded, reaching 84% by 6 months. Even greater falloff has been observed in some other studies, and is exacerbated by the Delta variant.

Covaxin: This inactivated virus vaccine developed and produced in India won WHO approval for emergency use on November 3^rd, on the basis of Phase 3 trial findings of 78% efficacy against any clinical COVID-19 and 93% against severe disease. The vaccine was only 65% effective against the Delta variant, though, and protection was lower in older people. Curiously, when I googled Phase 3 trial Covaxin the phrase “Major protocol violations occurred at the largest site of the Covaxin Phase 3 trial…” leapt to my eye. None of that text appears in the currently posted version of the preprinted manuscript, but from what I can track down the violations appear to be ethical rather than scientific, so that the efficacy figures probably hold.

Valneva: Another new entry, this one similarly based on an inactivated virus. Unfortunately we have no idea whether it actually works, despite a press release claiming, “Valneva Reports Positive Phase 3 Results.” Nonsense! Phase 3 studies are the kind that randomize tens of thousands of volunteers to get vaccine or placebo and follow them over time to see how many get sick. The Valneva studies described in this announcement are actually Phase 1-2, preliminary studies in a couple of hundred subjects that look at immediate side effects and how well the vaccine stimulates the immune system. Is Valneva misspeaking out of ignorance, or intentional mendacity?

The campaign in Italy: As compared to last spring far fewer people have been stepping up to get first doses, even as the government tries to make life miserable for the unvaccinated. Unless they’ve recently recovered from COVID-19 they have to perform, and pay for, antigen tests 3 times a week if they want to work at all – or if they want to enter a museum, a movie theater, a restaurant, or a soccer match. But it should be said that fully 87% of people over 12 have had at least one dose, and 83% are fully vaccinated, 76% of the total Italian population. If vaccination continues at the present snail’s pace through December, and if the EU regulatory agency grants full approval to one or more vaccines, Italy may choose the “nuclear option” and make vaccination mandatory for all, a choice endorsed by 63% of Italians. It would be unthinkable in the US for a pollster to even ask such a question.

The campaign in USA: The stick of vaccine mandates has been proving better at motivating hesitant Americans than the carrots of doughnut bribes, million-dollar lotteries, or hunting rifle giveaways. Take New York City municipal employees. As of October 19^th, the day before the city announced they’d all have to choose between getting vaccinated or being suspended without pay, only 71%  had had even one shot. A mere 13 days later, when push was coming to shove, 94% had gone for a first dose. Unfortunately the US continues to lag badly – only 80% of over-12’s have had a dose and only 69% are fully vaccinated, corresponding to 58% of the total population (again, Italy is 87%/83%/76%). And vaccination has been so politicized that novaxers are geographically clustered, which has led to disastrous local outbreaks in states from Alabama to Alaska.

The global campaign: Despite all the problems I discussed in my October 19th post, the portion of the population that’s received a dose of COVID-19 vaccine has edged its way up since then from 48.0% to 49.9% in the world, from 8.0% to 9.0% in Africa, and from 2.8% to 3.9% in low-income countries. India and Brazil, the second and third worst-hit countries after the US, are making huge strides. There’s still a long long way to go, but it’s good to see movement.

 

Variant watch

Mutation: an artist's rendition

Delta: The viral load in the noses of infected individuals is so high, even in individuals who’ve been vaccinated, that people with breakthrough infections transmit nearly as much disease to household contacts as patients who aren’t vaccinated.  

AY.4.2: This subvariant of Delta is thus far mainly confined to the UK, where people have dubbed it “Delta Plus.” It may be slightly more transmissible than its parent strain, but nobody yet considers it a Variant of Concern, and like many of my colleagues I think the alarmism around it is premature.

Mu: The variant that has dominated in Colombia is not thought to be more transmissible or more virulent, but judging from laboratory studies it is probably considerably more resistant to vaccines than even the Beta variant.

 

Spaghetti western nostalgia

Good, Select Subcommittee on the Coronavirus Crisis: It’s launched a congressional investigation into the conspiracy-mongering “America’s Frontline Doctors” group and its mercenary spinoffs. 

Bad, Radio City Music Hall: Its 2021 Christmas Spectacular will be in front of live audiences and with all employees fully vaccinated. Vaccination is nice, but that’s not nearly enough. Unlike Broadway and most other major New York City venues, RCMH is 1) not doing swab tests on performers or crew (regular testing enabled an outbreak at Aladdinto be nipped in the bud); 2) letting in spectators who are only partially vaccinated; 3) not requiring masks for either audiences or staff. Backlash from its employees may shame them into straightening up and flying right. 

Ugly: The image above is a still from this nasty video of two NYPD officers physically shoving a subway rider out of a station for the crime of asking them to put on face masks, as is required by law. Hundreds of cops have similar face mask complaints pending, and there’s no evidence that any of them have faced repercussions.  

 

Remember Centner Academy, the Miami school that said it would fire teachers if they got vaccinated against COVID-19? This headline describes their latest antic, sending a letter to parents that read, “Because of the potential impact on other students and our school community, vaccinated students will need to stay at home for 30 days post-vaccination for each dose and booster they receive and may return to school after 30 days as long as the student is healthy and symptom-free.”

The Florida Department of Education, somewhat to my surprise, put its foot down by threatening to withhold funding, and in the end the school folded.

 

Another bad call by the CDC

On November 8^th the United States will finally reopen its borders to travelers from some foreign countries, if they are fully vaccinated and present a recent negative swab. But on October 30 the Centers for Disease Control decreed that visitors under 18 not only will have no vaccine requirement but will not even have to quarantine on arrival. What on earth is Dr. Walensky thinking of? The policy includes the United Kingdom, America’s biggest source of overseas tourists, where a raging surge of COVID-19 makes even the US look good. And that surge happens to be driven by cases in adolescents. Since teenagers can spread the hypertransmissible Delta variant just as efficiently as adults, the CDC decision to let them loose in American movie theaters, stadiums, and restaurants fresh off the plane is in my opinion scandalous verging on criminal. The CDC seems to be putting more weight on the profits of the airlines and the tourist industries than on the health of the American people.

 

The plague-spreaders strike again

Infecting volunteers at the UK's Common Cold Unit

The COVID-19 challenge trial phoenix has risen from its ashes, with a bunch from Imperial College London already shooting the wild strain of SARS-CoV-2 up the noses of healthy unvaccinated volunteers between 18 and 30 years of age. This time around there are even more questions than with earlier iterations. Mainly, of course, the ethics of deliberately infecting people who while having a low risk of severe disease are definitely susceptible to long covid. Additionally, though, we now also need to ask what the point is of using the wild (Wuhan) strain when what people are getting are the more troublesome Beta, Gamma, and especially Delta variants. And, even more fundamentally, what is the reason for doing this stuff anyway? Originally the idea was to bypass some steps in testing, in order to get new vaccines out faster. Now that we’ve got many reasonably-to-very-good vaccines, the only excuse the researchers can come up with is “For new vaccines and antivirals, licensure based on immunogenicity or viral kinetics alone may be impossible, but human challenge studies could contribute efficacy data to complement larger-scale safety trials.” This sounds like a bunch of hokum to me.

 

COVID-19 fake news in Italy

Bufala (buffalo as in mozzarella) is the Italian word for hoax

From right-wing politicians, on the record

-       Swabs work better against COVID-19 than vaccines 

-       Germany has banned COVID-19 vaccines under age 18 because they are deadly.

-       The flu vaccine causes COVID-19

-       The Green Pass was invented in order to destroy small businesses and favor multinationals

-       People under 40 shouldn’t get vaccinated, because COVID-19 never kills them

-       My favorite, from League leader Matteo Salvini: the reason we have COVID-19 variants is that people are getting vaccinated

On the street, according to the Superior Health Institute and Health Ministry websites

-       Vaccines weaken the immune system, causing autoimmune diseases 

-       Getting a COVID-19 swab can damage your brain

-       The vaccines only work for a few weeks

-       Vaccines spread COVID-19

-       COVID-19 disappears in the summer

Meantime, back in the great USA, as of August YouTube had already removed more than a million videos spreading fake news about the pandemic.

 

Leaks 

The origins war shows no sign of winding down. Last August, in two reports released within days of each other, US intelligence agencies said they couldn’t decide between natural origin and laboratory leak. At the end of October, 5 agencies confirmed they think the SARS-CoV-2 virus hopped over from animals, with the FBI the lone lab leak holdout. The one thing everybody agreed on was that all the evidence is weak. All the intelligence reports seem to have brought is calls for more commissions, reports, and congressional investigations. 

Like everything else in the United States the question is exhaustingly politicized. The American public has made up its mind: most Republicans (natch) and even most Democrats (surprise!) now think the bug emerged from a lab near Wuhan. In the latest twist, Rand Paul and other Republicans are leaping on a letter from an National Institutes of Health official to claim the US was funding “gain-of-function” research in Wuhan, and implying that this research caused the pandemic. According to independent scientific fact-checkers, both assertions are bunk.

Now the World Health Organization, after running up once against the Chinese rubber wall, is giving the origins investigation another try. It would be nice if the Chinese weren’t holding their cards so close to their chest, but that’s their habit since forever, and it’s not just about COVID-19 – though at the beginning of the pandemic their coverup was particularly culpable. Many people care passionately about the origins issue, and it can’t get settled without a level of Chinese cooperation that is unlikely to be forthcoming. I don’t personally happen to share that passion, and like most scientists I stick with the zoonotic theory: that COVID-19 – like HIV, Spanish flu, Marburg virus disease, SARS, Ebola, Creutzfeldt-Jacob (Mad Cow), Zika, and smallpox – got to human beings by making the leap from an animal species. 

 

Will there always be an England?

Boris Johnson in the House of Commons, October 19, 2021

On July 19^th England declared Freedom Day! No more capacity limits, no more face masks except in hospitals, no more distancing, no more working from home! 

So how has that worked out? Compare it with Italy, which has kept up or intensified its mitigation measures: the UK has 8 times as many cases per capita, and 4 times as many deaths:

British National Health Service leaders have taken note, of course, and strongly urge a return to a mild set of pandemic restrictions they call Plan B. But the government is holding firm, proudly saying that yes, cases may well go over 100,000 a day (there are 42,000-50,000 lately) but they won’t lift a finger unless and until the hospitals are completely overwhelmed. It shocks me that the British Health Minister is going along with Boris Johnson on this; only one medical advisor has resigned over the issue, and even he advocates only very minor restrictions.

In case you’re curious, yes, the U.S. Senate does mostly mask up and distance, even though neither is required (left). The conservative Heritage Society (right) sure doesn’t, though: