RED ALERTS

 

Treatment update

Remdesivir, the ACTT-1 Study: The final results of the Adaptive Covid-19 Treatment Trial, treating patients moderately ill with COVID-19 pneumonia, have now been published and are consistent with the preliminary report a few months back: remdesivir shortened the average hospital stay from 15 days to 10, with a hint of lower mortality. OK, but not extremely impressive.

Remdesivir, the Solidarity Study: Results of the giant, open-label World Health Organization trial have now been pre-published, and at first glance seem damning: remdesivir didn’t improve ventilation rates, time to discharge, or mortality. But the report doesn’t say how long patients had had symptoms before starting the study medications. Nearly 3 out of 4 were either on oxygen or already on a ventilator, so had likely been sick for quite a while. Any antiviral is likely to work better the earlier it’s given, so these negative results need to be taken with a grain of salt.

Hydroxychloroquine: The final results of the UK’s large, randomized Recovery trial are in. It had to be stopped early, when interim analyses showed that hydroxychloroquine patients were significantly less likely to leave the hospital alive within 4 weeks and more likely to wind up either on a respirator or dead. Anyone still having hydroxychloroquine dreams should wake up.

SACCOVID^TM – A new drug from OncoImmune, Inc., who describe it as “an investigational immunomodulator targeting the innate immune system” whatever that means. The manufacturers describe interim data from a randomized, double-blind clinical trial where 203 American inpatients receiving only oxygen therapy received a single intravenous infusion of Saccovid or placebo. Those who received active drug died or needed a ventilator half as often as those who received placebo, and recovered more often and faster. This is particularly interesting because our one valid immune drug, dexamethasone, works only in far-advanced cases. If these data are bourne out by final, published results, the drug could be a major breakthrough.

LY-CoV555: On September 16^th Eli Lilly announced preliminary results using this monoclonal antibody, and they sounded great. Among 452 COVID-19 outpatients with mild-moderate symptoms, the drug supposedly achieved a remarkable 72% reduction in the need for hospitalization, from 6% after 3 doses of placebo to 1.7% after 3 doses of antibody, without significant side effects. BUT: a different trial, testing the same product in hospitalized patients, has suddenly been halted due to a “potential safety issue.” Did some awful side effect pop up? Did early results show patients got worse rather than better? The company ain’t saying. 

REGN-COV2: Two weeks later than Eli Lilly, Regeneron announced somewhat less impressive results using its own antibody cocktail vs. placebo, claiming only that patients who received active drug got better faster and had lower viral loads. They may have lost to Lilly in the race to announce results, but they won hands-down in the publicity department when their concoction was the one administered to Donald Trump. And now that safety concerns have forced one Lilly trial to grind at least temporarily to a halt, Regeneron is pulling still further ahead. They’re promising to distribute their product free of charge in the US but it will be sharply rationed – there are only 50,000 doses for more than 2 ½ million active cases. 

Another contender:  The Eli Lilly and Regeneron concoctions have been joined by an antibody trio perfected by researchers at Berlin’s Charité Hospital. It seems to prevent COVID-19 infection and to lessen disease after a viral challenge – in hamsters. Promising but very preliminary.

I do wonder whether all monoclonal antibody treatments might diminish a patient’s ability to produce his or her own antibodies, in which case short-term benefit might come at the cost of losing longer-term immunity. The antibody vendors must know the answer to that one by now, but they’re not telling.

Vitamin D: People with severe COVID-19 often have low blood levels of vitamin D, but this finding is hopelessly confounded by patients’ preexisting state of health – the frail and sick don’t get much sun. Now a small Spanish study randomized placebo-controlled trial of vitamin D in hospitalized patients with moderate COVID-19 has reported great results. Maybe too great, in my opinion – 50% of placebo recipients vs. 2% in the vitamin D group landed in the ICU. No medication for COVID-19 has had anywhere near that miraculous and impact on any outcome. But moderate doses of vitamin D are safe, and a case can be made for giving supplements to D-deficient COVID-19 patients. A bigger study, aiming at prevention rather than treatment, is now underway in the UK.

Tocilizumab (Actrema): One randomized, double-blind, placebo-controlled trial among hospitalized patients with COVID-19 pneumonia found only a somewhat shorter hospital stay in survivors. Now the manufacturer announcesthat in a second one those getting the drug were less likely to need ventilators but just as likely to die, and stayed in the hospital just as long. I am unimpressed.

Breast milk: Chinese scientists are suggesting that human breast milk might help prevent or treat Covid-19. What to make of that?

Vaccines

Johnson & Johnson/Janssen: I fell in love with their JNJ-78436735 vaccine. It requires only one dose rather than two, and is stable for months under refrigeration (no freezer needed). It worked well in monkeys, both for immune reactionand symptoms, though the symptom study used two doses of vaccine and didn’t do lung biopsies to prove its case. In Phase 1-2 human studies a single dose stimulated both antibody production and T-cell immunity – at the cost of some flu-like symptoms that fortunately hit older volunteers less. Their Phase 3 trial’s research protocol beats those of Moderna, AstraZeneca, or Pfizer hands down. First, their primary endpoint is not “any COVID-19” but “moderate-severe COVID-19,” including in older volunteers. Second, they plan to enroll 60,000 subjects, twice as many as their competitors. Third, they’ve picked high-risk locations in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States. Fourth, they require 2 months of follow-up for complications. And, finally, they’ve ruled out premature peeks at their results. BUT: the JNJ-78436735 story sadly hit a wall on October 13^th – all its trials were halted because of an unspecified disease in a volunteer. As I write we don’t even know whether that trial participant received vaccine or placebo, much less any medical details.

Moderna: According to their latest article, their mRNA-1273 vaccine produced an immune response in 20 people over 55, including 10 between 71 and 74. Similar results have been reported by Pfizer and, in a much larger group, by Johnson & Johnson. AstraZeneca and the major Chinese researchers have have only used younger research subjects.

Pfizer: This company, which has the weakest Phase 3 protocol of all for its BNT162b2 vaccine, for weeks conducted a shameless publicity campaign boasting that theirs will be the first vaccine approved in the United States, with hints at filing for an emergency authorization from the US Food and Drug Administration by the end of October, in time to give Trump an electoral boost. This was so outrageous, both scientifically and ethically, that 60 of America’s top physicians felt compelled to write a letter to the Pfizer CEO begging him not to do so. On October 15^th, he finally ate his words and said that application wouldn’t be filed until at least the second half of November. (Phase 1-2 results showing the vaccine was safe and stimulated an adequate immune response, prepublished back in August, have now come out in final form.)

Astrazeneca: The Phase 3 trial of one of the top vaccine contenders remains in limbo after the development of neurological conditions in two trial volunteers (one in July, one in September). The Food and Drug Administration is still reviewing safety data before it allows more subjects to be enrolled in the United States – news unlikely to reassure the vaccine manufacturers, or the public. 

Novavax: This US-based vaccine company, part of the Warp Speed gang, is a new entry for me – I missed its studies in monkeys, which showed a robust immune response, protection against colonization in the nose or the lungs after challenge with the novel coronavirus, and near-total prevention of lung disease. And its Phase 1-2 results in 105 volunteers, published at the beginning of September, which said the vaccine was safe and elicited a robust immune response. A Phase 3 trial kicked in 4 weeks later but’s it’s awfully small – even if they get all the 10,000 subjects they’re aiming at, there may not be enough COVID-19 cases among them to tell whether the vaccine actually works. They haven’t yet published their research protocol, but judging from the company’s announcement it steers clear of two major pitfalls: moderate-severe COVID-19 is a primary endpoint, and they’re not planning on premature interim analyses.

Down Under: A candidate vaccine developed at the University of Queensland in Australia has done well in hamsters, according to a press release. The first human volunteers were enrolled in mid-July, and Phase 3 studies are planned to start around the end of the the year. But thus far, as far I can tell, not a word of actual data has been published, prepublished, or even announced.

Human challenge trials: Buckle up. British researchers who have been threatening for months to deliberately infect human volunteers with COVID-19 in the name of speeding vaccine development are now plowing ahead. In January they’ll start puffing coronavirus into the noses of healthy young volunteers, to determine the minimal number of viral particles that will produce a measurable infection. Several months later they’ll enlist another bunch of volunteers, shoot them up with various vaccines, expose them to that minimal dose of coronavirus, and see what happens. The unethical nature of the whole endeavor – never in modern medical history has such a trial been done with an untreatable and potentially fatal germ – is in my opinion worsened by the plan to pay subjects something like $5000 for their participation. Even its main justification is questionable: by late spring, when the challenge studies finish, all the major vaccine contenders will already have the final results of their large-scale Phase 3 trials in COVID-19 hot spots.

Getting emergency approval for vaccines in the US: 

All but one of Phase 3 protocols share 3 worrying weaknesses:

1)    Trial subjects won’t be observed for long enough after vaccination for us to feel reasonably confident no major side effects are going to pop up;

2)    Trials can be stopped after very early peeks at the data, if a very few patients (32, for Pfizer) have gotten sick;

3)    Getting sick is defined as a positive COVID-19 swab pus even the most minimal of symptoms, such as a sore throat. 

Only Johnson & Johnson has ducked these bullets, and its trials are unfortunately on hold.

The US Food and Drug Administration developed its own, stricter criteria for emergency-use authorization. Incredibly, the White House attempted to block them, in hopes that some half-baked vaccine might get approval, possibly from Health and Human Services Secretary Alex Azar – bypassing the FDA – before the November election. On October 6^th, though, the Food and Drug Administration released their guidelines anyway. They define criteria for stopping trials early, require evidence that the vaccine prevents not just any COVID-19 but moderate-severe COVID-19, and demand that trial subjects be followed for possible vaccine side effects for at least 2 months after their second dose. The White House finally cried uncle and approved the guidelines – after they’d been posted. In the latest New England Journal of Medicine, FDA officials lay out their rationale for requiring lengthier follow-up, noting concerns that vaccine-induced immunity could fade quickly and observing that the World Health Organization requires a median 3 months' follow-up for COVID-19 vaccines in its own emergency use program. 

 

RED ALERT stampeding herds 

The real COVID-19 news of the week is bad: the White House’s all-out embrace of the herd immunity strategy, after they ran it up the flagpole a month ago and nobody saluted. I have dealt with this rotten idea before (see Surprises from Africa  to October and Got Them Phase In, Phase Out, Out of Phase Blues) but gladly repeat myself. Herd immunity, as the head of the World Health Organization recently reminded us, is a concept developed to help decide how many people need to be vaccinated in order for the unvaccinated to be protected. It would be, as the organization patiently explains, unethical to apply the concept to pandemic containment. Allowing the novel coronavirus to burn its way unchecked through the population of the United States, even with some attempt to shield the vulnerable (see RED ALERT Europe below), would lead to between 2 and 5 million COVID-19 deaths, and leave tens of millions of survivors with long-lasting symptoms ranging from exhaustion to brain fog to shortness of breath to heart failure – 10% of all COVID-19 patients become long-haulers.

The main instigator of herd madness is Trump’s chief advisor, radiologist Scott Atlas. He has now been backed up by a document portentously named the Great Barrington Declaration (Great Barrington, Mass., is home to a Koch brothers-funded think tank). This concludes: “Those who are not vulnerable [i.e. community-living, generally healthy people under age 65] should immediately be allowed to resume life as normal. Simple hygiene measures, such as hand washing and staying home when sick should be practiced by everyone to reduce the herd immunity threshold. Schools and universities should be open for in-person teaching. Extracurricular activities, such as sports, should be resumed. Young low-risk adults should work normally, rather than from home. Restaurants and other businesses should open. Arts, music, sport and other cultural activities should resume.” Tell that to the families of the more than 40,000Americans under 65 – about 2000 of them under 35 – who have died of COVID-19. Or to the myriad people with “mild” COVID-19 who remain sick for weeks, months, or perhaps forever.

The star Declaration signatories were 3: 

1)    Jay Bhattacharya, a Stanford epidemiologist and co-author with John Ioannidis of the infamous Santa Clara County pseudostudy of coronavirus antibody prevalence; 

2)  Sunetra Gupta of Oxford, best known for having come up in late July with the fantasy that the UK had already achieved natural herd immunity. Look at what happened in the UK just a month later:

3) Martin Kulldorff, a Harvard biostatistician with no pre-pandemic history of madness or skullduggery that I know of. 

The names of some of the other distinguished scientists who signed the Declaration, such as Dr. Johnny Bananas, Professor Cominic Dummings, Dr. I.P. Freely, Dr. Johnny Fartpants, and Dr. Person Fakename, may have been purged, but their presence in the original list speaks volumes about the credibility of the whole endeavor.

Other signatories have admitted ignorance: “I don’t know exactly how it would work,” “Measures for preventing coronavirus transmission are not my area of expertise.”

Within hours of the herd immunity news Anthony Fauci had labelled it “total nonsense”; other experts call it “ghastly,” “a dangerous fallacy,” “dangerous,” “mass murder,” and “a recipe for carnage.” You should know that Fauci, who is now being attacked openly by Donald Trump, has had to hire security to protect himself and his family after receiving death threats.

(When you mention herd immunity, somebody will jump in and say “Sweden.” I suggest you read Gretchen Vogel's excellent article.) 

Then there’s Manaus. In Surprises from Africa to October I suggested this city in Brazil’s Amazon region might be the only place in the world to have achieved herd immunity, following an absolutely horrendous COVID-19 epidemic. I guesstimated that 72% of the population of Manaus might have antibodies to COVID-19. Well, now Brazilian scientists with access to real data have prepublished an article concluding the real number is 66%. Can I pat myself on the back? …But even that 66% may not be enough for herd immunity, since Manaus is now seeing another surge in cases and hospitalizations.

 

Digging mass graves for Manaus COVID victims, April 2020

The White House seal of approval makes it likely that the slash-and-burn herd immunity idea, rather than remaining on the fringes where it belongs, may actually be put into place as a concrete strategy. Especially in the Trumpian heartland, where Republican governors follow their leader, and where masks, distancing, and other mitigation measures happen to be most needed at the moment. COVID-19 is on the attack in hitherto unlikely spots in deep-red Nebraska, Iowa, North and South Dakota, and Wyoming, plus Mississippi, Alabama, Tennessee, Oklahoma, Missouri, Kentucky, Indiana, and Minnesota. In the swing state of Wisconsin, the ICUs are so full they’re having to open field hospitals. 

One concrete way the White House is trying to implement the herd immunity strategy is by actively discouraging testing of asymptomatic people, and tracing/quarantining contacts. Herdist-in-chief Scott Atlas said, “When you start seeking out and testing asymptomatic people, you are destroying the workforce.” Is the guy simply, as one expert suggested, “In over his head”? 

 

RED ALERT Europe

The herd immunity debate can learn from Italy’s experience. My adoptive country succeeded better than most other European countries at tamping down the pandemic. At the end of the summer, though, a second wave started in 20-somethings who got the bug partying on vacation – the mean age of new cases was 30. Just what herd immunity champions want, right? But young adults do occasionally see their parents, eat in restaurants, work out in gyms alongside older people . . . so by now the average age is up to 42 or 43, COVID-19 wards are being reopened, and the number of COVID-19 patients in Italian ICUs has gone from 40-ish in mid-August to 870 on October 20^th. In Rome’s Lazio region two-thirds of the dedicated COVID-19 ICU beds are now full, with some hospitals overflowing. I feel the coronavirus’s grip tightening around me – for the first time in my 5 months back in Rome friends and patients are getting sick or being exposed, with barely a day passing without a request for advice.

The daily death toll is only just started to rise, but on October 20, terrifyingly, Italy had such a bad day and the United States such a good day that their number of deaths per million was an identical 1.5. 

The vast majority of new cases in Italy are transmitted within families, so I fantasize the young folk may have already infected nearly all the parents they can, so the second wave might be close to peaking. But Italy’s contact-tracing system is starting to be overwhelmed, and the government’s solutions (2 new COVID-19 decrees in the last week) are far from adequate. Yeah, ice cream parlors that don’t serve sit-down will have to close at 6 pm, staggered school hours may thin out the crowds on busses, and people are being encouraged to work from home. But that’s about it. They’re leaving the gyms open, allowing restaurants to keep serving customers indoors, stuck to the distancing standard of only 1 meter (3 feet), inadequately tutoring households on how to isolate COVID-19-positive members, and leaving the busses at “80%” capacity (and even that minimal limitation is never enforced).

Social non-distancing at an Italian restaurant, September 2020

Italy remains one of the best-off countries in Europe. Things are horrific in the UK, Spain, France, Switzerland, and much of eastern Europe such as Poland and the Czech Republic, with reopening plans getting rolled back everywhere. Even virtuous Germany, which beats out all the other major Western countries, has had to announce curfews for bars and restaurants and new limits on gatherings in places like Berlin where cases are rising.

 

RED ALERT TRUMP: The most dangerous COVID-19 lies at his Oct. 15 town hall

On herd immunity: Moderator: “Do you support herd immunity as a strategy? Essentially, just let people get sick?” Trump: “The cure can not be worse than the problem itself.” (Hey, wasn’t that a yes-or-no question?)

On protection against COVID-19: “You have a report coming out two days ago, that 85% of the people wearing masks catch it.” (Proving that one wrong isn’t rocket science.)

On advisor Scott Atlas and COVID-19: “He’s one of the great experts of the world.” (He’s a radiologist.) 

On observed vs. expected deaths during the pandemic: “We’re a winner on the excess mortality. And what we’ve done has been amazing. And we have done an amazing job. And it’s rounding the corner.” (US excess mortality is actually one of the highest in the world.) About that corner we’re rounding, here’s the map of new cases in the week ending October 17^th:

On health insurance: “We’re always protecting people with pre-existing conditions.” (Trump’s lawsuit to remove those protections will be considered by the Supreme Court this fall  – COVID-19 would be a pre-existing condition for millions of Americans.)

On QAnon:  “They are very strongly against pedophilia. And I agree with that.” Moderator: “But there’s not a Satanic pedophile cult being run by- Trump: “I have no idea.” (Not COVID-19, but I couldn’t resist.)

On being personally in debt for $421 million: “When you look at that, the amount of money, $400 million is a peanut.” (Ditto.)

 

Would that it were!

Curious how the Dems managed to pull the wool over your eyes? This guy knows: “Lawyer Dr. Reiner Fuellmich . . . is seeking to file an international class action suit for crimes perpetrated by those who he says used fraudulent testing to engineer a fraudulent pandemic.”