Stethoscope On Rome: January 2021

On January 21^st, 2020, a Washington State man just home from Wuhan became the first person in the United States to fall ill with what later became known as COVID-19. One year later…

Who’s winning, us or the coronavirus?

Here are countries’ total deaths per 100,000 population since the beginning of the pandemic:

And here’s the new cases per 100,000 in the last week:

If anybody’s winning, it’s sure not the United States.

To give you an idea of how the pandemic is proceeding, I’ll show you the daily deaths in a few countries of interest since the very beginning. I hope you’ll find it as fascinating as I do to eyeball the shapes of the curves, from maskless America to anarchic Italy, from virtuous Germany to controversial Sweden.

Treatment update

...and prevent COVID-19?

Tocilizumab: The results were already mixed enough without a new trial from Brazil adding to the confusion. They found that the drug not only didn’t help seriously ill COVID-19 patients but may even have increased mortality. I repeat once more: if tocilizumab does any good, it’s not much.

Convalescent plasma: More good news on the heels of the benefit to high-risk outpatients I reported last time. An observational study of hospitalized patients has found that those given plasma with high levels of antibodies were less likely to die (22.3%) than those who received antibody-poor plasma (29.6%). This is a valuable, low-tech treatment that should be used more, with pre-screening for plasma with high antibody levels.

Hydrogen peroxide: Gargle with hydrogen peroxide and you won’t get COVID-19? Yup, according to some Neapolitan and Milanese researchers. I’d classify that in the Italians are Dreamers Department.

Bamlanivimab: Lilly has been testing its monoclonal antibody, already shown to help people with mild-to-moderate COVID-19, as a preventive. And it seems to work, according to a press release saying that a single infusion cut symptomatic cases of COVID-19 among nursing home residents and staff by a whopping 80% over 8 weeks. But, hey, how about giving us a manuscript with all the data?

Lilly and Regeneron monoclonals: The US government and New England Journal of Medicine editorialists are pleading with hospitals to use them – 80% of the distributed doses are still sitting on shelves. I’ve discussed the daunting logistics before, but failed to mention another roadblock: though the drugs are provided free by the Feds, hospitals are saddled with the considerable costs of administering them by IV infusion.

Molnupiravir: Merck is testing this experimental oral antiviral on outpatients and inpatients with COVID-19. If it works (a big if, given the poor-to-mediocre performance of all antivirals studied thus far), it would be the first early treatment that doesn’t require intravenous infusion in a hospital setting.

Whipworm, one of ivermectin's prettier targets

Ivermectin: A Nigerian trial found patients that with mild-to-moderate COVID-19 become swab-negative a few days earlier on oral ivermectin (12 mg twice a week) than on lopinavir/ritonavir (two antivirals known to be ineffective against COVID-19). Ivermectin had no effect at all on symptoms, fever, or other clinical parameters. Patients were randomized, but the study drugs were given open-label rather than blind, and patients received azithromycin, heparin, and/or corticosteroids at the discretion of their doctors. This trial speaks against any real benefit from ivermectin, leaving me even more perplexed at the possibilistic position of distinguished infectious disease expert Paul Sax.

Natural immunity: I’ve mentioned that in one American study none of 1246 health care workers who were antibody-positive for SARS-CoV-2 (i.e. had been exposed) in April had developed symptomatic COVID-19 by November, as compared with 89 of 11,052 who didn’t have antibodies. Now interim results from the British SIREN study support those findings despite not being billed that way. SIREN followed 6614 National Health Service personnel with SARS-CoV-2 antibodies at baseline, and 14,173 without antibodies, for an average of 5 months. According to news reportsand to a summary in the BMJ, the results didn’t seem too promising, finding “44 potential reinfections,” for an “83% rate of protection from reinfection.” That’s OK, much better for instance than the AstraZeneca vaccine, but is far enough from 100% to suggest that COVID-19 survivors are at serious risk of reinfection and should be tested and vaccinated just like everyone else. If you read the full manuscript, though, you find a different and much more encouraging story. Of those 44 “potential” cases, only two were considered even “probable” COVID-19, and none were “definite.” The other 42 were “possible,” based on positive molecular tests for SARS-CoV-2 on screening swabs. The authors say that noninfectious RNA fragments left over in survivors’ noses likely account for most of their “possible” cases. They themselves calculate the efficacy of natural immunity as 99% against probable COVID-19, and 95%-plus against possible COVID-19. That matches or exceeds the protection afforded by our best vaccines.

Vaccine updates

Pfizer: Peter Doshi, an associate editor of the prestigious BMJ, has raised doubts about its efficacy, saying it may be closer to 20% than 95%. This is idiocy. The way he calculated that figure was to include all illnesses in the Phase 3 that were initially considered conceivably cases of COVID-19, such as people who had the sniffles and had a negative SARS-CoV-2 swab, as though the vaccine might be expected to prevent the common cold. An eminent Italian scientist and an Australian science writer have done better than I can at destroying his argument.

Johnson & Johnson: Probably the most exciting vaccine news is the publication of Phase 1-2 results showing that the one-dose Johnson & Johnson vaccine stimulates a strong immune response, with relatively few side effects, in hundreds of volunteers of all ages. These results remain only promising until real-life efficacy is demonstrated in the 40,000-person Phase 3 trials, whose results are due by early February. If it works, doses could get into arms as early as late February in the United States and April in Europe.

Merck: Having entered the vaccine race late, it’s already thrown in the sponge. Neither of its two candidate vaccines properly stimulated the immune system.

ReiThera’s GRAd-COV2: This made-in-Italy latecomer, which like AstraZeneca’s is based on an ape adenovirus, has supposedly been shown to be safe and to induce both antibodies and cellular immunity against SARS-CoV-2 in over 90% of 45 Phase 1 subjects. (Curiously, the chief researcher says, “we enrolled 100 people and 45 were vaccinated with different doses.” What happened to the other 55?) But the few results we’ve seen are underwhelming, with the vaccine inducing far fewer neutralizing antibodies than those that follow natural infection (last column):

Compare a similar graph for the Moderna vaccine, which (like Pfizer’s) gives higher levels than natural infection:

Even if the Phase 1-2 results were red-hot instead of lukewarm the company might not have proceeded with Phase 3 efficacy trials, for lack of funding.

Sinovac’s Coronavac: My last post mentioned a Brazilian trial that found an efficacy rate of 78%. Just a week later they’re revising that estimate drastically downward, saying it’s only 50% effective if you use a case definition similar to those used by Pfizer and Moderna. But the vaccine may in fact prevent 78% of moderate-severe cases. We can’t judge without much more data, but the Chinese have been responding to demands for it with obfuscation.

AstraZeneca: AZ will be considered for emergency authorization by the European Medications Agency on January 29^th. I hope the EMA reaffirms the caution and good sense it’s shown thus far by approving the vaccine, if at all, only for use in people under age 55, essentially the only group where it’s been tested. News sources in Italy think such an age limit is likely. One mystery for me is: where are further AstraZeneca results? Their only published Phase 3 articlereported interim analyses of 11,636 trial volunteers but said 23,848 volunteers had participated. One would think that some results on all 23,848 participants would be available by now, 7 weeks later.

I’ve been advising people to decline the AstraZeneca vaccine, which is only 62% effective even in people under 55 (who have more responsive immune systems). In the UK and hopefully elsewhere, AstraZeneca refusers will keep their place on priority lists and will be able to get a different product later. Amazingly, many poorly informed Brits are preferring the AstraZeneca vaccine, apparently out of nationalism. Note that the US is expected to hold out longerthan the EU before authorizing it.

One potato, two potato: The UK is now officially giving all vaccines in only one dose, promising a second one 10-12 weeks down the line instead of the 3-4 weeks in the clinical trials, with the aim of getting vaccine into as many people as possible. This is a huge gamble. British doctors are fighting back so hard that the government has been reduced to seeking endorsements from, for example, pathologists – experts in neither viruses, vaccines, nor living human beings. British plans may get squelched by Pfizer itself, which has threatened Quebec province to cut off supplies if they put such a policy into effect.

Briefer delays of the second dose are now approved by the CDC, allowing the interval to be stretched to 6 weeks if there’s a shortage. Though not desirable, this is at least not off the wall because the Pfizer vaccine is probably very effective, at least for a while, after a single dose. The company’s original Phase 3 paper claimed only 52% efficacy during the weeks between dose 1 and dose 2, but that was counting all new cases, even if they occurred before the immune system could possibly have produced antibodies. Looking only at cases beginning between day 15 (when antibodies are certain) and day 21 (when the second dose was given), UK authorities have convincingly recalculated the efficacy of a single dose at 89%. Yes, an Israeli study suggested a single dose is merely 33% effective, but that was mixing apples and oranges: the Israeli study looked at positive swabs, which were mostly asymptomatic. Pfizer and the British experts looked at disease, which is what counts. The Israelis happen to be uniquely placed to judge real-life efficacy of the Pfizer vaccine after fully vaccinating (2 doses) 128,600 people – only 20 of them have developed COVID-19 so far, and none became seriously ill.

Mix-‘n’-match, act 2: Following in the footsteps of UK authorities the CDC, anticipating temporary shortages in February and March, now says it may be allowable “in exceptional circumstances” to substitute a different vaccine for the booster, if the original vaccine is unknown or unavailable. But unlike the Brits, the CDC says the swap is only allowable between RNA vaccines. This is not an issue at the moment in the USA, where the only vaccines available (Moderna and Pfizer) are both RNA-based. But what happens if the adenovirus-vectored Johnson & Johnson or AstraZeneca get approved? Would the CDC, like the Brits, still approve changing horses in mid-stream? Hopefully the problem will never arise.

Vaccination campaigns

Vaccinated doctors outside the Spallanzani Hospital in Rome

Italy: The Italian campaign started surprisingly strong, was going full steam ahead – I had a dose on January 14^th – and seemed on course to achieve herd immunity around the end of September when 80% of adults would be fully vaccinated. But on January 15^th Pfizer suddenly announced it would be cutting back immediately on its vaccine shipments to the EU and Canada, while they revamped their Belgian factory. This drew understandable rage and possibly an Italian lawsuit for breach of contract. It seems the shortfall is 29% or less, and some vaccines are still being given, but most are being held back so people like me can receive our second dose on schedule. The vaccination of Italians over 80, which was supposed to begin in late January, may be postponed for as long as 2 months. I’m not sure why such a lengthy delay, since Pfizer will supposedly be back to delivering full rations this week. A week before vaccines start going into old folks’ arms, regional web pages will go live to take appointments – in Lazio, here or here– and General Practitioners will start notifying patients.

In Phase 1 only health care workers and nursing home residents were vaccinated, so appointments and administration in medical facilities were simple. But organizing vaccination locales for Phases 2 and onward, aside from a few doses administered in the homes of frail elders, will be more complicated. Primrose-shaped vaccine centers had been supposed to mushroom all over Italy as the backbone of the campaign. But now the authorities are leaning toward using the country’s shuttered convention centers, sports stadiums, army barracks, gyms, theaters, museums, and discotheques as vaccination hubs. A lot of improvisation will be needed, but improvisation is something Italians shine at.

Vaccine doses per 100 people

Israel: Now that close to half of Israelis have received a first dose of vaccine, they are probably going to start vaccinating Palestinian prisoners in Israel proper – but in the occupied territories they’re still not even vaccinating health workers, much less the general population.

The European Union: After Pfizer, AstraZeneca is now reneging on the supplies they promised to the EU, assuming their vaccine gets approved next week. This is not such a bad thing. If Johnson & Johnson (Janssen) comes through fast enough, Europe may not need to resort to the AstraZeneca vaccine at all.

The United Kingdom: the UK has painted itself into a corner by relying heavily on its local product, AstraZeneca-Oxford. (Valneva and Novavax won’t have Phase 3 results before March, GlaxoSmithKline-Sanofi not until the end of 2021.) Here’s its planned supply of doses:

For comparison, here’s the more balanced distribution in Italy (Curevac won’t be approved before late spring):

I’ve been accused on Facebook of being a “Brit-basher” for criticizing the UK’s vaccination campaign. On the contrary I’ve always admired the UK’s National Health Service both in theory and in practice. I’ve sent many of my own patients there to get top treatment for conditions including cancer, eye disease, brain tumors, lung disease, ulcerative colitis, even hemorrhoids… But how can I not criticize when, knowing AstraZeneca’s inferior performance and its lack of testing in the elderly, I read on the BBC, accurately summarizing government documents: “Experts have concluded that both vaccines are very effective, and have not stipulated a preference for either one in any specific population”?

United States: The vaccine rollout, called a free-for-all by the Washington Post and a dismal failure by Joe Biden, continues to be shambolic in many states, notably Florida. New York deserves praise for trying hard to manage rapid vaccination of vulnerable populations and keep from having to throw out expiring doses, while at the same time avoiding fraud and queue-jumping.

As if things weren’t made chaotic enough already by what turns out to be not an inadequate vaccine distribution plan but no plan at all, a final blow from Trump’s CDC made them worse by urging states to expand their vaccination campaigns immediately to include all Americans 65 and older instead of covering older people first. Plus perhaps all 110 million ages 16 to 65 with comorbid conditions. In New Jersey and Mississippi saying you smoke counts as a comorbid condition. Fortunately some states, including Alabama, are holding strong on more orderly vaccination programs.

Despite all the mess and all the uproar the United States is actually managing to get lots of doses into arms. The 9.3 million as of January 14^th corresponded to 2.8% of the American population, and now it’s up to 6.6%, better than most other countries. In the United States a major problem has been Pfizer shipping out so many doses that many risked expiring unused. When those frozen doses finally started running out, one of Alex Azar’s last acts at Health and Human Services was to promise to replace them fast with vaccines that had been being held for second doses. But this promise was a scam –the storehouses were empty and there were no spare doses to ship.

The Trump administration seems to have used $850,000 from the Paycheck Protection Program, created to help small businesses keep afloat through the pandemic, to finance anti-vax groups. Are we really surprised?

Vaccine doses administered per 100 people

Third World: 70 million vaccine doses have already been administered worldwide. But the World Health Organization has warned that the vast chasm between rich and poor countries in the rollout risks bringing the world to “the brink of catastrophic moral failure,” and even the business community is warning of its dangers. Now that Joe Biden has rejoined the World Health Organization on day 1 of his presidency, and pledged on day 2 to support the WHO’s COVAX initiative for getting doses to poorer countries, perhaps things will look up.

Variant panic

Train platform, London, last week

I am aware that my skepticism about the increased transmissibility of the British B.1.1.7 virus variant is a minority position. That doesn’t keep me from sticking to it. And I am pleased to see that the World Health Organization, in the persons of its COVID-19 Technical Lead Maria Van Kerkhove and the Executive Director of its Health Emergencies Programme Mike Ryan, now agrees with me. Both think that the vertical spikes of COVID-19 cases in several countries are not due to new variants but to “increased social mixing and reduction of physical distancing.”

There’s more. A leaked UK government document apparently – it hasn’t leaked far enough to be findable online – cites polls saying when people in England develop symptoms of COVID-19 only 17% seek swab testing, because they can’t afford to stop working. Seventeen percent!!! And even if they do get tested and test positive, only 1 in 4 comply with self-isolation. If, as these numbers suggest, the vast majority of contagious English COVID-19 patients are out and around, taking buses and hanging out in pubs, there’s no need to invoke a more transmissible strain to explain why cases are soaring.

And now comes Boris Johnson’s announcement that B.1.1.7 is not only more contagious but 30% more deadly. As a notorious skeptic, I’m suspicious. The responsible scientific adviser, Sir Patrick Vallance, has himself described the data as "not yet strong." I looked at his report, which concluded only that there “is a realistic possibility” of increased mortality. But it also found that 1) people with the variant were not more likely to require hospitalization than those with non B.1.1.7 strains; 2) those hospitalized with B.1.1.7 were not more likely to die; and 3) if only subjects with full follow-up were examined, there was no increased death rate. I invite my scientist-readers to take a look for themselves to help get the facts straight.

I was interested to see what a prominent coronavirologist (love that term!) has to say about a different variant that’s been accused of causing the god-awful spike in California: it’s likely the strain is no more contagious but simply “went along for the ride.” Same story, in my view, for B.1.1.7.

Another SARS-CoV-2 variant of concern, the Brazilian P.1 strain, is now taking off. As with B.1.1.7, it’s thought on theoretical grounds that the specific mutations it carries might increase transmissibility. There is very litle solid data available, but I’m slightly more open to the idea with P.1. It is dominant in the city of Manaus, which had such a horrific first wave of COVID-19 that it has been said to be the only place in the world that may conceivably have reached natural herd immunity, with 66% of the population infected by July and 75% by October. But in the last month there’s nonetheless been a horrific new spike in disease. As in the UK, the explanation may well lie in relaxed containment and holiday mixing. In Manaus, though, I’m less absolute in excluding the possibility the variant may be more contagious or more resistant to survivors’ antibodies.

Glitchville

Pfizer freezer

Near Bologna, a freezer malfunction put 1500 doses of the Moderna vaccine in jeopardy. The temperature alarm started sounding immediately, but two employees apparently ignored the beep-beep all night… 800 doses had to be thrown away, and the employees are being brought up on charges of dereliction of duty.

In Colorado, 400 doses of Pfizer went bad in a malfunctioning freezer. In California, 850 doses of Moderna were salvaged in the nick of time. In Boston 1900 doses of Moderna had to be scrapped when both the freezer and the alarm system failed. In Maine, 4400 doses of Moderna were tossed in the trash for the same reason.

In California, a cluster of severe allergic reactions to what may have been a bad lot of Moderna led the state to halt distribution of all 300,000 outstanding doses. (Generally speaking Moderna gives only a quarter as many anaphylactic reactions as Pfizer.)

Eight workers in northern Germany were accidentally injected with 5 times the proper dose of the Pfizer vaccine – probably getting an entire vial instead of a single dose. Four of them had to be hospitalized.

In India the rollout has been hampered not only by widespread reluctance to receive a half-tested vaccine, but by a flawed app that didn’t send out the appointment text messages.

IT failures have similarly prevented people with appointments from getting their shots in Houston, Staten Island, and New Jersey, and given ineligible people appointments in Chicago, Hackensack, Arizona, and Virginia. And that’s just on page 1 of my search results. A friend in California, enrolled in the super-efficient Kaiser Permanente system, said she was among 90,000 who phoned for an appointment on day one. She succeeded after 5 hours on hold.

Vaccine panic