COVID19 update, June 24, 2020: vaccines progressing faster than expected; more on dexamethasone and other steroids

(1) Chemical and Engineering News, the house organ of the American Chemical Society, has a cover story about current progress in vaccine efforts.

Large trials this summer and fall could provide the first evidence that some of the experimental COVID-19 vaccines are working. AstraZeneca, which is developing an adenoviral vector vaccine designed at the University of Oxford, is recruiting 10,000 people in the UK, 30,000 people in the US, and potentially 2,000 people in Brazil for its Phase III study to determine if the vaccine is effective. If the trial is successful, AstraZeneca says, it could start distributing the vaccine as early as September in the UK and October in the US.
 
Moderna plans to begin a 30,000-person Phase III study of its messenger RNA (mRNA) vaccine in July. The firm is working with the contract manufacturer Lonza to produce 500 million doses or more per year.

And J&J, which like AstraZeneca is developing an adenoviral vector vaccine, says it will begin its first clinical trial in the second half of July—two months earlier than anticipated. The trial will test the vaccine in 1,045 healthy volunteers in the US and Belgium. J&J is also trying to move faster on planning for its larger trials.

The Chinese companies Sinovac and China National Pharmaceutical Group—also known as Sinopharm—are prepping for Phase III studies of their vaccines outside China. Both firms are developing vaccines made from chemically inactivated SARS-CoV-2. They say people receiving their vaccines in Phase II studies developed neutralizing antibodies to the virus, but the data have not been published.

Pending a vaccine, monoclonal antibodies “could be a bridge”.

Lilly was the first company to begin clinical trials of monoclonal antibodies, discovered by the Canadian company AbCellera Biologics and the Chinese firm Shanghai Junshi Biosciences. It took only about 90 days from the start of AbCellera’s discovery program to the first injection of the antibody in a clinical trial.
“Typically, that process could take between 1 1/2 to 2 years minimum, so doing it in 3 months is extraordinary,” says Janice Reichert, executive director of The Antibody Society, a trade organization.
Others are also moving fast. Regeneron has begun two clinical trials of an experimental therapy that includes two monoclonal antibodies that target SARS-CoV-2. Tychan says it has begun clinical trials of its antibody in China.
 
By Reichert’s estimation, there could be upward of 20 SARS-CoV-2 antibody programs in clinical studies by the end of the year, and it should not take long to determine if these drugs are effective. Lilly says it could have data by the end of the summer. “The readout is pretty quick with COVID-19,” Reichert says. “You either get better or you don’t.”

(2) Dr. Seheult has an additional video on dexamethasone, and how this did not come out of nowhere, but built on early results from ad hoc, unsystematic treatment with various steroids. 

The received wisdom was to avoid administering steroids in respiratory infections, as they put a damper on the immune system and make the patient more vulnerable to bacterial superinfection. Especially in a hospital setting, with multiple-drug-resistant strains endemic, this is a major concern: most seasonal flu victims actually die from secondary infections rather than the influenza virus directly.

However, as doctors at hospitals treating COVID-19 patients started recognizing the signs of ARDS (acute respiratory distress syndrome) and cytokine storm, they started trying various immunomodulators, of which steroids are the most readily available. Since these earliest applications were often to the patients in greatest distress, results skewed negatively due to selection bias.

In early May, a preprint was released of a study in Michigan that showed a short course of methylprednisolone IV significantly reduced (p=0.005) escalation of disease severity, and reduced median length of hospital stay from 8 to 5 days (p=0.001). In plain English, p=0.005 means there is only a 0.05% probability, or 1 chance in 200, that the difference is due to the luck of the draw. With p=0.001, we’re talking 1 chance in 1,000 the difference is due to coincidence.

https://doi.org/10.1101/2020.05.04.20074609

Then of course the famous Oxford “Recovery” trial of dexamethasone happened and was published. This has a large, careful constructed sample and a solid control arm. Recapping from our earlier post on the subject

Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14).

p=0.0003, in plain English, means there are three chances in ten thousand that the difference is due to coincidence, p=0.0021 corresponds to one such chance in five hundred, while p=0.15 is a bit more than one chance in seven. 

What is the likelihood that a patient not on a ventilator needs to be put on a ventilator later? That is actually also fairly significantly lower on the steroid  (p=0.021, or 1:50 odds of this being coincidence).

This is likely to change treatment everywhere: dexamethasone is quite cheap and readily available, and in fact can even be administered orally. Better still: the mechanism of action is fairly clear: reducing the inflammatory reaction that has the patients’ own immune systems “killing the patients in order to save them”. Antivirals like remdesivir appear to be more effective in earlier disease stages: a synergy between the two can hopefully do a lot of good. (Alas, remdesivir is fairly difficult to synthesize and requires IV administration.)

 

 

COVID 19 update, June 5, 2020: ex-MI6 chief drops bombshell; “chaos disguised as strategy”; Trump admin selects shortlist of five vaccine candidates

(1) The former head of MI6 (the UK’s foreign intelligence service — its CIA if you like), Richard Dearlove, says flat-out COVID-19 was engineered in a Chinese lab but escaped from there. 

He continues:

Although he did not believe that the Chinese released the virus intentionally, Sir Richard told the Telegraph that the Chinese regime handled the outbreak very differently from the way a Western government might have dealt with it, and that the incident should be a wake-up call for the rest of the world on underestimating the scope of Chinese global ambitions. 
“Look at the stories… of the attempts by the leadership to lockdown any debate about the origins of the pandemic and the way that people have been arrested or silenced,” he said. “I mean, we shouldn’t really have any doubt any longer about what we’re dealing with. 
“Of course, the Chinese must have felt, well, if they’ve got to suffer a pandemic maybe we shouldn’t try too hard to stop, as it were, our competitors suffering the same disadvantages we’ve got. 
“Look, the Chinese understand us extremely well. They have made a study of us over the last decade or longer, particularly through attending our universities. We understand the Chinese very poorly. It’s an imbalanced relationship in that respect.” 
Australia has been taking the lead on pushing for an “impartial, independent and comprehensive evaluation” of the global response to COVID-19, an ambition which was agreed to by the World Health Organization in late May. China launched cyberattacks and trade restrictions against the Antipodean state in response. 
“I think it’s very courageous of the Australians to take China on,” Sir Richard said. “I mean, there’s an obvious, huge imbalance in terms of power, both economic and military and political, but they are showing the way. You have to have a critical relationship with China.” 
He urged the British authorities to do the same, calling for the government to scrap plans to place the construction of Britain’s new 5G network in the hands of Chinese telecoms firm Huawei, and to reduce reliance on Chinese-made personal protective equipment for health workers. 
“We need to go into reverse,” he said. “It’s important that we do not put any of our critical infrastructure in the hands of Chinese interests. So telecommunications, Huawei, nuclear power stations, and then things that, you know, we require and need in a crisis, like PPE.” 
“We have allowed China so much rope that we are now suffering the consequences, and it’s time to pull the rope in and to tighten the way we do business. It’s very, very important that we keep a keen eye on this and do not allow the Chinese to, as it were, benefit strategically from this situation that has been imposed on all of us.”

Wow.  

(2) Die Welt (in German) continues to pour withering criticism on the Swedish sonderweg. They call it “chaos disguised as strategy” (Chaos getarnt als Strategie). Private corporations are now stepping up with immunity testing for pay. Due to high demand, they had to limit their offerings to Sweden’s two largest cities, Stockholm (by far hardest hit) and Göteborg, but other companies are looking to fill the void. 

Sweden’s chief epidemiologist, Prof. Anders Tegnell, gave a remarkably self-critical interview on Swedish radio: “Too many have died too soon”. He regrets not having been more proactive to protect the most vulnerable. My translation (2nd hand via German): “I believe there is definite room for improvement in what we ‘ve been doing in Sweden, of course., And it would have been good if we’d known more precisely what to close to prevent infection spread.” Also, he said, if we’d encountered the same epidemic but with the knowledge we have today, then the correct course in his opinion lay intermediate between the road Sweden took and what the rest of the world did. “Unambiguously, we could have done better in Sweden, I believe.”

(3) Operation Warp Speed, an initiative of the White House, selected a shortlist of five vaccine candidates for mass manufacturing in the US

The five vaccines include Moderna’s mRNA1273, currently in phase 2 trials; AstraZeneca and Oxford University’s AZD1222, now in clinical trials at multiple UK sites; a candidate from Johnson & Johnson; a Merck vaccine based on that company’s successful Ebola vaccine; and Pfizer and BioNTech‘s BNT162.

The accelerated programs are funded through $10 billion from Congress and $3 billion directed for National Institutes of Health (NIH) research.

Earlier this week, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said he was confident more than one COVID-19 vaccine would prove effective in a reasonable period of time.

Francis Collins, MD, NIH director, said some vaccine candidates will be ready for large-scale testing as soon as the beginning of July. The phase 3 trials would involve as many as 30,000 volunteers for each candidate vaccine, with half the volunteers receiving a placebo, Collins told National Public Radio.

If successful, this will be the most rapid vaccine development program in history.

 

ADDENDUM: GenomeWeb reports that another Surgiscape-sourced paper, in the New England Journal of Medicine, has now been retracted. 

The Lancet and the New England Journal of Medicine have retracted two COVID-19 papers because of questions regarding the data used in the studies. The papers were both previously the subject of expressions of concern.

The now-retracted Lancet paper had reported that the antimalarial drugs hydroxychloroquine and chloroquine may increase the risk of death among COVID-19 patients, while the now-retracted NEJM paper noted that though cardiovascular disease increases someone’s risk of dying from COVID-19, ACE inhibitors did not increase that risk.

Both studies relied on a database run by Surgisphere, which said it had detailed data on about 100,000 COVID-19 patients from 1,200 hospitals around the world, but as the New York Times noted earlier this week, clinicians and medical researchers have raised concerns about the data it houses.

The authors of the Lancet study who were not associated with Surgisphere noted in the expression of concern that they would be seeking an independent audit of the data. However, in the retraction notice, they wrote that Surgisphere would not transfer the full dataset to its independent reviewers, citing client agreements and confidentiality. Because of this, the Lancet notes in a statement that three of the four authors — the fourth author being Surgisphere chief executive Sapan Desai — said they “can no longer vouch for the veracity of the primary data sources.” 

The NEJM retraction notice similarly says that the authors, this time including Desai, could not “validate the primary data sources” and requested a retraction.

COVID19 update, May 31, 2020: which patients benefit most from Remdesivir; asymptomatic infection rate; the post-lockdown economy; miscellaneous updates

(1) Dr. Seheult discusses remdesivir for different categories of patients, and suggests that the drug is most beneficial (in terms of quicker recovery) for patients sick enough to require oxygen, but not so sick as to require mechanical ventilation or ECMOs (“heart-lung machines”). In this latter group, the virus has already done so much damage that remdesivir amounts to “closing the barn door after the horses have fled”, while mild cases will resolve on their own.

The conventional division of patients is (averaged across age groups):

  • 80% self-limiting, self-resolving disease
  • 15% get more severely ill
  • 5% critically ill

So it would be the 15% where the drug can make most of the difference, probably by keeping patients from moving into the 5% critical group. 

(2) Dr. John Campbell’s video looks at the asymptomatic infection rate, which he frustratingly places “between 5% and 80%”, and briefly highlights different studies that arrive at wildly different rates. My working assumption all along has been “about 50%”. 

(3) The Economist has a somewhat pessimistic take on the post-lockdown economy. Note that at least some of the economic effects of the pandemic are also felt in countries that never locked down, like Sweden.

Relatedly, Die Welt (in German) looks at how in reopened Germany, spending habits have changed to the extent that some retailers say they don’t see the point of reopening. The main shopping streets have seen foot traffic dwindle by 30 to 75% (Berlin’s famous Kurfürstendamm was hardest hit). Stores with an online presence, who kept in touch with customers during the crisis, have weathered the storm better, while some with a primarily online business model have seen revenue rise (including a new online grocery shopping chain).

(3) Miscellaneous updates:

Moderna’s COVID-19 vaccines now moves into Phase 2 clinical trials, reports the Jerusalem Post, who also note that the chief scientific officer of Moderna is an expat Israeli. (Like in information technology, tiny Israel punches well above its weight in biotech.)

Forbes highlights what it calls the most important COVID-19 statistic: 42% of US deaths occur in a group that is just 0.6% pf the US population, namely care home residents.

Oddly enough: Monkeys steal COVID-19 testing samples in India. 

Tangentially related, the Daily Telegraph looks at what awaits Hong Kong under full ChiCom rule. The UK has offered asylum to Hong Kongers who still hold BNO (British National Overseas) passports. (This unusual type of passport does not come with automatic “right of abode” in the UK.)

COVID19 update, May 24, 2020: vaccine trails hampered by dwindling infections; phases in clinical trials; miscellaneous updates

(1) The Daily Telegraph reports that the Oxford/AstraZeneca vaccine trial is now running into an unexpected snag.

At present a Phase 2 trial is underway with 10,000 volunteers, half of whom get the vaccine, the other half a placebo. The idea is to compare the infection rates between the two groups in order to find out whether the vaccine does indeed have protective value.

But currently infections in the UK are falling to the point that simply not enough people may get infected to be able to learn anything from the trial.

(As related here previously, an earlier vaccine for the original SARS, developed by Janssen Pharmaceutica, was never taken into production because the epidemic died out before human trials could be completed.)

According to the Telegraph, three Chinese groups are running into a similar problem with their respective vaccine candidates.

A “plan B” that nobody dares to suggest would be a “challenge trial”. Here, a smaller group of volunteers would agree to be deliberately infected with the virus 2-3 weeks after vaccination. (Here a placebo control group would presumably be unnecessary.) Healthcare workers dealing with COVID19 patients would be another option for a challenge trial, as these would already run plenty of risk of infection. (The cynical mind wonders about recruiting volunteers for a challenge trial among the ChiCom regime fanboys one encounters in academia and the media.)

The Telegraph also addresses earlier reports that rhesus monkeys subjected to a similar challenge trial did shed viral particles from their nose at similar rates as unvaccinated monkeys. Lead developer, Prof. Adrian Hill, however waves this away, as “the monkeys had been deliberately “overdosed” on coronavirus in order to test for safety.”

“We used a really high dose and these guys gave it not just into the lungs and the nose. They gave it into the mouth, and they gave it into the eyes. They gave a huge dose. I mean, seriously, it’s that level of basic.”

UPDATE: Dr. John Campbell on recent vaccine trials

(2) What’s the deal with “Phases” in clinical trials actually? According to ClinicalTrials.gov definitions are as follows

* Phase 0 (a.k.a. Early Phase 1): exploratory trials with microbuses to investigate how or whether a drug interacts with the body.

* Phase 1: safety testing. “They are usually conducted with healthy volunteers, and the goal is to determine the drug’s most frequent and serious adverse events and, often, how the drug is broken down and excreted by the body. These trials usually involve a small number of participants.”

* Phase 2: effectiveness testing. The drug is tested on people who have the condition/disease that it is meant to cure or mitigate. There is almost always a control arm comparable in size and composition: patients in the control arm may receive either a placebo or (where there is one) the current “drug of choice’. Any adverse effects are monitored.

If the drug is found to have a statistically significant ‘therapeutic advantage’, then testing proceeds to 

* Phase 3: “A phase of research to describe clinical trials that gather more information about a drug’s safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. These studies typically involve more participants.”

If the drug passes that stage and gets approved by the FDA and/or its foreign counterparts, it goes to market. Any post-approval studies may be labeled Phase 4.

What if you have an unproven drug that might save a dying patient’s life, and no better option is available? Then a ‘compassionate use exemption’ applies, provided the patient, a licensed physician, and the drug manufacturer are all willing to try this ‘Hail Mary pass’, since the patient is otherwise doomed anyway. A treatment protocol is to be submitted to the FDA. A less formal version is how our first COVID19 cure (“patient #19”) with remdesivir came about.

Now when testing a drug, elaborate and costly as it may be, at least you have a population of patients already sick. With a vaccine candidate you have additional complications.

* You give vaccines to lots of healthy people, and the first rule of the Hippocratic oath (or its Jewish counterpart, the Oath of Assaf the Physician) is primum non nocere/above all, do no harm. 

* Normally, unless (see above) a challenge trial is set up, only a smaller or larger minority of vaccinated people will be exposed to the pathogen. That means that the sample sizes for phase 2 and 3 clinical trials need to be much larger than for a drug.

(3) Some links, you decide

* via David Bernstein, a piece in the Salt Lake Tribune (archive copy here, especially as the SLTrib is not accessible in Europe ) about some probable and unlikely infection scenario’s.  

* Michael Levitt, 2013 Nobel laureate in Chemistry, in an interview in the Daily Telegraph argues that lockdowns did not result in net saved lives and may indeed have had a net cost. I think he oversells his case, but let the man have his say and make up your own mind. https://www.telegraph.co.uk/news/2020/05/23/lockdown-saved-no-lives-may-have-cost-nobel-prize-winner-believes/

* an anecdotal data point: a woman who has been taking hydroxychloroquine for 19 years to mitigate her lupus now contracted COVID19 regardless, and predictably blames…

* hat-tip to Lissa Halley, a study tracing 455 contacts of an asymptomatic carrier (who was hospitalized for an unrelated chronic heart issue) revealed no infections among any contacts. I would like to see further confirmation, as zero infections out of 455 sounds almost too good to be true.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219423/

COVID19 update, March 31, 2020: a brief look at Belgium

Belgium, historically a crossroads between rival European powers, now is home to the European Union’s nerve center in Brussels. I have been following De Standaard (in Dutch) for updates on the situation there.
This article quotes virologust Steven De Gucht. A few bullet points:

  • 485 new hospital admissions in the past 24 hours
  • 94 new fatalities, but this included deaths since March 11 from care centers for the elderly that had not percolated through the reporting yet (all above age 65). Total mortality is 705, of whom 93 percent are over age 65
  • the youngest victim yet is a thus far unique case of a 12-year old girl. Her status deteriorated suddenly after 3 days of fever. [Cytokine storm?!] De Gucht calls for investigating this rare and anomalous case in detail
  • 876 new cases, the second drop in a row
  • hospital admissions, at 485, are likewise down for the 2nd time. Total COVID19 hospital population is 4,920 — that number keeps mounting as COVID19 patients tend to be in for long hospital stays. 168 patients were discharged today.
  • 1,021 patients total are in intensive care (an increase by 94).
  • 786 patients need respiratory assistance of some sorts
  • 20 are on ECMO (“heart-lung machines”)
  • the article is accompanied by the following infographic:
green=new hospital admissions, teal=ICU, red=deceased

Elsewhere today, the same paper quotes medical sources as saying, “we’re off the Italian track, but not yet onto the Scandinavian one” . The subtitle says, “wait another few days to see if we’re really past the peak”.

And in what sounds like a bold bet, Johnson & Johnson, parent of local Janssen Pharmaceutica NV,  is planning to take a vaccine into production even while the clinical trial is running. It expects to be up to full production early next year. The article quotes Johan van Hoof, director of the vaccines division of Janssen, as saying “Theoretically this could go wrong. But we have enough experience with vaccines to be very optimistic. This virus uses the same ‘key’ [i.e., the so-called “spike protein] to penetrate the lungs as SARS did. So we know we can protect people if we can make the right antibodies be produced by the body.” [A DNA vaccine for the original SARS that expressed the spike protein never saw wide application in humans as the epidemic died out first.]

UPDATE: this isn’t Belgium, but in New York, Rabbi Daniel Nevins, dean of the Jewish Theological Seminary, who recovered from a mild case of COVID-19 earlier this month, is now donating plasma for an antibody therapy trial. https://www.jpost.com/Diaspora/Rabbinical-school-dean-participates-in-experimental-coronavirus-treatment-622670

COVID19 update, March 30, 2020: the quest for a vaccine, high-throughput testing

(1) Mrs. Arbel forwarded a long article that peeks inside the frantic efforts to develop a vaccine. An archived copy is here. Basically, the first step, coming up with a candidate vaccine, has been drastically shortened thanks to modern advances in biotech, genomics, and proteomics. What still takes almost as much time as it used to is testing in healthy subjects:

(2) Mako N12 (Hebrew news site) has an article on a novel high-throughput testing assembly developed by two PIs at the Weizmann Institute in Israel, in collaboration with two academic hospitals, Tel HaShomer in Ramat-Gan (one of the five Tel-Aviv boroughs) and Assuta Ashdod. The system can process up to 384 samples at a time, for a maximum throughput of 20,000 tests per day. Aside from automation and “massive parallelization”, one innovation is that the samples are dropped immediately into a kind-of “fixation” solution, which renders them biologically harmless. This eliminates the need for elaborate biocontainment facilities. Apparently the facility is going through final approval procedures.

(3) “masgramondou” brought this article by Dr. John Lee in The Spectator to my attention: https://spectator.us/understand-report-figures-covid-deaths/ on why the CFR (case fatality rate) statistics differ so widely. This affects both the numerator (do you count everybody who dies from any cause while COVID19-positive, or do you only count if COVID19 is definitely the cause of death) and the denominator (do you test aggressively, or do you only bother testing when it’s already pretty sure the person is ill).

(4) Speaking of statistics and comparing apples to apples: I remember this morning Mrs. Arbel gasping at a report in the Jerusalem Post that such a large percentage of the Israeli patients are between 20 and 30 years old. However, this is not entirely surprising once you compare Israel’s population pyramid with that of, say, Italy:

Another factor, which Mrs. Arbel pointed out, is the widespread custom of long post-army treks. The tendency of our young people to congregate in tightly packed quarters and in general not to keep people at a safe arm’s length adds to the ease with which an infection can spread.
The comparatively young profile of our general patient population is reflected in the low percentage (below 2%) of critical cases: As of today, 4,347 Israelis have been diagnosed, but only 80 people in serious condition (including one 20-year old man) of whom 63 patients requiring ventilation. 16 people have died. About half the diagnosed people appear to be asymptomatic (for now).
The age profile of critical patients is much the same as everywhere else: older people with pre-existing health conditions (referred to in Hebrew as machalot req`a , literally “background diseases”), or very old people.

UPDATE: FDA gives emergency approval for chloroquine and hydroxychloroquine for COVID19