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.)

 

 

COVID19 update, June 16, 2020: Blue-chip Oxford trial finds inexpensive steroid dexamethasone saves lives in severe COVID-19 cases; flare-ups in Israel and in China

(1) [Hat tip: Yves not-Cohen]: via De Standaard and the BBC, Oxford University reports a breakthrough in the management of severe COVID-19 cases: https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf

I have blogged earlier about anecdotal reports that steroids (for the group I was quoting, methylprednisolone) were being used in an attempt to hold “cytokine storm” at bay, and intuitively this makes a lot of sense. But now we have a large-scale clinical trial to back it up.

A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone. Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%). 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). Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone. Given the public health importance of these results, we are now working to publish the full details as soon as possible.

In plain English, p=0.0003 means there are three chances in ten thousand that the difference is due to coincidence , p=0.0021 that there are 2.1 chances in a thousand of this happening. That the steroid would have no benefit in patients who show no signs yet of “cytokine storm” makes perfect sense.

The study’s authors tout this as the first drug that actually saves lives. Indirectly, Remdesivir and other antivirals may do so if given early in the disease progression, by preventing escalation to cytokine storm: once you get there, you have missed the boat for antivirals and need to focus on stopping the patient’s immune system from killing him.

That dexamethasone is a dirt-cheap drug that has been in common use for decades is of course a nice bonus.

(2) Related, via The Epoch Times (an expat Chinese newspaper fiercely opposed to the regime) a report by the British Heart Foundation about TRV027, an experimental drug by Trevena that restores the angiotensin II vs. angiotensin 1-7 balance (which the virus disrupts through binding to ACE 2 receptors) and thus tries to prevent excessive blood clotting at the source.

Also related, US Senate testimony  by Pierre Kory MD of the COVID19 Critical Care Group.

 

(3) Israel, after a lull and after essentially fully reopening, is now seeing a flare-up of about 200 cases per day. In part this can be ascribed to more intensive testing efforts: past data indicate we had about 10 undocumented asymptomatic or mild cases for each documented case.  (Yesterday, 13,425 were tested, of which 196 found positive.)

The head of the research division of the Maccabi HMO (one of the four authorized Health Maintenance Organizations in Israel, and one of the “big three”) explains to The Times Of Israel that this time around, most of the cases are children or young people (which are less vulnerable), and that many of the children are asymptomatic.

 

In Tel Aviv, which is seeing the fastest spread of the virus, some 57 percent of Maccabi members who tested positive in June are aged 18 or under, Anat Ekka-Zohar told The Times of Israel. There is a similar pattern in other central Israeli cities where cases are growing, she said. In Peta[c]h Tikva the figure is 77%, in Jaffa 60% and in Bnei Brak 43%.

Lots of the current adult carriers are aged 45 or under, Ekka-Zohar said. Some 73% of Maccabi members nationally who tested positive in June are 45 or under, and in Tel Aviv, the figure is 79%.

Maccabi, which is responsible for the health of 2 million Israelis, says that just 1.3% of the people it found to be infected in June are aged 75 or older, Ekka-Zohar said.

Looking at the figure for the 65-plus age group, which is considered the most at-risk of serious illness or death if infected, Ekka-Zohar said it stands at 6.7% for June cases. In April, that age group accounted for around 12% of Maccabi’s cases, she added.

The fact that the most vulnerable aren’t being infected in large numbers bodes well, Ekka-Zohar said, commenting: “It’s not going to provoke a crisis in terms of the number of hospitalizations or in terms of ventilators.”

 

(H/t: Mrs. Arbel.) A somewhat PG-13 rated piece of local humor about masks: the caption says “wearing your mask like thisis like wearing your underpants like that. [And underneath] Please wear your mask correctly.”

Israeli mask humor

(4) “Nothing to see here, move along.” The regime is now blaming “European salmon” for a new coronavirus outbreak in Beijing?! Yeah right — if you believe that, I have some beachfront land in Arizona for sale. Most likely, this is just the 2nd wave of the epidemic they claimed they had under full control. Remember this piece of advice by a Hong Kong resident (warning: language alert).