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.

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.)



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