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 11, 2020: vitamin D as “the low-hanging fruit of the epidemic”; deficiency statistics for Israel; first monoclonal antibody for COVID19 enters clinical trials

(1) John Campbell and Roger Seheult both again have videos on vitamin D

Apparently, the French medical academy now also got in on the act. Adapted from his notes: There is a significant correlation (95.4% confidence) between vitamin D deficiency and mortality from COVID-19. This phenomenon follows a North-South gradient, but Nordic countries are the exception, as foods there are routinely fortified with vitamin D (since the long subarctic winter otherwise causes major problems).  Spain and Northern Italy have counterintuitively high rates with vitamin D deficiency, as they do not normally fortify foods nor take supplements.

 

 

Now I got curious about Israel with its sunny climate, and found this in the IMAJ (Israel Medical Association Journal)

(journal issue from the publisher) (ResearchGate entry for paper)

 

As you can see in Table 3 (screenshotted below), there is a difference between Ashkenazi Jews (i.e., those whose ancestors came from Central and Eastern Europe), non-Ashkenazi Jews (in Israeli public discourse, actual Sephardim — descendants of the Spanish Expulsion — are commonly lumped in with Yemenite, Iraqi, Iranian,… Jews who descend from their own Diaspora branches), and Israeli Arabs. While there are some quite swarthy Ashkenazi Jews (as in: swarthy enough to pass for Arab), and conversely there are non-Ashkenazi Jews and Arabs who are quite light-skinned, the difference between the population averages is quite obvious. And indeed, this is reflected the vitamin D deficiency statistics below. Even with the small sample, statistics are significant at the 95% or more level.

Table 3 upper

Now elderly people of any ethnicity have more vitamin D deficiencies to begin with. So what is the sample is narrowed down to people aged between 20 and 50? That’s the lower pane of that table:

 

Table3 lower

Look, it’s a trade-off. Darker skin means you can spend more time outdoors in sunny climates without getting sunburned (the origin of the term “redneck”) or (G-d forbid) developing skin cancer. But it does make you more at risk  for vitamin D deficiency — and all that entails for the immune system —  if you live at northern(-ish) latitudes and/or spend most of your time indoors.

And you just have to stick the title of this paper in Google Scholar and look at the papers citing it to see a pile of studies linking vitamin D deficiencies with adverse outcomes for all sorts of illnesses. 

Medscape referred to vitamin D as “the low-hanging fruit of the epidemic”. It sure is.

 

(2) Chemical and Engineering News reports  that Eli Lilly has started phase 1 clinical trials with a monoclonal antibody. 

The discovery effort began at the end of February. Now, just 3 months later, Lilly says it has given the experimental antibody, called LY-CoV555, to the first participants in a Phase I clinical study of people hospitalized with COVID-19. The trial began more than a month ahead of the companies’ earlier goal of late July.

The 90-day turnaround from discovery to injection is likely a record for monoclonal antibody drug development. LY-CoV555 may also be the first experimental drug designed after the discovery of SARS-CoV-2 to be tested as a treatment for COVID-19. The dozens of therapies already tested in COVID-19 patients—including remdesivir, an antiviral made by Gilead Sciences—were discovered before the pandemic and are now being repurposed to fight the coronavirus.

LY-CoV555 targets the spike protein of SARS-CoV-2 and in preclinical studies prevented the virus from infecting human cells. Scientists hope that mass-producing these antibodies will help clear the virus from people who are already infected and struggling to recover. Antibodies could also be given to healthy people to help prevent an infection for a few weeks or months. That prophylactic approach could prove useful for high-risk people, including those with compromised immune systems and medical workers who face frequent exposure to the virus. […]

LY-CoV555 targets the spike protein of SARS-CoV-2 and in preclinical studies prevented the virus from infecting human cells. Scientists hope that mass-producing these antibodies will help clear the virus from people who are already infected and struggling to recover. Antibodies could also be given to healthy people to help prevent an infection for a few weeks or months. That prophylactic approach could prove useful for high-risk people, including those with compromised immune systems and medical workers who face frequent exposure to the virus.

Lilly’s program is one of about two dozen underway to develop monoclonal antibodies that target SARS-CoV-2. Several other firms, including Regeneron and Vir Biotechnology, expect to begin clinical trials of their antibodies in June or July.

The main goal of Lilly’s Phase I clinical trial is to see if LY-CoV555 is safe, but the company is taking the unusual step of including a placebo group in the study. That could provide early signs of whether the drug is working. Lilly says that it expects results by the end of June and that it will begin a larger, Phase II trial soon after if the drug appears safe.

Lilly has already begun large-scale manufacturing and is working on having several hundred thousand doses ready by the end of the year.

The discovery effort began Feb. 25, when AbCellera received a plasma sample obtained from a person who had been infected with SARS-CoV-2 and had recovered. That plasma contained precious B cells—the antibody factories of our immune systems. AbCellera scanned through more than 5 million B cells to find ones that made antibodies targeting the SARS-CoV-2 spike protein.

 

(3) Both masgramondou and a friendly writer sent me links to this article in al-Grauniad (https://archive.is/lkKN0) I am glad to see that exasperation at repeated “coat-turning” on lockdown and social distancing measures is not just the province of political conservatives and libertarians.