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 21, 2020: Dr. Matt Shelton on vitamin D; Harvard historian Niall Ferguson on how the pandemic exposed the “dysfunctional administrative state”; 2005 CDC paper touting chloroquine for SARS

(1) Dr. Matt Shelton, interviewed by Dr. John Campbell, tells us much more about vitamin D. Amusing statement: “Stay in the sun until you’re halfway to sunburned for your skin type, and you’ve had enough.”

(2) Niall Ferguson, about 10 minutes into this video from the Hoover Institute:

“The pandemic has revealed a terrible pathology at the heart of American political life, and it’s not the one you think. While the media endlessly pore over every utterance of President Trump, the real pathology that the pandemic has exposed is that we have a completely dysfunctional administrative state that is extremely good at generating PowerPoints and multiple-page reports, but when it comes to actually dealing with an emergency, is completely useless.”

Here’s another good one:

(3) My Facebook friend Jeff D. reminds me of a 2005 paper published by a group from CDC in the Virology Journal entitled: “Chloroquine is a potent inhibitor of SARS coronavirus infection and spread”.
http://doi.org/10.1186/1743-422X-2-69

And yes, that’s the old SARS-CoV-1, not the current SARS-nCoV-2 — but some of the people now doing all they can to “prove” HOcq doesn’t work would be quite embarrassed at this article.

(4) Meanwhile, Standard & Poor maintains Israel’s AA- sovereign credit rating, and predicts a “V-shaped recovery“.

Finally, another good one from Unherd: Prof. Karol Sikora, former head of The Who cancer program and Dean of the U. of Buckingham medical school, sounds a largely optimistic note.

 

COVID19 update: March 23, 2020. What's in a name?

A reader asked me whether the scientific name is coronavirus, COVID-19, or something else. Without getting into the dispute over the common names, let me address that question specifically.

In a nutshell, coronaviruses are one major family of viruses. What they all have in common is their structure: They consist of a single strand of RNA which encodes the genetic “payload” , a shell of envelope proteins self-assembling around the strand, and a bunch of spikes on the shell whose job it is to stimulate receptors in the cell wall and effect an opening for entry. The spikes look like a kind-of ‘crown of thorns’ under an electron microscope, hence the name ‘coronavirus’.

The most common subgroup humans get exposed to are one type of common cold viruses (although most common colds are caused by rhinoviruses, a different family). There are other coronaviruses that are endemic in poultry and cause upper respiratory tract infections there. Others are endemic in bats, etc.

Alas, some coronaviruses are quite deadly to humans: SARS-nCoV (severe acute respiratory syndrome, novel coronavirus), also known as SARS-CoV, is the one that causes the disease simply named SARS. Originating in horseshoe bats, it somehow crossed the species border and caused a nasty epidemic in mainland China and Hong Kong, with another outbreak hitting Toronto hospitals. CFR (case fatality rate) of the disease is very high, at 9.6%, but no overt cases have reportedly been seen since 2004.

Another is MERS-CoV, causes MERS (Middle East Respiratory Syndrome, one colloquial name being “camel flu”). It apparently crossed the species barrier from bats to camels and thence (possibly via camel-based food products) to humans. MERS has a very high CFR (case fatality rate) of about 1/3 of diagnosed cases, but has a very low reproductive number (in part because it is so deadly?): since it was first described in 2013, we’ve had only about 2000 cases ever worldwide. An outbreak in South Korea in 2015 when a businessman returned from the Arab peninsula appears to have been when the South Koreans got their ‘dress rehearsal’ for how to deal with the present emergency.

The present virus is known as SARS-nCoV-2 because its RNA sequence is so similar (82 % sequence identity) to SARS-nCoV. The mutations that make up the difference (single-strand RNA viruses mutate very rapidly — for reason I’ll explain elsewhere) appear to have had two primary effects: (1) the virus is less deadly; (2) the spikes are more efficient at stimulating ACE2 receptors (angiotensin-converting enzyme 2), which it exploits to enter cells. (Remember, a virus that cannot enter a cell and take over its replication machinery can’t do much of anything. Like a computer virus without a computer ;))

What happens once the virus is inside, by the way? The RNA goes to a ribosome, which are the cell organelles that acts as  protein ‘assembly plant’ of our cells. Gene expression in our cells involves chunks of DNA getting copied onto “messenger RNA”, which then makes its way to the ribosome and gets translated into a protein (by assembling amino acids according to what the “tape” says, until it hits what biologists call a “stop codon”: an “end of message” marker, so to speak). When the viral RNA enters the ribosome instead, that merrily carries out the work order written on the “imposter”, such as the enzyme needed to clone the viral RNA (RdRA, or RNA-dependent RNA polymerase), the envelope proteins, and the spike proteins. There is considerable speculation that the spike proteins in SARS-nCoV-2 are more effective than those in SARS-nCoV.

COVID-19 (coronavirus disease, [first outbreak in] 2019) is what WHO settled on as the name for the disease, not the agent.

UPDATE: statistician and software developer Charlie Martin weighs in more on the Italy data.
And a Japanese financial website reports that the campaign to get the residents of Wuhan to “thank” their dictator backfired badly.
Also, some signs that maybe the anomalously good statistics from Japan may be the product of selection bias: see here (especially the comments) and here. One of the articles, however, made a collateral point I’ve brought up here before:

Cases of seasonal flu have been declining for seven straight weeks, just as the coronavirus was spreading, indicating Japanese may have taken to heart the need to adopt some basic steps to stem infectious diseases. Tokyo Metropolitan Infectious Disease Surveillance Center data shows that influenza cases this year are well below normal levels, with nationwide cases hitting a low according to data going back to 2004.


Also, after Sen. Rand Paul (R-KY), German Chancellor Angela Merkel is the latest politician to go into 14-day quarantine after the doctor or nurse who gave her a standard flu vaccine tested positive for COVID-19.

UPDATE 2: leaked documents appear to indicate that the claim that “there are no new cases in Wuhan” needs to be taken with LOTS of sodium chloride.

UPDATE 3: on the other hand, there is some good news hidden in all the bad (via Instapundit):
And this one gets the Möbius Dick Award: NYT claims travel restrictions didn’t work in China — for the period they weren’t implemented