"These complications, which at times are the only features of #COVID19 clinical presentation, have occurred even in cases with mild symptoms and in people who did not experience any symptoms" science.sciencemag.org/content/early/…
a 🧵to explain 1/
For those who don't know me, I'm a cardiologist, have been for 35 years, and still practicing. And seeing patients is still my favorite part of what I get to do.
I tried to read all that's been written in English to date on this topic and to contextualize it in this essay 2/
The virus can get into the heart and specifically heart muscle cells because it is drawn by ACE2 on the surface of these cells, along with cooperation of cofactors, such as heparin sulfate. That entry has been confirmed by autopsy series 3/
"These are some of the most important clinical trials in history, affecting a vast majority of the planet’s population. It’s hard to imagine how much higher the stakes can be to get this right. Cutting corners should not be an option." 1/ nytimes.com/2020/09/22/opi… @nytopinion
The primary endpoint in these trials— infections—will likely be mostly mild. For example, in the @pfizer trial, a sore throat and a + PCR test counts as an event. Are these the infections that we want to suppress with a vaccine? Is that a good proxy of effectiveness? 2/
There are interim analyses, some w/ stopping rules during the trials
—4 looks for Pfizer, 1st is at 32 events
—2 looks for Moderna, 1 look in Astra Zeneca (US) trial
—A trial could be stopped on the basis of very limited number and severity of such events, declaring efficacy 3/
We have the protocols. Now we know how there will very likely be an Emergency Use Approval (EUA) for a vaccine prior to November 3. The company and political motivations are fully aligned. 1. The criteria for an EUA is that it "may be effective" fda.gov/regulatory-inf…
2. Nearly every day we hear from @pfizer's CEO @AlbertBourla that they will know if their vaccine is working by the end of October.
Only the Data and Safety Monitoring Board is reviewing the data at specific intervals, the interim analyses
So how will they (Pfizer) know that?
3. The 1st interim analysis for that trial is at 32 events, infections, which can and likely will be mild. The stopping rules as reviewed by @biosbenk@EmoryRollins are "aggressive" and "unusual" for the number of interim analyses (4) and Bayesian approach github.com/benkeser/pfize…
I've spoken with the @Sherlock_Bio team who are adapting this for a home test and I hope they can accelerate the process. We still need @US_FDA to accept home testing— to date they've been quite resistant.
Why is this important? 1. This is the 1st clinical trial of a drug specifically designed for #SARSCoV2. All previous trials were repurposed drugs (HCQ, dexamethasone, Remdesivir, etc). Safety data are encouraging
2. The class of drugs has the potential to be used as a prevention in high-risk individuals, and intervention in mild to moderate covid (as in the current trial) or severe, subcritical. The data from non-human primates supports this multi-pronged use.
2. We need a coordinated response of "all these public health things that people don't always appreciate, they add up." Some places in the US are doing it well.
Explains forward and backward contact tracing.
3. On herd immunity confusion, a term that is usually in the context of vaccines. See below.
We need to focus on "proactive strategies to protect people"
Why is stopping a #SARSCoV2 vaccine trial early such a bad idea?
A proper clinical trial is statistically powered to make a call at its completion
There's wobble, random chance, in events during a trial
The true beneficial effect has turned out less in some trials stopped early
The trials are reportedly powered to detect 50% efficacy w/ a lower 95% CI of 30%. That's not nearly as high as ideal
— could even exaggerate that
— could impact other placebo-controlled trials
— could also miss relatively rare but important adverse safety events
My podcast w/ Paul Offit, one of the world's leading lights on vaccines, regarding #SARSCoV2 vaccine development medscape.com/viewarticle/93…@Medscape
It's rich and I'll summarize key points here 🧵 1. "It's an unprecedented moment...as long as the Phase 3 trials don't get truncated"
2. Things we're learning about the virus
--not affected by seasons
--can cause a vasculitis
--unusual multi-system inflammatory syndrome in children
--strong predilection for nursing homes
This will likely (hopefully) not turn out to be any signal of trouble at all. But it reinforces the principal concern for safety for such programs that will ultimately be implemented in tens of millions of healthy people.
Apparently the individual w/ the adverse event has a transverse myelitis, a neurologic condition which can result from infections or an immune system disorder. The adenovirus component of the vaccine may have been a trigger nytimes.com/2020/09/08/wor…
Just published @CellCellPress is the most extensive study of the immune response in covid-19's multisystem inflammatory syndrome in children (MIS-C) cell.com/cell/fulltext/… by @karolinskainst
—Key differences v. Kawasaki and acute covid-19
—Candidate autoantibodies identified
Other recent publications on MIS-C and the immune response
That means another 24,000 participants need to get their 2nd dose still, which occurs a month after the 1st.
Then 2-3 weeks to get the full immune response.
Then exposure to infections
Then moderate or severe infections as events
Pfizer CEO: "We expect by end of October, we should have enough...to say whether the product works or not."
The 1st interim analysis is at 32 events statnews.com/2020/09/02/exp…@matthewherper@statnews
Even 32 events for placebo, 0 vaccine (likelihood ~0) wouldn't cut it to stop 3/
Today we learned ~1/3 Big Ten athletes who were #COVID19 + had abnormal heart MRIs, consistent w/ myocarditis, even those without symptoms. If anyone still is questioning whether this virus attacks the heart, it's denialism.
There have been multiple reports of heart involvement with #COVID19, including young athletes, and replication of @GladstoneInst iPSC-> heart cell findings. Very little is known about heart inflammation among asymptomatics (unlike lung Δs)
Documented #SARSCoV2 particles in heart cells in a tragic case of an 11-year-old girl
A little primer on independent Data and Safety Monitoring Boards (DSMB), who will be reviewing the #SARSCoV2 vaccine trials to adjudicate safety and efficacy, making recommendations to the clinical trialists 1/
Consists of a multidisciplinary group of several members: clinical trialists, biostatistician, bioethicist, and experts in topic (virologist, immunologist, epidemiologists, vaccinologists)
The timing/schedule of data review usually based on enrollment 2/
The data are teed up by the biostatisticians. The DSMB is blinded to vaccine or placebo groups. There is ordinarily a time lag/gap from the "cleaned" dataset reviewed by DSMB that is behind ongoing events 3/
Iceland was one of the best performing countries vs #COVID19, starting PCR screening in January, before there was even a patient diagnosed. As a result, along with tracing/isolation, they have a seroprevalence of only 0.9% (US is now >14%, estimated) and IFR 0.3%.
The editorial is rich with context nejm.org/doi/full/10.10… 1. "Unprecedented snapshot of seroconversion rates" with various antibody isotopes, different antigens 2. 56% cases confirmed by virus (PCR) testing so 44% infections would've been missed w/o antibody 3. 2 Waves graphic