—Ebola is again short, and WHO is again late with their report.  No new cases from what I can gather, and most of those under surveillance as known contacts should be wrapping up in the next week or two.  As COVID starts to roll through Africa, this may get a little more dicey.

Coronavirus
—Lot to cover this week.  I will try to be brief.

—First, quick comment on last week’s think piece link to Epsilon Theory because I got some questions.  Linking is not endorsement of -everything- in those other writers’ pieces.  While I love me some Ben Hunt, he was gilding the lily a bit when suggesting the way flu deaths are counted is to nudge you to get a vaccine.  The estimate part is true—they are estimated from pneumonia rates for the same reason COVID cases are a judgment call between “contributing” and an “underlying” cause of death as discussed in a previous update.  But most people don’t get the flu vaccine because you are scared if you don’t you will actually die (if you’re pregnant though, that actually is a good thought to have and why you should get the flu vaccine).  Personally, I get the flu shot every year because some protection is better than none and the bona fide flu sucks.  I really don’t want to be laid up for a week feeling like a truck hit me, which is what happens every time I have ever caught the flu.  You are probably the same.  I understand Ben’s point, but that particular little bit was a reach.  The link was really more for the zeitgeist, which I think Ben captured well.

—This week in coronavirus conspiracies was an apparent viral Facebook post, which became an alarmist e-mail chain mail.  I am just going to post my response in case you come across it (you’ll recognize it based on my response).  It will also say something to the effect of “WELL WELL WELL” and “follow the money” if that helps recognition:

Gilead filed a patent for the use of remdesivir against coronaviruses in 2015.  They still hold the patent.  The patent -is- the lifeblood of any pharmaceutical company—you don’t just give those away and you certainly don’t want hangers on.  Chinese researchers in Wuhan filed a patent to use it as a treatment against COVID-19, and a company named BrightGene in China notified the Chinese government they were prepared to make it.  The Chinese patent filing has not been ruled on, and on face, would violate Gilead’s existing IP.  Even if China allows it, only valid in China and is also a “method of use” patent which is weak sauce in the pharma world.  BrightGene is flagrantly violating Gilead’s IP and is outright stealing from them.

Remdesivir is certainly not a cure and has not been advertised as such.  It’s merely one drug that has shown some degree of effectiveness in a clinical trial.

Unitaid is not a corporation where any of the named parties could even profit.  Unitaid is a non profit organization started in 2006 by the French government, and receives funding from France, Brazil, Norway, Chile and the UK.  Bill and Melinda Gates Foundation also donates.  This probably has more to do with Unitaid’s work on malaria (a major objective of the Gates Foundation AND an interest of France, who still does a lot of business in its former colonies, many of which struggle with malaria) than ability to profit from a non government health research organization.  Unitaid doesn’t own or file patents, and has donors, not owners and they are most definitely not a “patent sharing subsidiary” of Gilead.  They don’t donate to political campaigns that I can find.  They did negotiate a price reduction for second line HIV and malaria medications and the Clinton Foundation provided money for purchase and distribution to in need countries at those prices.  Only “support” of Hillary I could find in a few minutes of googling.

Yes, the US supported coronavirus research in Wuhan to the tune of $3.7 million through NIAID.  Conditions for foreign institutional support via NIAID include talent, resources and populations not present in the US or augmenting US, and not already being done in the US.  To study SARS, the US went to where SARS was—East Asia.  Wuhan happened to have a facility already dedicated to the study of SARS.  For comparison, the annual budget of the NIH is $39 billion, and they gave $51 million for first year funding for a collaborative influenza vaccine research network in the hopes that we might one day have one flu vaccine to rule them all—just last year.  Given the dollar amount and purpose, I’m not particularly concerned that this research support was some dark nefarious conspiracy.

—But you absolutely can follow the money in other news this week!  Moderna made big headlines on Monday when they announced Phase 1 results of their vaccine had good safety data, and in 8 patients (low numbers are typical for Phase 1, whose goal is to see if the drug is safe at the doses that are planned to use), antibodies to SARS-CoV-2 were seen after administration of the vaccine.  All of that is public domain, and that is the extent of commentary on their Phase 1 study.

To follow the money (and you should), start here:  https://twitter.com/TESLAcharts/status/1262427914643083265

Now, my understanding is that large and off-pattern purchase of Moderna stock by its CEO on May 12, shortly before their Phase 1 announcement, probably didn’t technically violate any rules.  In fact, I would be willing to bet it was carefully checked so that it would not be in violation of any rules.  Still, it does look a little funny, huh?  But hey, he believes in his own company, so sure, I suppose it’s credible that he quit a multi-year pattern of persistently selling its stock to load up right there on May 12th.  Probably believes in it so much that he didn’t immediately turn around and sell all those new shares when the stock jumped more than 20% from its May 12th price.

Probably.

At the close on Monday, Moderna announced a new capital raise of $1.25 billion.  This would be at the new, higher price Moderna reached Monday, meaning Moderna gets handed more capital (which they will admittedly need for Phase 2 and 3 trials of the vaccine), but existing shareholders would not be diluted nearly as much by this capital raise.

That was also really good timing.  Moderna’s CEO seems -really- good at timing things like this guys.

Equally interesting in that twitter thread is the absolutely true statement that the “vaccine czar”  Dr. Mancef Slaoui had options on 156,000 shares of Moderna from his most recent stint on their board of directors.  Dr. Slaoui came under some criticism when taking the job, precisely for those options, as Moderna has received nearly $500 million in federal grants to speed vaccine development.  Critics felt this might be a potential conflict of interest.  Dr. Slaoui disagreed, and kept those options.  

Until Tuesday morning.  

Yes, conscience got the better of Dr. Slaoui, and, no doubt wracked by any suggestion, any hint that he might not be suitably detached from Moderna’s efforts to evaluate them solely and dispassionately on the merits, he sold his entire position:

Assuming he got just the price for the $1.25 billion capital raise the night before, Dr. Slaoui grossed a little under $12 million before taxes.  

It’s nice to see doing the right, ethical thing has tangible rewards sometimes too, is it not?

Dr. Slaoui was good to his conscience, and boy was his conscience good to him!  He followed his guiding set of ethics, integrity and principles to sell at or near the highest possible point on the week.  What are the chances?

You get what you give, ladies and gentlemen.  Put good out in the universe, and good just comes right back at you, amirite?

But Dr. Slaoui and Mr. Bancel were not the only Moderna principles with excellent timing.  Here is how Moderna has been doing this week, including timing of massive, multimillion dollar sales of stock by its CFO and its chief medical officer all in one chart:

Everyone in the Moderna C-suite, and even former board members now guiding vaccine efforts for the country, has just incredible timing on their trades.  Odd for them to unload if they are about to cure a once in a generation pandemic, though, huh?

If this whole vaccination gig doesn’t work out, I think all of those boys have a strong future on Wall Street.

Rarely is such remarkable mastery of buy low, sell high demonstrated—for the entire world to see.

—“…deriving their just powers from the consent of the governed…”  Is this justice?  Do you still consent?

—Corruption is not capitalism.

—Sorry… not sure where those last two bullets came from…  

—Anyways, China had to escalate to full provincial re-lockdown this week.  That involves about 100 million people.  There is apparently a lot of work related border crossing between the affected areas and Russia, and Russia is still very much climbing the epidemiological curve with SARS-CoV-2 right now.  

This illustrates a couple key points.  First, expect occasional local-regional flares like this.  Second, this is a way some of them will happen.  People from a place running just a little hot travel, and bring the virus with them.  If the place they go gets hit too quickly, or is just a little asleep at the wheel in detecting and testing, enough virus can be re-introduced to trigger a flare, and some degree of re-lockdown will become necessary.

I keep getting asked about travel.  I would not recommend international travel for this reason right now.  Within country, if you are in a place that is easing restrictions and going to a place with easing or eased restrictions, take all reasonable precautions.  But just understand this is the risk.  You won’t necessarily be able to predict the where and the when of some of these more localized flares.  They will happen though.

—Much pearl clutching over news Donald Trump is taking hydroxychloroquine.  Look, I still don’t know if it’s effective or not.  Data has been mixed.  Donald has been exposed to SARS-CoV-2.  The White House was using a less than stellar rapid testing system and some people have popped symptomatically positive who may have been around him.  His age and body habitus put him at higher risk.  In reason number 8,457 for why you -don’t- want to be a personal physician to the President, you’re damned if you do and damned if you don’t.  If Donald catches COVID, that’s a bad look.  Are you going to do nothing?  But what are you going to do?  Hydroxychloroquine may be effective—and it’s approved for malaria prophylaxis already.  For decades.  It’s just not used as much in parts of the world where Plasmodium falciparum, one of the more common species of the parasite that causes malaria (and a more severe form of malaria at that), has grown resistant.  Hydroxychloroquine is on the list of essential medicines precisely for its ability to prevent and treat malaria.  

So I understand why the White House medical staff might have chucked it at Donald is all I’m saying.  Long history with that drug in medicine, known quantity in terms of safety and side effects to watch for, and you are succumbing to the terrible pressure of being the President’s doctor by doing something.  Primum non nocere arguments aside.  

Whether it’s actually doing anything against SARS-CoV-2 is another question.

But I can say with full confidence that Donald is much, much less likely to come down with malaria in Washington D.C. right now while taking prophylactic doses of hydroxychloroquine!

—Before you laugh too hard at that, fun historical tangent, malaria really was a problem across much of the US, including the D.C. swamp, for a very long time.  Shortly after WW2, the US declared war on mosquitoes, and won that one too:

—Mostly by mass application of DDT, from carpet bombing runs in planes, to literally painting walls of homes and schools in the stuff.

—Back to coronavirus though.  South Korea showed that patients who have symptomatically recovered from SARS-CoV-2, but still have virus detectable by PCR, do NOT appear to be transmitting the virus:  http://www.koreaherald.com/view.php?ud=20200518000772

So one of the challenges of molecular microbiology, like PCR to detect a specific bacteria or virus, is that you will detect the nucleic acid of the target (RNA or DNA) equally well if that target is living or dead.  Or coated in antibody, and effectively inactivated.  PCR cannot tell what the bacteria or virus target is doing, only that it is there.  This has been a clinical challenge, even for us, because we get these patients who will have PCR detectable virus, but totally recovered symptomatically.  This has also been a big debate for clinical trials, because no one has any idea what amount of virus detected is actually dangerous to others, or indicates clinically active disease.  Most have just followed trends showing that virus starts high (especially in very sick patients) and then trends down over time as the immune system catches on and drives it out.  

But the bane of my existence in fellowship was the early summer, or when a new resident or fellow came on and order quantitative virus testing too soon after starting a treatment.  Often, you would detect similar levels the next day, and they would freak, assuming the virus was “resistant” since its numbers didn’t move.  And we would have to explain that dead virus and live virus looks the same to PCR, and they would need to give it a little time while the drug is on board and check again.

Just something to keep in mind.  Low or no symptoms, and barely detectable virus, is probably just proving that the ol’ corona was there—or just getting started, depending on the patient’s presentation.

—A flurry of articles tying the immune reaction to SARS-CoV-2 to severity of disease.  A couple from China, in various degrees of pre-publication so I won’t link them, but suggesting a distinct progression of infection with SARS-CoV-2 and massive immune system over-reaction leading to damage to multiple organs in the severely affected patients.  Again, think of the Ah-nold and commando colleagues laying waste to an acre of jungle for a twig snap from last week’s update.  Most interesting to me was the link they made with IL-6 expression in particular.  IL-6 is a signal to your immune system.  Higher levels of IL-6 were correlated with more severe disease.  You also tend to have more IL-6 expression the older you are—it’s part of what the aging literature sometimes and some places refers to as “inflammaging”, or the generally more inflamed state of getting older.  

Now, we tend to see more severe disease with COVID-19 in older patients.  This IL-6 correlation may just be because they were looking at more severe disease; more elderly patients get more severe disease; they already have higher IL-6, and so IL-6 correlates to severe COVID-19 purely by happenstance as a marker of older patients. However, it is tempting to hypothesize that IL-6 may prime the immune system to make some bad choices when confronted by SARS-CoV-2.  It may be possible that the higher level of IL-6 makes our commando squad juuuust a little extra jittery, and juuuust a little more likely to go full auto at the snapping of a twig.  Coupled with elderly patients not having as much jungle to spare (especially if comorbid with other disease already), and you have the recipe for a real bad time with SARS-CoV-2.

It will be interesting to see how that story develops.

Along a similar line was this paper:  https://www.sciencedirect.com/science/article/pii/S0092867420306103?via%3Dihub  I’m going to bring the money quote from the abstract here:  “Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.”

So what that is saying is that 40-60% of patients they tested, with no known exposure to SARS-CoV-2, had T-cells already primed from previous exposure to SARS-CoV-2’s common cold cousins to react to SARS-CoV-2 as well.  There is enough overlap that those T-cells recognized SARS-CoV-2 as a coronavirus, kinda’ like one they had seen before, to start responding.  In particular, those are CD4+ T-cells, which do a lot of the “decisions” for how your immune system will respond to a particular threat.  I will leave the specifics beyond the scope given the general audience joining us.  

But again, this raises some tantalizing hypotheses.  We know that a huge chunk of people who get SARS-CoV-2, but have only mild, or sometimes no symptoms.  Are these the patients who caught the “right” cold, with enough overlap that their immune system is just curb stomping SARS-CoV-2 the moment it shows up?  Conversely, are the patients being hospitalized actually a subset of these patients with CD4 T-cells who met a SARS-CoV-2 cousin already—and for some reason, in that subset of patients, those primed CD4 T-cells choose poorly and tell the immune system to full auto level the jungle (maybe down some of the same paths IL-6 triggers)?

And if we can control that immune reaction more appropriately, changing the immune system’s approach from the Marine Corps’ “kill ‘em all, let God sort ‘em out” to more of a SEAL sniper locked onto SARS-CoV-2, can we get patients out of the ICU and out of the hospital beds?  If we can, we turn SARS-CoV-2 into a nothingburger, even without a vaccine.  

Remember, the threat is the hospitalization rate of SARS-CoV-2, and its ease of transmission.  We definitively win by taking away either that hospitalization rate (effective treatment against virus and/or immune over-reaction to virus) or ease of transmission (vaccine, herd immunity, social distancing until vaccine or herd immunity reached to flatten the curve).  

Spit balling out loud though—all opinions still my own.

—Lastly, economic front.  With regional shut downs like China continuing to crop up (and vaccine or trial proven treatment still months, at best, away), expect continued supply chain challenges.  Some countries are still climbing the curve.  Brazil and Russia are getting hammer timed right now.  Africa is just starting the early stages. They will cause supply chain disruptions on their own, or also provide a nidus for re-introduction of SARS-CoV-2 forcing local or regional re-quarantines.  

It will be a very unusual year.

While things are re-opening, re-opening remains slow.  Reports from Macy’s through Starbucks show improved sales from last month, but still enormous (50-65% or better) reductions in year over year traffic for May.  That’s not a V-shaped curve.  

The virus catalyzed, but did not itself cause the economic hardship.  Those headwinds will continue.  Take care of your neighbors.  Some of them are undoubtedly hurting.

—Love in the Time of Coronavirus (back this week):

—Your chances of catching Ebola are equivalent to your chances of catching malaria in Washington D.C.

—Your chances of catching coronavirus remain quite good no matter where you are in the world.  Be prudent.  

<Paladin>