As reminders…

Alpha–Variant first identified in the UK

Beta–Variant first identified in South Africa

Gamma–Variant first identified in Brazil

Delta–Variant first identified in India

Also as a reminder:

Ebola:

–The outbreak in the DRC is up to at least 8 cases with up to 6 deaths as of Sunday, with a cluster of suspected patients being tested as of 30 October. No report on their results yet. The new positives represent geographic spread in the greater Beni area, so I would expect more cases for the next several weeks. They are still managing contact tracing as best they can, with reasonably high success rates (especially compared to the last big outbreak in this region). More ring vaccination is being laid down as well to contain the outbreak. No clear word on if the geographic spread also includes new cases outside of known contact tracing–if it does, ring vaccination will be more difficult, but still possible given these numbers.

Just to belabor the point one more week though, this current outbreak, even though small case numbers so far, absolutely highlights the ability of re-emergent infectious Ebola from a recovered “Ebola Jane” to trigger sustained community spread. The smart thing would be to get ahead of this before one of these start in a place with less experience in Ebola, but expecting the smart thing to happen seems more and more fanciful in the world in which we increasingly find ourselves. I don’t know when, I don’t know where, but I do suspect we will be covering exactly such an outbreak one day, and the media and world writ large will be just shocked that it happened.

Coronavirus:

–Obviously leading off is all the vaccine news this week, arguably (we’ll get to that in a second) the biggest news is the CDC’s approval of the Pfzier mRNA based SARS-CoV-2 vaccine in its pediatric, ages 5-11 dosing, making the vaccine available to this age group.

This will be a challenging section for me to write, for a number of reasons, and I ask your forbearance and kindness. The challenges include, in no particular order of importance as all contribute:

1) The politicization of vaccination. There will be a tendency to view anything I say through the lens of politics, and you may find yourself parsing the tea leaves to see if I am making a statement of identification with one tribe or another. Please do not use this lens, and watch yourself if you find yourself applying it.

2) The unavoidable, visceral emotional context to any health and safety issue for kids in this age group. There is justifiable concern for direct threat of severe COVID in this age group; although their risk of severe disease is lower than any other demographic, it is not zero.

We’ll put some numbers to these risks.

Of the ~2 million confirmed and reported infections in this age group, there have been ~8300 hospitalizations, to put severe COVID into perspective. Of these, 94 have died. Of those hospitalized, more than 2/3rds had underlying conditions, most commonly obesity and asthma.

As we mentioned, these rates are approximately equivalent to an already vaccinated 40 year old.

That said, while the rate of death from COVID is low in the 5-11 group, they have the highest risk of MIS-C. This is the Kawasaki-like disease we discussed previously. Based on the best available data, that happens in ~400 out of every 1,000,000 infections in this age group. With a little less than 2 million confirmed cases of COVID in the US among those aged 5-11, we would expect about 800 total cases of MIS-C in this age group.

Of those with MIS-C in this age group, about 9% get myocarditis from SARS-CoV-2 itself.

So we’ll ball park 40 cases of myocarditis from SARS-CoV-2 itself in this age group (and about 80 total)–or ~0.00004% incidence.

It is worth mentioning that these estimates are for confirmed and reported COVID positives among this 5-11 age group. Antibody prevalence studies suggest that up to 42% of kids in this age group have encountered enough SARS-CoV-2 to have made antibodies for it. That would change your denominator of ~2 million known cases to 11,760,000. That would make your risk of myocarditis from SARS-CoV-2 itself in this age group about 0.000007% incidence.

Overall, I think we can safely say the risk of myocarditis in kids of this age group from the virus itself is somewhere between 0.00004% (4 zeros) and 0.000007% (5 zeros). Overall mortality is similar.

3) The unavoidable, visceral emotional context to any health and safety issue for kids in this age group also applies to risks from the vaccine as well.

We will put some numbers to this. In Pfizer’s study, 16 kids who got placebo got symptomatic COVID versus 3 kids who got the vaccine with breakthrough COVID. They did not test for asymptomatic COVID. This is the 90%+ effectiveness you are reading about.

As we mentioned, there were no significant side effects in the available data (which has still not been published that I have seen). As we also mentioned, the study could not be powered to detect the known myocarditis association with the mRNA vaccines seen in other age groups. As the vaccine rolls out now to 28 million kids in the US ages 5-11, there is a risk the myocarditis seen in other age groups will be seen in this age group as well.

The highest risk group for myocarditis associated with the mRNA vaccines is males age 16-17, where the incidence rate is 0.007%, and roughly 0.0007% on the lowest end with other age groups. So we can estimate that the risk of myocarditis associated with the vaccine will likely be 0.0007 (3 zeros) to 0.007 (2 zeros) when all is said and done in the 5-11 age group. Could be a little less, could be a little more.

To summarize the myocarditis numbers then:

–Risk from SARS-CoV-2 itself in ages 5-11 is 0.00004 to 0.000007% (4 to 5 zeros)

–Risk from mRNA vaccine associated myocarditis estimate based on other age groups is 0.0007 to 0.007% (2 to 3 zeros). I want to be clear that this is an estimate–we don’t know the “true” incidence yet, before you “@” me for “tHe RiSk fRoM tHe VaCcInE iS hIgHeR”. We just don’t know yet, and this reduced dose for this age group should reduce the vaccine risk from the numbers quoted. This is JUST back of the envelope to give the perspective of BOTH sides in this highly charged vaccine debate.

4) For perspective on just how unlikely myocarditis is from EITHER the virus OR the vaccine in this group, an illustrative experiment you can do at home!

Get two six sided dice from your Monopoly set. Roll them twice. Your goal is to roll a “12” (a six on each dice) twice, and directly in a row. So a “12” followed immediately by another “12”.

That is the rough equivalent of the “3 zero” myocarditis risk.

Let me know when you have done that. Go do it, and come back when you have succeeded (or given up at how futile it seems).

Give up yet? Odds are overwhelming that you have given up out of boredom. The “4” and “5” zero odds are even less like than that.

5) But here’s the big challenge with unavoidable, visceral emotional context to any health and safety issue for kids in this age group.

Everyone is going to err on the side of caution. Even you! You will err on the side of caution here!

My problem, and why I am so hosed writing this section, is what you will define as “the side of caution.”

One set of people is going to look at the unbelievably unlikely event of a bad outcome with infection in this age group, and say “that risk is too high–vaccination full speed ahead!”

Another set of people is going to look at the risk of unbelievably unlikely event of a bad outcome with the vaccine in this age group and say “that risk is too high–maybe let’s not be the first in line…”

And you are both going to parse every word I write here, every syllable, every sentence, like casted runes or dealt tarot cards, trying to decide if I agree with your personal risk tolerance or not.

Because that is just human nature, and this is precisely where the damnable politicization of vaccines meets the raw emotion of health and safety of kids this age. The kids we would all jump in front of a truck for.

“Absalom, O Absalom, my son, my son…”

6) I don’t blame you for that. Just please recognize that risk benefit is a spectrum, and where the exact line is drawn is different for different people for different reasons. There is more feelingsball than math to where you draw your line, if you are honest, and ascribing bad motive to someone who draws the line slightly different than you, while tempting and very human, is not the whispered advice of the angel of your better nature. The motivation of each group is the same–it is the feelingsball of risk perception that is different. You are merely emphasizing protection from different perceived risks.

Each of which is about as likely as rolling two 12s in a row.

7) Both Mount Vernon Doc, arguing against mask mandates and Random Oklahoma Doc Overblowing Ivermectin Overdoses Like A -Lot- are out there. Which is to say you find credentialed hysterical crazy for both sides of the debate, mostly because they too are human and have been consumed by the politicization of all things.

8) What I expect to happen as a result of this approval then:

• There will be (and in many places already is) a mob on the vaccines as soon as they are available. Lines will be long at least into this week, and there will be much angst if deliveries of vaccines are slow to be delivered. Which seems likely at some point in at least a few states and places, since <waves hand in general direction of current supply chain malaise>
• Vaccine mandates from school districts, cities and states will follow soon (and in fact, are already starting). These will be contentious and go about as well as the recent mask mandate debates. All because politics remains everything and we are, somehow, incredibly, still cranked to maximum stupid.
• Mask mandates will start to go away with vaccine adoption.

My opinion, and solely my opinion, without review or approval by my employer is the CDC made a mistake by allowing immediate roll out to the entire age group at once. Because I expect an emotionally tense mob scene wherever the vaccine is available, inevitably, some of the high risk kids who should be first in line, will not be. From a medical ethics perspective, I would have been much happier if the CDC had endorsed a “high risk first” rollout, similar to what happened with the adult vaccines when they were first available.

Speaking of similarity to the adult vaccines, you can probably treat before and after with a child safe NSAID like Ibuprofen to reduce some of the “Pfizer flu” and other immune mediated side effects of the vaccine. But I am not your healthcare provider, this is NOT medical advice, and always use all medications at doses and in indications according to their label under the supervision of your healthcare provider. Thank you for understanding.

Also, before you ask “should I for my kids yes or no…” let me stop you right there. I am NOT a pediatrician, let alone your kids’ pediatrician. The best people to guide your decision for your children are you and your pediatrician, who knows your child’s medical history (I don’t), and can help you work through your choice. Please contact them, and thank you for understanding.

–While on the subject of Pfizer and vaccines, there was a publication of an investigative report of a whistleblower in the BMJ–which is unusual in that it is NOT a scientific paper, and something you usually find in investigative reporting in legacy media.. You can find the publication here: https://www.bmj.com/content/375/bmj.n2635

Again, I stress that all comments below on this are my own, and have not been reviewed by my employer. You should also understand that I will be choosing my words fairly carefully here.

The crux is that a whistleblower has alleged several serious compliance issues during her employment with a contract research organization (CRO) that provided and oversaw several clinical testing sites for the adult Phase 3 study of the Pfizer vaccine. The most serious of these include reports of adverse events not being followed up promptly, opportunities for unblinding some, if not all, of the 1,000 participants enrolled via this CRO and falsification of data (although it’s not clear if this is just poor record keeping and error correction practices).

First and foremost, if this was the only CRO and sites to have these issues on the study, 1,000 patients is not enough to change the major clinical conclusions of the study. Second, in terms of adverse events, the complaint is that they were not investigated in a timely manner, suggesting that they were still recorded and accounted in the safety reporting.

However, if there was opportunity to unblind these particular participants (which is to say that the researchers and/or patients themselves may have known if they got the vaccine or placebo, and could interpret, for example, that minor cough or slight fever or maybe an achy joint one way or another based on that knowledge to either over or under-emphasize it), and/or data recording problems, then the data from these patients is unreliable. That may mean up to and including removing them from the larger data set, and recalculating some of the statistics.

So far, the complaints only involve problems with this particular CRO. Pfizer worked with a number of CROs and academic sites to stitch the giant Phase 3 together. Problems at one does not mean there were problems at all. As the study sponsor, Pfizer and BioNTech do have ultimate responsibility on the conduct of the research at all participating sites. I will say that in general, more is expected of the biggest, most experienced “kids” in drug development as well–regulators expect Big Pharmas with decades in the industry to “know better.” The FDA has issued a statement that they are aware of the complaints and reiterated their confidence in the overall data set. They did on site inspections of 9 of the >150 participating sites, but none of those 9 included this CRO.

There is a spectrum of CROs and academic sites in terms of their experience in clinical trial research and the enormous and finely detailed record keeping that goes into what is called “good clinical research practices”. There is also a spectrum among pharma companies and biotechs in their dedication and fastidiousness to highest quality research. I had not heard of this CRO prior to this complaint. As to where Pfizer falls on that spectrum, I have no comment, and thank you for understanding.

I have no doubt, with the publicity, that additional reviews of oversight and performance at other sites in this study will be forthcoming to see if this was a more generalized problem, or just an issue with this particular CRO.

Regardless, let’s keep in perspective a few key things. Millions of people worldwide have now gotten two doses of the Pfizer vaccine (including me). If the 1,000 patients involved in this whistleblowing complaint somehow managed to hide some awful and common adverse effect, we would have seen LOTS of it by now. As it stands, the biggest and most famous severe risk is myocarditis, particularly after the second dose, and highest risk among young males. We covered just how rare that is above. If it had caused the study to grossly overestimate the efficacy of the vaccine, we would see that too by now. Instead, as we have covered over these many months, the vaccines have been effective against hospitalization, severe disease and death, even in the face of several new, more contagious variants. Compared to unvaccinated people with no prior SARS-CoV-2 exposure, the vaccine has consistently reduced the risk of hospitalization or worse by about 10-fold. Consistently.

The biggest problem is that in a high profile, high stakes clinical trial, there may have been problems with sufficient attention to detail and scientific rigor in at least one participating CRO. Which may suggest an oversight issue by the trial sponsor, and also raises questions about how and why regulatory reviewers around the world did not detect these issues with this CRO at the time of submission. Based on the real world experience with the vaccine, I don’t think there is a clinical surprise or dark secret lurking here. Again, the hundreds of millions of doses out there already would have found it.

There is yet another threat to throw a log on the Bonfire of Institutional Credibilities though, because if confirmed, the issues raised by the whistleblower do go to confidence in data integrity, oversight and/or regulatory review.

–And finally on the vaccine beat, Moderna is not expected to complete an FDA safety review to extend the availability of their vaccine to teenagers until early 2022.

–In other coronavirus science news this week, the CDC released a study comparing natural immunity after recovering from SARS-CoV-2 to vaccine induced immunity. You can find the publication here: https://www.cdc.gov/mmwr/volumes/70/wr/mm7044e1.htm?s_cid=mm7044e1_w#contribAff

The short version is that the CDC study, involving retrospective review of 7,000 patients from last fall until fairly recently across 9 states concluded that vaccine induced immunity was 5x more effective than natural immunity in preventing hospitalization in breakthrough infections of SARS-CoV-2.

“Isn’t that the exact opposite conclusion from a much larger study done in Israel on ~800,000 people?” I hear you ask, Hypothetical Reader.

And yes, it is.

It is…surprising…given the effect size (13x in favor of natural immunity and 5x against natural immunity) and sample size in both studies for them to come to precisely opposite conclusions and with high statistical significance.

It is very improbable for that to occur.

Populations (US vs Israeli) may account for some of that difference, but it seems unlikely. The major potential explanations are that the the Israeli study focused on its delta wave period only, and so the natural immunity cohort was more likely to have actually contracted SARS-CoV-2 during the entire pandemic up to and including the delta wave. The US study reflects multiple variants of SARS-CoV-2 prevalent at the time, and by going earlier in the pandemic, may have a higher chance of including false positive screening tests as “recovered” patients from earlier in the pandemic. Basically, the later in the pandemic you look, the more likely people were to have ACTUALLY been exposed to SARS-CoV-2–so the study with earlier time points includes periods when not as many people had been SARS-CoV-2 exposed. Hopefully that is clear. The CDC study also did not count cases until patients were at least 90 days after the second dose of vaccine or their previous positive COVID test. The reason for that is not immediately obvious, unless they were looking for a period of “waning” immunity. It’s also not clear in either study if there is a behavior difference between those who got the vaccine versus natural immunity–was one group also more likely to use social distancing measures than the other, take more risks like concerts etc. after diagnosis or vaccine?

Regardless, the best that can be said is that natural immunity DOES confer some protection from subsequent infection. What protection level that is relative to the vaccine is questionable, as we now have two large studies in direct conflict on their conclusions, and it’s a question of which study you weight a little more.

–Speaking of diagnostic tests, this got published, but I am not the corresponding author and again any questions should be directed to the corresponding author: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab912/6413724 Thank you for your understanding.

–Lastly for the science heavy portion, met someone recently who was hospitalized with COVID and came out with new onset Type 1 diabetes on the back end, which recalled to mind the question of how common that might be as a consequence of COVID. This got raised by a reader during the India delta wave, when India was discovering a large number of new cases of diabetes, but was confounded a bit by India’s existing rate of diabetes. Was COVID just bringing patients to the hospital that would not have otherwise gone for their diabetes to be discovered, or was the virus itself somehow predisposing diabetes?

There is still not a real clear answer. There are some studies enrolling patients with new onset diabetes after COVID to try and get a handle on it, but the best meta-analyses are relatively dated now. The best estimate from those is a surprising 14.4% new onset diabetes rate in those who get hospitalized by COVID: https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14269 That seems high, and even the researchers there say a lot more work needs to be done on this to determine if it’s the virus sure and how common this really is.

–Yes, this intel review stating that both natural origin and lab accident are plausible, and without access to Wuhan’s lab notebooks, may not get settled definitively is pretty much what we have been saying for awhile.

We can neither confirm, nor deny, that the authoring agencies are reading our update.

–And finally, around the horn, cases in general continue to abate. So far, there is no epidemiologic cause for alarm from the newer variants of delta first identified in South Africa and the UK that we mentioned previously. Cases in both those countries remain flat. Russia, the Ukraine, Germany, Greece, Austria and a few other select European locations are seeing new increases in cases. In the US, cases continue to decline, although the rate of change to that decline is slowing. You are now down to about the peak of the alpha wave in terms of daily new cases, for comparison purposes. China is also dealing with a new large outbreak. Numbers remain as unreliable as ever there, but more city wide mandatory screenings and restrictions are occurring across a broader geographic area.

–On the socioeconomic front…

Speaking of China, they imposed price caps on coal to stabilize prices, but are now having some issues with runaway liquid natural gas prices. The Chinese government also caused a panic this week by “encouraging” citizens to stock up on supplies for daily household needs, apparently suspecting these may be occasionally difficult to come by over the winter. This, predictably, led to panic buying, similar to CostCos across the US getting cleaned out of toilet paper early in the pandemic last year.

Again, picking up a few extras of the non- or slowly perishables for your daily needs over the next weeks and months is a reasonable and relatively inexpensive hedge against current supply chain issues.

Speaking of those supply chain issues, we again have a “best of times, worst of times” update this week. There is a lot of good, deep, experienced color to some of the issues that have snarled US ports here in a post that went viral this week: https://medium.com/@ryan79z28/im-a-twenty-year-truck-driver-i-will-tell-you-why-america-s-shipping-crisis-will-not-end-bbe0ebac6a91

On the more positive side, US Steel in their Q3 update reported that the chip shortage that has been plaguing many companies all year may finally be abating some. They are seeing increased orders from car makers, who are starting to get more chips to build more cars. For what it’s worth, Goldman Sachs apparently had predicted Q4 of this year for current inventory easing for chips. Goldman’s other supply chain predictions are here:

1. improved chip supply driven by post-Delta factory restarts (4Q21) and eventually by expanded production capacity (2H22 and 2023);
2. improved US labor supply (4Q21 and 1H22); and
3. the wind-down of US port congestion (2H22).

Similarly, the CEO of GXO, which is a US based warehouse operator, was quoted on their Q3 call as saying that more goods are finally getting to their warehouses, suggesting that supply lines may be slowly untangling (see Goldman’s prediction 3. above). The cost to get an international container to ship your goods is still astronomically high (consistent with the current supply chain problems), but has at least leveled off recently as well.

Things are not likely to improve dramatically soon–but those are at least some cautiously optimistic signs that cascading disruption will NOT become cascading failure. Energy remains the wild card, though, and prices are still high for most sources of energy, consistent with a continued supply crunch.

In this background, we are starting to see some definitive shutdowns in the US due to vaccine mandates. You have double digit shutdowns of fire companies in NYC, as well as massive staff shortages in NYC police precincts due to suspensions for noncompliance with vaccine mandates among firefighters and cops. Today there are pictures of growing piles of uncollected trash on the streets, with reports of up to 20% of NYC sanitation workers on suspension for not complying with vaccine mandates either. How the new executive orders for large employers and healthcare, to be enforced by OSHA by the holidays, that President Biden announced today will start to factor in is anyone’s guess. TSA, for example, is coming up on their “vaccination or suspension” deadline. And while Southwest has not had the same publicized flight cancellations, this past week was American Airline’s turn to blame staff shortages and “inclement weather” (that affected no other airline flying to the same cities) for a rash of several hundred flight cancellations. Suffice to say, the socioeconomic upheaval over vaccine mandates is likely not over in the US, so again, expect supply at the stores, travel efficiency and services to be a little touch and go for awhile as the economy digests all of this.

–Finally, your chances of catching Ebola are equivalent to the chances that the US government, investigating the US government’s role in the horrific fatal droning of an entire Afghani family after the US government mistook them for ISIS-K terrorists in the US government’s recent ignoble Afghanistan retreat, would find that the US government did anything wrong in murdering that entire family: https://www.latimes.com/world-nation/story/2021-11-03/pentagon-watchdog-finds-no-misconduct-in-deadly-afghan-drone-strike

–Your chances of catching coronavirus are equivalent to the chances that something was probably wrong in the intelligence, and decisions on that intelligence, that led up to those childrens’ deaths.

<Paladin>