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:

–<deep sigh>

I am struggling to come up with the best place to start this week…

Every week I go in with the optimism that I will have a short little write up this week. Yet this will be third week in a row that’s going to be on the long side. And I’m still not going to touch on everything from just this week…

<deep sigh again>

–Alright, I guess we’ll kick off with the latest viral sensation, “Mount Vernon School Board Doc”. This actually happened nearby me. For the record, I was not at the meeting, and I am not this doc. There has been some “misinformation” whac-a-mole on some copies of his spiel by YouTube, so I am not going to link it since the abridged version I was sent by a reader may not be long for the world. In fact, when I finally listened to his full 6 minute or so statement, it was on a copy of the full school board meeting that day from a reader who has family that works in that district, and told me about when this guy got up for his remarks.

So thank you to all who sent along this guy’s comments..

For background, these are comments made by a local doctor at the Mount Vernon School Board meeting recently, where there has been debate among parents about back to school COVID precautions, policies and regulations. This is not the only school board in the area struggling with questions around what to mandate and what to make recommended. Nor are these issues unique to this part of Indiana either, I suspect.

In my mind, you have two main camps at odds, and doing battle through the school boards over the same questions. For vaccine eligible high school kids, do you mandate vaccination to come back to school? For elementary age kids, who are not vaccine eligible, do you mandate wearing of masks? You have one camp that wants no masks or vaccines, and another that wants mandates for vaccines and/or masks. Neither side seems happy that all of the school boards have taken the same middle road as the health departments and said they are recommended, but not mandated, and you can make an individual choice.

In my opinion, and this is just my opinion, each group is trying to impose the choice they would make (get the vaccine and/or wear masks) on everyone else. And because it involves their kids, the risk emotion will triumph over reason is high.

The “War of the Karens”, if you will. Where yes, in taking this to the school board meetings, they are absolutely asking to speak to the manager….

So that’s the background into which “Mount Vernon Doc”, or MVD (as I will refer to him henceforth), gets up to speak to board. MVD never actually states his recommended course of action to the board in his spiel, but from the arguments he is making, my guess is that he is against mandates for vaccines and masks, and may even be against recommendations. But I would confirm the latter with him just to be sure, because I don’t want to assume and go further than his actual beliefs.

Let’s go in order of MVD’s arguments though. I will provide my comments in italics.

Preamble: We start with some argumentum ad hominem accusing the CDC and ISDH of “not listening to the science” and making recommendations against the “rules of science”. He does not blame the school board for this, since they are not expert enough to know how the CDC and ISDH are screwing up.

As for the CDC, well, see some of commentary on their recent performance in last week’s update. MVD is going to get to that same study I critiqued though–and <SPOILER ALERT> make the exact same interpretation error CDC did…

Argument 1: MVD claims that masks are useless because “all respiratory viruses” are known to transmit via aerosols, which get through the masks in common use. MVD states the CDC and the NIH funded the research that shows this, but don’t publicize that.

In its response to his statements, local news coverage of the ISDH response included a link to the CDC’s summary of studies behind its recommendation for mask use. I have included the most salient here, direct from that page, which show that use of masks does, in real world settings, significantly reduce your individual risk of exposure to SARS-CoV-2:

“An investigation of a high-exposure event, in which 2 symptomatically ill hair stylists interacted for an average of 15 minutes with each of 139 clients during an 8-day period, found that none of the 67 clients who subsequently consented to an interview and testing developed infection. The stylists and all clients universally wore masks in the salon as required by local ordinance and company policy at the time.³⁶ In a study of 124 Beijing households with > 1 laboratory-confirmed case of SARS-CoV-2 infection, mask use by the index patient and family contacts before the index patient developed symptoms reduced secondary transmission within the households by 79%.³⁷ A retrospective case-control study from Thailand documented that, among more than 1,000 persons interviewed as part of contact tracing investigations, those who reported having always worn a mask during high-risk exposures experienced a greater than 70% reduced risk of acquiring infection compared with persons who did not wear masks under these circumstances.³⁸ A study of an outbreak aboard the USS Theodore Roosevelt, an environment notable for congregate living quarters and close working environments, found that use of face coverings on-board was associated with a 70% reduced risk.”

You can find that here, including community level studies of universal masking and effects on new infection rates. Spoiler alert–the virus is slowed, but not stopped at the public health level, by masks. Which we covered here just two weeks ago.

So if you are Karen Squad “Mask ‘Em All to Keep SARS-CoV-2 Out”, well, in fairness to MVD, the preponderance of evidence suggests you will NOT keep SARS-CoV-2 out. If you want your individual kid to minimize their risk of catching COVID, yeah, masks would be a good idea if they are not yet eligible to get the vaccine. That will reduce their chances of inhaling enough of a bolus of virus to cause meaningful infection. On the other hand, if you are on Karen Squad “No Masks In The Schools”, it won’t hurt your kid if other kids want to follow the science and reduce their individual risk. I also think most kids are used to masks enough by now that no one will be made fun of for wearing or not wearing a mask. There are wayyyyyy more important things going on in TikTok, YouTube, Robolox and Minecraft for the kids to care about masks.

Argument 2: MVD states that “no one” can make the virus go away, and that viruses with animal reservoirs, like coronaviruses, cannot be successfully eradicated by vaccination.

This is true (although I am not aware of anyone who has identified an animal reservoir for SARS-CoV-2 specifically). As we have said before here, eradication of SARS-CoV-2 is unlikely–if for no other reason than I don’t think you will ever get universal enough vaccination to do it. But you don’t need to vaccinate to eliminate the virus, and I don’t believe the CDC or ISDH has pushed for eradication, in fairness to them. While they have raised the threshold for herd immunity from 70 to 90% now, that’s still less than 100%, and implies recognition that the virus will survive. It just won’t be able to find enough susceptible hosts rapidly enough to threaten entire healthcare systems again with its hospitalization rate. And again, cannot stress enough, it’s the “bed’s taken” risk of a hospitalization from a highly contagious virus that can spread quickly, to put a lot of people in the hospital at once, that is the real threat of SARS-CoV-2. And if we’re not at the end of that threat, we are pretty damn close…

Argument 3: MVD claims the vaccines are actually making things worse, via antibody dependent enhancement, or ADE. That came up on Rogan recently too, for the record, and MVD cites previous attempts at SARS-CoV vaccines (the original SARS from 20 years ago) that died in the laboratory because animal studies showed ADE, as well as a failed RSV vaccine from, I want to say the 1970s, that failed clinical trials because of ADE.

ADE does happen, and MVD is actually correct in these citations. What happens is that you have antibodies that don’t neutralize the virus, but bind it, making it a target for macrophages to eat (as we mentioned in the vaccine compare/contrast last week). Except the virus can survive and replicate in the macrophage, and oops, also happens to shift its cytokine production, and screws up the “training” of the T- and B-cells that the macrophage would ordinarily do. This causes the virus to escape the immune system more easily, and can lead, paradoxically given it’s an immune reaction to the virus!, to worse disease. Low titers of non-neutralizing antibodies tend to be especially adept at this in petri dishes and animal studies.

Here’s what MVD -didn’t- mention when he was expertly reviewing the literature for the school board–we know about ADE. You can find commentaries and papers in the scientific literature as early as July of last year saying that vaccine manufacturers and “antibody for treatment” manufacturers (like Regeneron and Eli Lilly–again, thank you for your understanding on limited commentary here) need to watch for ADE as they develop these treatments.

So here’s a report in Nature https://www.nature.com/articles/s41421-020-00199-1.pdf investigating the antibodies to the receptor binding domain of the spike protein. These are the neutralizing antibodies generated by the vaccines, and the target for the antibodies in the Regeneron (and others) antibody treatments. The authors report that antibodies to this domain neutralize SARS-CoV-2 AND cross react to neutralize SARS, but more importantly for us show NO evidence of ADE. Yes, they looked for it!

Here you have a more comprehensive discussion of ADE in these treatments, including citations for recombinant spike protein studies in mice and monkeys (the same spike protein used in the available vaccines) showing NO evidence of ADE: https://www.nature.com/articles/s41564-020-00789-5.pdf Yes, that was also in Nature, which happens to be one of the top scientific journal titles. A little surprising MVD’s research on ADE managed to miss ALL the SARS-CoV-2 specific examples where they looked for it, and cited only old studies on other respiratory viruses…

Hopefully he can add these to the flash drive he gave to the school board.

That second Nature citation above? Also included convalescent plasma studies when they tried treating patients with antibodies from people who had already recovered from SARS-CoV-2. There were thousands of them; it was real world follow up; there was no evidence of ADE involving SARS-CoV-2.

Finally, one more for MVD’s flash drive, this is specifically testing the Moderna vaccine in a mouse model looking for ADE. Didn’t find any.

There is NO evidence of ADE with SARS-CoV-2 in any of the laboratory testing with the spike protein in animal models, or convalescent plasma from patients. And thank God for that.

Finally, the proof of the pudding is in the eating–we would be seeing worse outcomes in vaccinated patients if this were true. Same for patients receiving the treatment antibodies for acute SARS-CoV-2. As it stands, you are somewhere between 2-10x less likely to be hospitalized with SARS-CoV-2 if you are vaccinated (not what you would expect if ADE were a thing here) and 97% of deaths in Indiana (similar for the entire US) since the delta wave started are in UNVACCINATED patients, per the ISDH’s response to MVD. That’s real world evidence suggesting ADE is not a significant thing in SARS-CoV-2, and is not being elicited by the vaccines.

Not really a separate argument, but MVD misinterprets a study to bolster his claims:

MVD cited the Massachusetts outbreak study the CDC published in the MMWR that we dissected last week. MVD’s argument is that the 74% of SARS-CoV-2 PCR positives (with some cold/flu symptoms) who were vaccinated as reported in that study “proves” that ADE is happening.

MVD fails to mention that this degree of “breakthrough” is a huuuuuuge outlier among all other published reports of vaccine breakthrough percentage, which is quite small. We’ll cover some of them in a bit later on. Suffice to say, as we pointed out last week, all a positive SARS-CoV-2 PCR proves is that the virus is there. Equal Ct values between vaccinated and unvaccinated patients in that study proves everyone was probably exposed to the virus at roughly equal rates. However, the limitation of that study was that they only tested for SARS-CoV-2–and the data is better better fits a hypothesis that another virus capable of causing cold/flu symptoms was present and circulating. If so, the SARS-CoV-2 vaccine would NOT be expected to stop it, and thus symptoms in SARS-CoV-2 vaccinated patients should appear at the same proportion as the population that has recevied the vaccine. That is exactly the proportion in that study.

For a guy who just minutes before was reminding everyone that there are quite a lot of cold/flu viruses that are circulating constantly, some even from animal reservoirs, it is surprising, to say the least, that MVD did not independently arrive at this same interpretation of the distinct possibility another virus was circulating heavily in Massachusetts at the same time that study was done.

Argument 4: A surge of delta in summer is also proof that ADE from vaccines has disrupted people’s immune systems, allowing a respiratory virus to break out when ordinarily they “wait” until the fall for vitamin D levels to drop and immunity to them to thus wane.

Except for that inconvenient spike that happened about this exact same time last year, when there was no vaccine at all. That was as high as the alpha spike this spring. Summer spread is NOT due to ADE from the vaccine, my man.

I would argue that this summer’s spike is higher because delta is more contagious and there has been more social interaction this summer versus last—even accounting for the Memorial Day and Kaiser Chief’s Best Hits experiments that helped drive last year’s summer spike.

Greater frequency and spread of cold/flu viruses in the winter is better explained by people spending more time indoors to stay warm, in closer quarters coupled with the cold temperature assisting droplet formation in your lungs as you exhale, for more efficient viral transmission. Might immune systems be weakened in the winter due to dropping vitamin D levels? That’s really tough to prove causality in either direction–all you have is association studies with potentially confounding variables that are difficult to adequately control. So I wouldn’t go as far as MVD does and claim vitamin D levels as the driving cause for cold/flu seasonality.

Lastly, seasonal variability among the cold/flu viruses is complicated. Different families of virus tend to strike at different times–including periods during the summer when Vitamin D should be at its highest:

Argument 5: MVD cites an outbreak of mumps in the NHL some years back where several of the unvaccinated’s only exposure to mumps was a few players with mumps cases despite childhood vaccination. The implication here is that the mumps vaccine was the source of the mumps (despite the players being vaccinated decades prior) and I guess he implies that the SARS-CoV-2 vaccines might be doing the same? He doesn’t explicitly make that claim though. This mumps citation just kind of…is…. here.

The NHL outbreak happened in 2014. In part, it was due to the age of the players in the NHL at the time, as there were plenty of guys still playing who were born between 1970 and 1992. In the US, children in that era only got one dose of the MMR vaccine (and adults from that era, many of the readership, are actually the adult population in the US most at risk for mumps!). After 1992, that was changed to two doses for improved efficacy and longer duration of protection. On top of that, many players in the NHL are from Canada, and Canada at the time was slightly enriched for people foregoing the MMR vaccine due to the now retracted as utterly fabricated Wakefield vaccine autism study.

So not -quite- the same reason that MVD is inferring in bringing up this mumps argument, basically suggesting that the vaccinated were giving the virus to the unvaccinated.

While in the NHL case, the outbreak was due to introduction of the virus from a region with higher spread due to falling vaccination rates coupled with a susceptible adult population, all playing a close quarter contact sport frequently (a good way to spread mumps), it’s worth mentioning the risk of back mutation from attenuated virus vaccines. Because I think what MVD is trying to imply is that attenuated virus vaccines can and, rarely, do back mutate to the fully infective version. Thanks to a super timely reader question last week, we covered this in the compare/contrast old vs. new vaccine technologies section.

Unfortunately for MVD, this is apples to oranges comparison, because this risk ONLY applies to attenuated virus vaccines.

None of the SARS-CoV-2 vaccines in use in the USA are attenuated virus vaccines.

In fact, back mutation to a live version of SARS-Cov-2 is impossible with the spike protein only, mRNA and viral vector vaccines currently being used. They contain only the spike protein of SARS-CoV-2, not the full virus. These COVID vaccine strategies don’t make dead or weakened SARS-CoV-2 viruses that might not be dead enough or weak enough to give unvaccinated people the virus. There is no “shedding of pathogen” with these vaccines, as MVD infers might be happening–because the complete pathogen -isn’t- there. Again, these vaccines are similar to the Hep B vaccine in that only one critical protein of the virus is used for the vaccine. The difference is the SARS-CoV-2 vaccines use -your cells- to make the protein, instead of growing them in a vat like for Hep B. There is no way for, and no record of occurrence of this impossible that I am aware of, the Hep B vaccine to give Hep B to the unvaccinated. Doesn’t happen. Same level of “no f’n way” for the spike protein only, mRNA and viral vector SARS-CoV-2 vaccines.

There are dead whole virus COVID vaccines out there–some of the Chinese vaccines are these–but none are available in the US to be relevant to what MVD is trying to do at this school board meeting.

Argument 6: MVD assumes that the public health goal is to “eliminate infection” entirely, and says the vaccines will not stop people from getting symptomatic SARS-CoV-2 or at least popping a SARS-CoV-2 test positive (I am inferring the latter from his actual words–he didn’t state that explicitly).

It is true you will not eliminate SARS-CoV-2 infection entirely. As we have said, you will not stop the -presence- of the virus, which is all a positive PCR in an asymptomatic patient proves. Regardless of vaccination status. Good news is that you -don’t need to stop positive PCR tests- or -cold/flu symptoms- to stop the threat of SARS-CoV-2!

Again, cannot stress enough, to stop SARS-CoV-2 at a pandemic, public health threat level, you need to keep people out of the hospital and out of the ICU. We will be covering shortly how the vaccines are -absolutely- still doing that, even during the delta wave!

To his, and one Karen Squad’s inferred argument though, if the other Karen Squad’s goal is to keep SARS-CoV-2 out of the schools entirely, even mandating vaccines will not do that. But they will absolutely, and significantly, reduce the threat of severe SARS-CoV-2 to your child if they are vaccine eligible and get vaccinated. And you will end the ability of SARS-CoV-2 to threaten the healthcare system when enough people are resistant to hospitalization or worse by SARS-CoV-2, either by vaccination (quicker) or the natural immunity route.

Argument 7: MVD states that he has treated, in acute, ambulatory settings, 15 patients with Vitamin D, Ivermectin and zinc, and none of them, NONE OF THEM, have gone on to the hospital!

Cool case series, bro. Do you know what would happen if I took a 15 patient open label phase 2 study with no placebo control in a disease setting where you would have excellent expectation that all 15 would have been equally fine had you done nothing and let the disease run its natural course (this is the “study” he has effectively run here) to the FDA and asked for approval of my super awesome treatment regimen?

First, they would do this:

Then probably this:

And finally, this:

Since most, if not all, of those 15 patients he treated were unlikely to go to the hospital anyways, his results are easily possible by chance alone. This is why we do clinical studies on meaningful numbers of patients, with control of as many variables as possible–to let a molecule tell us if it’s a useful drug beyond any reasonable doubt.

That said, taking some vitamin D daily, either by sun or by a few thousand IU of supplements is never a bad idea, from bone health on down. But vitamin D isn’t really going to cure COVID and clinical trials on vitamin D in treating COVID have thus far struck out. Arguable if high vitamin D levels help in prevention, but, still, you have had two consecutive summer spikes of COVID when vitamin D levels should be at their peak, plus pandemic spread in countries with abundant sun and high average vitamin D levels, so even prevention may be difficult to prove.

As for Ivermectin, as we mentioned, the definitive studies are already underway. With standard of care (placebo) controls and lots of patients (enough to do actual stats on!) and everything. Really!

As for zinc, a randomized clinical trial published by JAMA looked at high dose zinc supplementation, with and without vitamin C supplementation, in reducing severity and duration of symptoms of COVID in an ambulatory setting–so the exact setting that MVD was treating his case series.

There was no significant difference in duration of symptoms or severity for patients treated with either supplement, or in combo with the supplements, versus standard of care.

The zinc isn’t doing anything.

So in summary, well, again, MVD didn’t exactly state what policy, specifically, he was arguing against. Presumably mandates for vaccines and masks in schools, given his arguments. Maybe against even recommending them, since he spends a lot of energy arguing that they are counter-productive? While he is right in saying that vaccines and masks will not eliminate the possibility of SARS-CoV-2 exposure entirely, there is an awful lot of what he said he that is either apples/oranges comparison, ignores the SARS-CoV-2 specific data, or just is out of context or misinterpreted.

As my organic chemistry professor once told me after I, the spokesman for my small group, had presented our answer to a problem only to realize we had accidentally created a structure with one bond too many:

“It takes a lot of courage to stand up in front of everyone and fail.”

–My O-chem professor, who is still a dick

MVD is very courageous.

–As for the War of the Karens? Look, it’s your kid, I get it. You want to do everything possible to protect them. Among every parent’s worst fear is that your kid gets seriously ill. And you would do anything to stop that if you could, even trading places with your child to be sick in their stead.

If you think vaccines and mask mandates will keep your child from being exposed, well, again, remember the Black Death “choose your own adventure.” Once a pandemic is out, it’s out, and you will eventually be exposed to it. Also, just look at last year. I know my kid got quarantined twice for classmates who tested positive–and that was WITH mask requirements and strict social distancing in the classroom already. Mandates will not keep the virus out of schools.

It’s going to get there. Now, will high mask usage and high vaccination percentage reduce the rate and chance it penetrates? Perhaps, bordering on probably. How much is tough to calculate–there are too many variables at play. I fully expect to get another quarantine call at some point this year, masks in school or no masks.

So if the argument for a mandate is to keep the virus out entirely, yeah, that’s a waste of time. That’s futile.

On the other hand, the evidence is very much for the personal protective effects of the vaccine and, yes, masks. If your child is eligible for the vaccine, the best way to protect them is the vaccine. I know that concern over the side effects of the vaccine is a major driver for hesitancy. Honestly, that is probably motivating the other posse of Karens, who are trying to protect their children from that they perceive is a greater danger of side effects from the vaccines.

One team of Karens is trying to save the other from being the parent who did NOT mask/vaccinate and whose kid got sick with COVID and held the “winning” bad outcome lottery ticket (I would not envy being that parent). The other team of Karens is trying to save the other from being the parent whose kid held the “winning” bad side effect outcome from vaccination, or having to wear useless, uncomfortable masks. Each by imposing their risk/reward evaluation on the other.

And making the school boards arbitrate, and fight the proxy war between them.

How bad of an idea is this? Well, headlines yesterday from Tennessee where a mandate was the final decision of one local school board, and threats that the losing Karens would “find” the vocal members of the other side.

Again, the dial is cranked to maximum stupid, and just isn’t letting up…

Personally, I think the “recommended” language and solution is probably the right one. Each camp can decide for themselves how to best protect their children.

What we do need, though, is greater clarity for the individual risk/benefits for masks and vaccinations than MVD (and, frankly, a LOT of the media) are providing. That way, parents can make a more informed decision on risk/rewards. I actually think that would cause more parents to follow some of the recommendations, or at least better understand where each side is coming from in the risk/benefit analysis they see for their kid.

This war, and belittling the other side (often on political lines), helps no one. Hopefully, things settle a bit as the school year grinds along…

–“But I keep seeing headlines lately that more kids are being hospitalized! Isn’t the delta especially dangerous for the children?” I hear you ask, Headline Readin’ Hypothetical Reader. If you read the articles, what you find is reports of admissions versus beds in pediatric units. In some cases, the pediatric units are getting crowded. In others, they actual bother to try to provide context by comparing the pediatric admissions versus case volumes in June. Uniformly, in June. When COVID was at its lowest and before the Delta wave had seriously begun. So what do hospitalizations from delta actually look like in the under 17 set currently?

You will notice that pediatric admissions in the CDC’s large ass data set lag the fall of 2020 wave, and the alpha wave earlier this spring. Despite delta having higher total positive cases than the alpha wave.

That is also true for adults:

Please note the Y-axis on those two graphs is different. The adults scale in thousands of cases; the kids in 10s.

Anecdotes be anecdotes–best available data is NOT consistent with delta being uniquely more difficult on children.

–Next up is the other section I was debating leading with. We are going to march through a number of recent published and pre-published papers (some have been making headlines), doing a deep dive on delta, antibody/vaccine effectiveness against delta, and breakthrough risk with vaccines.

But first, I think we should review the pathology of COVID-19.

COVID-19 is the respiratory disease caused SARS-CoV-2. SARS-CoV-2 is a coronavirus that uses the spike protein on its surface to bind to the ACE2 receptor and invade human respiratory epithelial cells, and will directly invade endothelial cells lining blood vessels. It may also invade olfactory receptor cells, leading to loss of smell. The direct damage to respiratory epithelial cells will lead to inflammation in the lungs and shortness of breath, and as the immune system catches on to the fact that a virus is present, flu like symptoms of fever, chills, and muscle pain start as the immune system goes to war. In most patients, the combination of B-cell antibodies to the new invader and T-cells hunting down infected cells clears the virus. Antibodies stop SARS-CoV-2 outside the cells from binding to ACE2 receptor to cause new infections, and gets them eaten by macrophages or swept out of the body. T-cells kill virus once it’s inside infected cells to stop it from being produced.

In a subset of patients, and we still don’t have a great way to predict exactly who, this response is not effective enough. Obvious categories of patients with lower immune function, like the immunocompromised, elderly, obese and diabetics, struggle to clear the virus efficiently. Less commonly, but still happens, patients without obvious immune issues have an immune system that “chooses poorly.” Preponderance of evidence still suggests that a B-cell heavy response too early is the culprit.

When that happens, the virus lingers on at a relatively high level. These patients are more likely to wind up in the hospital, often due to shortness of breath from accumulating damage in the lungs. The immune system in some of these patients, but not all, panics because it is not clearing the virus. A “cytokine storm” erupts, which can carry over into sepsis and multi-organ failure, as the immune system goes Ah-nold and levels entire acres trying to kill the virus. This can take place, and often does, even after the virus is actually starting to clear, cut down along with the acres of proverbial jungle. But damage to the lungs and other organs can be significant in these patients–they tend to wind up in the ICU. Some of them will die if the damage is severe enough.

The main threat of the virus is the proportion of patients whose immune system, either by its “choice” of an inefficient response, or other conditions that cause the initial response to the virus to be inefficient (like obesity, diabetes, age etc.), is unusually high for a cold/flu virus.

This means a lot of people can wind up needing to be hospitalized at the same time by a highly contagious virus hitting a bunch of them, spreading easily. They will need to be hospitalized until their immune system gets a handle on the virus, and those whose immune system panics severely will need the ICU until the virus is gone and the immune system calms down.

The direct mortality of the virus is higher the older you are, but below 65 years of age is approximately the mortality of a bad flu season.

The direct threat is not the -main- threat though.

It’s the hospitalization rate, causing all cause mortality to rise because too many beds and healthcare resources are diverted to treating COVID and less available for heart attacks, strokes, car accidents etc.

So to beat the main threat of the virus, you need to reduce its ability to hospitalize patients and keep them there.

You can do that by vaccination, which will reduce the spread of the virus from patient to patient. Vaccinated patients get a wall of antibodies to the spike protein, ideally stopping the virus from ever reaching enough of your lung cells to cause hospitalizable disease. There is good evidence that both vaccinated and previously recovered patients also get specific T-cell responses, able to handle the virus even if it gets into your cells, so long as they can find it quickly enough.

Alternatively, or additionally, you can interfere with viral replication, to help the body manage the level of virus, in the hopes that you can get patients out of the hospital faster, and have fewer immune systems panic in response to a viral load that doesn’t look like it’s going down fast enough to your immune system.

Lastly, alternatively or additionally, you can better identify the patients whose immune system is freaking out–the earlier the better–and try to chill the immune system out.

So where are we right now?

In the US, and increasingly in other countries, you have improved resistance to that initial infection. Recovered patients and vaccinated patients are less likely to be successfully infected (in terms of enough virus being there that you get symptoms, including the cold/flu fever/chill of your immune system deciding it needs a big response). This reduces the number of people that the virus can send to the hospital at one time. That’s important.

The virus has evolved in response to be more infectious though, getting better at sneaking into a narrow window before the immune system of even recovered and vaccinated patients can recognize that its there.

We do have drugs that will help clear the virus in acute infections. The antibody treatments (like Regeneron and Eli Lilly–again, thanks for understanding), for example. There are other antivirals that may help. Ivermectin, if it proves itself in clinical studies, works here as well.

What we are missing still is better recognition of whose immune system is freaking out, and highly effective treatment to it. We are better about when to start steroids to calm the immune system out, but that’s a big gun, and gets dicey if the virus is still pretty active at the same time. There are drugs that modulate the immune system more specifically that appear to help, and others still coming up in clinical trials.

There is less emphasis, and less need to be concerned about variants in the future, if, in addition to high population resistance to spread (by vaccine or natural immunity) we have effective treatment as well that keeps the vast majority, if not all, of COVID infected patients out of the hospital. I feel that important point gets lost a lot debating vaccine mechanisms, risks/benefits, mandates, politics etc.

The vaccines are not the only tool–and in fact, with an effective enough treatment regimen, aren’t even necessarily the best tool at stopping COVID from clogging up a health care system. Which again, is its main pandemic threat.

–The tools we currently have are reducing this threat. You can scroll back up to the COVID-NET numbers. Despite the higher positive case counts in the delta wave, a -much- smaller percentage of them are converting over into hospitalizations compared to previous waves. We are very much in the end game.

–So keep all of that in mind… Now, onto Scientific Paper Fest…

–We’re going to start with two new releases by the CDC in last Friday’s MMWR.

–The first is “Rapid Increase in Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant–Mesa County, Colorado, April-June 2021” by Herlihy et al. The key elements of this paper are that delta quickly took over as the main variant in this two month span, and was higher as a percentage of identified variants than other counties in Colorado. Mesa County also had a lower than average vaccination rate than the overall Colorado average at that time (36% vs 44%).

Of the 1,945 positive cases in the county during that period (twice as high per capita than the Colorado average–so yes, delta appears more contagious), 142 of them required hospitalization. The vaccine effectiveness against symptomatic disease was 78% in Mesa county, which was slightly lower than the 89% for the rest of Colorado. This suggests a “breakthrough” risk of infections from the delta variant.

During this period, Mesa County had a 7.3% hospitalization rate for COVID cases, versus 6.9% for Colorado as a whole. The hospitalization rate was 0.6% for those UNDER 17 (it was 1.3% for the rest of the state in this age group, for the record), 5.5% for adults 18-64, and 31.5% for those 65 and older (unsurprisingly given trends we have seen before).

It should be mentioned that Mesa County’s hospitals were NOT overwhelmed during this period.

Of the 142 patients hospitalized, 34.5% went to the ICU. Again, taking up ICU beds is the main way COVID threatens us all from a public health standpoint. The fatality rate among the 142 hospitalized patients in Mesa County was 15.5%, driven heavily by the 21 deaths out of 23 ICU admissions among those 65 and older. The virus is still bad news for the elderly.

The overall case fatality rate for all 1,945 positive results in Mesa County was 1.5%.

Importantly, only 7% of the positive test results in Mesa County were in vaccinated patients. The older you were, the more likely you were to be positive even with a vaccine though. The 65+ set saw 61 positive vaccinated cases among 222 total positive cases among those 65+.

This may explain why the county saw 7 residential care outbreaks during this period with at least one delta variant case, despite 87% average vaccination rates for residents and 50% for staff. 5 of the 7 outbreaks involved at least one case in a fully vaccinated resident or staff member.

So what do we learn from this?

• We learn that delta breakthroughs are not common, but are happening. The authors state, and I agree, that it’s not clear from this data if this is just from higher circulation of delta (and thus more -chances- to fail) or intrinsic to delta itself.
• The older you are, the more likely a breakthrough positive is.
• Total CFR is 1.5%, but risk of death for all age groups accelerates dramatically if you are sick enough to wind up in the ICU. The vaccines dramatically reduce your chances of being one of the people in the ICU.
• Total hospitalization rate is about 6-7%, give or take, for COVID right now, at least in Colorado. This did NOT collapse health care systems there.

–Second paper, also from the CDC last Friday in the MMWR, “Reduced Risk of Reinfection with SARS-CoV-2 After COVID-19 Vaccination, Kentucky, May-June 2021” by Cavanaugh et al. In this paper, they scoured the patient tracking information from the Kentucky Electronic Disease Surveillance System for patients who were positive from March-December 2020 for SARS-CoV-2 by PCR or antigen test (a potential weakness, as the antigen test is less specific, and may have a few false positives there).

Then they looked to see who among ALL those patients (a lot) had a SECOND positive test reported in the database between May 1-June 30, 2021. So of the 250,000-400,000 positives, depending on how you want to estimate the total positives during the March-December 2020 period, only 246 had reinfections between May 1-June 30, 2021.

So you can “back of the envelope” about 1 in 1000 to 1 in 2000 chance of reinfection, although somewhere there is an actual statistician screaming into the void at me for that kind of estimation.

They matched those 246 patients for age, sex etc. as best they could with two other patients from the overall positive database on a 1:2 basis, and within 1 week of the initial positive test. So each reinfection was matched to two other controls.

Now, to be clear, that doesn’t necessarily mean they were in the same geography or at the same bars/events/workplace/home etc. where the reinfection happened. Some or all of their results could be explained by differences in exposure risk between the 246 cases and the controls.

But then they looked to see how many of the reinfections had been vaccinated versus the controls who had been vaccinated between their first positive test and the reinfection window of May-June 2021.

In short, patients who were vaccinated after their first positive test were 1.58 to 3.47 times LESS LIKELY to be re-infected.

Moving the odds of reinfection from about 1 in 1-2,000 to 1 in 2-4,000–at best.

Other limitations of the paper, aside from the exposure difference mentioned above, are patients who got vaccinated out of state will be misclassified (they only had Kentucky’s vaccination records for their cases and matched controls), the possibility of false positives (especially when including the antigen positive cases), and vaccinated patients may be less likely to get tested, overestimating the re-infection risk reduction benefit.

So this is trying to show that there may be some benefit to getting the vaccine even if you were already infected and recovered. However, it just moves your re-infection risk (really, risk for a second positive test–they did not differentiate for symptoms or not on the “re-infection”) from really low to slightly lower than really low.

–Next up we are going back to July of this year for “Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization” published in Nature by Planas et al. out of France. They grew delta in the lab from a sample of a patient returning to France from India and did pretty comprehensive testing of antibodies available for SARS-CoV-2 treatment (Regeneron and Lilly’s), antibodies from patients with 1 or 2 doses of the vaccines, and convalescent patients, including patients who recovered less than 6 months previously and more than 6 months previously.

Their key findings:

• Beta is actually more resistant to neutralization than delta. However, based on geographic spread and variant dominance, I would say it is clear that delta is much more contagious.
• In petri dishes, both of the antibodies in the Regeneron cocktail for acute SARS-CoV-2 treatment are still effective against both beta and delta. According to these authors, neither of the Lilly antibodies have appreciable activity against beta, but one of the two is still active against delta. That is all I will say about this finding, and thank you for understanding.
• They tested patient sera from patients who got the Pfizer or AZ vaccines. 95% of those who got two doses of the vaccine (including the AZ) were able to neutralize delta out to 16 weeks post vaccination, despite neutralizing antibody titers that were 3 to 5 fold lower against delta than against alpha. In short, two doses of the vaccine generates enough of a “wall” of antibodies that sheer force of numbers of antibodies overcomes the fact that they don’t “stick” to delta quite as well.
• Among patients who had recovered from previous COVID infection, 76-92% of these patients had antibodies that were able to neutralize delta up to 6 months after their previous COVID infection.
• However, that immunity wanes over time. Among patients who had COVID about a year ago and got better, only 47% of them had antibodies that neutralized delta.
• BUT, if they had been vaccinated within that year after COVID, 100% of those patients were able to neutralize delta–suggesting that rechallenge by the booster, or probably even the virus, will “raise the wall” of antibodies again.
• Now, the waning immunity they did see though may argue for a reason for a booster. Coupled with the Colorado data for the 65 and older, I think there is good reason for a booster at least among the ol’ folks. Younger cohorts, without comorbidities… well… ask again later.
• BUT, before we sell out on boosters, this was all in petri dishes. We don’t know how quickly an immune system that is vaccinated to, or recovered from previous, SARS-CoV-2 infection will ramp back up on rechallenge. For example, the results suggest that delta will get past the wall of available antibodies in ~53% of the people who got COVID a year ago, with no vaccine in between. That means the virus may get enough copies of itself through the wall of antibodies to start invading respiratory epithelial cells. If it gets to enough cells, the patient may get COVID symptoms again–breakthrough infection. However, the immune system will reactivate the memory B- and T-cells we know are created by vaccination or successful recovery, so the symptoms are not likely to last long or be as severe as if there had been NO previous infection (or vaccination). That may explain why vaccination, even with delta breakthrough, is associated with LESS risk of hospitalization. I don’t think there has been good evaluation of previous infection beyond the Isreali reports, which again suggested that breakthrough is less common among naturally recovered patients, and also less likely to result in hospitalization or death.
• The other big limitation, which the authors themselves acknowledge, is that they did not test T-cell responses. Again, I think there is a preponderance of evidence that suggests T-cells, in particular, are critical to effective control of SARS-CoV-2 before the immune system freaks out and hospitalization happens.
• In short, the paper shows that antibodies against SARS-CoV-2, in some of the available treatments and/or generated by vaccination or recovery from prior infection, are effective against delta variant, and enough neutralizing activity is present for at least 16 weeks for vaccines, 6 months for recovered patients–at a minimum, and likely higher given the immune system will respond with memory cells if the patient is exposed to delta.

–Next up, we have a pre-publication “Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence” from Puranik et al.

“OMG!!! THIS IS THE PAPER THAT SHOWED THE PFIZER VACCINE IS ONLY 42% EFFECTIVE AGAINST DELTA! AND MODERNA WAS BETTER, BUT ONLY LIKE 70 SOME PERCENT EFFECTIVE AGAINST DELTA!” I hear you say, Headline Readin’ Hypothetical Reader.

And yes, indeed, this -is- the study that you have seen in headlines claiming that the Pfizer vaccine “is only 42% effective versus delta, and Moderna is better!”

Headlines without relevant context again though, man, I tell ya’….

Thank God I’m here to actually read the paper, because clearly no one writing news headlines actually did. But I repeat myself…

Alright, breaking this down, what you have is a ginormous case control study of patients from the Mayo Health Clinics in Minnesota and Florida, and some of their other satellite locations, from January to July 2021. There are ~67,000 patients matched for age, sex etc. and divided out as roughly equal groups for ~20,000+ patients based on who got Moderna or Pfzier or no vaccine so far during that period. So BIG study. What are the key findings?

• That “42% effective against delta” for Pfizer and “76% effective against delta” for Moderna headline? Yeah, that is better read as effective against a positive SARS-CoV-2 test result. They did NOT differentiate that based on symptoms. This stat is medically meaningless to me without that context, and should not be allowed to survive peer review.
• So for stats from this paper that we actually care about medically in terms of COVID pandemic response and management, the Moderna vaccine is 91.6% effective against hospitalization (95% CI 81-90.6%) and the Pfizer vaccine is 85% effective against hospitalization (95% CI 73-93%)–yes, Virginia, even from the mighty delta variant.
• The stastistically inclined among you will notice two things about those hospitalization stats. 1) The 95% CIs cross, so there is NO significant difference between the two vaccines in terms of their effectiveness against hospitalization. The same is true for ICU visits and death in this same study, by the way. 2) Those are -awfully- wide CIs for a study involving over 67,000 patients. How did that happen?
• Probably because among those who got the Moderna vaccine, only 6 were hospitalized (2 to the ICU) while 11 who got the Pfizer vaccine were hospitalized (1 to the ICU). Total positive tests were low as well, even among all these patients, and yes, even including patients from Florida, where you have probably heard from headlines there are high numeric counts of new cases. That means small numbers for the actual comparisons, and broader CIs than you would have otherwise suspected.
• Among the unvaccinated, however, you had 82 in the hospital, with 17 to the ICU, and 4 deaths (consistent with the Colorado data above).
• The only deaths were among the unvaccinated. That’s worth repeating.
• There were only 38 positive tests among the 21,079 patients with the Moderna vaccine contributing to the study, only 70 positive tests among 21,946 patients with the Pfizer vaccine, and 310 out of 24,444 patients with NO vaccine. So vaccination was also, overall, associated with a lower risk of a positive test (symptomatic or asymptomatic–we don’t know).
• You were about twice as likely to wind up in the hospital with a positive test if you were unvaccinated versus either vaccine (15.7% vaccinated versus 26% unvaccinated). The CFR among the unvaccinated positives is consistent with the Colorado data above. Again, no one who got vaccinated died–even among the ICU visits.
• If I were Pfizer, I would be -super- pissed about how this study was covered by the media.

But I am almost certainly screaming into the void on this one. They are already quoting unnamed “senior Biden officials” about the drop in effectiveness (the headline in all caps from our Hypothetical Reader above) as saying “if that’s not a wake up call, I don’t know what is.”

–I refer you to the “Star Trek” meme at the beginning, and remind you that the dial is still stuck on absolutely maximum stupid.

–Lastly in Science Paper Fest, we have “Elapsed time since BNT162b2 (Pfizer) vaccine and risk of SARS-CoV-2 infection in a large cohort”, a prepublication paper from Israel et al. out of, well, Israel. But that’s the lead author’s last name too, for the record…

Breaking this one down is pretty short. They followed 33,993 patients who had received the Pfizer vaccine AND got a RT-PCR COVID test at least two weeks after their last vaccine dose sometime between May 15 and July 26th of this year–so during the delta spike. 608 patients had a positive test result (they do not break down by asymptomatic versus symptomatic again, which is really a recurring problem right now).

The main findings:

• Patients who got their second dose at least 146 days (little under 6 months) before the their PCR test were more likely to be positive than more recently vaccinated patients.
• Older patients (over age 60) were betwen 2-5 times to have a positive test
• Now, without a breakdown of symptoms and severity, hard to know how excited to get about this data.
• But it suggests the possibility that vaccine protection may start to wane after about 6 months (at least for the Pfizer vaccine), and perhaps a little faster in older patients.
• This is probably why Israel is planning a booster program, particularly for older patients. Don’t be surprised if that idea spreads.
• For what it’s worth, my ~8 months post vaccination (with Pfizer) antibody check came back yesterday. I still have somehow managed to avoid being infected by the ‘rona (or the wall o’ antibodies from the vaccine stomped the ‘rona I met before it could establish and my immune system start making antibodies to the other proteins of the virus as well). However, my antibody titer is still sky high–about 5 times the upper limit of quantitation for the assay, and well above the titers believed to confer immunity to at least the wild type strain (and delta, if we extrapolate the petri dish data from the French above, for example). That’s just me though–and anecdote be anecdote.

–Hitting a few other items quickly…

• Reports that a cholesterol drug, fenofibrate and fenofibric acid, reduced coronavirus replication in human cells in a petri dish by 70%. Made some headlines late last week, but will need clinical trials to verify. A couple early ones are already going, so we’ll see if anything comes of this. These drugs are already out there and cheap, so, like Ivermectin, if they can prove themselves in a legit, well powered study, would be a great option to disrupt the “viral replication” phase we discussed in the pathology of COVID refresher above.
• Israeli media has the top line for a Phase 2 of a CD24 targeted therapy that calms the immune system down, preventing the Ah-nold reaction when tested in several Greek hospitals. 90% of the patients receiving the drug were discharged in 5 days from the hospital. This uses a slightly unique delivery system, similar to the lipid droplets of the mRNA vaccines, called an “exosome.” So far no major safety issues. A placebo control Phase 3, the next major proving ground, should be starting soon and they aim to complete it by the end of the year. I mention it only because it’s a relatively unexplored frontier thus far in COVID therapeutics, and yet another leg of how to keep COVID out of the hospitals that we discussed above in the pathology refresher.
• Finally, the Danish WHO Chief was quoted by local media as saying that it is now believed “probable” that patient zero for the pandemic was a Wuhan lab researcher infected either in the lab or while doing field work collecting samples from bats. Again, chance of propaganda abounds, and I will be surprised if we have convincing and clear proof of origin in our lifetimes. Our kids might find out one day though.

–Around the horn quickly, Epiforecasts now has the US Rt as less than one, suggesting lower highs in new cases are coming, and right on track for the current delta wave to follow dynamics seen in the UK and India.

Be cautious of articles out there touting the “exploding” cases in places with high vaccination rates like Iceland and Gibraltar. Yes, there is high vaccination. Yes, delta is now there too. Yes, they are seeing an uptick in cases. These are almost always expressed as a percent increase off the most recent low of hardly any cases because the overall numbers are, well, not that impressive. Breakthrough is happening (see the stats and papers above), but it’s still a whole lot less likely with vaccination. Iceland has already capped its delta wave in a couple of weeks, and will likely drop new cases precipitously soon (Rt is below 1 per Epiforecasts). Gibaltar’s wave is already on the downtrend (Rt is 0.62).

South Africa is stablizing a long, slow downtrend after its recent spasm of demonstrations and riots.

Australia is locking down entire cities again as it climbs a long delta wave. For the record, vaccine rollout in Australia has been a little… troubled. Only 19% fully vaccinated (another 18% partial), which is barely ahead of the world average but lags most of Australia’s peer nations.

In China, domestic air travel rates have plummeted. Lockdowns continue to spread. And China has just partially shut down the port of Shanghai, which is the third busiest container port in the entire world. Expect some weird supply chain fluctuations again over the next couple months.

–Finally, your chances of catching COVID in most places in the world remain equivalent to the chances that no one, and I mean no one, parties hardier or loses more laptops with incriminating video and texts, than Hunter Biden. Yes, this is in reference to Hunter on video doing drugs with a hooker while talking about a third stolen laptop that went missing while he was on a 10 day bender in Vegas with “Russian drug dealers”–like I said, no one parties harder. If you have no idea what I’m talking about, this story is most easily found internationally and is listed as a full on “blind spot” in the US by Ground News…

Again, can’t recommend that app enough if you want to be sure you’re not missing something just by virtue of your preferred news sources’ editorial selection process…

<Paladin>