Yes, yes, I know and we’ll get to the obvious in the coronavirus section. But the Ebola update is short, so we’ll start there as per usual.

Ebola:

Guinea is currently treating one confirmed case and 2 suspected cases (which have been either confirmed or released by now). This has moved the 40 day with no new cases clock back a bit. Contact tracing and isolation are both problems right now, and the WHO reports a distinct possibility that unrecognized transmission chains are active and could risk geographic spread. So Guinea appears to be with us for a little while longer at least.

The DRC on the other hand officially hit its 40 day mark with no new confirmed or suspected cases. That said, the WHO also stated there are untraced known contacts still out there in this more rural region of the DRC, and a re-emergence is not out of the question, even though it has hit their usual definition for “end of outbreak.”

Coronavirus:

–Super slow news week, right? So the big news is clearly the medical holds on the J&J and AZ vaccines around the world, including the current pause in the J&J vaccine in the US.

So here’s what’s going on with that. First, recall that you have two main “families” of vaccines out there right now. The Pfizer and the Moderna vaccines are the mRNA based vaccines that were approved first, but are the newer technology. These are mRNA packaged in tiny lipid droplets to mimic SARS-CoV-2 infection and cause your poor dumb ribosomes to make SARS-CoV-2 spike protein, which is then recognized by the immune system and allows you to form antibody and specific T-cell responses to the spike protein for protection from the virus.

The other “family” of vaccines are the J&J and AZ vaccines. These use DNA for the SARS-CoV-2 spike protein packaged in an inert virus coat (an empty adenovirus, to be specfic).

The other major difference between the two is that the mRNA vaccines “grew up” (went phase 3 studies with) a two dose regimen. You get the first, then a few weeks later you go back and get the second. With the second shot, they are 90% effective in preventing SARS-CoV-2 infection (even mild disease). We have discussed that there is data out there showing that even one shot of the mRNA vaccines may prevent 70% or so of SARS-CoV-2 vaccines. We’ll get back to that point shortly. Coming on later, the AZ vaccine was used heavily as a single shot in the UK, while the J&J vaccine was expressly tested as a single shot vaccine. These are especially useful in patient populations that are migratory, or otherwise difficult to get in for return visits. So the homeless, for instance–a single shot vaccine is a great choice for them. Same for those who don’t have consistent access to transportation or the nearest vaccine distribution clinic is already a bit of a hike.

However, the choice of vehicle (what carries the mRNA, tiny lipid droplet, or DNA, empty adenovirus shell, respectively, to the cell) appears to be significant.

The rumblings of rare blood clot events that caused some pauses in Europe on the AZ vaccine have been seen in 6 patients in the US (with one death), causing the FDA to pause distribution of the J&J vaccine this week. In both the AZ and J&J vaccines, the presentation is the same. Typically within 7 to 13 days of the shot, the patient will present with muscle aches, chest pain, shortness of breath (on exertion), perhaps cool and cold digits that are suddenly turning blue, or altered mental status. This is because they are throwing blood clots inside their blood vessels.

Having your blood clot randomly within your blood vessels is, medically speaking, a problem.

In addition, the number of platelets in their blood will be -significantly- low. Ordinarily, low platelets are risk for increased -bleeding-, but in this case, platelets are low because they are being activated like crazy even though they should not be active. In fact, they are being burned up faster than they are being replaced.

At least for the AZ vaccine, German scientists have linked this to sudden appearance of an anti-platelet factor 4 antibody. We’re going to gloss on the gory scientific details of that, except to say that the same antibody is responsible for the equally rare (and serious) clotting disorder called “heparin induced thrombocytopenia” (aka HIT). In HIT, rare patients receiving heparin to stop new clotting will make this antibody on accident, and start clotting even faster. It’s a medical emergency and requires keeping everything containing even the slightest bit of heparin away from them while their anticoagulation is switched from heparin to something else (usually the oral Factor Xa inhibitors). Since heparin is such a good anticoagulant though, it’s still frontline in most patients who need anticoagulation–we just know to be aware of what HIT looks like and what to do in case you happen to be giving heparin to a patient holding the “lucky” lottery ticket for making anti-platelet factor 4 antibodies to wind up with HIT.

–Based on the numbers of known patients with these clotting events after the J&J and AZ vaccines, the risk is literally 1 in a million. Your average 18 year old still has a much higher (>100 fold) chance of dying directly from COVID itself than developing clots after these vaccines.

—That said, part of the pause in the J&J vaccine is for the FDA to describe the problem and symptoms, and collect more data. There may be other cases of this clotting side effect that were not detected at the time. After that, it becomes a matter of weighing the risk of this side effect (and ability to manage it) versus the benefit of having another large supply of effective COVID vaccines.

–This also looks suspiciously like a class effect, which is to say that it may not be a coincidence that the two vaccines that use this method of entry into cells have this same rare side effect.

–This is also why post market surveillance (and Phase 4 studies, which are often safety studies after drug approval for a deeper dive into possible side effects) are such an important part of the drug development process. It is precisely to detect these kind of 1 in a million, but serious, side effects–since the clinical trials themselves do not enroll a million patients at a time to find them (they would take too long to get -any- medicine out in a timely fashion, and not even Big Pharma could afford studies that large).

—Also important: There are NO known reports of this clotting issue so far with either of the mRNA based vaccines (Moderna and Pfizer).

–Around the horn, India is still getting all blowed up by new cases, parts of Brazil are struggling with overwhelmed hospitals as a more contagious variant has become dominant and in places without adequate vaccination or prior infection rates for significant herd immunity. Getting herd immunity up, by vaccine or previous infection, is now the entire game.

–In the US, the nationwide trend is a slow rise higher. ICU and hospitalization rates are finally starting to tick up, but you have to squint hard to see that. In general, the rate of increase in new cases is much slower than the fall/winter wave and slower than mid-summer increase in cases after the Great Memorial Day Experiment and waves of summer protests. In other words, still tracking with CDC’s projections from January for virus mutants that are more contagious but still controlled by the vaccines (like the UK variant, which is now the dominant strain in many places in the US).

Your local results will vary greatly. Texas, for instance, is still trucking along at a very stable, low rate, with no major increase in new cases. As we mentioned last week, Michigan, on the other hand, is in the midst of a major spike which looks to have flattened off so far this week, and Pennsylvania’s case velocity is a little worrisome that they might be next. The governor of Michigan requested additional doses of vaccine be sent to Michigan to help control the spread. The Biden administration denied that request; the CDC suggested that Michigan perhaps look to lockdown again.

Those are both -political- decisions. I am not going to comment on the wisdom (or lack thereof) of either of them.

What I will say instead, and was brought up in mainstream reporting on the refusal to send more vaccine to Michigan, is that, coupled with the J&J pause, there is an opportunity to revisit ways to stretch the existing vaccine supply.

For example, the UK has been doing reasonably well with its nationwide single vaccine only strategy to get at least one dose on board as many people as possible. In fact, UK readers found a discrepancy in the stats from Johns Hopkins I cited last week on total % vaccinated versus the UK’s numbers–Johns Hopkins was only counting those as fully vaccinated who had received two doses. We have also discussed publications (granted, generally small numbers) showing that among healthcare workers with prior PCR positive COVID infection, strong antibody responses were seen with just the first dose of the mRNA vaccines. So you might also consider giving one dose to anyone who had PCR proven COVID before, as that “booster” might be all they need. It will be interesting to see if any of these shifts occur in the next couple of weeks.

–In other vaccine sadness, Israel published data this week showing that the variant first identified in South Africa may get through at least the Pfizer vaccine (which was the one they were focusing the publication on). However, the case numbers involved were quite small as there is not much of the South African variant spreading in Israel right now, making statistical certainty a bit elusive. Their percentage numbers imply broad consistency with the “back of the envelope” we did previously for re-infection risk (approximating vaccine breakthrough risk) of the South Africa variant using the known re-infections in South Africa.

–In better vaccine news, the mRNA vaccines now have 6 month follow up data from the Phase 3 studies on persistence of antibodies. The antibodies, at least, remain quite high 6 months after the second dose. This implies protection, but no one is still sure how high is enough for protection, especially from some of the newer variants where, at least in petri dishes, antibodies needed to win by sheer force of numbers.

Again, too, T-cell mediated immunity may be even more important. We know the mRNA vaccines generate T-cell response too. We don’t have an easy way of measuring its activity or persistence in the clinic though.

I had my 3 months post vaccine (I got two doses of Pfizer as a reminder) blood draw for antibodies last week–my antibody levels are down from the 1 week post second shot draw, but are still quite literally off the chart.

–Finally, I’m running short on time for this one this week (and wanted to at least cover the vaccine parts), so main bullet points on a reader submitted question from some points raised by another physician testifying on COVID before an Idaho congressional meeting:

• Ivermectin is anti-parasitic drug used to treat various kinds of worms in both humans and pets. It’s basically a neurotoxin for worms (you are safe because it cannot cross the blood brain barrier to get to the receptor it targets in your CNS). Like hydroxychloroquine, ivermectin has been used for decades, is a generic, and is on the list of essential medicines for its activity against parasites. There are some very small studies out there suggesting ivermectin may work against early and active COVID. It is worth mentioning that the companies making ivermectin, who have all the financial incentive in the world if the drug is useful against COVID, are on record in the media stating that these studies are way too small to be conclusive. A recent double blind randomized study of 476 patients in Colombia was published in JAMA early last month and showed no difference in duration of COVID symptoms in patients treated with ivermectin versus placebo–however, the trend was in favor of ivermectin and a larger study might be more conclusive, as the authors state. Regardless, ivermectin is investigational (clinical trial) use only for COVID in the US. The WHO’s stance is similar and can be found here.
• Vitamin D and COVID. There is some time spent in that testimony on the bold assertion that we “don’t have a cold and flu season, we have a low vitamin D season” (because cold and overcast weather makes you less likely to get the 10-30 minutes of sun exposure that is all you need for a full day’s supply of vitamin D). However, that does not explain the spike last summer after the Great Memorial Day/Kaiser Chief Greatest Hits experiments in the US, nor the spread of COVID in Southern hemisphere countries with nation high peaks in some cases during their summer months, nor the eventual spread to countries the testifying physician cites as models for vitamin D testing and supplementation in their population. The virus is the virus. HOWEVER, we have discussed previously that vitamin D levels do roughly correlate with risk of COVID severity in some studies, with lower vitamin D correlating to a higher chance of severe COVID. But, age and obesity dominate those as risk factors (granting there may be confounding, as elderly patients and obese patients are less likely to be out in the sun, and elderly patients for sure are more prone to lower vitamin D levels). As I mentioned before, I take 2,000 IU per day of Vitamin D regardless and have for years–especially since I spend most of the weekdays indoors in a lab. A lot of that has to do with bone health though, where Vitamin D’s evidence is strongest. You can read a short article from the Mayo Clinic on Vitamin D supplementation here.
• The other courageous assertion in the testimony was that this is the “first time” we have “developed vaccines for diseases where we already have effective treatment.” Just to kill this quick, and with fire, Prevnar, better known as the pneumococcal vaccine, is a vaccine for strains of bacteria that cause pneumonia. It’s given to children and older populations where immunity is waning, and pneumonia starts to be a life-threatening risk again. The first pneumococcus vaccine was developed in the 1980s. Meanwhile, antibiotics, which can treat those same bacteria effectively, have been around since the 1940s. We made the vaccine anyways because an ounce of prevention is worth a pound of cure–and prevents opportunities for the bugs to become resistant to the treatment. If you can prevent AND treat the few cases the trickle past your prevention, you have contained the disease that much more strongly. We did the same thing with the meningococcal vaccine (also for bacteria, this time causing meningitis). So no, COVID is by no means the first time we have done vaccines AND treatment at around the same time, let alone vaccine after treatment.

–Life in the Time of Coronavirus:

–Your chances of catching Ebola this week are equivalent to the chances that Usher bucks are still acceptable for Louwill Lemon Pepper BBQ wings, even if they are frowned upon in exchange for um, performance, services…

–Your chances of catching COVID this week are equivalent to the chances that someone, somewhere, in this great wide world of ours, is furiously turning “Usher Bucks” into a cryptocurrency token or NFT.

<Paladin>