a schedule board with 11a-5p COVID Vaccine and 2:30 Ice Cream, among other things
This is the best daily schedule Ever.

It’s all alphabet soup in the end

So Johnson & Johnson have submitted their data to the FDA for emergency use authorization (that’s EUA for those of you who speak alphabet soup). The data on this one are super interesting, so I’m going to talk about some new things we know! 

What is an EUA, anyway?

An Emergency Use Authorization means that (1) an emergency exists involving some kind of serious or life-threatening health condition (it is all alphabet soup here) (2) there are no traditionally-approved treatments for this condition (3) the FDA have reviewed the existing data on an intervention (could be a procedure, a medication, a device, etc) and it looks like it might have a benefit even though the full criteria for FDA approval have not been met. 


Sometimes, later information comes out that makes it clear that the intervention is not, in fact, helpful, and the EUA gets revoked. We have seen that several times with this pandemic – with certain COVID tests, with certain medications, and even with certain kinds of personal protective equipment. The FDA continuously evaluates the information that’s available to them. 


What manufacturers are hoping for, of course, is that the long-term data will support full FDA approval in the end. An EUA is not a shortcut to approval – it’s a tool that we have to use when lives are at stake and we can’t afford to wait for the usual (potentially years-long) process to grind along. 


What about the Johnson and Johnson vaccine? 

J&J applied for EUA for their vaccine on Friday. It’s a single-dose adenovirus vector vaccine (they are still running trials on a 2-dose version), so this vaccine works a little differently than the two vaccines currently on the market. Basically, J&J are using an adenovirus – a particular type of virus that’s really good at getting the body’s attention, thanks to the fact that they infect pretty much everybody (this is another common cold-causing virus) – and have modified it so that it’s not so good at actually copying itself any more. What it does do is present a set of instructions to the cells (just like the mRNA vaccines) to make viral spike proteins.


This vaccine uses DNA — so it depends on the body to translate the instructions for making spike proteins into mRNA and take them to the factories. It can’t actually affect the DNA that’s inside your cells already (and neither can the mRNA vaccines); it simply doesn’t have the enzymes to unzip your cells’ DNA and break it apart. 


J&J enrolled a little over 43,000 people in their global trial, and saw 468 symptomatic cases of COVID-19 in that trial. They designed the study to look for moderate to severe COVID-19 at 14 and 28 days after vaccination, as well as for all symptomatic infections. They also did genetic tracking on the types of COVID-19 infections they saw. 


So what did they find? A couple of interesting things. 


The vaccine was 66% effective in preventing moderate to severe COVID-19 at 28 days after vaccination — and there was enough data to say that in the US, it’s more like 72%. That’s not as good as the 94-96% prevention that Pfizer and Moderna have reported, but it’s still pretty substantial; about as effective as the adult pneumonia shot (Pneumovax23 in the US). There’s a bit of more important information in the report, though: J&J reports no cases of COVID-related hospitalization or death after day 28 in the vaccinated group. 


This is a vaccine that protects people. It’s a good vaccine! 


It may not be quite as amazingly amazing as Moderna and Pfizer’s prevention numbers (although preventing hospitalization and death is a BIG deal), but it has pretty solid safety information: there were no cases of anaphylaxis reported during the trials, and the placebo arm reported higher rates of serious adverse effects than the active vaccine arm. J&J notes that this is actually not the first vaccine candidate using this technology (their Ebola vaccine was actually approved in Europe in 2020), and that they’ve seen similar safety profiles in those long-term trials. This is a vaccine whose driving technology has a longer-term track record.


This vaccine also has some ability to see through a false nose and sunglasses! It’s not perfect; it did show decreased efficacy against the South African variant B.1.351 (remember: this variant coronavirus is super friendly AND doesn’t quite look like its wanted poster), but still protected people about half the time. That’s not bad! It’s about as good as the old shingles shot was for shingles prevention (the new one is almost 90%).


We have some pre-print data that suggests Moderna and Pfizer’s vaccines work to neutralize the mutant viruses in test tubes — but humans are not test tubes, pre-print data still needs outside eyes to look at it, and so we don’t know what the real-world effects will be. 


And this is where I remind you that variant B.1.351 has been seen in the United States, and this is why — even when you’re vaccinated — it’s still important to wear your mask, keep your respectful social distance, and avoid spending time with groups of people indoors, especially if there is eating and drinking involved.



kid in a mask

These numbers really are good ones

The last few diaries have been pretty intense. It’s time for something a little lighter, I think. 


My office staff have been getting pretty good at fielding inquiries about the vaccine lately. I hear them on the phone sometimes: “Yes, you can call 211 or I can help you get registered.” “Well, I got my shot and I’m feeling just fine.” “Let me send a message to your doc so we can get the best advice for you.” 


My news feed is full of a mélange of articles about coronavirus outbreaks, Disney World (I cried when I cancelled my February plans), Dungeons and Dragons, and vaccine news. I keep an eclectic mix of sources flowing; sometimes I click on articles I know I’m going to disagree with just so that I don’t lose perspective, and sometimes I send myself articles that I think I could probably use for later.


I learn something every time I write one of these diaries, so that makes it worth all the effort. If you’re itching to see where I get my information (I keep a very casual bibliography!) I’ve compiled all of my entries at d20doc.com with source links.

So let’s talk about the vaccine news, shall we? 

Some sobering statistics, first, to get your math brains warmed up: The first death from coronavirus in the United States was on February 6, 2020. On May 28, 2020 the United States passed 100,000 deaths from coronavirus. On September 22nd we crossed the 200,000 mark; on December 14th, 300,000. Yesterday – January 19th – we passed 400,000 deaths from COVID-19. Over the last one year we have seen the time it takes for 100,000 people to die from COVID-19 shorten from four months (May to September) to four weeks. 


A third of those deaths were in people over the age of 85. Two-thirds of them were in people over the age of 75. Four-fifths of them were in people over the age of 65. And 95% were in people over the age of 50. 


If you are young, and relatively healthy, your chances of surviving a coronavirus infection are really quite good. I’ve talked a little bit in another vaccine diary about some of the things that might linger without killing you, and on another day I’ll cover the data regarding what’s called morbidity from COVID-19, because the death statistics (the mortality) of this virus are really only the first few paragraphs of the story. 


But today I want to talk about hope — hope that you can measure in numbers. 


New England Journal of Medicine, December 10th, 2020: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine (the Pfizer data) is published. Four days later, the United States will have lost the entire population of Pittsburgh to COVID-19. The Background of the article’s abstract  closes with the sentence “Safe and effective vaccines are needed urgently.”


If you can’t sleep tonight, read the Pfizer article. It’s full of words like “lipid nanoparticle–formulated” and “modified intention-to-treat (mITT) efficacy population” which make the right people very excited, and sometimes make everyone else go cross-eyed. That’s how scientific journal articles are written – full of very specific and highly technical terms – and it’s part of why everyone who hasn’t been studying Doctor as a second language has trouble understanding what it all means. 


Here’s what Pfizer’s data says, in plain English: “We saw protection beginning about 12 days after the first dose and improving dramatically at 7 days after the 2nd dose. We observed 170 cases of symptomatic COVID-19 that were diagnosed at least 7 days after the 2nd dose, and only 8 happened in our vaccine group. We observed 10 cases of severe COVID-19 out of 170 cases. Only one of those happened in our vaccine group.”


New England Journal of Medicine, December 30th, 2020: Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine (the Moderna data) is published. The United States has lost another 40,000 people. Safe and effective vaccines are still needed urgently, and Moderna starts throwing around the “lipid nanoparticle-formulated” terminology from the get-go. 


Moderna says: “We had symptomatic COVID-19 confirmed in 196 people in our trial; only 11 of those cases were in the vaccinated group. We had 30 cases of severe COVID-19 and one death in our trial. All of those cases were in the unvaccinated group.”


Let’s talk about that for a moment. 


These trials were not designed or powered to test whether or not the vaccines will prevent severe COVID-19 (remember those terms? It means that we don’t have the numbers to make statements about severe COVID-19 with certainty, no matter how much my brain is screaming “THAT CANNOT BE RANDOM” at me). But they were designed and powered to test whether or not the vaccines will prevent symptomatic COVID-19. And they showed that they can do that just about 95% of the time. 


We have a long way to go yet before we are ready to abandon masks and social distancing. There were 49.2 million adults in the United States over the age of 65 in 2016. That’s a lot of people at increased risk! I know a few of those folks, and they are pretty cool people who make the world a better place. They also desperately want to see their grandchildren, and it is cold outside in Indiana in January.


If you are fully vaccinated (not the day after your second Pfizer or Moderna jab, but 7 to 14 days after it) then your risk of contracting coronavirus from your grandkids is significantly less than it was before you got your shot. It’s not zero! This isn’t a perfect protection! But if your family has been careful all the way around (that means wearing masks all the time outside your immediate family group, avoiding indoor gatherings especially if people are unmasked or eating and drinking, socially distancing in public, and staying clear of spaces that make those precautions difficult) then you should have a conversation – with your doctor, with your loved ones, and with yourself – about the benefits and risks of getting to see the people you have been isolated from for so long. 


Because the more people we vaccinate, the more people we protect – and when my careful precautions meet your 95% protection, we can create a safer space for both of us.

And you can’t put a number on that kind of hope. 





a negative BINAXNow Covid test

My brain is wired for panic

At one week out from my vaccine, I’ve had no new concerns. I have friends and family members reporting fever, fatigue, malaise, nausea, and vomiting – sometimes after the first dose – so I’m grateful to my immune system for all the favors it’s doing for me. Keep it up, immune system!


I’ve had a news article come up on several of my feeds lately, and so today’s diary is going to be about the Norway data and reading breaking medical news articles.


The article in question, depending on your news source of choice, begins with the headline “Norway Raises Concern Over Vaccine…” or “23 Die After Pfizer Vaccine…”; and that’s certainly a headline that will raise concern. I’m concerned! But we’ve been talking a lot about science lately, and the way that our brains tell us things that may or may not be strictly true, so I’m going to take you through a deep dive into the publicly available information and what it means from a scientific standpoint.


The article I’m using is from the British Medical Journal (a peer-reviewed publication with reasonable standing in the medical community, so a source I trust), but it reflects most of the same information you’ll find from any news source that is doing its research: Norwegian physicians had reported 23 deaths in patients who had recently received the Pfizer coronavirus vaccine. Those deaths were in care home patients (nursing home patients), many of whom were “very frail”. Some of those patients underwent autopsies and Norwegian health authorities felt that the side effects of the vaccine may have contributed to the deaths of the patients. 


I’m going to walk you through the way I responded to this information, and let’s see where it takes us, shall we? 


Brain (FULL PANIC MODE ON): That’s a lot of deaths! What’s going on?!! Why are all these people dying  in Norway?! I need to call my nursing homes and make sure nobody is dead!! What if I have been telling people bad information?! What if I’m a bad scientist and a worse doctor?! 


My brain is very excitable. It is also basically programmed for threat avoidance, because our brains are supposed to keep us alive, so it’s better in general if they’re a little paranoid (especially if you’re living in a world full of unpredictable things actively trying to kill you, as humans have done for much of our history). But that means that sometimes we have to take a moment, let the initial shock and awe wear off, and take another look at what we’re seeing. 


So let’s take a look, now that my brain has stopped running in panicked circles and screaming, shall we? 


Step 1: How reliable is the source of my information? 


I had the same general headline from multiple news sources, which is usually (but not always) a positive sign of reliability, and so I walked it back to a medical journal that I trust for confirmation. 


The data itself comes from Norway – which has a centralized government-funded health care system, in which enrollment is automatic. Citizens have the option to purchase private insurance, but only about 10% of the population has done so. The relationship between the Norwegian government and the citizens of Norway is generally good. This means that they have ready access to certain health data through national registries, and the information we are being given is likely to be reliable. 


Step 2: What are the actual facts being reported? 


BMJ reports upwards of 20,000 doses of Pfizer’s vaccine were administered in Norway in the last few weeks and 23 deaths were reported in frail elderly patients “shortly after” receiving the vaccine. 13 of those deaths have been investigated — and it was felt in those cases that vaccination responses may have contributed to the deaths. The article also notes that around 400 deaths a week occur in care homes in Norway on a normal basis.


We are not given a clear definition of “frail” or “elderly”, although both of those terms are kind of a “we know it when we see it” thing for doctors. We also are not given any information about whether the reported deaths are more than the usual number expected. Remember — Norway is monitoring its citizens’ health just as closely as the US is (maybe more closely) and so it’s expected that medical personnel should report EVERYTHING so that the data scientists can sort it out. 


Step 3: What is the relationship between the facts? 


There is a potential correlation between administration of the vaccine and death in frail elderly patients. That means that it’s possible that these two numbers are going to move together:  if more frail elderly patients are vaccinated, then more of them will die shortly after the vaccination at a rate of about 10 deaths per 10,000 doses administered. It’s also possible that these two numbers have nothing in common, and as more frail elderly patients are vaccinated, more of them do very well. 


There is also concern for causation: in the patients whose deaths have been investigated thus far, it’s possible that vaccine responses may have been a factor in their deaths. That’s certainly a point of concern, and one that I’m going to be following for more information on.. 


Step 4: What other information do I already have that is important to consider? 


Pfizer did present data on safety in patients who were age 80 and up — but as widespread vaccination programs take place, we have rapidly exceeded the number of people enrolled in clinical trials. That means that instead of 73,000 data points (Pfizer enrolled 43,000 people and Moderna enrolled 30,000 people in Phase 3) we have over 12 million in the US alone. 


The more data we have, the smaller our p value gets, and that means that we can be more confident when we say that a particular reaction is (or is not) likely to be related to vaccination.


I take care of frail elderly patients in care homes on a regular basis. I worry about things like fevers, not eating well, vomiting, and diarrhea in those patients. They don’t have a lot of extra reserve — so when they get dehydrated, low on electrolytes, or hypoglycemic (low on blood sugar), that can be a really serious event that they may not be able to recover from. So I can certainly understand from a medical standpoint where enthusiastic vaccine responses (the kind that sent my otherwise-healthy colleagues home from work for a day) might have a devastating effect on someone without that reserve. 


Step 5: What am I going to do with all this information?


I’m not going to let my brain tell me to panic. Panicking does not help me be a better doctor, and it does not help me provide better information to my patients. 


I AM going to flag this topic in my mind as something that I want to continue to learn more about — I expect more data to come out as scientists and doctors across the world continue to observe and report what they are seeing, and I want to know what the data says. Because this is important. 


I AM going to use the information I have to inform my discussions with frail elderly patients and their families. It’s going to be important to talk about the possibility of an enthusiastic vaccine response and what that means, as well as to talk about what their risk of catching COVID-19 is and what that means. I can’t make a decision about vaccination for my patients and their families; my job is to be the best resource that I can be for them, and to help them make the best decision they can for themselves — and that decision may be different from one patient to another. 


Step 6: Keep learning. 


Never stop learning. Never stop asking questions. 

And don’t be afraid to say “I don’t know, but I’ll find out.”





I am a process nerd.

I had a migraine this morning, but I am prepared to blame it on a combination of staying up until 1 AM playing Dungeons and Dragons and waking up to snow all over the ground this morning. From a vaccine standpoint, I have no complaints. 


In case you missed my Wednesday midday post, Indiana has opened their vaccination program to ages 70 and up! The Department of Health was not quite prepared, I think, for the number of registrations they received: my news alert at noon on Thursday reported that more than 250,000 Hoosiers ages 70 and older had already scheduled appointments, and many people are reporting long wait times through the 211 helpline. That’s exciting news but also highlights the immense amount of coordination and infrastructure support that is needed to perform mass vaccination (something your public health departments help to coordinate on an annual basis in flu vaccine season). 

A little talk about vaccine storage 

The CDC has updated their current recommendations for vaccination to include people ages 65 and over as well as those under 65 with high-risk health conditions, but some parts of the country hospitals and health systems are still struggling to get enough supply to vaccinate their workers – while in other systems, calls are going out at the end of the day to avoid wasting already-drawn vaccine doses due to no-shows or appointments being left unscheduled. That’s a problem. 


There are a lot of factors that play into the supply and demand equation here, and supply-chain logistics is not something that I’m prepared to write a blog post at this time (also: that discussion is Fraught with complexity beyond my skill level). I’m also not prepared at this time to engage with the larger discussion of “who should get vaccines first,” because that is also Fraught. But one of the aspects I am prepared to talk about is the delicate timeframe we’re playing with here, and why we can’t just put the syringes back in the refrigerator for tomorrow. 


Remember, both of the current vaccines are mRNA vaccines, and RNA is very fragile. Both Pfizer and Moderna have wrapped that RNA up in lipid nanoparticles (that’s little fat bubbles, for those of you playing the ‘plain English’ game), and in order to keep the whole thing from just falling apart into a tiny greasy mess it has to be kept super cold. 


Pfizer’s vaccine is the fiddliest: it’s good in an ultracold freezer (-70°C/-94°F) for 6 months, on dry ice (replaced every 5 days) for a month, and in a hospital refrigerator for 5 days. Moderna’s vaccine is much easier to store – it can stay in a regular freezer until its expiration date, instead of Pfizer’s ultracold one, and lasts thawed for 30 days in a hospital refrigerator. For both vaccines, once the vial is punctured and you mix it for administration (at room temperature) it’s good for six hours.  You can’t go backwards – once the seal is broken those doses have six hours to be given or they’re lost as the mRNA degrades. 


That’s a problem, and one there really isn’t a good way to solve other than keeping those “call lists” and reminding people to hang on to their vaccine appointments. These vaccines just aren’t built to sit around, and Pfizer’s candidate especially requires a special ultracold freezer to store it. That’s a huge investment — and when we start talking about hardware requirements to distribute a vaccine, we start talking about disparities of distribution (which is another post in itself).


There’s a new kid strolling casually onto the block, though: Johnson and Johnson (referred to as J&J for the rest of this post) have announced some preliminary results of their phase 1/2a studies just this Wednesday, and they are seeing neutralizing antibodies in 90% of recipients at day 29 after the vaccine, with 100% of recipients showing neutralizing antibodies at day 57 and antibodies lasting to day 71 (that’s the last day they took data before publishing). This one-shot adenoviral vector vaccine is probably going to be stable in a regular freezer (-20°C/-4°F) for 2 years and refrigerated for more than 3 months. 


Let’s break down the science talk on that, shall we? 


I talked in an earlier post about how an mRNA vaccine works (10-second recap: mRNA is a set of instructions for your cells to print their own Wanted posters with the image of a particular part of the coronavirus spike protein), and that’s how both Pfizer and Moderna vaccines work. The J&J candidate is an adenoviral vaccine instead. It’s built on the technology that J&J (operating as Janssen Pharmaceuticals, their R&D arm) used to produce their Ebola vaccine, which has been in development since 2014 and was approved in Europe earlier this year. 


Adenovirus vaccines use an actual virus that has been heavily modified so that it can no longer use humans to make a zillion copies of itself (remind me sometime and I’ll talk about the crazy things that viruses do inside your cells). The adenovirus itself is just a string of DNA wrapped in a package of proteins called a capsid, which is the part the immune system sees. Human immune systems are equipped to produce a robust response to adenoviruses in general. As a viral researcher, that means I can stick some easily-recognized parts of the virus I *actually* want the immune system to destroy into the capsid, and count on your immune system going bananas about it. 


Specifically, the participants in J&J’s trial are showing the development of neutralizing antibodies in every participant within 2 months after a single shot. Neutralizing antibodies are the blockers of your immune system. They grab onto viruses and prevent them from infecting cells in the first place, so this is a genuinely promising result from technology that’s been under development for quite a while and has already been successfully used in another vaccine.  


This data is also just the Phase 1/2a preliminary data, which is a great excuse to talk about how clinical trials work, the importance of blinding, and why things seem to be moving so very swiftly these days!

What’s up with the speed of vaccine trials and the Emergency Use Authorization? Can I really trust this information? Everything is happening so fast! 

The short answer is: we have rearranged the way trials are structured and allowed for a temporary authorization based on the data that’s available at this point; all of this is still being studied so it’s important to participate in post-vaccine monitoring. 




Traditionally, when you have a new therapy (a drug, a vaccine, or some cool intervention) that you think will be effective for treating a disease, you perform human trials (after all the preliminaries) in four phases. Each phase is independently structured, and researchers fully complete one phase before moving on to the next. 


Phase 1: Safety. A small group of volunteers who understand that the thing you are doing to them is hopefully-but-not-definitely safe are given gradually increasing doses of your drug-or-vaccine. Samples are taken to look at blood levels, where appropriate. Participants are closely monitored for toxicity. The goal of Phase 1 trials is to answer the question “What is a safe dose range for this drug?” 


Phase 2: Efficacy. A larger group of volunteers are divided into a “control” and several “interventional” arms. The control volunteers are given a placebo (in medication trials, this is a sugar pill; in vaccine trials it can be a saline solution), while the interventional volunteers are given  possibly-but-not-definitely effective doses. The goal of Phase 2 trials is to answer two questions: “How much drug should be given?” (Phase 2a) and “Does this drug work at all?” (Phase 2b).


This is where J&J have currently stopped. They’ve released the results of phase 1 (safe dose range) for and 2a (effective dose) for all trial participants, but they are still doing some data analysis in their 65+ participants. That’s expected at the end of January. The conclusions drawn from the data we have available from the trial at this point are: 

  1. This vaccine appears to be safe  
  2. The dose used appears to be effective at inducing an immune response. 

We are pretty sure that – given the antibodies being measured – the vaccine will be effective, but we can’t say that for sure because that data hasn’t been released. That’s the Phase 2b question.


One of the ways vaccine manufacturers have saved time is by combining phases 1 and 2 or phases 2 and 3, depending on the information that’s already available.  That means they’re running multiple studies simultaneously based on “best guess” numbers (J&J is actually still collecting data on whether a 2 dose series will be better than a 1 dose protocol, for example). That saves time. 


Once Phase 2a and 2b are completed, trials move into Phase 3, which is the large clinical trial phase. In medication trials, the experimental medication is compared to existing therapies; in the coronavirus vaccine trials the experimental vaccine is compared to a saline injection (because there is no existing therapy). Again, the experimenters and the participants are “blinded” — who gets the treatment and who gets the placebo is kept secret — because this phase is designed to answer the question “What can we expect in the real world?”


This is the part where the statisticians get involved, because things happen in the placebo arm of a trial too. People in both arms of a phase 3 clinical trial are still people, and they are still going about their daily lives, with a range of experiences that affect their health and well-being. In a well-designed trial, your statistician has suggested enrollment numbers that should help your trial take all of these things into consideration. Your statistician has also helped you set an interim analysis point (more on this in a minute).  


People who are enrolled in a clinical trial are being monitored for any and every side effect they choose to report. They are also being monitored for evidence of the *endpoints* of the trial (in the coronavirus vaccine trials, this has generally been “did you get symptomatic COVID-19?”) Those reports are then handed to statisticians, whose job is to break down the reports and answer two questions: “Did this event happen *a meaningful number of times* more often in the intervention arm than the placebo arm?” and “Did this intervention accomplish the goal *in a meaningful way*?”


We have computers to help with those analyses, thankfully. Even more thankfully, we have statisticians who are trained to select the right analysis for the problem, because even though math itself is pretty cut and dried, choosing the math you do can make a dramatic difference in the appearance of the final results. 


Phase 3 clinical trials traditionally last for quite a long time! Because of this, researchers can set an interim analysis point in their trials: This is a point where they can step back, take a look at the data, and decide if the information they have is *overwhelmingly* in favor of the intervention they’re testing. In that case, they may decide to stop the trial early (so everyone can get the benefit of the intervention) and continue analyzing data in Phase 4 (the part where we continue to collect data after a drug or intervention is released to the market). 


That’s what happened with the Pfizer and Moderna trials, and what J&J hopes will happen in their trial: the interim analysis showed an overwhelming benefit in favor of vaccination (with regard to symptomatic coronavirus infection) and so the decision to move for Emergency Use Authorization was made. It means that we don’t have as much data as we normally do from a clinical trial, though, so it’s a decision that should not be made lightly. It’s also a decision that ideally is made based on pre-established criteria (remember when I said it was super important that the trial protocols were made public in advance?) so that the decision is not influenced by the hopes of the researchers.


We all have skin in the game when we do something; one of the hardest things to do is to admit that the medication you have worked so hard to develop does not do the thing you wanted it to do — or that it has side effects that are unacceptable and so won’t ever be useful. It’s important for scientists (who are regular people, after all) to build safeguards into their trials to help prevent this bias from slipping in and affecting their decision-making. 


It’s also important to have someone else review the data – preferably someone who is invested in the field and so is familiar with the general shape of the terms you’re going to be throwing around (nothing gets in the way of critically analyzing a paper by having to go look up what “in S-specific CD4+ Th1 and Th2 cells and in CD8+ T cells” means) – to look for issues with the study design, the statistical analysis, and the conclusions that you’ve drawn. It turns out that double-checking your work is super important! 


The process of double-checking scientific work is called peer review. In general, the medical journals that doctors rely on for their scientific information are referred to as peer-reviewed publications, meaning that any paper submitted to that journal goes through a peer review process before it can be published. It adds a layer of extra trust to the results of the paper — but it is not foolproof, and journals have been known to retract papers if it turns out the information they contain is inaccurate or misrepresented.


The Emergency Use Authorization (EUA) is another peer-review tool that allows the rapid-but-provisional approval of a drug, device, or intervention. Normally, the FDA review process takes about 10 months, as the agency reviews all of the available information and independently evaluates the benefit the new drug will bring to medicine, as well as the risks it may pose. Under the EUA process (as we’ve seen) that 10 month timeline can be shortened to “days-to-weeks”. A product that is being submitted for EUA is generally something that is urgently needed and has relatively strong information supporting its safety and effectiveness. 


Because EUA approvals are based on a rapid review of early data, the manufacturers are required to provide ongoing updates regarding their continued study of the intervention. In the case of the coronavirus vaccines, the FDA has required a minimum of 2 months of data on safety following the final dose in the vaccine series, which is a much shorter followup interval than we normally see in a vaccine trial, and continued updates on their trial data over the next several years.


An EUA is a temporary authorization only; ultimately the vaccines that we are seeing will need to undergo a full review and obtain FDA approval, but their manufacturers will need to produce long-term data in order to obtain that approval. In the case of the coronavirus vaccines, the FDA has required a minimum of 2 months of data on safety following the final dose in the vaccine series, which is a much shorter followup interval than we normally see in a vaccine trial, and even the best physicists have not yet figured out how to manipulate time to get two years’ worth of safety data into two months. 


Are you still with me? We’re into the home stretch. 


Normally, once an intervention has completed 3 phases of trials and undergone full FDA approval, the drug companies begin manufacturing plans. In this case, manufacturers began ramping up to full-scale production of their vaccines in July, at the beginning of Phase 3 testing. That allowed Pfizer and Moderna to have doses of their vaccines ready to roll the day they were approved — but put them at significant financial risk if the trials were not successful. 


So a lot of moving parts have been collapsed, abbreviated, combined, and restructured to allow this ultra-rapid timeline to proceed. When this happens, it requires everyone involved to be extra diligent about what they’re doing, how they’re analyzing it, and how they interpret the conclusions. 


In the case of the coronavirus vaccine, the data we have appears solid, the endpoints and interim analyses were determined in advance, and the conclusions are supported by the data. That’s good.  But the information we have right now is NOT final, and that is important to remember. The vaccine manufacturers have not closed their trials — they will be continuing to monitor trial participants for the next 2 years — and it’s important for people who are being vaccinated to participate in reporting their own experiences with the vaccine. 


The more data we collect, the more we know. And the better our answers will be. 






I was vaccine hesitant, too

Today’s update: If I push on the spot where I got my shot it’s a little sore. Otherwise, I’ve been in excellent health.  I continue to hear reports of low-grade fevers, fatigue, and headaches from others, so do be aware your experience may not be quite as uneventful as mine. It all depends on how enthusiastically your immune system gets involved, and how sensitive you are to that activation.


I have a confession to make: As delighted as I am to have received my shots (and my delight and enthusiasm are not feigned), I spent the greater part of 2020 skeptical about the creation of, development timeframe, and efficacy of any theoretical coronavirus vaccine. I spent several months in the late summer and early autumn anxiously fretting about political pressure and the timeline of a vaccine release. I made up my mind that I was going to wait – 3 to 6 months, approximately – after the large-scale release of any purported vaccine before I got my shot. 


I worried about timing. I worried about who I could trust. I worried about what would happen if this shot didn’t actually work well enough to stop the pandemic (at one point, we were hoping that the vaccine would be 50% effective). 


So what changed? 


In September, a number of major vaccine manufacturers released their trial protocols. Part of being a responsible scientist is designing your experiments in advance, and releasing the trial protocols meant basically that the manufacturers told us what they were looking for, how they were measuring it, and what the criteria were for announcing success before the formal end of the trial. 


Understanding what we were testing gave me more confidence than any ongoing news scrutiny — and knowing the numbers that would indicate a tentative success (something that many trials, not just these, have baked into their protocols) – publicly – in advance – restored additional confidence. 


And so when the data was released, and the early results were tallied, my questions were no longer about fundamental issues of trust (although one should always continue to ask questions). They were about points of science – in a field where my training gave me enough knowledge to know what to ask. And that’s how I found myself getting my shot in December – and excited to do so – but still wearing my mask, even now. 


One question tonight.

It was going to be two – but I write really long posts.  So tomorrow: mRNA and vaccination while pregnant or breastfeeding.

Why are we talking about vaccinated people spreading coronavirus? Wasn’t that the point?


Short answer: About one in 20 people who are vaccinated are still going to get symptomatic COVID-19 (although it’s likely to be milder), and we don’t know how well the vaccine protects against infection that doesn’t cause symptoms. 


Long answer: Ready for some math? 


Remember when I said that the vaccine manufacturers told us what they were looking for? That’s a really important point in understanding what’s going on here. You see, when the vaccine trials were designed, they were designed to test for efficacy against symptomatic infection. Pfizer and Moderna both tested any trial participants who showed symptoms as part of their protocols, but they did not perform routine surveillance testing (testing everyone in the study, symptoms or not, at regular intervals) as part of their protocols. 


There’s a lot of math that happens when you design an experiment. Most of it revolves around eliminating the possibility that any results you have are actually due to random chance. I’m not going to delve deeply into statistics here, because honestly very few people find it super interesting (I do!) — but here’s an example of why it’s important to have a statistician involved when you plan your experiment. 


Let’s say I’m going to do a classic coin flip experiment. In order to decide whether the coin I have in my pocket is actually fair, I will flip it five times. My mind tells me that if I flip this coin and get five heads in a row, then the coin is obviously not fair, right? Probability tells me that about 3% of the time I’m going to get 5 heads in a row on 5 flips with a perfectly fair coin. This number – the probability that random chance has accounted for my results – is known as p.


And maybe for a coin flip, 3% (that’s a p of 0.03) is an acceptable chance to take. When people’s lives are at stake, researchers like their numbers to be a little more definite, so they involve a statistician to help design the test. In the coin flip above, if I expand my number of flips to 10, there is a 0.09% chance (for a p of 0.0009) that all 10 will be heads by random chance. That’s a much smaller number – and more on the scale of what we’re looking for. 


Pfizer and Moderna both released their interim trial data for symptomatic coronavirus infections (the thing the trial was designed to test) – and that data showed 94-95% effectiveness with a p <0.0001. That means that with regard to symptomatic infections, the numbers we are seeing are less than 0.01% likely to be due to random chance.



Neither trial was designed (built specifically to eliminate outside factors) or powered (with the statistician involved up front) to look for asymptomatic infections. That means that any information coming out of those trials (and there is some) about asymptomatic infections is being done as a retrospective or “look back” analysis. There may be enough data to give us an answer (Moderna has submitted some numbers coming from the tests they administered at the time of second vaccination) but it’s never going to be quite as solid as the conclusions that the trial was actually designed to draw. 


That means – ultimately – we don’t know how well this vaccine protects against asymptomatic infections. And because up to 40% of infections in unvaccinated people are asymptomatic, that’s a pretty large “don’t know”. If you add that to the 5% of people (1 in 20) who are vaccinated who may still get infected, that’s enough wiggle room for a lot of viruses to slip through. 


I’ve been playing role-playing games since high school (if you hadn’t figured out by now what a huge nerd I am). 1 in 20 happens a lot more often than your brain tells you it should, even with the very best dice.


We still have a lot to learn. In order to save as many lives as possible while scientists take the time they need to learn it, I’m going to keep wearing my mask and keeping my distance. 


Just in case. 


Because every single one of you is that important to me.