Johnson & Johnson and the EUA application

Posted on by Dr. Nykki
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.

 

 

 

Reasons to delay vaccination until you can talk with your doctor

Posted on by Dr. Nykki

a vaccine certification

Who should not get vaccinated (right now)?

Vaccine eligibility in Indiana (this is where I live, so it’s the state whose health department notifications I receive) was updated this morning to include people ages 65 and up. If you (or your loved one) need to sign up then it can be done through ourshot.in.gov or by calling the 211 line. Your local Area Agency on Aging (wow, say that three times fast) can also assist you. If you or your loved one are a long-term care resident then several pharmacy groups have been working to vaccinate people where they live. If you are a health care worker or you come into regular contact with infectious material then you can also be vaccinated (ourshot.in.gov or 211). 

 

I’m told that your public library may be another place where you can get help signing up for your vaccine (I cannot say enough good things about public libraries)!

 

My Facebook feed is full of people I love getting vaccinated on a regular basis, and I’m so excited about that! I do want to cover a question I promised I would come back to in more detail, though: 

Do you have any info on not getting a vaccine if you have allergies?

Things I know should make you talk to your doctor or delay signing up: 

  • If you have a known allergy to PEG (polyethylene glycol), polysorbate, or any other of the (very short) list of vaccine components, talk to your doctor before you sign up because you may be at increased risk of an allergic reaction
  • If you have a history of severe reactions or anaphylaxis to another vaccine or infused (IV) medication, talk to your doctor to make a decision based on your particular case. 
  • If you had your first shot and had anaphylaxis (or any serious reaction) to that shot, talk to your doctor before you commit to another. 
  • If you have dermal fillers (a type of injectable treatment for wrinkles and aging skin) then your response to the vaccine may include a (treatable, mild) reaction at those sites and you should talk to your doctor to know what to expect.
  • If you are actively under quarantine for COVID-19 exposure please don’t come in to get vaccinated while you are under quarantine. We don’t think your immune response will be fast enough to prevent development of COVID-19 and you’ll expose everyone at the vaccination site.
  • If you are positive for COVID-19 please wait until your isolation period is over and your symptoms are resolved. You may consider delaying a little longer (up to 60-90 days), depending on your personal risks of exposure and the vaccine supplies where you are located. 
  • If you’ve had another vaccine (flu, shingles, pneumonia shot, etc) you should wait 14 days before your coronavirus vaccine (and wait 14 days after it before you get any other vaccines) because we don’t know if there are any interactions that would affect your immune system’s response. 
  • If you received a monoclonal antibody infusion for COVID-19 specifically, we are recommending you wait 90 days after the infusion, because we don’t know exactly how those synthetic antibodies will interact with the vaccine.
  • If you have HIV or are immunocompromised, we have some data on how the vaccines work, but not as much as for people with more robust immune systems. These vaccines CANNOT give you COVID-19 (remember that post on how they work?) but you should talk to your doctor about the latest information.  
  • If you are in super fragile health and a day or two of feeling awful might actually kill you, talk to your doctor before you get your shot. 

 

And one more: If you are pregnant. 

 

The World Health Organization has released a statement about pregnant people and the Moderna coronavirus vaccine, and it’s just about as long as anything I could have written. I’ll try to summarise: 

 

“We don’t have enough data about this vaccine in pregnant people to make a definite statement about its safety (or about how well it works). The science behind the vaccine suggests that it should be safe, and animal studies have not shown any harm, but until we have a meaningful amount of data from actual pregnant people, you should talk with your doctor about your personal risk of contracting COVID-19 and severe disease, then make a decision based on the benefits to you and the fact that we don’t know for sure whether there are risks.”

 

That’s still a lot. The CDC’s recommendations at this point take a couple of pages and are roughly the same (“people who are pregnant and part of a group recommended to receive a COVID-19 vaccine may choose to be vaccinated”) 

 

What this amounts to is: We think this is probably safe, but we don’t have the data to back it up yet, and as responsible scientists we feel that we need to tell you we are making an educated guess about the safety of these vaccines in pregnant people. 

 

That’s a pretty long and relatively specific list of reasons not to get vaccinated. 

A couple of things that are not on the list:

  • Medications: I am not currently aware of any medications (other than the vaccines and monoclonal antibodies I mentioned above) that are a concern with the COVID-19 vaccines. The trials were performed on people with a variety of common diseases, and people were instructed to keep taking their regular medications. There’s no noted concern in the published data for any medication interactions. 
  • There’s been a little chatter about whether it’s okay to use acetaminophen, ibuprofen, and aspirin type medications to treat your post-vaccine symptoms. A review paper published in 2016 looked at the available data on whether these medications affected your immune response. It turns out that they might decrease your response a little bit! However, that effect is small, and because vaccines are designed to create a robust (strong) immune response, it may not make a real-world difference. We don’t know for sure.
  • Asthma: We are good to go, asthmatics! If you have particularly severe asthma, then check with your doctor. 

 

Happy vaccinating! 

 

 

 

A quick look at the news from this week…

Posted on by Dr. Nykki

a vaccine parking sign

A long week

This week has been complicated. I owe a lot of people gratitude – more, I suspect, than I know – for the grace I have been given. You had better things to do than to wait an extra hour in the office/wonder overnight if you’re going to get the medicine you need to feel better/change your plans because I forgot what mine were. So thank you…because you know who you are.

My rural hospital has administered over 3,000 COVID-19 vaccines, and we continue to vaccinate more than 150 people a day. That is a number that makes me smile.

This week has been a very busy week in COVID news! I am going to try to put together some information over the weekend, but here’s what I’ve been hearing about (did I miss anything? Let me know!) 

  • The B.1.351 COVID-19 variant (South African) appears to be wearing some pretty rockin’ sunglasses and auditioning for the Virus Cheer Team. I’d like to take a look at what we know about the existing (and upcoming) vaccines and their effectiveness against this variant in particular.
  • Speaking of upcoming vaccines, Johnson & Johnson have released the next round of their data and it’s pretty interesting. What do we know about the new kid who’s getting ready to move into the vaccine block?
  • There’s a lot of talk about wearing two masks these days! What does that mean, why would we do it, and is there any good practical information that doesn’t come in an infographic about covering your nose (cover your nose!)?
  • WHO has made a statement about vaccine administration with pregnant people that merits an update to a previous post about vaccines and pregnancy (short version: Definitely talk to your doctor if you are a pregnant person who is eligible for the vaccine). 
  • We’re having conversations about teachers returning to schools in several major metropolitan areas, as well as smaller ones – some with, some without the vaccine. What does the science say about in-person schooling?

That’s a super busy news week! It’s a pity I’ve been in meetings pretty much all my spare minutes – although some of them were very interesting (I got in on a CDC webinar, and the Indiana Department of Health is still working on a lot of things that aren’t COVID-19 too.)

What did I miss?

 

 

Vaccine Mutations and the New Normal

Posted on by Dr. Nykki

 

a masked dad and child

Everything mutates. 

We went to the Children’s Museum this weekend. We wore our masks and admission was limited to 25% of museum capacity (and it was not full), and we stayed in our pod. We saw an uncomfortably large number of noses poking out in some areas of the space and a comfortably cheerful number of museum staff reminding us not to let our noses poke out. 

 

Being fully vaccinated gave me a strange sense of comfort, even though I wore my mask the whole time and sanitized my hands every twelve steps. It was interesting to watch my spouse – who has not spent a lot of time outside the home since last April – try to walk the balance between extroversion and caution. We are going to have a lot to re-learn as a society, I think. 

 

A dear friend of mine who doesn’t always agree with me asked an interesting question, and it dovetails with another question that I’m starting to hear in medical conversations as well, so today’s diary ambitiously attempts to cover both of them:

What about the virus mutations? Will the vaccine protect me from them? 

How does this all end? We can’t go on forever the way we are, so what happens in the long term?

Short answer: We don’t know (yet), but we have some educated guesses, and most of them revolve around our experience with other respiratory viruses (coronaviruses, influenza viruses, and the like).

 

Long answer: Science (primarily virology and epidemiology) ahead! 

 

I briefly covered viral structure in general in another post, but it’s going to be important to the conversation ahead, so let’s go ahead and talk a bit more about that as it relates to SARS-CoV-2. This is a coronavirus – part of the coronaviridiae family, which are a relatively small group of enveloped RNA viruses with pleomorphic properties, bearing club-shaped surface proteins and measuring about 100nm in size on average. 

 

In other words, humans have defined coronaviruses as a specific set of little bags of proteins covered in knobs. It’s the knobs that are going to be the focus of our discussion, and specifically the S (spike) protein in the knobs, which is the part that connects to your cells and allows a coronavirus to infect them. 

 

When that happens, the S protein plugs into an ACE2 receptor on your cells, inserting itself like a clumsy sort of key into a loosely-constructed lock. We’re not going to go into the biochemistry of all of this (I hated biochemistry, I’ll be honest), but this connection allows the envelope of the virus to fuse with the cell it’s infecting (imagine a couple of soap bubbles merging, only one of them is full of instructions for making a zillion more bubbles). The virus inserts its instructions for assembly into the “host” cell’s manufacturing sites and then its work is done. The host cell makes a bunch more viruses, which go out and infect other cells, and so on. 

  

There are seven different strains of coronaviridiae that are known to infect humans. We discovered SARS in 2003, MERS in 2012, and COVID-19 in 2019, which makes them all still newcomers on the global disease playing field, and all three remain deadly at this point. Those are the big players in the coronavirus game, if you will, with COVID-19 actually having the lowest kill rate of the three. 

 

The other four strains are the coronaviruses mentioned on bottles of Lysol and cleaning wipes since well before 2019; these are the sort of low-grade obnoxious respiratory virus that contributes to the group of symptoms known as the “common cold”. Common cold coronaviridiae are the ideal future of SARS-CoV-2: the virus eventually becomes nothing more than a nuisance to the vast majority of humans. Unfortunately, it may take a while – especially for a slowly-mutating virus like this one – to get there. 

 

Which brings me to the topic of vaccines, mutations, protection, and adaptation. 

 

Viruses mutate. When a zillion copies of a virus are being produced, there will inevitably be some errors introduced into the RNA as it’s being copied. Sometimes, those errors in copying produce changes in the virus that help it in some way. Changing a single amino acid – for example, let’s switch aspartate to glycine at position number 614 – means the spike protein connects more easily to the ACE2 receptor, which means the virus can infect cells more easily, which makes it easier for it to spread from person to person.  Now let’s call it the D614G strain and sound like a virologist, and then publish a paper about the new mutation we’ve found. 

 

Because science is moving so FAST these days, we may choose to publish a pre-print version of the paper to the Internet, in order to get our conclusions out into the open so others can use them. That pre-print version has not, however, been peer-reviewed (remember peer review? It’s where other scientists look at your data and your conclusions to double-check, in case you missed something) and so it’s important for other people to remember that when they’re reading your conclusions.

 

A lot of the information about the recent viral mutations: B.1.1.7 (UK variant), B.1.351 (South African variant), P.1 (Brazilian variant) and G614 (oh hey you know that one now!) is still in pre-print or pre-published data. That means that I may be able to get my hands on the information (thanks, IU School of Medicine) but I am still waiting for people who are specialists in the field to look over these papers for things I may not know I should be concerned about before I trust their data.

So here’s what we do know: 

 

Increased transmissibility (person to person spread) does not necessarily mean that a variant is more deadly.  The G614 mutations (and there are several) have not seen an increase in hospitalization rates despite becoming more dominant than the original strains. We don’t have enough data to be sure about the B.1.1.7 variant yet; it may be a bit more serious than the original, but only a bit. 

 

What increased transmissibility does do is increase the risk that at-risk persons are going to become infected, just because it’s easier for this variant to spread from person to person. It’s a much friendlier and more outgoing version of the virus – it’s likely to be on the Virus Cheer Team and the Virus Student Council. However, both the G614 and B.1.1.7 variants appear to be effectively prevented by vaccines at this point. They may be fun and outgoing, but they still look enough like the Wanted poster that nobody is going to be fooled for long.

 

Other mutations in the spike protein give us more cause for concern. These are the mutations that change the way it looks to your antibodies — the viral equivalent of a dye job and a pair of shades in the dark. B.1.351 is one of these mutations – it may have increased transmissibility, since it is now the dominant strain in South Africa – but it probably is not as attractive to neutralizing antibodies in a test tube. 

 

All of this data, as of right now, is in pre-print status. That means it’s still being looked at. It also means that this is New Science! A lot of it is happening in the lab at this point, so that’s another important factor to consider. 

 

Bodies are super cool and extremely adaptable, and the things that happen inside your body are the result of complex interactions between all of your cells and systems, so the things that happen in a test tube (in vitro for you language nerds) may not happen the same way (or at all) in your body (in vivo). We’ve seen this with the initial antibody studies on COVID-19: early studies showed a rapid drop-off of antibodies in just a few months; the reality seems to be that people who have had COVID-19 retain their protection pretty well for much longer. 

 

So what does all that mean for my ability to go watch a movie or safely reschedule my Disney trip sometime in 2021?

 

It means that if you are at high risk of dying from COVID-19 or of having long term complications of the disease, you absolutely should be having a conversation with your doctor about being vaccinated, because this virus is unlikely to go away any time soon. That protects you from symptomatic infection, which is important! It reduces your risk of hospitalization and death. 

 

It means that if you are not at high risk of dying from COVID-19 you should strongly consider being vaccinated when you are eligible. I understand that you may be waiting for more data, and it’s happening all around us! You are still at risk of long-term complications from a coronavirus infection, and that is no laughing matter. 

It means that we will — at some point — have to adjust the vaccines we have as the virus mutates. We know how to do this; we do it every year with the influenza vaccine as influenza strains mutate and fight for dominance. The rest of the vaccine will remain unchanged, so we will not have to go through new trials, but when that happens, vaccinated folks will probably need to get a booster shot. 

 

It means that going forward, when you are sick, you should probably wear a mask (correctly, according to the best science that is available at that time) if you have to go out in public. If you are at high risk of getting sick and need to go out in public (because we do not live in a perfect world of protection) then maybe you will always want to wear a mask.  

 

It means that each of us is going to have to engage in a personal calculus of risk and reward for each activity that we participate in. If you see someone wearing a mask – now and until we come up with something better – you should assume that they are doing the best they can to protect themselves and the people around them, and you should respect that as a fellow human being. 

 

And until we have a whole lot of people vaccinated (I don’t know how many! That number is one that I don’t have data on yet), you should plan to wear your mask in public even if you feel well, to keep a respectful distance from people who are not in your pod, and to avoid crowding together in poorly ventilated spaces. 

 

Don’t be afraid. We know so much more than we did a year ago, and we are learning more every day. 

But be thoughtful. Be kind. Be a human in a world full of other humans, all of whom are complicated and messy and full of conflicting needs and desires. Plan your activities according to whether or not they can be performed in a way that keeps you and the people around you safe.

 

And remember that as we learn more – innovate more – understand more – we get better and better at making ‘safe’ look like ‘the old normal’ again. 

 

 

Vaccine Schedules

Posted on by Dr. Nykki

 

Dr. Nykki's mom and granddad
Two people who are excited about this vaccine – my mom and her dad – from my 2017 archives

Introducing Mom…

Today, my mom called me to let me know that she had received her first shot of Pfizer’s vaccine. She’s a pretty healthy not-too-much-over-70 woman who assured me that the biggest symptom she has had so far was a feeling of amazement and dawning relief. 

 

We are all carrying around a lot of stress and anxiety — for so many reasons — and I think it’s important that we continue to acknowledge that. It’s okay to feel anxious! It’s also okay to be tired of living under a burden of constant vigilance, because that is emotionally and physically exhausting, and we have been living under COVID vigilance since roughly March of last year to varying degrees. 

 

Take care of yourself, if you can, this coming weekend. Go outside if that’s feasible for you, and take some time to breathe fresh air (if you are quarantining or isolating, then take appropriate precautions to avoid others breathing your freshly-exhaled air, but get some fresh of your own). Write a letter to yourself or so  meone you care about (It’s okay! Wash or sanitize your hands after handling your mail because that’s good practice any time you handle something a zillion people and machines have been touching, but the risk of getting COVID from your friend’s letter is minimal, if any). Make some tea, if you enjoy tea. Take a long bath. Get dressed in nice clothing if you have been living in sweats. Exercise if you have not been (exercise outside if you can): exercise triggers your body’s natural antidepressants. 

 

None of this is going to make it okay that we’re living lives of vigilance and separation. But the really amazing thing about human beings is how good we are – when we let ourselves – at finding creative ways to solve our problems. Give yourself permission – because I am giving you permission – to be your most amazing self this weekend. I’m interested to know what that looks like, if you decide you want to share.

Mom had a vaccine question for today’s diary: 

 

What happens if I don’t get my second dose right at 21 days (or 28 days)? What if my second shot is late?  

 

Short answer: 

 

You’re still considered to be fully vaccinated, even if your second shot is waaaay after your first, although we don’t have data to give you a definite answer beyond 6 weeks yet. That’s consistent with our recommendations for all the routine vaccinations you’re likely to get — we don’t generally restart shot series. 

 

Long answer: 

 

Most vaccines – regardless of the trick they use to do it – work by invoking your immune system’s short-term defenses and long-term memory cells. For vaccines that are given in a series (like your childhood shots are), each shot builds on the memories of the one before it, reinforcing the protective responses of your immune system to create long-lasting defenses. 

 

Let’s look at tetanus as a great example. The idea behind tetanus vaccination is to protect you from Clostridium tetani infection, which causes tetanus (cheerfully known as lockjaw to some folks). C. tetani lives in dirt and makes a toxin that causes serious muscle spasms, and getting tetanus naturally does not protect you from future infection (yikes!). Fortunately, we have an extremely effective set of vaccines to help your body protect itself against tetanus. We measure that protection by checking levels of tetanus antitoxin. 

 

The first dose of a tetanus vaccine creates almost no protection — but it primes your immune syste for the next; after the third dose nearly every vaccine recipient has high enough levels of tetanus antitoxin to safely step on a dirty nail without getting lockjaw (I don’t recommend stepping on nails regardless). That protection lasts for about 3-5 years, so we give a booster shot to kids who are entering kindergarten, and another one in the early teenage years. At that point you may be protected to some degree for 20-30 years because your immune system remembers – but we still currently recommend a booster every 10 years to keep the memories fresh, and if you happen to encounter a dirty nail we’re going to give you a booster dose to make extra sure you stay safe.

 

If you happen to miss out on one of those childhood doses, we don’t make you restart the series – because we’re counting on the long-term memory cells (remember the memory B and memory T cells? We talked about those a couple of weeks ago) to pick up where they left off with the next vaccine in the series. For almost every vaccine on the market (exceptions: certain cholera and typhoid vaccines), that remains true; we recommend a minimum time to wait between vaccine injections in order to let your body finish round one of recognizing and remembering so it can launch its best response to round two, but there is no maximum time. 

 

The data we have at this point is only good for a delay of about six weeks between vaccines, and only on the Pfizer vaccine. Because Moderna’s vaccine is so similar, we are making an educated choice to treat it similarly, and as we continue to vaccinate more people – and make difficult decisions about how to distribute a limited vaccine supply – we may learn more (scientists love data! Even if it’s not in a controlled experiment) and be able to expand that information. 

 

For now, if you have gotten two doses of the Pfizer or Moderna vaccines – spaced at least 21 (Pfizer) or 28 (Moderna) days apart (the CDC says you can have a grace period of up to 4 days early), then you are considered to be fully vaccinated. 

 

And thanks for asking the question, Mom!

 

A little bit of hope

Posted on by Dr. Nykki

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. 

 

 

 

 

Martin Luther King Day: The Tuskegee Experiment

Posted on by Dr. Nykki
a graph showing increased rates of death and hospitalization in blacks from COVID
graphic from #thisisourshot Facebook Community

Trust is a hard thing to measure

Today’s diary picture is the first one that is not from my own personal camera; I am sharing it from the #thisisourshot community because this graphic is relevant to the day and the topic at hand. 

 

I sort of miss my daily “how are you doing?” texts from the CDC (I’m fine, V-safe, thanks for asking), but I’ve graduated to weekly check ins at this point. One of my nursing homes has had their first round of vaccinations rolled out, and tomorrow I’ll be at the second for an update. All of my frail elderly folks are doing great following dose #1, as are the not-so-frail and not-so-elderly folks who are residing there. 

 

The Norwegian health authorities have a simply lovely website, and I stopped in there today to see what the latest word was (they even provide it in English for those of us who don’t speak Norwegian!). And the latest word is this: For the vast majority of elderly people living with frailty, any side effects of the vaccine will be outweighed by a reduced risk of a severe COVID-19 disease course.

However, for people with severe frailty and those with a very short life expectancy, even relatively mild vaccine side effects can have serious consequences. Any benefits of taking the vaccine may be small. For these patients, their doctor should make a careful overall assessment and, in consultation with the patient and their relatives, decide whether the patient should be advised to take the vaccine.

There’s a lot happening in the vaccine world right now! I want to talk about a whole lot of things! But today is Martin Luther King day, and while I was reading the Johnson and Johnson phase 1-2a results paper in the New England Journal of Medicine the other day for my pre-diary research (remember that diary? We have another vaccine coming!), something caught my eye.

 

That something was this sentence: “The demographic characteristics of the participants in our trial confirm the lack of representation of minority groups.” In other words: this trial’s participants overwhelmingly identified as White.

 

Why does that matter? 

 

It matters because communities of color have been disproportionately affected in this country by this pandemic. The CDC’s data on race and ethnicity in COVID-19 cases shows that Black patients who get COVID-19 are 3.7 times as likely to be hospitalized and 2.8 times as likely to die as are White patients. Hispanic and Latinx patients are 4.1 times as likely to be hospitalized and 2.8 times as likely to die. American Indian/Alaskan Natives are 4 times as likely to be hospitalized and 2.6 times as likely to die. In short, these are numbers that can help us identify the groups of people who are at increased risk of hospitalization and death from COVID-19.

 

It matters because when Pew Research surveyed Americans about their attitudes toward a coronavirus vaccine in late November of 2020, 61% of White and 63% of Hispanic respondents said they would “probably” or “definitely” get a vaccine if it were available at that moment, but only 42% of Black respondents said they would. Those are all numbers that need to be substantially higher, but when a group of people who are at increased risk of hospitalization and death reports that only about 40% of them are willing to take a potentially lifesaving vaccine (Pfizer released their Phase 3 trial data on November 18th, the day this survey opened), then we should – as scientists – ask why. 

 

This is a diary about race and medicine. It may be uncomfortable to read. It is uncomfortable for me to write. I have taken more deep breaths in the last two paragraphs than in all my previous diary entries combined, and I haven’t even gotten to the story I want to tell today. 

 

This is a diary about how – when the Indiana State Department of Health and the Fairbanks School of Public Health began a landmark study of population-wide coronavirus prevalence in Indiana – they had to make a special effort to collect enough data from minority communities to satisfy the statisticians (this whole study is an amazing demonstration of what public health research looks like, by the way). 

 

It is a diary about why the National Medical Association (did you know about the National Medical Association? It was founded in 1895 after the American Medical Association refused to admit Black physicians as members) felt the need to convene a task force composed of So Many Specialists to meet with Pfizer and Moderna and independently review the data from both trials specifically with regard to the enrollment of Black participants. 

For the record, the NMA task force concluded that “Both the percentage and number of Black people enrolled are sufficient to have confidence in health outcomes of the clinical trials.” and re-emphasized the >94% efficacy of the vaccines and the safety profile across age, gender, race, ethnicity and for adults over 65 years of age. That endorsement is important. 

 

It is a diary about a 2002 study published in the Archives of Internal Medicine (put on your statistics hat: this study had a P of <0.01, meaning the results are less than 1% likely to be a random fluke of data) that found 41% of Black respondents did not trust that their physicians would fully explain research participation, compared to 23% of White respondents. Same study: 45% of Black respondents believed their physicians exposed them to unnecessary risks compared to 34% of White respondents.

 

This is a diary about trust. 

 

It is a diary about a legacy of injustice that has come to be symbolized in the medical community by the word Tuskegee. And that is the story I want to tell today — not because I want to shame my colleagues, or point fingers, or cast blame — but because there is a reason many Black patients do not trust their physicians, or government-sponsored vaccine programs, or public health authorities. And as a medical profession, we are going to have to get pretty comfortable with being uncomfortable if we truly want to help our patients in the best way we can. 

 

So stay with me for a little bit. I’m going to keep this strictly to the facts. 

 

The Tuskegee experiment (full name: “Tuskegee Study of Untreated Syphilis in the Negro Male”) is not – by any means – the sole driver of Black patients’ mistrust in the medical institution. It is, however, a powerful example of the real events that inspired that mistrust. And it was carried out at the Tuskegee Institute in Macon County, Alabama, by the United States Public Health Service. 

 

A word about syphilis, first: this is largely a sexually transmitted disease, but when left untreated can cause liver and kidney damage, dementia, blood vessel and heart damage, severe pain and death. It can be spread from an infected mother to an infant before birth and has permanent effects on growth and development. It is difficult to eradicate and can lie dormant for years. Today, syphilis can be effectively treated with long courses of penicillin, but in 1932, there were no effective treatments (arsenic and other toxic heavy metals were favorites for treatment). It represented a significant public health concern. 

 

Fact: In 1932 the Tuskegee Institute partnered with the US Public Health Service to conduct a study on the “natural history of syphilis”. The study was intended to observe and record the ways that syphilis manifested itself in Black Americans. It was supposed to last 6 months. 

 

Fact: 600 Black men – most of them poor sharecroppers, most of them illiterate – were enrolled in the Tuskegee study in 1932. They were promised free medical care, rides to and from their clinic visits, free meals on exam days, and burial insurance. For a sharecropper in 1932, this was quite a lot! The researchers told the men that they were being treated for “bad blood”, which was a catch-all term used for a variety of ailments at the time. About 400 of these men had syphilis, and about 200 of them did not. The precise numbers vary from report to report. 

 

Remember where I said the study began in 1932 and was supposed to last 6 months? 

 

Fact: In 1947, penicillin became widely known as the drug of choice for treatment of syphilis. None of the enrollees in the Tuskegee study were offered treatment with penicillin. Researchers continued to observe their subjects. A draft report from 1949 recounts the deaths of 140 men in the study in the first 16 years.

 

Fact: In 1968, a report from the ongoing study notes that 373 participants were known to have died (there’s no breakdown of cause), and only 89 participants showed up for their yearly medical examination. Of those, 53 were men who had syphilis. The report notes that only 4 of these patients remained completely untreated; 13 had been treated with penicillin (by 1968 a well-established standard treatment) and the rest with arsenic and heavy metals. The next year, an ad hoc committee met and decided that — despite moral and ethical concerns raised by committee members — the study should continue until all the participants had died. 

 

Fact: The Tuskegee study ended in 1972 when the Associated Press broke the story of a forty-year experiment in non-treatment of syphilis. Public opinion led to Congressional hearings, changes in the rules around study design and consent, and a $10 million settlement for survivors and their families out of court. 

 

Are you uncomfortable? Because I am. 

 

It’s easy to say that an experiment like the Tuskegee study could never happen today – but 1972 was not so very long ago, and this is just one entry in the long history of the interactions between the medical community and communities of color in the United States. There are a lot more stories to tell. 

 

This is a diary about rebuilding trust. 

It’s a diary about becoming comfortable with being uncomfortable. 

It’s a diary about getting vaccines into the arms of the people who are most at risk. 

 

It’s a diary about a dream. 

 

 

 

 

Norway’s Death Reports in Frail Elderly; reading a medical news article

Posted on by Dr. Nykki

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.”

 

 

 

 

Clinical Trial Design and The Fastest-Developed Vaccines Ever

Posted on by Dr. Nykki

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. 

 

This is a SUPER LONG READ.

 

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. 

 

 

 

 

Nursing Home Day

Posted on by Dr. Nykki

Memory Care

Quick update tonight: I had a headache this morning, but I went to the gym anyway and by the time I was done doing a ridiculous number of squats it had gone away. One of my partners had to call out sick today after their second dose, though. Your mileage may vary. 

 

Today’s everyday superpower I have manifested: being home in time to say goodnight to all three of my children. 

 

I’m unlikely to get to a full Vaccine Diary tonight;  on Tuesdays I come home late, eat dinner while my shower warms up, and then go back to all of the less-urgent messages I didn’t answer during the day.  So here is a vignette instead. 

 

Tuesdays are nursing home days, and no matter how much time I spend there these days, it’s never enough. I find myself holding hands in the memory care wing, carrying on conversations born in Wonderland, finding graceful ways to exit a never-ending loop of unlost memories.  

 

We had a coronavirus outbreak in this facility. Many of the patients whose hands I am holding today are survivors of it. They are more fragile than I remember them being before; less fragile than they were when I came – clad in disposable gown and gloves, surgical booties and bonnet, face shield and N-95 mask – to see them on the isolation ward. 

 

None of them are the same as they were. 

 

And neither, really, am I.