The One That's All About Vaccines
This episode is brought to you by 2020.
As promised, we (Rebecca+Ted; no distinction between writers this week, it's a joint effort) are taking this week off from our usual infertility narrative to talk about a different topic. Vaccines!
Drug development is complicated. It's also super important right now. So we’re going to simplify things. A bit.
BRAND NEW BREAKING NEWS STORY: There's a kinda big-deal virus going around atm. This virus causes a disease that can be very serious...and has caused a lot of damage. Smart people around the world have been working overtime to find a way to fix the problem, because we really, really need this problem to stop.
Engineer speaking: Let's break it down. We can think of crisis strategy in a three-pronged approach: prevention, containment, and treatment.
Prevention tries to stop the problem in its tracks.
Containment tries to stop the problem from spreading more.
Treatment tries to make sick people healthy again.
Vaccines are one part of the prevention plan for COVID-19.
As STEM professionals, we’re going to talk about that vaccine development in layman’s terms.
HOT TAKE: Unless a vaccine is made and deployed right, it’s basically worthless – and could be incredibly dangerous.
If anyone tells you that they can get you a vaccine in record time, think about it for a second. That person is telling you that they can make science happen on a set schedule. That’s optimistic, at the very least. If that person has anything riding on that particular schedule, that should say something.
Let’s get into this.
Stick with us. This is gonna get technical in parts. We’ve provided summaries, gifs, and comic relief wherever possible. If we’ve oversimplified or misstated things, let us know and we’ll update ASAP … we never want to spread misinformation, but, like, DEFINITELY not about this.
This is also a bit long. Grab a cup of coffee and settle in.
What are vaccines?
A vaccine is a product that holds inside a tiny, weakened part of a biological substance that causes a disease.
It’s not going to make you catch the disease; but, when your body’s exposed to this small, deactivated sliver of usually-dangerous biomatter, your body completely freaks out and protects itself by making antibodies. And strengthening its immune system.
So, by making very specific shields, and also putting up a gigantic wall.
This process protects your body from the specific disease the vaccine targets. If - later, after you’ve had the vaccine - you get exposed to non-weakened, very active versions of that germ, your body’s gonna be, like, hey dude, we see you, and there’s no way you’re coming in.
Maybe think of antibodies like very tiny, very specific bouncers that are very good at their job? Vaccines give you those bouncers. (Oversimplification, but I’m not here to write a scholarly article.)
Sometimes, the immunity vaccines confer is permanent. (Your bouncers have tenure.)
Sometimes, it’s not. (You’re hiring seasonal bouncers, and you’ve gotta do it every year before it gets busy.)
There are some people who actually can’t get vaccines. In those cases, people who can get vaccines are helping protect those who can’t, as well. It’s a pretty cool opportunity for humans to come together for a common goal and carry those who need help. As the last page of the Martian puts it:
“Every human being has a basic instinct to help each other out. It might not seem like it, but it’s true.
“If a hiker gets lost in the mountains, people will coordinate a search. If a train crashes, people will line up to give blood. If an earthquake levels a city, people all over the world will send emergency supplies. This is so fundamentally human that it’s found in every culture without exception. Yes, there are assholes who just don’t care, but they’re massively outnumbered by the people who do.” (Andy Weir, The Martian)
And, anyway, that’s pretty cool. Over to Ted.
OKAY. Before we go further, let's take a step back from COVID and talk about another vaccine.
AKA the seasonal flu shot. It’s generally accepted as a good idea and my company strongly encourages people to get it, in order to maintain morale and productivity and reduce sick time. (Rebecca: "My company strongly encourages it, too." [LOOKS AT SELF IN MIRROR, WINKS])
Anyway. It’s helpful for keeping you healthy and protecting friends who might not have gotten it. So are other vaccines - here's a handy chart:
Top medical professionals work year-round with the FDA to develop each annual flu vaccine. Does it immediately 100% protect you from getting the flu? Nah. It takes time for your body to grow flu resistance (make shields, build wall), and the vaccine contains a bunch of flu strains in order to maximize the chances of stopping the popular flu variants that year. It’s like wearing layers when you go hiking; it takes time to warm up or cool down, and more combinations of shirts gives you the ability to adapt to changing temperatures.
OK, but the virus that causes COVID-19 is new and different. It’s objectively an emergency situation. To make the vaccine, we're deliberately going as fast as possible with as many shortcuts as possible.
But! Before we get to shortcuts and codes and emergencies, let's talk about what normally happens.
We'll go into recipes for vaccines in a hot second, but, first, keep in mind that you need LOTS of VERY IMPORTANT RESOURCES to make a vaccine, including:
People.
To make a vaccine that does its job well, we need many thousands of patients. We need diverse populations to see effects in different demographics. To give a sense of scale, Drugmakers Moderna, Pfizer, and J&J have revealed that they are using pools of 30k–60k participants each for their final clinical trials.
Time.
Enough time to safely go through vaccine trials, and to learn from them effectively. Different companies are going about this...differently. For example, Moderna and Pfizer require 2 shots per person, separated by a few weeks. That requires even more time - including lengthy observation periods to check for side effects.
Note that the FDA has always planned to follow those rules regardless of any administrative complaints - in some cases, overriding the wishes of people with a lot of power.
Data.
Enough data to demonstrate that a vaccine is good enough for approval and use. More is better. We want ALL the data.
A Delivery Plan.
THIS WILL BE A BIG DEAL. Manufacturing and delivering the vaccines will be a truly herculean task. Like, crazy tough.
It’s also arguably the most important, because a vaccine doesn’t REALLY help you unless you and your community gets it.
Once a vaccine is go for launch, demand for it will skyrocket. Companies will need to produce millions (or billions!) of doses ASAP – while also making the usual amounts of other vaccines for measles, etc.
Okay. Let's get down to nuts and bolts. Over to Rebecca.
How are vaccines usually made?
So, here’s the general process:
- Scientists have to figure out a way to SAFELY grow, harvest, and deactivate a duplicatable version of the biological substance causing the disease. This step involves cultivating that living stuff in a growth medium like yeast or eggs and figuring out a way to SAFELY remove it from that medium. And then get it super clean. (So, basically, this is Step One, but it’s also like fifteen steps in itself.)
- In order to make the vaccine do what it’s supposed to do - to strengthen the immune response - sometimes the pure antigen is mixed with nonspecific immune boosters and stabilizers to make the vaccine easier to transport and store.
- Then you have to figure out an equitable, safe distribution strategy.
The end.
Okay, yeah. That’s the recipe for a vaccine.
[DISCLAIMER: most vaccines are like this. There is a LOT of different tech going into modern vaccines. We’re innovating a LOT of new things. But! This is ‘most vaccines’, for what that’s worth.]
ANYWAY. Do we have any processes in place to make sure that we follow a recipe well, we use the right ingredients, and the resulting vaccine is safe?
As it turns out, we do.
The Development of New Vaccines (Safely, with Lots of Redundancy and Paperwork)
Let’s go through the steps of making a vaccine again. There are six major things you gotta do, in this order:
EXPLORATORY EXPERIMENTATION: This step is when scientists are doing their initial experimentations in a lab to make the first draft of a vaccine: isolating the virus, killing it, purifying it, and making it into something that could, in theory, work.
PRE-CLINICAL TRIALS: VOCABULARY TIME! The term ‘pre-clinical’ or ‘non-clinical’ refers to tests or procedures that don’t happen on humans. (When I worked at a pediatric hospital in nonclinical research, I worked with tissue we obtained primarily from mice. We use these animals as model organisms to build and test therapies to use later in humans.) There are a couple of different types of preclinical studies (in vivo! in vitro!), but the idea is to make an animal model of something that could probably work in a human.
As a purely fun thought exercise, here are a few average timelines for the length of preclinical studies in vaccine development:
- 1-5 years (NCBI)
- 1.5-3 years (FDA protocol via California State University)
CLINICAL TRIALS: VOCABULARY TIME! ‘Clinical’ testing refers to anytime where we’re experimenting with humans. Clinical trials involve three phases (Phase I, II, and III), each with larger and more diverse patient populations. (Phase I will involve only like twenty people; Phase III, thousands.)
VERY IMPORTANT NOTE: Because safety, ANYTIME we’re talking about clinical testing, we’ve SUCCESSFULLY completed A WHOLE FREAKING LOT of preclinical studies. As a rule, we do not inject anything into a human until we see really, really good data from animal studies that tells us that that thing at the very least will not kill that human. Very uncool groups of people have tried to skip this step in the past. (I want to go to sleep tonight, so I’m not googling it, but I’m sure extremely uncool people are doing it now…albeit, hopefully without any kind of governing body supporting them.) It is not something that should ever, ever, ever happen.
OKAY, here’s where I can sorta talk from experience again. I’ve worked in data for pharma coordinating clinical trials.
CLINICALS TAKE FOREVER AND A DAY. THERE IS JUST SO MUCH GOING ON.
I mean:
Getting the right patient populations? A million years.
Finalizing a protocol, or at least getting it to a usable, mutually-agreed upon point? At least four centuries.
Generating a framework to deal with the data output, so you can learn from the trials? I mean, not that long, we could do that part pretty quickly.
Putting a first group of people through the study, which includes getting real people out of bed and getting them to go to one location which usually doesn’t have great directions and not cancelling at the last minute and throwing everything off? FOURTEEN EONS (including, like, three false starts).
Analyzing the information from the first go-through and coming up with a new plan if there was any weird data (which there ALWAYS IS)? MILLENNIA.
I’ll stop being dramatic. Average length of clinical phase of vaccine development, according to GAVI (a worldwide partnership of really smart and incredibly heroic vaccine people, including the WHO and UNICEF) is usually 10-15 years.
Why does this take so long? Because you need to repeat your results to prove they’re good ones, because stuff ALWAYS goes wrong in science and you need to take a minute, learn from the data, and start over, and when you introduce human volunteers into the equation all hell breaks loose.
And, ultimately, try as you might:
You can’t make science happen on a schedule.
That’s why this stuff takes so long.
(Trust me. I tried to make science happen on a schedule…and, as a result, I only have a weird third of a PhD. It just doesn’t work.)
ANYWAY after preclinical AND all three clinical phases are complete, a new vaccine still has to pass three hurdles:
- Regulatory review and approval: MOUNTAINS of paperwork, audits, analysis, and other fun stuff. This usually is too high a mountain to successfully cross. MIT did a study: “Approval rates ranged from a high of 33.4 percent in vaccines for infectious diseases to 3.4 percent for investigational cancer treatments.”
- Manufacturing mayhem: Assuming the vaccine gets approval, you then have to figure out how to make it on a mass scale and distribute it safely.
- QC: And that process has to be reviewed, audited, and approved.
of Pharmaceutical Manufacturers & Associations
Okay, let's get the engineer back in here to talk about distribution:
Factories are typically built brand new for new vaccines with hyper-specialized equipment. These each take ~5 years each to build, and cost 3x the price of normal drug factories. At least 7 COVID-19 vaccine factories are already being built, even though most of them are for drugs that probably will not be authorized, so the plants will not be used. The few that are built for the right drug will face demand faster than they can possibly produce.
AND they will have to maintain quality control for everything. They will have to be certain that every worker, every robot, every culture vat, and every vial are correct every time.
It also takes resources to get vaccine doses to people who need it. Those billions of doses have to be transported EVERYWHERE IN THE COUNTRY. Carriers are used to doing that for normal vaccines. Now suddenly they are preparing to fly 20 BILLION doses with special constraints, before anything has been approved. Every single dose will have to be constantly chilled at either 32°F or -94°F. (That’s 'cold' and 'waytoodamncold'.) Between 5% and 20% of doses are expected to be wasted by temperature problems. And all that is BEFORE it gets to your ZIP code.
The military will help. They are good at handling crises. They plan to have an “operation center that will tell us at any given time exactly where every dose of vaccine is.” Their role will be only logistical; “federal military personnel will not be involved in touching the vaccine or administering it” to civilians.
That’s all really FREAKING important. Lots of people could get very very hurt if any.single.one. of those steps has a problem.
The director of the CDC expects that such distribution for ordinary Americans will not be ready until mid-2021.
Yet the CDC has notified state health departments to be ready to distribute a vaccine by November 1st.
New York will have additional independent panels, composed of scientists, doctors, and public health experts, to (A) review the safety and efficacy data and (B) make a distribution plan to build confidence after federal approval.
Okay, I think we’ve rammed this point home: In a normal universe, in a normal situation, it takes a really really really long time to make a viable, trustworthy, effective vaccine.
Or - at the VERY least - far longer than, say, ten months.
However, we’re currently living through abnormal times. Which brings me to my next question:
Can We Do This Faster, Because 2020?
I’m rewatching the Marvel movies rn (clearly), and, it’s like, if Tony Stark could make an arc reactor in a cave or synthesize the element Badassium from the model of a fairground, can’t we do this a lil more efficiently?
There’s gotta be a safe way to speed this up, right? More people will volunteer, we’ll get our best scientists on it, we’ll do the vaccine equivalent of getting distilleries to make hand sanitizer, we’ll compact the timeline. Because we’ve got to, right? People are dying.
It would be so great to do that. I agree.
But!
It goes against the very heart of science to speed things up if it makes the process worse.
And there are some parts of the vaccine recipe and testing timeline that you just can’t practically shorten. Like the amount of time you watch volunteers who have taken a test version of the vaccine, for example.
Anyhoo, the NYT did an analysis on this back in April, and it turns out that there are two viable (but not great) ways to speed up vaccine making process:
Main idea: Instead of making one plan and sticking to it through the length of the trial (v scientific, v comforting, v reliable), scientists change the plan for current trials as they learn from new data in real time. This is not incredibly safe, but, you know, desperate times.
SPEEDING UP THE TIME BETWEEN PHASES
Main idea: Using preliminary data from one Phase 1 trial to start a Phase 2 trial instead of waiting for Phase 1 data in triplicate, etc.
And…that’s it. Those are the two ways. Gavi is hopeful that a combination of new tech, necessity-induced innovation, and collaboration (e.g., the whole world is working on this!) will yield a good outcome.
Okay, so far, we’ve talked hypotheticals. Let’s stop that. Back to Ted.
The Status of COVID-19 Vaccines, As of Right Now-ish
FIRST THINGS FIRST: In a major scientist power play (and a THANK GOD one at that), earlier this year, the CEOs of nine major pharma companies signed a pledge regarding vaccine development. It states that the “FDA has established clear guidance for the development of COVID-19 vaccines and clear criteria for their potential authorization or approval in the US. FDA’s guidance and criteria are based on the scientific and medical principles necessary to clearly demonstrate the safety and efficacy of potential COVID-19 vaccines.” They pledge to “only submit for approval or emergency use authorization after demonstrating safety and efficacy through a Phase 3 clinical study that is designed and conducted to meet requirements of expert regulatory authorities such as FDA.”
TL;DR: They won't speed up science unsafely and badly in the name of getting a result out by an arbitrary and highly convenient deadline. Breathe in that sweet, sweet integrity.
Moving on.
Here’s one tracker's main takeaway (emphasis mine): “Five candidates...are currently in Phase II/III or III trials. Taking the pandemic approach for development, most developers have scaled up manufacturing in advance of the efficacy trial results. The Oxford candidate leads the way with an estimated capacity of 2.94 billion doses by the end of 2021, followed by Novavax (1.35b), Pfizer/BioNTech (1.3b), Moderna (0.95b), and Sinovac (350m).”
There we go: The most promising, advanced trial we currently know about is projecting mass distribution ONE YEAR FROM NOW.
Granted, I only have access to easily-available stuff on the internet. Obviously, people with more authority than I do have more information than I do, and it’s very possible that those making decisions in the USA right now know about a v promising vaccine candidate that’s just around the corner.
Go back to the hypotheticals for a moment. I find that extremely, extremely unlikely. Anyway, another source:
NYT also has a vaccine tracker with nice graphics. There are six vaccines mentioned in it that have been approved for extremely limited use - think, for soldiers, etc - and none approved for American use (China, Russia, and the UAE currently have them.) When you filter by American large-scale trials, you’ll see that none - not even Pfizer - is really anywhere close. (Pfizer’s current timeline cites the end of 2021.)
VERY impressive by all standards - it’s important to note that a LOT of people are working REALLY REALLY hard to make that very accelerated timeline happen!
It’s also important to remember back to what we said above: You can’t make science happen on a schedule. Those deadlines are made to be pushed back.
And anyone who’s saying anything about vaccines being widely available before then is trying to sell you something.
But Wait! There's Another Way?
...or is there? (Spoilers: Not really, tbh.)
Vaccines represent one way to help stop spread of a disease: making individual people (or, hopefully, entire communities) very unlikely to get sick because they have the armor and bouncers they need. Another strategy that you might have heard about is called herd immunity. With herd immunity, you’re hoping to make….entire communities very unlikely to get sick.
If you’re reading carefully, you might note that that’s what I just said is the goal of vaccines.
Yep! According to Harvard Health, “Herd immunity is usually achieved through vaccination, but it can also occur through natural infection.” The type of herd immunity you’re hearing about in the news is trying to do it the second way, which is like trying to climb to the top of the Empire States Building, but skipping the elevator, and wearing flip-flops made of bricks.
The same Harvard article notes that we need 60-70% of the population to get COVID and recover safely before we can even think about herd immunity. Getting there would mean that a lot of people would die…and, because this is a new virus, we’d be exposing those people to a lot of unknown long-term effects. Not a super ethical solution. And, as it turns out, there’s a much easier, less-bad way to achieve the same goal…and it rhymes with ‘maxine’.
Russia and China already started to give COVID-19 vaccines to their citizens…without great safety or effectiveness knowledge, though. Can you imagine the dumpster fire if the US hyped a vaccine that was bad at preventing the disease and also screwed people???
We like ethics and science. So we’ll stick with doing things the right way.
It’s time to wrap this up. We’ll be back to our regularly scheduled infertility programming next week. Stuff is happening! But, until then: Say it with me.
Vaccines are complicated.
They take a long time to make (properly).
There are reasons for that.
If anyone tells you that they can get you a vaccine in record time, think about it for a hot second. That person is telling you that they can make science happen on a set schedule. That’s optimistic, at the very least. If that person has anything riding on that particular schedule, that should say something.
Be skeptical.
Be safe.
One last thing: Just for kicks and giggles, I (Rebecca) wanted to note that a very early version of this post contained this helpful chart:
Marriage: It's all sunshine and daisies until your wife manages to turn your carefully-curated data into ALL POLIO, ALL THE TIME.
And on that horribly depressing note, we'll see you next week.
Some References (Others are linked in text.)
https://www.jnj.com/biopharma-leaders-unite-to-stand-with-science
https://www.wsj.com/articles/covid-19-vaccines-whats-coming-and-when-11598882964
https://www.wsj.com/articles/fda-to-issue-guidance-on-covid-19-vaccine-approval-11593516090