How to Make a Coronavirus Vaccine
You there! Want to make a coronavirus vaccine? Come on, I'll show you how.
Today we're going to dive into the biology, behaviour, and evolution of COVID to better understand how coronavirus vaccines work. If you actually want to make a coronavirus vaccine at home, start by getting a PhD and moving into a Moderna lab.
SUMMARY: COVID-19 is a novel virus. So when it started spreading among humans in 2019, no-one had any immunity. Now, with the introduction of various COVID vaccines, herd immunity is technically possible, if (at the very least) 70% of any given population is immunised. With herd immunity, cases will still appear when people travel to or from affected areas, but the current large-scale outbreaks will end.
Are Viruses Alive?
Viruses don't fit the definition of living organisms. In the case of coronaviruses, you're looking at a squiggle of genetic material inside a protein membrane. No cells, no nerves, no energy.
In fact, viruses lack all the critical structures to self-regulate and process energy. They can't even replicate without hijacking the reproductive mechanisms of our living cells.
But viruses are not inanimate either. They do adapt and evolve thanks to mutations in their RNA. And natural selection gives them adaptive mechanisms to shift between dormant and active phases.
Viruses are unique in this respect. They belong in a whole other category unto themselves. They are pseudo-lifeforms.
The 7 Types of Coronavirus
There are seven types of coronavirus that infect humans (and many more in other animals, preparing to jump the species barrier).
Four types of human coronavirus (called 229E, NL63, OC43, and HKU1) cause common colds, which means you've already had a number of coronavirus infections in your life. They've been around for millennia, with their symptoms described in ancient medical texts.
Three types of human coronavirus (called SARS, MERS, and COVID-19) are new. They came about in the last two decades by evolving in other animals and jumping the species barrier to infect humans.
The recent outbreaks of SARS and MERS were relatively well contained. But nature's latest viral antagonist is really getting carried away with itself. The best way to understand why COVID is such a big deal is to compare it to the flu.
COVID vs Flu
COVID-19, which creates the disease SARS-CoV-2, is highly contagious. The R (or reproduction) number of a disease is the average number of people that an infected person will pass the virus on to. While the flu has an R number of 1.3, the original strain of COVID-19 is nearly twice as infectious with an R number of 2.5. And it's evolving to be even more contagious: the latest UK variant of COVID has an R number of 3.75.
Then there's the mortality rate. Worldwide, the flu kills 290,000-650,000 people each year as a result of complications. By contrast, in the last year COVID has killed 2.46 million people. Without lockdowns this number would have been many multiples higher.
It may not be that COVID is deadlier than the flu on an individual level. Mortality estimates rely on comparing deaths from flu (which is easy in developed nations where deaths are registered) as a proportion of total flu cases (which is hard because most people treat the flu at home). But the reason COVID kills more people overall is that it's novel with a higher infection rate—and until 2019 we were all COVID virgins.
Like the flu and the common cold, you can get COVID-19 twice. That's because viruses mutate over time: the more people they infect, the more they replicate, mutate, and evolve. And viral evolution is many orders of magnitude faster than human evolution. Viruses can produce a new generation of offspring within hours; in humans it takes decades. That's an arms race we can't win naturally, which is why we need to make a coronavirus vaccine if we want to beat it.
How Does Coronavirus Work?
The novel coronavirus travels as an aerosol—a suspension of fine particles in the air. Aerosols drift around like vapour which is why COVID-19 spreads more easily indoors and when people talk, shout, and sing. This is why it's a good idea to avoid churches, rallies, and bars during a coronavirus pandemic. You can also help stop the viral particles entering your body by wearing a mask.
A symptomatic person with COVID-19 carries trillions of coronavirus particles in their airways. Every time they breathe, talk, cough, and sneeze, they eject tens of thousands of viral particles into the air. These particles can enter your body via your mouth, nose—and even your eyes.
Inside your body, the viral particles make their way to the back of your nose and throat. They attach to your cells by binding a spike protein, lock-and-key style, to a corresponding protein receptor in your cell membrane. This perfect fit is a result of nature's classic trial-and-error routine: evolution.
Each cell engulfs the virus by surrounding it with its fatty membrane. Imagine dipping a chicken nugget into BBQ sauce until it's fully submerged. That has nothing to do with this, I just thought it would be a nice thing to imagine. Now the membrane-bound virus is now inside the host cell. It injects its genetic material (its RNA) into the cell.
The invasive RNA now floats freely inside your cell cytoplasm. Like Romeo at a Capulet masquerade party, it's operating undercover and your cells can't tell the difference. How weird is that? The genetic material of a virus is built from the very same components as your own RNA. Or maybe it's not so weird at all, considering both evolved on the same planet. It tells us that, very distantly, we are actually related to the virus that's trying to kills us.
And this is why, when your cell replication workers discover the viral RNA, they mistake it for your own human RNA. (RNA is the tweaked version of DNA before it's expressed.) The viral RNA is translated into proteins to make new viral particles. Chemical interactions compel them to self assemble and—BAM!—you've replicated a virus. No sex required.
"No sex?!" you cry, aghast.
Nope. This is essentially cloning, or asexual reproduction if you want to think of it that way. Just how bacteria do.
There is an exception to this rule. Occasionally, viruses can undergo sexual reproduction if a cell is infected with two similar strains at the same time. The newly cloned body parts of each strain mingle to produce hybrid offspring, which is one way that mutant strains form. But much more often, viruses reproduce from a single parent.
This viral replication occurs at scale until the cell is positively brimming with an army of millions. The host cell has no chance. Eventually it bursts and dies, having fulfilled its ugly destiny.
The swarm goes on to infect more cells, scaling up the rate of infection exponentially. All of this takes place during the ~5 day incubation period, where infected people are contagious but not symptomatic.
Where do viruses come from? One hypothesis suggests that viruses evolved first from complex molecules, even before there were single-celled organisms. They may even have contributed to the rise of cellular life on Earth. Another hypothesis suggests viruses arose from genetic elements that gained the ability to escape and move between cells. Read up on the Regressive, Progressive, and Virus-First hypotheses.
*Awards issued by myself—to myself.
**The after party was amazing.
***The after party went on to win dozens of after party awards.
****These after party awards were also issued by me.
How Does The Immune System Work?
After a few days of covert infiltration, the increasing volume of viral particles triggers an immune response. White blood cells called lymphocytes make their coordinated attack:
- T cells (T because they mature in the thymus) are covered in receptors which recognise the viral spike protein. They bind to the virus, once again by lock-and-key style, and disarm it.
- B cells (B because they mature in bone marrow) produce pathogen-specific antibodies which circulate and lock on to the virus, marking them for destruction by other immune cells.
To help things along, inflammatory chemicals called cytokines make their way to the brain and trigger a fever. Cranking up your body temperature helps lymphocytes to recognise infected cells.
But it takes your body several days to make B cells and T cells tailored to COVID-19. And this latency gives the virus the opportunity to make a real mess of your insides.
What Does Coronavirus Do To The Body?
You've got a fever, you're coughing, and you're fatigued. Life's not fair. But you're fighting trillions of viral particles right now. In a week or so you'll feel much better.
Or not. Around 20% of people infected with coronavirus need hospital treatment because it blasts through the upper respiratory tract and reaches the lower respiratory tract, known to you and I as the lungs.
Things aren't looking good. Down here, the coronavirus attacks the cells that make up the lining of the lungs. They damage the air sacs that exchange oxygen and carbon dioxide to your bloodstream. So now it's hard to breathe.
Once infected, lung cells fill up with fluid which lets in a secondary infection: bacterial pneumonia. Now your immune system is fighting two types of invasion.
Ventilators are very handy at this point, as you struggle to breathe enough oxygen to stay alive. About 5% of coronavirus patients end up in intensive care. And that's if they're lucky. Some nations are so overloaded by COVID that their hospitals can't accept new coronavirus patients. People die from respiratory failure in their homes.
What happens next just takes the biscuit. Remember those cytokines? They were very helpful in boosting the immune response. But now they're freaking out. In a cytokine storm, the immune response goes into overdrive. Immune cells start attacking both infected and healthy cells.
The lungs fill with fluid, and inflammation ramps up further. Then the whole body joins in, leading to organ failure. Even with treatment, the death rate from a cytokine storm is around 30%. We really need to deal with this pandemic thing. I'm so glad you volunteered to make a coronavirus vaccine.
How to Make a Coronavirus Vaccine
It's now February 2021, and more than 200 million doses of COVID vaccine have been administered. The vaccines in circulation came from a pool of more than 100 new COVID vaccines in development.
Every time you encounter a virus, either through natural exposure (to a complete active virus) or vaccination (with an incomplete or inactive virus), your immune system steps up. Over the course of a few days, it creates the corresponding antibodies and builds up its pathogenic library. These blueprints help it respond faster next time you encounter the disease.
This is why you only get German Measles once. Of course, some viruses are so prevalent that they mutate often—and your old textbook editions become out of date. There is concern that the COVID vaccines we have today may no longer be effective in the future, and just like the flu, we may need an annually updated vaccine to keep our libraries relevant.
There are a few ways to make vaccines, and scientists have gotten pretty innovative under the pressure of the pandemic. Some vaccines work by introducing just part of coronavirus into your body—the spike—to create an immune response without a full blown infection. Others introduce viral mRNA coding just for the spike and not the complete viral body. Let's look at how these vaccines were developed.
In March 2020, a team at the University of Texas decoded the molecular structure of the spike protein by examining the complete COVID-19 genome. COVID's RNA turned out to be 30,000 nucleotides long, making up just 15 genes. For comparison, humans have 3 billion nucleotides which make up 30,000 genes.
Genetic analysis of COVID-19 reveals it's an 89% match to the SARS virus which jumped from bats to humans in Guangdong province in 2002. It's also a 92% match to coronavirus in pangolins, and a 96% match to coronavirus in bats in the Yunan province. Since the pandemic began, further studies of viruses in bats have revealed many more types of betacoronavirus which could make the species jump to humans and create future disease outbreaks.
From the complete COVID-19 genome, the Texas team inferred which genes translate to the spike protein. Those spike genes were replicated, then injected into mammalian cells in the lab. Being agreeable chaps, the cells started translating the genes and throwing off spikes for the team to study. They used cryo-electron microscopy to create a 3D molecular map of the protein spike.
The colour coding below reveals how certain genes relate to certain proteins which make up the spike. See how these proteins fold together into a specific functional shape. This level of analysis was critical to developing an effective COVID vaccine.
Traditionally, vaccines contain entire viral particles that have been weakened or inactivated to train up the immune system without causing disease. There are COVID vaccines in development that do just this. But they take a lot longer to produce in the lab.
The need for a faster solution prompted teams from Moderna, Pfizer, and BioNTech to take a different approach. Their vaccines introduce only the RNA that codes for the coronavirus spike, stripping it down to the bare essentials and having our bodies do the viral replication usually done in the lab. These are the mRNA vaccines in circulation today.
After receiving an mRNA vaccine, your muscle cells use the partial genetic code to produce coronavirus spikes en masse. Peak levels occur 24-48 hours later and are sustained for a few days. When the vaccinated cells die, the debris spills out and your immune system responds.
One downside of using mRNA vaccines is they need to be kept super cold. The Pfizer-BioNTech vaccine needs to be stored at -70°C (-94°F) lest the mRNA breaks down. It degrades within five days in a standard freezer at 0°C (-32°F).
There are ways around this, such as modifying the mRNA and cocooning it at the molecular level. Moderna claims to have cracked the problem, offering an mRNA vaccine that can be stored in standard freezers for up to six months. This overcomes considerable logistical problems and ensures fewer COVID-19 vaccines go to waste.
Another downside to these COVID vaccines is the double dose requirement. As with the MMR vaccine, not everyone develops a strong immunity after a single exposure. In the case of coronavirus, a second dose after 21 days is needed to generate sufficient immunity across a population.
How Vaccines Undergo Clinical Trials
Although you can make a coronavirus vaccine in just a few days, it takes many months to check it actually produces sustained immunity—and doesn't do more harm than good. This is why all vaccines go through comprehensive trials to determine dosage, formulation, side effects, adverse effects, and overall efficacy.
For example, an untested vaccine could turn out to be 95% effective but have catastrophic side effects, like causing infertility or brain damage. The widescale fallout could be even worse than the virus itself. Similarly, a vaccine that's safe but only produces a short-lived result is a poor allocation of resources against a ticking clock.
Here's a breakdown of how vaccines go through clinical trials::
- Preclinical Trials are typically performed on animals. Successful tests of coronavirus vaccines on mice progressed these vaccine candidates to human clinical trials.
- Phase One Trials involve small groups of healthy humans to compare the effects of the vaccine against a placebo vaccine. Antibody production, health outcomes, and side effects are measured, with dosages starting small and scaling up across the groups.
- Phase Two Trials use hundreds of healthy participants to reveal the immune response across a more diverse population. Different schedules of dosage, timing, and delivery method (eg, needle injection, oral dose, or the emerging microneedle array) are explored.
- Phase Three Trials involve thousands of human participants to test the vaccine at greater scale. Toxicity, efficacy, and serious adverse events are monitored. The UK's 1Day Sooner campaign sought participants to be vaccinated and then, somewhat controversially, actively infected with COVID to speed up the trial process. After this phase the FDA reviews all the data and approves the vaccine for general use.
- Phase Four Trials examines after-market data where long-term immunity, adverse events, and drug interactions are monitored. This continues for years.
The eager beavers among you can volunteer for COVID-19 vaccine trials, although you have to be aware of the risks and sign a hefty legal disclaimer. Things can and do go wrong in clinical drug trials, and healthy people have died as a result.
Here's a pretty shocking documentary about what happened when a phase one drug trial went horribly wrong in London in 2006.
The coronavirus pandemic created such turmoil that governments did something they've never done before: mass production of multiple vaccines before they received FDA approval. By backing every horse, they hoped to guarantee a stockpile for when one or more of those horses finished the race.
A vaccine isn't the only pharmaceutical player in the coronavirus pandemic. Scientists and doctors on the frontline are exploring multiple coronavirus treatment options, including the use of existing FDA-approved drug combinations and the antibody-rich blood of COVID-19 survivors.
But post-pandemic life is a long way off. A vaccine or other preventative drug solution is the only foreseeable route to slowing the coronavirus death count, now more than 2.46 million worldwide.