How to Make a Coronavirus Vaccine
Here's an illustrated look at the not-so-humble coronavirus and how mRNA vaccines defend us from it.
The coronavirus is a relatively simple particle. You're looking at a squiggle of genetic code, stored inside a shell lined with spikes.
That's it. Viruses are very different from bacteria: they're not cells, they don't possess organelles, and they can't replicate without hijacking our own biological machinery.
Viruses aren't even technically alive. They're pseudo-lifeforms. They do, however, evolve at the hands of random mistakes made by our cells when copying their genetic code.
And that's how there are seven coronavirus species that can infect humans today.
Genetic analysis shows coronaviruses have been around for millennia. It's likely that ancient Egyptian medical texts were describing the 229E coronavirus which still circulates in numerous strains today.
In recent years we've seen a surge of new coronavirus species arising from dense population hubs. These are not just new strains but entirely novel species, thought to have jumped from bats to humans.
The SARS and MERS outbreaks were relatively well contained, but nature's latest viral antagonist has really gotten carried away with itself. A epidemiological comparison with the flu helps us see how:
In a typical year, influenza viruses kill 290,000-650,000 people worldwide. In the last twelve months, however, COVID-19 has killed 2.5 million people in spite of lockdowns. We can't just sit back here and let nature take its course.
How Does Coronavirus Work?
Symptomatic COVID sufferers carry trillions of virus particles in their airways. Whenever air leaves their nose or mouth, the coronavirus travels as an aerosol—a suspension of fine particles that drift around like vapour.
Only a relative few need to enter your nose, mouth, or eyes to start an infection. Once inside, the virus makes its way to the back of your nose and throat, where it binds to target receptors embedded in your cells. This lock-and-key action allows the virus to enter.
The host 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 that the membrane-bound virus is welcomed to the party, it injects its genetic material (its RNA) into the cell cytoplasm.
The invasive RNA makes its way to the cell nucleus to be copied. The duplicate strands then head over to the factory floor to be translated into proteins.
When the cell workers discover the viral RNA, they mistake it for human RNA. That's because they're both made up of the same four nucleic acids: adenine, uracil, cytosine, and guanine. These four bases code for the same amino acids, which in turn fold up to make proteins, essential to viruses and humans alike.
Indeed, the fact that we're all made of the same fundamental molecules means that, very distantly, we're related to the viruses that are trying to kill us.
Next, chemical interactions compel the proteins to self assemble and—BAM!—you've replicated a coronavirus. No sex required.
"No sex?!" you cry, aghast.
Nope. This is essentially cloning, or asexual reproduction, although there is an exception to this rule. Occasionally, viruses can undergo sexual reproduction if a host cell is infected with two related strains. The RNA can mingle to produce hybrid offspring, which is one way that mutant strains form.
Typically, though, the coronavirus is cloned at scale until the host cell is brimming with an army of new viral offspring. Eventually it bursts and dies, having fulfilled its ugly destiny.
The swarm goes on to infect more cells, and the rate of infection scales exponentially. Welcome to the incubation period.
*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 The Immune System Fights Back
After a few days of covert infiltration, the growing viral load triggers an immune response. Two types of white blood cells, called lymphocytes, make their coordinated attack:
- T-cells circulate the body to seek and destroy infected cells. The tell-tale markers: viral antigens left behind on the cell membrane when the virus entered. T-cells bind to these antigens and release cytotoxins to kill the infected cells.
- B cells produce pathogen-specific antibodies which circulate and lock on to the viral particles to neutralise them.
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. Some 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.
In other circumstances, around 50% of patients with severe respiratory distress die while on ventilators. But with COVID-19, that death rate jumps to 80%. This was one unexpected complication of dealing with a novel disease. Now, ventilator use in coronavirus patients has pulled right back.
What happens next just takes the biscuit. Remember those cytokines? They were 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 whole pandemic thing.
How to Make a Coronavirus Vaccine
Every time you encounter a virus, either through immunisation or infection, your immune system makes a targeted response. It produces pathogen-specific antibodies to combat the invasion, then stores them in its antibody library for future reference. This helps it respond faster the next time you encounter the virus.
This is why you only get German Measles once. Your immune system reacts faster on subsequent infections, eliminating the virus before it becomes harmful and your body produces symptoms. So why can you catch the flu more than once?
Some viruses are so prevalent that they mutate often—and your old textbook editions become outdated. The flu strain you picked up two years ago has evolved so much that your textbook is now irrelevant. Viral evolution is many orders of magnitude faster than human evolution, producing a new generation of offspring within hours. That's an arms race our immune systems can't win on their own.
There is a concern COVID-19 will follow the same path. It's unlikely we'll eliminate COVID-19 from the entire human population (which we did with smallpox by adopting an aggressive vaccine strategy) so the disease will continue to circulate and evolve. If COVID circulates in sufficient volumes, the rate of evolution could be so rapid that annually updated vaccines are the only way to prevent routine reinfection.
Types of Vaccines
There are a few approaches to vaccine development, and scientists have gotten innovative under the pressure of the coronavirus pandemic.
- Entire Vaccines take two forms. "Live attenuated vaccines" like BCG and chickenpox use a weakened form of the entire virus to produce an immune response. They don't usually cause disease, but people with poor immune systems can develop a weak infection. "Inactivated/dead vaccines" like influenza and polio require multiple doses to generate an immune response—but they can't cause disease in the recipient.
- Fragment Vaccines or "subunit vaccines" like meningitis B and HPV strip down the active ingredient to key fragments of the virus. They target proteins or sugar molecules: biological markers for your immune system to identify without being exposed to the entire pathogen.
- Genetic Vaccines or "nucleic-acid based vaccines" are a cutting-edge type of vaccine which introduce fragments of viral RNA into the body. A nucleic-acid vaccine for HIV is in the clinical evaluation stage, while several RNA-based COVID-19 vaccines were fast-tracked in 2020. Vaccinated cells use the genetic strings to replicate key fragments of the virus, thereby training up your immune system without exposure to the entire virus.
Let's now look at the process of making an RNA vaccine against COVID-19 and how it progressed through clinical safety trials.
How Do Coronavirus Vaccines Work?
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 just 30,000 nucleotides long, making up just 15 genes. For comparison, humans have 3 billion nucleotides which make up 30,000 genes.
An initial genetic analysis of COVID-19 revealed it's an 89% match to the SARS virus which jumped from bats to humans in 2002. This finding prompted suspicion that COVID arose from a lab in Wuhan which was studying genetically modified versions of SARS. But correlation doesn't equal causation. COVID-19 is a closer match to other coronaviruses circulating in the wild which have not yet jumped the species barrier. It's a 92% match to coronavirus in pangolins, and a 96% match to coronavirus in bats.
From the complete COVID-19 genome, the Texas team inferred which genes code for the spike protein. They injected the spike genes into mammalian cells in the lab and, being agreeable chaps, the cells translated them to produce spikes for analysis. The team then used cryo-electron microscopy to create a 3D molecular map of the protein spike.
Here's a simplified version of their results. The colour coding reveals how the genetic sequence relates to various proteins that make up the spike. These proteins fold together to form a specific functional shape: the key which fits the biological lock embedded in your cells.
This level of analysis was critical to developing a nucleic-acid based COVID vaccine, chosen because it strips everything down to the bare essentials. Without introducing the entire virus, it eliminates the risk of causing COVID-19 in recipients. And without needing to grow viruses in the lab, it speeds up the vaccine production process.
It means that vaccine developers like Moderna, Pfizer, and BioNTech only produce viral RNA fragments—the spike source code—and your body does the work of converting that into spike proteins. Peak levels of spike production occur 24-48 hours later and are sustained over a few days. When the vaccinated cells die, the viral fragments spill out and your immune system responds.
The "m" in mRNA vaccine stands for messenger. It's a way of distinguishing the type of RNA at play in different parts of the replication process. mRNA is newly synthesised genetic material which travels from the cell nucleus to the ribosomes which translate it into amino acids.
The Downsides of Genetic Vaccines
When it's outside the body, mRNA is sensitive to temperature and is at risk of breaking down. The coronavirus vaccine by Pfizer-BioNTech needs to be stored at -70°C (-94°F), and degrades within five days in a standard freezer at 0°C (-32°F).
Fortunately, science has a solution for us. The mRNA can be modified and cocooned at the molecular level to reduce its sensitivity to temperature. The Moderna vaccine uses such solutions, allowing doses to be stored in standard freezers for up to six months. This breakthrough overcomes huge logistical problems associated with distribution and ensures fewer COVID-19 vaccines go to waste.
Another downside to nucleic-acid based vaccines is the need for repeated dosing. Although they're the most labour-intensive to produce and come with a risk of disease, live vaccines stimulate the strongest immune response in most people. Partial vaccines and genetic vaccines comes with fewer risks, but not all recipients develop sufficient immunity after just one dose. Currently, COVID mRNA vaccines require a second dose after 21 days.
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 short-lived immunity is a poor allocation of resources against the ticking clock of a rising death toll.
Here's a summary 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 groups.
- Phase Two Trials use hundreds of healthy human participants to show 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) may be explored.
- Phase Three Trials involve thousands of human participants to test the vaccine at scale. Toxicity, efficacy, and serious adverse events are monitored. The UK's 1Day Sooner campaign sought Phase Three participants to be vaccinated and then, somewhat controversially, actively infected with COVID to speed up the trial.
- FDA Approval sees all the clinical data undergo review by an expert panel. If all the safety criteria are met, the FDA approves the vaccine for general use in the community.
- Phase Four Trials examine after-market data where long-term immunity, adverse events, and drug interactions are monitored. This continues for years.
The clinical trial process is inherently risky because it introduces novel drugs, vaccines, and medical devices into humans for the first time. Initial testing on non-human animals mitigates some of the risk, but ultimately, the only way we can know how a drug works in humans is to test it in humans.
Here's an illustration of that process going wrong in a Phase One drug trial that took place in London in 2006.
A coronavirus vaccine isn't the only pharmaceutical player in this pandemic. At the treatment level, doctors on the front line are exploring new coronavirus therapies, including the use of existing FDA-approved drug combinations and the antibody-rich blood of COVID-19 survivors.
However, in terms of prevention, achieving herd immunity with a safe and effective coronavirus vaccine is the only way to reduce infection rates, stall the evolution of the virus, and slow the runaway death count.
It's not yet known what rate of vaccine uptake will give us herd immunity. It's heavily dependent on the broader efficacy of the vaccines and the overall rate of transmission of COVID. Initially, experts suggested that vaccinating 60-70% of a population against coronavirus would protect the remainder. Now, there's evidence we may need as much as 90% uptake: a hard pill to swallow in a time when anti-science ideology and vaccine fear propagates large pockets of society.
If you're on the fence about getting a COVID vaccine, my advice is this. At the very least, trust that science is well-intentioned towards the preservation of humanity. But nature? Nature doesn't care if you live or die this year—and the emergence of coronavirus proves just that.