We’ll need extraordinary measures to produce a Covid-19 vaccine

We’ll need extraordinary measures to produce a Covid-19 vaccine
Image: Carlo Cadenas for Quartz
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Now that the global pandemic is in its second month, municipalities and countries are considering ways they could possibly return to business as usual while avoiding secondary and tertiary outbreaks. As they mull over these plans, they’re eying a key development in public health: vaccines.

Already, vaccine developers, who consist of non-profit research groups, universities, and traditional drug companies, have entered the race at an unprecedented speed. Best-case scenarios cited by Anthony Fauci, the director of the US National Institute of Allergy and Infectious Diseases, estimate that the world could have a vaccine in 18 months.

In the vaccine development world, that’s essentially breakneck speed. Normally, that process takes a decade or longer, from the start of research to a product that can be administered in a doctor’s office or a pharmacy.

At the time of writing, there are over 120 candidates making their way through some sort of testing. Eight have already reached early safety trials in people. Though news articles have already begun speculating which of these candidates may “win” the race or “be first,” it’s unlikely that the process will produce a single winner.

In order to meet the demand for a vaccine that is truly global, researchers will need to use everything at their disposal. And that probably means we’ll need more than one kind of vaccine.

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What’s in a vaccine

In general, vaccines all have the same job: to familiarize the body with a pathogen that it hasn’t yet encountered. B cells, which are part of the immune system, build up specific antibodies against the pathogen. That way, if an infection  does show up in the future, the antibodies are ready to attack it. They can fight off the infection before it has a chance to make us sick, or at the very least speed up the recovery process.

This requires a little molecular catfishing—which products like ordinary drugs can’t do on their own. “[Vaccines are] really a biological product. They come from living organisms,” says Laetitia Bigger, the director of vaccines policy at the International Federation of Pharmaceutical Manufacturers and Associations.

Broadly speaking, however, there are three kinds of platforms, or forms, that vaccines against viruses can take: inactivated or weakened virus vaccines, subunit vaccines, and nucleic acid vaccines.

Inactivated or weakened virus vaccines, like the one used for chickenpox and some versions of  the flu vaccine, are actually just copies of the virus that have been genetically or physically modified (with the help of heat or toxic substances like formaldehyde) to cause only a mild infection, or none at all. The benefit of this kind of vaccine is that it’s the closest to an actual infection, meaning the body is able to build up a strong antibody defense that lasts for several years.

But there’s a major risk with these kinds of vaccines. “The worst thing that could happen is if the virus reverts and becomes activated,” says Malcolm Duthie, professor in the department of global health at the University of Washington. This risk is heightened for people who are already immunocompromised. Developing these kinds of vaccines requires specific facilities with strict safety precautions in place.

Viruses are essentially non-living parasites, and they can’t multiply outside of another biological host; growing billions of copies of viruses for these vaccines has to be done in human cell lines. Therefore, anyone working on these vaccines needs intensive protective equipment that keeps them safe from any of the cultured viruses, the chemicals used to weaken them, and also protects the cultures from outside contamination.

Safety concerns mean this kind of vaccine platform is not always the most attractive candidate for researchers and companies to investigate. Currently, only nine of the Covid-19 vaccines in development take this approach.

Subunit vaccines, which make up the majority of Covid-19 vaccine candidates, work differently. Instead of using a knocked-out copy of an active virus, these vaccines are composed of specific proteins found on the virus or bacteria. Tetanus, HPV, and pneumonia vaccines are all subunit vaccines. For SARS-CoV-2, developers are looking to recreate the spike protein (S-protein for short) that adorns the virus’ shell and opens human cells for infection. The hope is that this protein on its own is enough of a prompt for B-cells to make antibodies—and it doesn’t carry the risk of an actual infection.

Subunit vaccines rely on other living organisms to produce the target proteins. Usually, scientists will use a genetically modified strain of bacteria like E. Coli or fungus like yeast to produce billions of copies of the desired proteins, a process that requires huge vats for fermentation. Think beer brewing, but with bigger equipment—vats that contain thousands of liters of trillions of microbes, nutrients, and the proteins they produce. Once scientists have amassed sufficient amounts of these proteins, they purify them through a filtration process. This way, only the desired protein makes it into the final vaccine product. And, like weakened vaccines, the environment still has to be completely sterile.

Some subunit vaccines rely on inserting just these proteins into a media that can be injected into the body. Others, like a leading candidate from researchers at Oxford University, involve putting the genetic blueprint to make these proteins into another weak pathogen—like the virus that causes measles or an cold—and having that pathogen make and spread the harmless S-protein around. These vaccines are called vector vaccines and, theoretically, even just the target proteins they produce—along with some other lab-made proteins called adjuvants, molecular footprints that signal to the body to treat the vaccine proteins like an attacker—should prompt the immune system to ramp up antibody production.

These vector vaccines need a combination of equipment, a similarly sterile environment, genetic engineering capabilities, vats and cell culture media to reproduce to grow these genetically-engineered viruses at an enormous scale, and proper equipment to knock them out.

A scientists in a blue lab coat is making
Best case scenario: A race with multiple winners.
Image: Sean Elias/Handout via Reuters

These approaches have all worked against other infectious diseases in the past, which means that there’s a good chance that they could work for SARS-CoV-2. But building the proper facilities and staffing them with employees with sufficient know-how takes between five years and a decade, says Bigger.

Instead of building new facilities to take on these vaccines, it’d be prudent to repurpose existing factory lines to produce these newer products. But not every factory has all the equipment needed to produce these different platforms.

There’s another, potentially faster option that vaccine developers could go for: a vaccine platform called nucleic acid vaccines. This platform takes out the middle step of rejiggering another microbe to make target proteins.

The goal of nucleic acid vaccines is to get a person’s own cells to make the target proteins, rather than another microbe. By introducing genetic material that codes for the same kinds of protein markers in subunit vaccines, scientists could, at least theoretically, get the body to generate its own chemical catfish to trick its immune system.

The advantage of this approach is that nucleic acid vaccines are much faster to develop, Duthie says. As soon as scientists sequence a new virus or bacterial pathogen, they have the code they need to insert into a DNA package to be delivered to our cells. All they would need to do is reproduce the particular genetic sequence en masse. To do this, vaccine manufacturers would need to have supplies of specialized chemicals and protein building blocks to build the genetic material from scratch, and machines called thermal cyclers to piece them all together.

The only problem is, this type of vaccine has never been approved before. Scientists have considered them for a potential universal flu vaccine because they’d be so easy to make and refine but they never came to fruition. “To date, the immune responses have been fairly weak with these vaccines,” Duthie says, which means that those who received those vaccines didn’t develop immunological protection against these viruses.

Currently, over 20 SARS-CoV-2 vaccine candidates in the pool use some form of the nucleic acid platform approach; one of them, produced by the small Cambridge, Massachusetts-based biotech company Moderna, was the first to move on to safety clinical trials last month. The company also received nearly half a million dollars from the US federal government to scale up production and support more clinical testing down the line.

If the gamble pays off, it’d be huge not just for Covid-19, but for all future pandemics. Figuring out how to make sure that DNA- or mRNA-based vaccines protect against future infections would drastically speed up the production time for vaccines against other novel pathogens. But even if this tactic works for SARS-CoV-2—a big “if” that will take months to discern—there’s still a question of how to produce enough doses of the vaccine and get it to everyone that needs it.

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From the lab to the world

That 12 to 18-month figure in which experts like Fauci predict we could have a vaccine doesn’t include how long it will take to manufacture all of those new vaccines and distribute them globally. How long that will take depends more on what kind of vaccines ultimately prove safe and effective against SARS-CoV-2.

For routine vaccines like the flu, manufacturers have figured out how to regularly roll out slightly modified vaccines twice per year (once for the northern hemisphere flu season, and once for the southern). Researchers at the World Health Organization evaluate all the evidence of possible flu strains and decide which ones vaccines manufacturers should make. For a novel virus hitting the entire globe at once, there’s no time to build entirely new factories to meet global demand. “We’re talking about scales of vaccines that haven’t been done before,” Duthie says. “When we start talking about doses [for any vaccine], 10 million was regarded as a lot. Now we’re sticking a ‘b’ on that figure.”

Duthie is also the vice president of Host Directed Therapeutics Bio Corp, a small Seattle-based startup that has also entered the Covid-19 vaccine race. His team’s approach is a hybrid, like the Oxford scientists’ approach: They’re inserting bits of SARS-CoV-2’s genetic material into parts of a non-replicating viral vector—essentially, biological bits that look like another virus, to help bits of SARS genetic material enter our cells. So far, they’re still in the animal testing stage of development, but they’ve spoken with several drug manufacturing companies to see how they could scale up production if they ever need to.

Each of the three broad platforms of vaccines puts different stressors on manufacturing plants. Without enough plants that can handle these different stressors, a vaccine can’t reach the public. Realistically, when vaccines start to show efficacy in human trials, existing drug manufacturing plants will have to repurpose their equipment to meet new needs. To truly meet global demand, several kinds of vaccines will have to be developed at once. Each factory can specialize in the vaccine type it has equipment for. That’s why it’s critical that research continues across multiple types of vaccines and hybrids.

The more options manufacturers have, the faster they produce any kind of vaccine for Covid-19.