How to supercharge vaccine production for the next pandemic

To defeat the next pandemic, the world needs year-round facilities pumping out vaccines for threats old and new.

The Covid-19 pandemic is still a threat. The virus is currently walloping India, Brazil, and other countries, and new waves could yet erupt in places where the pandemic had been suppressed.

But the devastation of the past year has come with one big silver lining: a massive leap forward in vaccine development.

The Pfizer/BioNTech, Moderna, Johnson & Johnson, and AstraZeneca/Oxford vaccines were made possible by recent innovations in vaccine platform technology. Vaccines, which generally required the use of dead or inactive viruses, used to take years to develop. The new generation of mRNA vaccines (in the case of Pfizer and Moderna) and adenovirus vaccines (in the case of Johnson & Johnson and AstraZeneca) has simplified the process of developing vaccines for new diseases.

What used to take months and years can now take weeks — or less. In the case of the Moderna vaccine, for instance, it took three days. The “recipe” for the Moderna vaccine was developed in January 2020, before Covid-19 even flared up in the US.

But it’s one thing to come up with a vaccine, and entirely something else to manufacture it on a mass scale. That’s where the world has stumbled and where concerted planning now can make sure we’re prepared for the future. If we’re to have a better chance to fight the next pandemic — and there will be a next one — the US needs to build on these vaccine tech innovations and make investments to establish permanent facilities producing mRNA and adenovirus vaccines.

The need for such infrastructure has been made clear by this pandemic. Because mRNA and adenovirus tech is so new, the government and industry have had to put together the infrastructure to rapidly produce millions of vaccines on the fly. The result has been a rush to scale up previously fringe manufacturing techniques as quickly as possible — an impressive effort, but one that’s still fallen short of need.

Moreover, in the cold logic of profit-maximizing, just-in-time manufacture of vaccines has proven to be inadequate to meet a global challenge of this magnitude. A vaccine production system with plenty of slack, one that can be pivoted to mass production of different vaccines at a moment’s notice, is what the US and the international community should be building toward.

“We need a ready response mechanism for vaccines to be developed and manufactured at a grand scale during any infectious disease emergency,” Amesh Adalja, an infectious disease physician and senior scholar at the Johns Hopkins Center for Health Security, says. Andy Weber, a former assistant secretary of defense for biodefense and fellow at the Council on Strategic Risks, concurs: “The goal needs to be to compress the times along the whole system.”

Vaccine facilities that are up and running 365 days a year — and that could be redirected to pump out different vaccines depending on the outbreak — would be a tremendous weapon for global public health.

And the cost would be well worth it. More than 3.4 million people around the world have died from Covid-19. The cost to the world economy totals $22 trillion. A plan for permanent mRNA vaccine facilities that run all year long could cost as little as tens of billions of dollars in government spending a year — a rounding error next to the Biden administration’s multitrillion-dollar stimulus and infrastructure plans, and a small fraction of the cost of the pandemics the spending would prevent.

The leap in vaccine development has put us in a better position to fight the next pandemic, but only if we build the infrastructure to do it.

The promise of mRNA and adenovirus vaccines

Until 2020, vaccines were largely produced using four methods, outlined by my colleague Kimberly Mas in the video above.

The two most common types of vaccines involve using either an “attenuated” virus — that is, a virus that has been considerably weakened — or an “inactive” virus. Both approaches prompt the human immune system to respond by developing antibodies, without actually inflicting a full-on infection. An example of the attenuated-virus type is the measles vaccine; the seasonal flu vaccine tends to be the inactive type.

A third type of vaccine uses just a part of a virus; the Hepatitis B vaccine works this way. Finally, a fourth, less common type of vaccine uses a weakened version of a toxin secreted by a bacterium (in the case of vaccines targeting bacteria rather than viruses). The tetanus shot is made with this method.

The problem with these methods is that none of these vaccines could be developed particularly rapidly. They require constant experimentation, years of trial and error, before hitting on a variant of the pathogen or toxin that was weak enough to avoid bad symptoms in the vaccinated but strong enough to protect against the real deal.

mRNA vaccines, the first two commercial examples of which are the Moderna and Pfizer/BioNTech Covid-19 vaccines, work differently. They use synthesized messenger RNA (mRNA), a type of genetic instruction that tells cells how to create specific proteins. If you inject mRNA from a pathogen into an organism, its cells will produce some of the pathogen’s proteins, prompting the organism’s immune system to develop antibodies against the pathogen.

Adenovirus vaccines, like the Johnson & Johnson and AstraZeneca/Oxford Covid-19 vaccines, use a similar principle, but with DNA inserted into a harmless virus carrier (typically “adenoviruses,” a category that includes the viruses that cause the common cold and pink eye as well as harmless viruses of the kind used as vectors) rather than mRNA.

These are known as vaccine “platform” technologies because they provide a generalized approach that can be used to target a lot of different diseases. Instead of spending years tweaking weakened versions of viruses, researchers can simply sequence the virus, produce an mRNA or adenovirus vaccine based on it, and then test that vaccine.

Moderna designed its Covid-19 vaccine over a weekend in January 2020, two months before the pandemic hit full force in the US. A virologist named Eddie Holmes had tweeted out the genome of the virus on January 10; on January 13, Moderna used that genome to develop a vaccine candidate. It took another 11 months of rigorous testing for the FDA to allow the vaccine to be used. The adenoviruses weren’t developed quite as fast, but the process wasn’t too shabby — AstraZeneca’s trials started in April 2020.

This has been great news for ending the Covid-19 pandemic. But it’s what lies ahead for these platform technologies that’s truly exciting. Part of why testing these vaccines took so long is that no mRNA vaccine had even been found effective before Covid-19; adenovirus vaccines had more of a track record, but are similarly a recent innovation.

But now we have several vaccines suggesting these vaccine platforms can work. That suggests we can develop vaccines much more rapidly the next time a major outbreak of not just a coronavirus but other infectious diseases occurs.

Suppose the year is 2025. H5N1, a.k.a. “bird flu,” becomes transmissible via air, either naturally or because of an accident at one of the labs that is currently trying to make it airborne (yes, this is a real thing that people are doing for some reason). If this had happened during the bird flu scare of the mid-aughts, vaccine development could’ve taken years. But because of the Covid-19 experience, labs in 2025 will be able to quickly sequence the airborne strain’s genome and develop mRNA and adenovirus candidates.

But then comes the hard part.

Why we didn’t make mRNA and adenovirus vaccines fast enough

The rapidity of vaccine development enabled by mRNA and adenovirus platforms is fairly miraculous. But the situation is more complicated than the hopeful story above suggests. Recall that the Moderna vaccine, designed in January 2020, wasn’t okayed by the FDA until December 2020.

Some delay like that is inevitable and desirable. There is a chance of bad side effects from untested vaccines, and you want to do basic safety and effectiveness tests before going to massive worldwide deployment. We can speed up the testing process for vaccines in future pandemics using techniques like human challenge trials, and compressing phases of testing, but there will always be some delay between the vaccine’s formulation and its approval.

Where there’s more room for improvement is the period between when the vaccines were approved (December 2020) and when they became plentiful enough that any adult in the US who wanted one could get one (late April 2021). That’s “only” a few months, but between December 11 (when the Pfizer/BioNTech vaccine got an emergency use authorization) and April 19 (when the Biden administration announced all adults would be eligible for vaccination), 268,632 Americans died of Covid-19. A more plentiful vaccine stock earlier on could have shaved tens if not hundreds of thousands of deaths off of that total.

So, why didn’t we have a bigger stockpile? It’s largely not due to intellectual property concerns that have generated a lot of ink and controversy. As Recode’s Rebecca Heilweil explains, there are technical bottlenecks that make mRNA vaccine production hard to ramp up:

mRNA can’t just be injected into the body by itself. It’s too fragile and would be destroyed. That’s why vaccine researchers use lipid nanoparticles to protect the mRNA molecules as they travel through the human body.

Making lipid nanoparticles on a scale that could contend with the demand for Covid-19 vaccines is not so easy, especially while the pandemic is still raging. One challenge vaccine manufacturers face is having to find specialty ingredients for lipid nanoparticles.

In particular, Covid-19 vaccine manufacturers are racing to find a special kind of charged lipid called ionizable cationic lipids, which essentially facilitate the entrance of the mRNA into the cell. These ionizable cationic lipids are made synthetically in what can be an incredibly complex process, and can require between 14 and 20 steps, according to Padma Kodukula, the chief business officer at the genetics medicine company Precision Nanosystems that works on mRNA and lipid nanoparticle technology.

Beyond just producing these difficult-to-produce lipids, vaccine producers have to carefully combine the lipids with the mRNA for their vaccines, a difficult and proprietary process that is essentially done in-house. Derek Lowe, a biologist and blogger at Science magazine, has detailed how this works for Pfizer and Moderna:

Turning a mixture of mRNA and a set of lipids into a well-defined mix of solid nanoparticles with consistent mRNA encapsulation, well, that’s the hard part. Moderna appears to be doing this step in-house, although details are scarce, and Pfizer/BioNTech seems to be doing this in Kalamazoo, MI and probably in Europe as well. Everyone is almost certainly having to use some sort of specially-built microfluidics device to get this to happen — I would be extremely surprised to find that it would be feasible without such technology. …

These will be special-purpose bespoke machines, and if you ask other drug companies if they have one sitting around, the answer will be “Of course not”. This is not anything close to a traditional drug manufacturing process.

Because this is all so new, pharmaceutical companies had nothing close to the necessary capacity to produce enough mRNA vaccines for everyone in the US who wanted one in January. And they still don’t have enough capacity to produce enough for everyone in the world who wants one right now.

It’s a similar story for adenovirus vaccine production, which has a different process but experienced no less a bottleneck at the manufacturing stage.

These bottlenecks could continue to be a problem in the coming years and against future pandemics. Pharmaceutical companies are efficient profit-seeking beasts biased toward just-in-time manufacturing and other low-slack, higher-profit technologies. They’re not going to keep more mRNA and adenoviruses facilities around than they need during non-pandemic times.

“It’s going to be very hard to convince a company to keep a mothballed facility going,” Adalja says. “How are you going to make this something that’s not adverse on ROI [return on investment] for a pharma company?”

This is where a concerted government effort to build and maintain this infrastructure comes in.

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What a real investment in vaccine infrastructure involves

So let’s think about that hypothetical 2025 bird flu outbreak again. We have four years to prepare for it; that is plenty of time to ramp up mRNA and adenovirus manufacturing capacity so that we have plenty of slack.

But that slack won’t arrive naturally.

Weber, the former assistant secretary of defense for biodefense, has pushed for what he dubs a “10 + 10 Over 10” plan to prevent biological threats in the future. It is essentially a big government investment that could enable the kind of infrastructure necessary to have gotten to full vaccine availability in the US in, say, one or two months, not five.

The plan calls for $10 billion in additional annual funding for the Department of Defense, and another $10 billion per year for the Department of Health and Human Services, devoted to anticipating pandemic and other biological risks, for at least 10 years.

With that funding, government could finance the infrastructure for year-round vaccine manufacture. There are already several ideas on what that infrastructure might look like. Adalja highlights a 2016 proposal from the pharmaceutical firm GlaxoSmithKline for a “biopreparedness organization,” or BPO. GSK describes this as “a dedicated, permanent organisation operating on a no-profit, no-loss basis and focused on designing and developing new vaccines against potential public health threats. The pathogens to be targeted would be selected and prioritised with guidance from independent public health experts.”

In GSK’s proposal, the BPO would be based at a GSK facility in Rockville, Maryland. But in the real world where GSK doesn’t decide everything, the group could be more ecumenical, funded by governments, corporate and foundation philanthropy, and other sources, and working with a variety of university researchers and biomedical companies.

Another option is increasing the capacity of an existing organization, like the Coalition for Epidemic Preparedness Innovations (CEPI), launched in 2016, and having it take ownership of these slack facilities.

The key is that these facilities need to be active during non-pandemic times, otherwise their expertise and readiness could deteriorate. Weber, for instance, has proposed in an interview on the 80,000 Hours podcast and elsewhere having the facilities produce common cold and flu vaccines during non-pandemic times. Currently, flu vaccines are produced months ahead of flu season using a guess at what the dominant flu strain might be, but mRNA vaccines theoretically allow faster turnaround, with more precise targeting of flu variants.

Then, if a much more pressing threat than the flu arises, mRNA and adenovirus manufacturing plants can swap to producing vaccines for the new threat. They could even produce vaccines months before they’re approved by the FDA, stockpiling in cold storage in the event of approval.

Another idea would be to use the facilities to produce vaccines for endemic tropical illnesses and donate them to developing countries. There are efforts underway, for instance, to produce an mRNA vaccine for malaria, a disease that kills some 400,000 people every year, primarily in Africa. If such vaccines prove to work, and US government-funded facilities produced them on an ongoing basis in non-pandemic times, the result would be thousands of saved lives in the developing world and a US that is dramatically more prepared for the next pandemic.

The key, though, is funding. It “will come down to appropriations,” Nicolette Louissaint, executive director of the health care supply chain preparedness group Healthcare Ready and a veteran of the 2014 Ebola response, told me. “If we do not find ways to make sure that that level of preparedness investment can be maintained, in whatever our post-Covid world will be, we will find ourselves again at the next pandemic or catastrophic event, having to reinvest in a lot of this capacity.”

Pharmaceutical companies are not going to go this big on their own, and there’s no guarantee that the government will fund them sufficiently without pressure. In 2020 — during the pandemic — the Trump administration cut the DOD’s chemical and biodefense programs by 10 percent, with much of the cuts going to the vaccine component of the budget. To set this vision in motion, the US needs to not just reverse cuts like that but spend much more, in line with Weber’s $20 billion per year proposal.

That’s something President Biden and his Democratic allies in Congress could achieve if they include this kind of funding in his infrastructure package. But they need to make an affirmative choice to prioritize preventing the next pandemic.