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How you can enhance vaccine manufacturing for the following pandemic

The Covid-19 pandemic is still a threat. The virus is currently affecting India, Brazil and other countries, and new waves may break out in places where the pandemic has been suppressed.

However, there is one major silver lining to the devastation of the past year: a massive advance in vaccine development.

Pfizer / BioNTech, Moderna, Johnson & Johnson and AstraZeneca / Oxford vaccines were made possible by recent innovations in vaccine platform technology. Vaccines, which generally required dead or inactive viruses, took 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) have simplified the process of developing vaccines for new diseases.

What used to take months and years can now take weeks – or less. For example, with the Moderna vaccine, 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 develop a vaccine and quite another to make it on a large scale. This is where the world has stumbled and this is where concerted planning can ensure that we are prepared for the future. If we are to have a better chance of fighting the next pandemic – and there will be another – the US must build on these vaccine technology innovations and make investments to establish permanent facilities to manufacture mRNA and adenovirus vaccines .

The need for such an infrastructure was made clear by this pandemic. Because mRNA and adenovirus technology is so new, government and industry have had to put together the infrastructure to quickly produce millions of vaccines on the fly. The result has been a rush to scale previous fringe manufacturing techniques as quickly as possible – an impressive effort, but one that is still insufficient.

Furthermore, just-in-time manufacturing of vaccines in the cold logic of profit maximization has proven insufficient to meet a global challenge of this magnitude. The US and the international community should work towards a vaccine production system with a lot of scope that can be converted to mass production of various vaccines in the short term.

"We need a response mechanism so that vaccines can be designed and manufactured on a large scale during an infectious disease emergency," said Amesh Adalja, an infectious disease doctor and senior scientist at the Johns Hopkins Center for Health Security. Andy Weber, former Deputy Secretary of Defense for Biological Defense and a member of the Council for Strategic Risks, agrees: "The goal must be to compress the times across the system."

Vaccine facilities that operate 365 days a year and that could be rerouted based on the outbreak to pump different vaccines based on the outbreak would be a tremendous weapon for global public health.

And it would be worth the cost. More than 3.4 million people have died of Covid-19 worldwide. The cost to the world economy is $ 22 trillion. A year-round permanent mRNA vaccine facility could cost as little as $ 10 billion in government spending a year – a rounding error alongside the Biden government's multi-trillion dollar economic and infrastructure plans, and a small fraction of that cost the pandemics would prevent spending.

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

The promise of mRNA and adenovirus vaccines

By 2020, vaccines were largely made using four methods that my colleague Kimberly Mas described in the video above.

The two most common types of vaccines involve either the use of an "attenuated" virus – that is, a virus that has been severely weakened – or an "inactive" virus. Both approaches cause the human immune system to respond by developing antibodies without actually causing a complete infection. An example of the type of attenuated virus is the measles vaccine; The seasonal flu vaccine is usually inactive.

A third type of vaccine only uses 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 that is secreted by a bacterium (in the case of vaccines that target bacteria rather than viruses). The tetanus shot is done using this method.

The problem with these methods is that none of these vaccines can be developed particularly quickly. They require constant experimentation, years of trial and error, before encountering a variant of the pathogen or toxin that was weak enough to avoid bad symptoms in the vaccinated but strong enough to protect themselves from real business.

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 make certain proteins. When you inject mRNA from a pathogen into an organism, its cells produce some of the pathogen's proteins, causing 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, the common cold and pink cause eye viruses as well as harmless viruses such as those used as vectors) instead of mRNA.

These are known as vaccine "platform" technologies because they offer a general approach that can be used to control a wide variety of diseases. Instead of spending years tweaking weakened versions of viruses, researchers can simply sequence the virus, make an mRNA or adenovirus vaccine based on it, and then test that vaccine.

Moderna developed its Covid-19 vaccine over a weekend in January 2020, two months before the pandemic took full effect in the United States. A virologist named Eddie Holmes tweeted the genome of the virus on January 10th. On January 13, Moderna used this genome to develop a vaccine candidate. It took the FDA another 11 months of rigorous testing to allow the vaccine to be used. The adenoviruses didn't develop quite as quickly, but the process wasn't too shabby – AstraZeneca's trials began in April 2020.

This was great news for ending the Covid-19 pandemic. But what lies ahead of us for these platform technologies is really exciting. One reason these vaccines took so long to test is because no mRNA vaccine had been found effective prior to Covid-19. Adenovirus vaccines have had more of a track record, but are also a new innovation.

But now we have several vaccines that suggest these vaccine platforms can work. This suggests that the next time not just coronavirus but other infectious diseases break out, we can develop vaccines much faster.

For example, let's say the year is 2025. H5N1, also known as "avian flu," is transmitted (yes, it is.) Via the air either naturally or due to an accident in one of the laboratories currently trying to get it into the air a real thing that people are doing for some reason). If this had happened during the avian flu scare in the mid-1980s, vaccine development could have taken years. With Covid-19 experience, laboratories will be able to quickly sequence the genome of the airborne strain and develop mRNA and adenovirus candidates by 2025.

But then comes the hard part.

Why the world wasn't making mRNA and adenovirus vaccines fast enough

The speed of vaccine development enabled by mRNA and adenovirus platforms is pretty wonderful. However, the situation is more complicated than the hopeful story above suggests. Keep in mind that the Moderna vaccine developed in January 2020 wasn't approved by the FDA until December 2020.

Such a delay is inevitable and desirable. There is a potential for side effects from untested vaccines, and you'll want to do basic safety and efficacy tests before they are used in massive amounts around the world. We can speed up the vaccine testing process in future pandemics using techniques such as human challenge testing and compressing testing phases, but there will always be some delay between vaccine formulation and approval.

Where there is more room for improvement is the period between the vaccines' approval (December 2020) and when they became so numerous that any adult in the US who wanted one could get one (late April 2021) . That's "only" a few months, but between December 11th (when the Pfizer / BioNTech vaccine received emergency approval) and April 19th (when the Biden government announced that all adults were eligible for vaccination in Question come) 268,632 Americans died of Covid-19. A more plentiful supply of vaccines could have shaved tens of thousands, if not hundreds of thousands, of deaths from it earlier.

Why didn't we have a larger supply? Much of this is not due to intellectual property concerns, which have generated a lot of ink and controversy. As Rebecca Heilweil from Recode explains, there are technical bottlenecks that make it difficult to boost the production of mRNA vaccines:

mRNA cannot simply be injected into the body on its own. It is too fragile and would be destroyed. This is why vaccine researchers use lipid nanoparticles to protect the mRNA molecules on their way through the human body.

Making lipid nanoparticles on a scale that could compete with the demand for Covid-19 vaccines is not that straightforward, especially while the pandemic is still ongoing. A challenge for vaccine manufacturers is to find specific ingredients for lipid nanoparticles.

In particular, the manufacturers of Covid-19 vaccines are looking for a special type of charged lipid, ionizable cationic lipids, which essentially facilitate the entry of the mRNA into the cell. According to Padma Kodukula, chief business officer of genetics medicine company Precision Nanosystems, which is working on mRNA and lipid nanoparticle technology, these ionizable cationic lipids are synthetically produced in an incredibly complex process and can take between 14 and 20 steps.

In addition to making these elusive lipids, vaccine manufacturers must carefully combine the lipids with the mRNA for their vaccines. This is a difficult and proprietary process that is essentially done in-house. Science Magazine biologist and blogger Derek Lowe detailed how this works for Pfizer and Moderna:

Converting a mixture of mRNA and a range of lipids into a well-defined mixture of solid nanoparticles with consistent mRNA encapsulation is the difficult part. Moderna appears to be doing this step in-house, although few details are available, and Pfizer / BioNTech appears to be doing this in Kalamazoo, MI and likely Europe as well. Everyone will almost certainly have to use a purpose-built microfluidic device to achieve this. I would be extremely surprised to find that this could be done without such technology. …

These are tailor-made special machines. If you ask other drug companies if they have one, the answer is "of course not". This is nothing like a traditional drug manufacturing process.

Because this is all so new, drug companies didn't have anywhere near the capacity to make enough mRNA vaccines for anyone 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.

Similar is the case with the manufacture of adenovirus vaccines, which has a different process but was no less of a bottleneck in the manufacturing phase.

These bottlenecks could also be a problem in the years to come and against future pandemics. Pharmaceutical companies are efficient, for-profit beasts geared towards just-in-time manufacturing and other low-slack, higher-profit technologies. You will not have more mRNA and adenovirus facilities nearby than you need in pandemic times.

"It will be very difficult to convince a company to keep a mothballed facility running," says Adalja. "How can you ensure that a pharmaceutical company's return on investment (ROI) is not affected?"

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

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What a real investment in vaccine infrastructure

So let's reconsider the hypothetical avian flu outbreak in 2025. We have four years to prepare for it. That is enough time to increase the production capacity for mRNA and adenoviruses so that we have a lot of leeway.

But this loophole won't come by itself.

Weber, the former assistant secretary of defense for biological defense, has pushed for what he calls "10 + 10 over 10" to prevent future biological threats. It's essentially a large government investment that could enable the infrastructure needed to achieve full vaccine availability in the U.S. in about a month or two, rather than five months.

The plan provides an additional $ 10 billion per year for the Department of Defense and an additional $ 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 this funding, the government could finance the infrastructure for year-round vaccine manufacturing. There are already several ideas of what this infrastructure could look like. Adalja highlights a proposal from the pharmaceutical company GlaxoSmithKline for 2016 for a "Biopreparedness Organization" (BPO). GSK describes this as “a dedicated, permanent organization operating without profit and loss, focused on the development and development of new vaccines against potential public health threats. The pathogens to be targeted would be selected and prioritized under the guidance of independent public health experts. "

According to GSK's proposal, the BPO would be located in a GSK facility in Rockville, Maryland. In the real world, where GSK doesn't decide everything, the group could be more ecumenical, funded by government, corporate and foundation philanthropy, and other sources, and partner with a variety of university researchers and biomedical companies.

Another option is to increase the capacity of an existing organization like the Coalition for Epidemic Preparedness Innovations (CEPI) launched in 2016 and take ownership of these Slack facilities.

The key is that these facilities need to be active in times when there is no pandemic, otherwise their expertise and preparedness may deteriorate. For example, Weber suggested in an interview on the 80,000-hour podcast and elsewhere that the facilities manufacture cold and flu vaccines in times of no pandemic. Currently, flu vaccines are manufactured months before the flu season, with estimates of what could be the dominant strain of flu. However, MRNA vaccines theoretically allow for faster processing with a more precise targeting of flu variants.

Then, when a much more pressing threat than the flu emerges, mRNA and adenovirus manufacturing facilities can switch to making vaccines for the new threat. They could even manufacture vaccines months before they are approved by the FDA and, if approved, store them in the cold store.

Another idea would be to use the facilities to produce vaccines against endemic tropical diseases and donate them to developing countries. For example, efforts are being made to produce an mRNA vaccine against malaria, a disease that kills around 400,000 people each year, mainly in Africa. If such vaccines prove effective, and U.S. government-funded facilities continuously produce them in times of no pandemic, that would be thousands of lives saved in the developing world and the U.S. dramatically better prepared for the next pandemic.

The key, however, is funding. "It will depend on the funds," Nicolette Louissaint, executive director of Healthcare Ready and 2014 Ebola Response Veteran, told me. "If we can't find ways to ensure this level of readiness investment is sustained in our post-Covid world we will find ourselves at the next pandemic or disaster event and have to invest a lot in this capacity. "

Pharmaceutical companies will not be that big on their own, and there is no guarantee that the government will fund them adequately without pressure. In 2020 – during the pandemic – the Trump administration cut the DOD's chemical and bio-defense programs by 10 percent, with much of the cuts going to the vaccine component of the budget. To get this vision going, the US must not only reverse such cuts, it will have to spend much more, commensurate with Weber's $ 20 billion a year proposal.

That is what President Biden and his Democratic allies in Congress could achieve if they add this type of funding to their infrastructure package. But they have to make a positive decision to make preventing the next pandemic a priority.

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