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A blueprint to vaccinate the world

March 26, 2021

Why we need to vaccinate the world

To a citizen of a rich country, it may feel that the Covid vaccination program is going fast. By summer, it’s reasonable to expect that more than 75% of the adult population of the USA and UK will have had a first dose of the vaccine. The EU, Japan and other developed nations will be not far behind; most likely they will reach that milestone in the autumn.

But this is not fast enough. Billions of people will still be left unprotected, mainly in the developing world. India and China have made impressive strides, but it is unlikely that the whole world will have been vaccinated until the end of 2022 – and even that is optimistic.

This is too slow; much too slow. We need to speed the process up, enormously. The costs and the risks are too great.

here is an obvious humanitarian cost. Already, more than 2 million people are dead, with more dying each hour; on top of that, there have been at least 100 million confirmed cases, many of them causing severe, lasting illness.

This is worsened by economic damage. The International Monetary Fund estimates that the cost of the pandemic is $28 trillion. Even medium-sized economies, such as Britain or France, are losing more than $1bn every day that it continues. Nobel-prize winner Michael Kremer estimates that every month that we shorten the pandemic is worth $500bn. It is worth spending billions of dollars just to speed up our recovery by a single day.

Most alarmingly of all, as long as the virus is still out there, it is still mutating. We have warned for months of this threat, and it is now obvious that the virus is getting better at evading vaccines. Every extra infection is a risk; the billions more infections we will likely see over the next two years are a huge gamble.

The only way to solve this is to accelerate our plan to vaccinate the world.

How do we vaccinate the world?

We have to do two things:

1) Make vaccines for every person in the world – around 15 – 20 billion doses with wastage – and distribute them.

If we’re not fast enough to prevent major mutations, we’ll need to vaccinate the world all over again to tackle new strains, which will mean rapidly making and distributing billions of doses again. Even if we do prevent major mutations, we need to be ready with billions of doses because if immunity fades after a year or two, we’ll need to continue vaccinating.

An annual program to vaccinate billions is possible:

We do it already with the flu. Just as with flu, we need to be ready to develop new vaccines every year, and distribute enough to vaccinate the world. It will need a larger-scale program – we give about 1.5 billion people the flu vaccine per year; this would be several times more – but it’s possible to do that.

Scaling up vaccination capacity will have knock-on benefits: it will give us the infrastructure to tackle future pandemics, as well as this one. Future pandemics, especially flu pandemics, are a much bigger threat. While seasonal flu is generally milder than Covid, new strains might not be, and flu mutates much faster, making it harder to contain. Extra weapons to fight flu would be of huge value.

So how do we actually make enough vaccine?

We need to address three major roadblocks:

1) Vaccine Manufacturing Capacity

2) Supply Chains

3) Next Generation Vaccines

Vaccine Manufacturing Capacity

The challenge

Producing enough vaccine, quickly enough, is an under-appreciated challenge. Even if every manufacturer delivered on their projections, most calculations predict that it will take two years to vaccinate the planet.
Unfortunately, this may be too optimistic. Industry analysts Airfinity suggest that many vaccine factories are running well behind schedule.

There’s a further challenge: the risk of vaccine nationalism. It will be hard to get countries to share their vaccines equitably with other countries that have less, so the ideal vaccine strategy has to include vaccine production sites distributed around the world.

Airfinity production estimates
Airfinity estimate that every major vaccine factory globally is behind schedule.

The solution

Right now, there are only four messenger RNA vaccine factories in the world, all of them in either the USA or the European Union. Others are being built, but on the current trajectory that number may only double by the end of 2021. To defeat Covid, we need a dramatic global expansion of messenger RNA capacity.

We propose a network of seven RNA vaccine factories capable of vaccinating the entire human population quickly. They would be created by building, or converting, pharma-grade manufacturing plants. These factories should be distributed across the world so that most of the world’s population lives within a few days’ travel of at least one.

A global vaccine network would bring several advantages:

– Greater volume.

– Reduced risk should anything happen to one site; fewer eggs in one basket. In recent months, major vaccine sites have been threatened by fire and floods. The world almost lost millions of doses of vaccine, which we could ill afford. The more factories there are, the more resilient we are to the loss of one.

– Interchangeable inputs – if any factory has a problem sourcing or making a vaccine component (for instance, the nucleotides that make up the active mRNA ingredient), then they can be sourced from another site.

– Reduced incentives for vaccine nationalism. By creating a worldwide network we both reduce the national pressure on vaccine deliveries, and encourage countries to understand that their deliveries rely on a free flow of trade.

These plants would be built to be interchangeable, and would make most of their own raw materials, only importing the most specialised ingredients.

At GreenLight we can already manufacture many of the key ingredients for an RNA vaccine from yeast, sugar and water. We, and other biologics companies should be able to make a replicable process for virtually all ingredients in the next few months.

Compared to most vaccine factories, these are cheap: We estimate $200 million each. The world loses that much money to the pandemic in less than an hour, so the costs are negligible. We think they should be built within existing pharmaceutical production facilities which carry out microbial fermentation; there are many such sites in the developing world. With a priority focus it would likely take nine to twelve months to build a facility capable of producing enough doses for 1 billion people a year.

Supply chains

The challenge

One year ago, messenger RNA was produced only in labs. Since then we have been moving to make billions of doses of vaccine. So it’s not surprising that supply- chain challenges already seem to be causing delays in vaccine production.

That has created a challenge sourcing enough ingredients, in particular:

– DNA templates

– Enzymes that assemble the RNA strand

– Pharma-grade nucleotides, the building blocks of RNA

– Capping agents, which stop RNA degradation by the human body, and make the RNA more effective

– Lipid nanoparticles (LNPs), the packaging that delivers the RNA into your cells

– Fill and finish is backlogged

Of those six, the three challenges we see are supplies of nucleotides, lipid nanoparticles and capping agents. Suppliers of all these ingredients are trying to scale up their production quickly, far beyond what they previously made.

Nucleotides are widely made for food, but there are very few producers (e.g. Roche) who make them to pharmaceutical grade. At GreenLight we make our own, using yeast as the main ingredient.

There are relatively few LNP producers – for instance, we believe there are only two in Europe. This has already led to difficulties. The Wall Street Journal has reported that ‘Pfizer and its partners incurred a three- week delay securing enough raw materials to make the lipid nanoparticle’.
Finally, capping agents. There are very few capping agent suppliers – in fact for chemical capping there is only one supplier, Trilink. There are a few more for enzyme caps.

Crucially, the supply of the different ingredients are not independent problems. For instance, better LNPs can mean that less mRNA is needed for the vaccine; so if we can reduce the quantity of nucleotides needed if we improve our choice of LNP, or, conversely, if we can produce RNA more easily, we will be less constrained in our choice of LNP supply.

The solution

1) Some companies may have already solved these problems in-house. For instance, GreenLight Biosciences can make its own pharma-
grade nucleotides.

2) Suppliers can more easily scale up when they have a predictable demand. Knowing that they need to supply the ingredients for 15 billion doses, not 2 billion, as currently planned, will allow suppliers to plan.

3) Supplies can more easily be moved to where they are needed.

Our prediction, going from our experience and the experience of our friends in the industry, is that many of the supply chain challenges can be fixed with a year of collaboration.

Next generation vaccines

The challenge

Innovation by the RNA industry has been very impressive. But we need to keep on innovating, to solve two big challenges.

First, we need to adapt our vaccines to keep ahead of the virus as it mutates. All vaccine developers, including GreenLight, are adapting their vaccines to new variants. Luckily messenger RNA, as a platform technology, is quickly adapted.

Secondly, the first generation of RNA vaccines has technical challenges which make it harder to provide in adequate quantities. Those challenges are cold-chain distribution, a two-dose regime, and high prices.

The solution

We need to keep improving and adapting our vaccines to deal with these challenges. Countries with weak health infrastructures need single- shot vaccines with greater thermal and physical stability.

A single-shot vaccine will make compliance more effective. The USA struggles to get compliance with multi-dose vaccines. One review of multi-dose vaccine programmes found that as little as 40% of patients completed them. This problem will be even worse in countries with weaker health systems – which are often the places that struggle most to control Covid, as we have tragically seen in Brazil.

Injected vaccines are also a barrier; ultimately, a nasal vaccine might be the ideal solution.

We need to develop a vaccine that can be delivered at regular refrigeration temperature. While RNA vaccines so far have had to be stored at minus 20 degrees, this is not inherent to the technology. For instance Curevac’s vaccine, currently in stage III trials, keeps in a fridge for up to three months.

Finally, costs must come down. RNA vaccines, at $10-40 per dose, are significantly more expensive than the cheapest alternative vaccines, currently the Oxford/AstraZeneca at around $3-5 per dose. Again this is solvable: scaling up production and improving technology, including easing the cold-chain issue, should naturally bring prices down. Our projections are that the RNA industry should be competitive with other types of vaccines within the year

Conclusion

The last year has been a showcase for the power of science and of human ingenuity. To go from discovering a new virus to getting a vaccine for that virus into millions of arms within a year is extraordinary, when the normal process takes a decade or more.

But we are not competing against our own expectations – we are competing against the virus. Even this astonishing, unprecedented effort might not be enough, if we do not vaccinate enough people fast enough to suppress the pandemic.

Luckily, there are simple things that we can do. Building the seven factories we envisage could scale up production enough to dramatically change the speed of rollout; and the cost of each would be negligible, compared to the cost of the pandemic itself. Improving vaccine technologies and supply chains would make it easier to get into people’s arms in developing nations much faster.

None of this is insurmountable or even especially technologically challenging, and mRNA vaccine technology is ideally suited for the task.

With political will and a vanishingly small amount of up-front cash, we can see a return to normalcy