麻豆传媒

IN KALAMAZOO, Michigan, millions of vials of a covid-19 vaccine may soon be rolling off production lines. There are still many hurdles to leap before that vaccine 鈥� the candidate from US drug company Pfizer and its German partner BioNTech 鈥� or any other is approved and distributed, but governments, manufacturers and shipping firms around the world have already spent months preparing for what happens next.

That comes down to a simple but easily overlooked fact: a vaccine by itself is useless. 鈥淰accines don鈥檛 save lives,鈥� says at the Immunization Action Coalition in the US. 鈥淰accination does.鈥�

When a covid-19 vaccine is approved, it will trigger a staggeringly complex chain of events. These events must occur in perfect lockstep using a global supply chain that needs to reach even the planet鈥檚 most remote areas 鈥� the same supply chain that left parts of the world in desperate need of things like disposable gloves and protective equipment just months ago.

鈥淭he scale and magnitude of what we鈥檙e talking about doing is just unparalleled,鈥� says director of vaccine delivery at the Bill & Melinda Gates Foundation. The list of potential catastrophes has been keeping Levine up at night for months. But overcoming these logistical challenges is what it will take to end the pandemic. And 鈥渢he key to overcoming complexity is planning and planning early鈥�, says Levine.

Exactly depends on how effective the vaccine is, and how long the immunity it provides lasts (see 鈥�Vaccine front runners鈥� ). , head of Gavi, an international group that promotes vaccine use around the world, puts that figure at 60 per cent. Given we now number 7.7 billion, and most of the vaccine candidates in late-stage trials require at least one booster, that is a staggering 9 billion or so doses.

鈥淭he fact is vaccines don鈥檛 save lives 鈥� vaccination does鈥�

Ramping up production of a newly approved vaccine can take up to a year in normal circumstances, says , a health systems expert at North Carolina State University. This time, pharmaceutical companies began readying mass production lines well in advance of any results from late-stage clinical trials. Pfizer and BioNTech plan to make enough doses to vaccinate 25 million people by the end of 2020, and 630 million people in 2021. The University of Oxford and AstraZeneca had planned to deliver 30 million doses of their vaccine to the UK government by the end of September, but a delay to their trial forced them to .

Making all this vaccine requires a lot of upfront cash, which many countries have provided as a combination of traditional grants and advance purchase orders. These orders give governments the right to buy a given number of doses for a specific price if and when they become available, enabling firms to ensure they will recoup investments in research and manufacturing capacity, says intellectual property specialist at Stanford University in California. Exact details of the agreements, including what money will be paid if a vaccine doesn鈥檛 pan out, haven鈥檛 been made public, but that鈥檚 standard for these contracts, says Ouellette.

According to the US Biomedical Advanced Research and Development Authority (BARDA), the US government has invested $6.5 billion in covid-19 therapeutics and vaccines predominantly as part of , the country鈥檚 effort to deliver 300 million doses of a vaccine, with initial doses available by January 2021. That includes at least $1 billion each to Novavax, the University of Oxford and AstraZeneca, GlaxoSmithKline and Sanofi, and Johnson & Johnson, which owns the pharmaceutical company Janssen. A states that the Massachusetts-based biotech firm could receive as much as $1.5 billion in exchange for 100 million doses if it hits aggressive deadlines. Pfizer and BioNTech have a similar agreement with the US government for up to $1.95 billion for 100 million doses. All told, the US government will own more than .

The UK government , agreeing to buy a total of at set prices from at least six firms.

鈥淭he world has no experience administering a vaccine and a booster on this scale鈥�

For many countries 鈥� though notably not the US 鈥� some of these payments have been made via that allows higher-income countries to pool vaccine purchasing power, while subsidising injections for lower-income nations. The goal is to produce and equitably distribute 2 billion doses of vaccine by the end of 2021.

Some of the specialist products that are critical to vaccine production can be harder to come by. These include a substance derived from horseshoe crab blood that is uniquely sensitive to toxins and so used to detect contaminants in vaccines. This precious substance costs more than $13,000 per litre. There are synthetic alternatives, but they still face regulatory hurdles. So far, suppliers are confident they will meet the surge in demand: the three US providers estimate they can in a single day to run the tests necessary for 5 billion doses of covid-19 vaccine.

Ahead of time

Some of the vaccine candidates 鈥� though currently not any of those using new mRNA technology 鈥� will also require adjuvants, which help improve the immune system鈥檚 response to a vaccine by boosting antibody production. This makes vaccine supplies go further, requiring a smaller dose per person. In May, GlaxoSmithKline announced it had of its AS03 adjuvant for pandemic vaccines.

Once vaccines have been approved and manufactured at scale, the challenge remains to package, ship and administer them to more people and in a shorter period of time than ever before. While supplies like alcohol swabs, gloves, bins for used needles, pallets, plastic wrap and syringes can all be made by a wide array of manufacturers, the scale of the demand may be hard to cope with. BARDA estimates that the US alone will need up to 850 million syringes for covid-19 vaccination. UNICEF has already begun stockpiling 1 billion syringes in warehouses in Denmark and Dubai as part of COVAX, says Robert Matthews, a contracts manager at the UN agency.

One of the challenges UNICEF faces is that vaccines are shipped by air and can arrive almost anywhere on the planet in one to three days. Syringes, being bulkier and with a shelf life of around five years, are typically sent by boat and truck. They can take two to four months to reach their destination.

The aim is to avoid delays by getting syringes closer to where they will ultimately be needed as far in advance as possible, says Matthews. 鈥淭his helps mitigate potential supply risks of lockdowns or export bans or shipping congestion around ports, and enables further distribution much more rapidly than we would otherwise be able to do.鈥� Each year, UNICEF provides 800 million syringes for various vaccination campaigns. It 鈥� 3.2 billion.

Once all of the ingredients are assembled, covid-19 vaccines will be stored and shipped in special glass vials. These are resistant to shattering at temperature extremes and less chemically reactive than standard glass, meaning they are less likely to interact with the vaccine, says Ken Falkowitz at labware manufacturing company DWK Life Sciences.

Earlier this year it was feared that the world would quickly run out of the vials, which are almost exclusively made from borosilicate glass. The main worry is that this glass requires special sand, says Falkowitz, and a breakdown at any point in the chain could bring vaccination efforts to a halt.

Those concerns led to to ramp up production of these vials, which can each hold between two and 20 doses. The world鈥檚 leading borosilicate glass manufacturer, Germany鈥檚 Schott, , and says shipments have already gone out to North America, Europe and Asia. Falkowitz says that DWK Life Sciences recently merged with German glass-maker M眉ller + M眉ller to bring the new firm鈥檚 annual production capacity to 600 million vials. BARDA, for its part, has invested in US firms to produce an additional 284 million glass vials for covid-19 vaccines, including , the firm that makes Pyrex. These measures should be enough to prevent shortages, says Falkowitz.

Once the vials are filled, they will need to be distributed 鈥� and quickly. The ailing airline industry is on standby. The International Air Transport Association has estimated that providing a single dose to everyone on the planet would require enough vaccine to fill .

How they are transported is another challenge: all 12 of the leading vaccine candidates will need to be kept cold to stabilise the sensitive ingredients. Moderna鈥檚 mRNA-1273 will need to be stored at -20掳C, a temperature that can be reached by most household freezers. Pfizer and BioNTech have said that their candidate, also an mRNA vaccine, will need to be far colder: -70掳C. That requires special freezers that can reach -80掳C, the kind used to store things like bacterial cells in labs or sperm in fertility clinics.

Pfizer has designed new insulated, suitcase-sized containers that will be packed with dry ice to maintain temperatures below -70掳C and can keep the vaccine stable for up to 15 days. Each container can hold up to 4875 doses and will need to be refilled with 23 kilograms of dry ice every five days.

But there is reason to hope that mRNA vaccines may not need such a deep freeze. Research by two teams working on vaccines that use this technology but are in early stage trials has revealed that they may be stable for months at 4掳C, the temperature of a standard fridge. That would be a game-changer for distribution (see 鈥淧fizer covid-19 vaccine may not need to be kept at -70掳C after all鈥�).

However cold the requirements, keeping these vaccines at the right temperature is crucial, says , a specialist in operations management at Johns Hopkins University in Maryland. Large shipping companies like UPS and FedEx are already preparing. At some air hubs in the US and Europe, UPS is building freezer farms. Each of the 600 freezers in one of its farms will be able to hold 48,000 doses of vaccine.

Maintaining the cold chain in the air and in warehouses is relatively straightforward, as long as transport companies have the right equipment and a steady supply of electricity. Things get trickier when products are on the road. The World Health Organization has for everything from the way coolers are packed to how to account for airflow inside freezer trucks. But it gets most difficult in the 鈥渓ast mile鈥�, according to Dai. In low and middle-income countries, drivers on motorbikes typically deliver vaccines and other medical products to villages in remote areas.

Unanticipated shortages

This is why vaccine specialist at the University of Witwatersrand in South Africa, is more bullish about the two covid-19 vaccines currently in late-stage trials from Janssen and Novavax. These would be shipped frozen, but manufacturers already know they can be stored at 4掳C.

All of these necessary supplies and arrangements are what the world knows that it needs, says at Healthcare Ready, a US-based non-profit that helps government and hospitals address medical supply chain issues. More worrisome are unanticipated shortages, she says. 鈥淭here are a lot of hypotheticals and you have to plan and prepare for all of them,鈥� says Louissaint.

Having a distributed global supply chain can be an advantage for manufacturers, says Phil Ashton at a UK start-up that uses artificial intelligence to manage supply chains. Mapping out alternatives in advance may be crucial in overcoming inevitable problems. 鈥淵ou need to have the right infrastructure and capacity in place to handle what鈥檚 going to be a relatively short, sharp shock to the supply system,鈥� he says.

The simple fact is, coordinating the administration of a vaccine and booster on a global scale isn鈥檛 something the world has experience with. 鈥淭here鈥檚 no muscle memory to vaccinate people at that scale throughout the world, at levels that are needed to open up society,鈥� says , director of the Yale Institute for Global Health. It is the biggest logistics challenge in history. 鈥淭hat鈥檚 what keeps me up at night. Countries are not ready for this,鈥� says Omer.

There will also be political challenges to overcome, not least the willingness of people to actually get vaccinated (see Heidi Larson interview: How to stop covid-19 vaccine hesitancy). In a , more than 70 per cent said they were likely to get a covid-19 vaccine. But vaccine hesitancy varied widely by location. While 90 per cent of people in China said they would get one, that was the case for only 55 per cent in Russia. 鈥淧eople have to trust the process and believe that their best interest is being considered,鈥� says Marcus Plescia, chief medical officer at the Association of State and Territorial Health Officials, a non-profit US public health organisation.

There may be other issues too. In the UK, for instance, there are concerns that changing trade agreements under Brexit could delay the transit of vaccines or even leave them stranded at the border. There is also the problem of how to ensure access to vaccines for everyone, not just people in wealthy countries, says Rees. That is why the COVAX partnership was launched in June. Whether it will be enough to overcome the influence of remains to be seen. A recent said that the UK has secured enough doses for five injections per person, while Bangladesh only has one dose for every nine people. The US may also wind up with excess vaccine.

However, as this pandemic has shown, we are inextricably connected. This may be to our benefit when it comes to global supply chains. But it will be our undoing if we fail to recognise that countries can鈥檛 go it alone. 鈥淎s long as we leave a region or country without access, the virus will come back,鈥� says Rees.

Keeping cool

The fact that the vaccine developed by Pfizer and BioNTech needs to be stored at -70掳C has raised concerns about its distribution. But it may not need to be kept so cold. Anna Blakney鈥檚 team at Imperial College London found that their mRNA vaccine candidate is stable for months at 4掳C. That is also true of an mRNA candidate from CureVac in T眉bingen, Germany. It should be the case for the Pfizer vaccine too, says Blakney. 鈥淚 guarantee that they are doing the exact same studies.鈥� All three vaccines encase RNA in droplets of fat, called lipid nanoparticles, made by the Canadian firm Acuitas. Company director Thomas Madden says deciding to store the vaccines at -70掳C was due to 鈥渁n abundance of caution鈥�, but that 鈥渢here鈥檚 no technical limit鈥�. Michael le Page