Inside the global scramble to build and deliver COVID vaccines

So, we have our vaccine formulated. Is that the end of the manufacturing process? Not quite. We now move to what’s called fill-and-finish, which means getting the formulated vaccines into the containers, usually vials, but sometimes prefilled syringes or blow- fill-seal mechanisms for vaccines packaged in plastic. Some vaccines are lyophilized (or freeze-dried) and made into a powder that helps with long-term stability. Fill-and-finish rarely gets much attention, probably because it seems routine and low-tech compared with the science that comes before. But fill-and-finish is often the key to the entire enterprise, especially if you want to produce large numbers of vaccine doses quickly. 

That’s because, while it sounds simple, most small vaccine manufacturers simply don’t do it. They don’t have the facilities, the staff, or the desire. So, they tend to outsource fill-and-finish jobs to a limited number of specialist contract companies, which are usually booked up for months, and so rarely sit idle waiting for a global pandemic.

Vaccine manufacturing is tough enough for vaccines that have been produced before. It’s still a big ask to get each of the steps right every time. But because COVID-19 was a new disease (although we had experience with other coronaviruses, which was lucky, as some of the vaccine science had already been worked out) and the vaccines we were going to need had not been developed before, much less manufactured on the kind of scale we were going to require, we knew that manufacturers were going to have to invest serious money to build the production lines, work out the vaccine formulation, and commit to huge, new fill-and-finish contracts. And to make enough vaccine quickly enough to fight the pandemic, they would need to make these investments at risk— before they had a working, safe vaccine approved and ready to go.

Within a few months of the COVID-19 outbreak, there were dozens of vaccine candidates being developed, which used all the different established mechanisms for developing vaccines.

But many were taking newer, and in some cases completely novel, approaches. These vaccines didn’t rely on using whole viruses to stimulate the immune system; instead, they tried to do the same job using just a small piece. This is seen as safer than using whole viruses, but it makes the manufacturing job more complicated. Many companies, for example, thought they could make COVID-19 vaccines based around viral proteins, such as those the virus uses to infect cells (so-called spike proteins). The original, even most optimistic estimates guessed that it would be 18 months to two years before vaccines would be available—and in small numbers; but because the science of a stabilized prefusion spike as an antigen had been proven for other coronaviruses, which was itself an advance in vaccinology, many different groups used this technology, leading to a much higher success rate than in standard vaccine development. Such subunit vaccines tend to not produce as strong an immune response as whole viruses, so more effort is needed to find the right adjuvant additives, and thus the vaccine formulation.

The most complicated vaccines developed against COVID-19 were mRNA vaccines, which introduced new complexities related to formulation and delivery, but were also a novel class of vaccines. These take the vaccine a step further away from the actual virus by injecting people with a strand of genetic material that allows their own cells to make a piece of the spike protein, which then triggers the immune response.

The manufacturing of mRNA vaccines offered some serious advantages over conventional production techniques. These vaccines were the first not to rely on living cells—no more eggs or cell lines!—because the mRNA strands could be synthesized from reagents and enzymes in a lab, and this would speed things up significantly. Also, they could be made from the published genetic sequences, so no biological material needed to be transported. But they also looked—at least initially—to be a real nightmare to formulate and had challenges in stability.

It wasn’t enough to inject them into muscle tissue, as we do with conventional vaccines, and then rely on circulating immune cells to find them and trigger the protective response. Because these new vaccines needed to borrow the cell machinery of the person being vaccinated (to produce the viral protein), the companies needed a way to get the mRNA strands into enough of the individual muscle cells, after the vaccine was injected. And human cells have evolved to be fussy about what they allow inside.

To get around that, and into the cells, the mRNA strands needed to be coated in a fatty skin. Called lipid nanoparticles, their creation is a laborious skill that depends on special chemicals and numerous steps. And even once the lipid nanoparticles were available, companies needed to invest in specialized equipment that could reliably and precisely pump and squirt miniscule volumes of liquid around to get the mRNA inside or cleverly have the particle form around the mRNA itself. Although mRNA vaccines were new and had been hard to develop, they are incredibly fast to produce and ended up being the most commonly used COVID-19 vaccines in high-income countries—and, as we will see, by COVAX.

The process of manufacturing vaccines can be temperamental, unstable, and unpredictable. But that’s nothing compared with how people can behave. Faced with new discoveries—and amplified by the stress of a pandemic—they sometimes retreat into fear of the unknown or into the latest conspiracy theories. And even when people understand how important, and how safe, vaccines are, getting doses to the people who need them requires mass organization to produce the vaccine, create the systems to deliver them, develop messages to counter the inevitable misinformation, monitor side effects, find ways to reach the most marginalized and those at highest risk, and share the know-how so that vaccines can be made at scale across the world."

Reprinted from Fair Doses: An Insider's Story of the Pandemic and the Global Fight for Vaccine Equity by Seth Berkley, MD, courtesy of University of California Press. Copyright 2025.