Vaccine science has come a long way since the 18th century, when Edward Jenner used pus from a milkmaid’s sore to stop a child from catching smallpox.1 Since then, various vaccines have been developed, and they have subdued many diseases that used to rampage through helpless populations. Even early and relatively crude vaccines dramatially reduced the number of deaths caused by disease. How might today’s increasingly sophisticated vaccines fare?
These vaccines, which include synthetic, recombinant, and DNA vaccines, embody the latest insights of molecular genetics and related disciplines, but they may fail to realize their full potential. The problem isn’t in research and development, which has progressed quickly. It is, rather, in production, which simply hasn’t kept pace.
Fortunately, there are signs that innovation in vaccine production is shifting into high gear. For example, vaccine manufacturers are beginning to leverage process technology that already benefits the broader biotechnology industry. Like producers of biologics, producers of vaccines must coordinate subprocesses and maintain aseptic conditions. Shared problems may call for common solutions—continuous processing and disposable system components. Also, vaccine-specific innovations, such as the adoption of cell culture–based systems, are finally maturing. Tetanus vaccine, it might be noted, is still made in accordance with processes set out by the World Health Organization (WHO) in the 1950s.2
Vaccine firms, like firms across the biotech industry, want new production methods out of a desire for efficiency. More effective platforms have the potential to reduce the cost of goods and shorten time to market. But there are also other, more vaccine-specific issues driving the search for novel technologies.
“It is essential,” says Nicolas Kressmann, spokesperson for corporate public relations at Sanofi, “that we continue to explore new approaches to prepare for and respond to emerging infectious diseases caused by unpredictable viruses and bacteria, as well as look at ways to improve existing vaccines and develop novel vaccines for priority disease areas like seasonal and pandemic influenza, meningococcal disease, respiratory syncytial virus, and so on.”
Sanofi, though its subsidiary Sanofi Pasteur, is one of the world’s largest vaccine suppliers. Kressmann sees the need to accelerate production in line with growing demand as a major manufacturing innovation driver.
“It takes between 6 and 36 months to produce, package, and deliver high-quality vaccines to those who need them,” he observes. “It includes testing each batch of vaccine at every step of its process, and repeat quality control of batches by different regulatory authorities around the world.
“Vaccine manufacturing is a biological process where a very high level of expertise is required. We need to continually adapt production processes to satisfy evolving regulatory demands, which vary country by country.”
The need for faster production has also been recognized by technology suppliers, says Daria Donati, PhD, director, business development and innovation, GE Healthcare Life Sciences (recently acquired by Danaher). “Speed is paramount when dealing with disease outbreaks,” she says. “There are two critical elements: identifying a suitable antigen to induce a specific immune response, and the capability to make it or its vector available in a short time frame.”
One of GE’s solutions has been to develop what it calls turnkey facilities. The company claims that these complete, out-of-the-box manufacturing platforms reduce production lead times.
Immunization groups, such as UNICEF, the Global Polio Eradication Plan, and the Gates Foundation, are also calling for faster production technologies, says Pierre A. Morgon, PharmD, a member of the board of directors at Univercells. He adds that “increasing awareness about global epidemics and the need for adapted rapid response capabilities, embodied by the Coalition for Epidemic Preparedness Innovations, are increasing market demand for novel sustainable and responsive production models.”
Innovation also gives vaccine firms a chance to reduce costs, says Janice Paquette, head of bioprocessing, segments, process solutions, MilliporeSigma.
“A central part of MilliporeSigma’s mission and corporate responsibility program focuses on finding cost-effective ways to accelerate vaccine development and manufacturing,” she says. “Our approach includes collaborating with leading research institutes to introduce new technologies that will advance the global vaccine industry as a whole.
“We directly support companies in emerging economies by sharing our expertise, helping streamline manufacturing processes, and supporting technology transfers and local facility start-ups.”
In monoclonal antibody (mAb) production, many operations have been standardized. CHO-based expression systems, for example, are used by many developers, and the technologies required to use them are widely available.
Vaccine production has not seen such standardization. “Due to competing alternatives for vaccine processes—such as Vero, Sf9, BHK, yeast, eggs—the vaccine industry has become fragmented and a less attractive space for technology development,” explains Paquette. “Such complexity also makes it hard to leverage cumulative learning, which should be applied across the development pipeline.”
Lack of standardization means higher production costs and, ultimately, higher prices. This is a problem because, to be of maximum benefit, vaccines need to be accessible to as many people as possible.
“Manufacturing technology development by providers often reflects the investment targets and interests of the industry,” Paquette notes. “Due to the complex and slow pace of vaccine commercialization coupled with manufacturing expectations for lower cost of goods, the vaccine manufacturing space is historically not as well catered as mAbs or other biopharmaceuticals.”
But Paquette believes this will change as technologies used in other fields are adopted by vaccine developers. “The recent surge in interest for viral gene therapies is likely to benefit a viral vaccine, as newer platforms are developed for virus production,” she says.
This view is shared by Annelies Onraedt, PhD, marketing director, Pall Biotech, who says manufacturing technology advances in other fields have application in vaccine production.
“As continuous manufacturing approaches are starting to break through in mAb processing, we also see there is much promise for their application in viral vaccine manufacturing,” she notes, “both in cell culture and in downstream processing.
“In the latter case, the application of membrane chromatography together with a continuous multicolumn chromatography approach can help improve throughput. Furthermore, new initiatives—such as the development of novel ligands to address selectivity limitations and enable affinity purification—are emerging. Together with high-surface-area supports, these initiatives should offer further process improvements.”
Which came first: the chicken or the egg? The answer to this famous paradoxical question, as anyone with even a basic grasp of evolutionary biology will tell you, is the egg.3 And eggs also come first in influenza vaccine production, or at least they do at the moment.
Most commercially available influenza vaccines are produced in hen’s eggs.4 Candidate viruses are injected into eggs, allowed to replicate, and then harvested. The viruses are then inactivated, and their antigens are purified and used to make the vaccines.
While this process is effective—it has been used to make influenza vaccines for 70 years—in the past decade, there have been efforts to culture viruses in the petri dish. One of the big concerns is that a pandemic affecting hens may one day limit the supply of eggs.
Although some progress has been made in cell culture–based production,5 the high costs associated with the approach have limited its adoption. But cell culture flu vaccine production is being reassessed, says Morgon from Univercells.
“The recent rise in interest for this technology stemmed from the search for non-egg-dependent influenza vaccine production in case of a pandemic that would decimate the flocks producing the specific-pathogen-free eggs,” he explains. “The level of interest is still high, especially in the United States, where the selling prices of influenza vaccines are high enough to ensure profitability despite higher costs of goods for cell-based influenza seasonal vaccines.”
This point is echoed by Kressmann, who says interest in using cell culture methods to bolster egg-based vaccine production was the driver for Sanofi’s acquisition of Protein Sciences in 2017.6
“Sanofi acquired Protein Sciences and its recombinant DNA platform to offer two influenza vaccine production technologies: traditional egg-based vaccine and vaccine manufactured with recombinant methods,” he elaborates. “More than 150 million doses of flu vaccines are needed each year to help meet public health demands in the United States. For flu production, modernized egg-based flu vaccines are the most reliable and cost-effective method capable of delivering the large number of safe and effective doses needed to meet the nation’s seasonal and pandemic flu coverage needs.”
The fact that vaccines are made in smaller batch sizes—relative to other biopharmaceuticals—is also shaping how production systems evolve, according to Pall Biotech’s Onraedt. “Vaccine batches are smaller than typical batches seen with recombinant proteins and mAb,” she says. “Depending on the vaccine, the production runs during a limited time per year, in so-called campaigns. Consequently, facilities configured for multiproduct manufacturing have been standard for a long time, which is why single-use systems have been so heavily adopted by vaccine manufacturers.”
Single-use technologies are also helping the vaccine industry to address another of its biggest challenges, namely, the need for sterile filtration. Sterilization is challenging in vaccine manufacturing, particularly if the product involved requires an alum-based adjuvant. The size of the alum component makes sterile filtration impossible, which means many final vaccine production steps need to be done in aseptic conditions.
One way around this, according to Onraedt, is to use disposable technology: “As many process steps are run in aseptic conditions, manufacturers have turned to single-use, closed systems. Here the assurance of sterility remains of high importance and can be addressed by the use of very sensitive integrity test methods such as helium integrity testing in addition to a strong Quality by Design approach.”
A booster shot
Manufacturing innovation will revitalize the vaccine sector, declares Diem Tran, spokesperson for Vaccines for Europe, a sector group of the European Federation of Pharmaceutical Industries and Associations: “Innovation drives significant improvements in discovery, development, manufacture, and delivery of vaccines. New technologies improve and will continue to control of these complex manufacturing processes and increase robustness and accelerate quality controls.
“These innovations and scientific progresses will enable development of ready-to-use vaccines and new administration methods beyond injections, facilitating implementation of vaccination programs. This will provide innovative solutions to effectively produce complex products to deliver life-saving vaccines.”