Chickens harbor influenza strains that can mutate, jump to humans, and cause a pandemic. But pandemic influenza could soon be preventable.Credit: Panyawat Boontanom/EyeEm/Getty Images
In early December 2020, Margaret Keenan became the first in the world to receive an approved COVID-19 jab. No previous vaccine had been developed in less than four years, but the Pfizer/BioNTech mRNA vaccine received by the 91-year-old in Coventry, UK, had reached the clinic in just 11 months. By June 2021, regulators had fully approved 8 COVID-19 vaccines, and no fewer than 92 others were being tested in clinical trials, thanks to seismic mobilization of scientific expertise. In the race to develop those vaccines lies lessons for preventing future global outbreaks—including the inevitable return of pandemic influenza.
“So much of the community responding to COVID is from the influenza research and development space,” says Marissa Malchione, senior associate for Influenza Vaccine Innovation at the Sabin Vaccine Institute. “If we can harness that knowledge and experience, it could really propel progress towards next-generation, broadly cross-protective vaccines for influenza.” The following key lessons, drawn by experts in the field, offer a path forward.
Build on a strong foundation of basic research. Chinese scientists reported the SARS-CoV-2 genome sequence in mid-January, and within weeks researchers at the US National Institutes of Health (NIH) and Moderna were able to develop its highly effective vaccine for COVID-19. Vaccine development benefited from knowledge acquired during and after the 2002 SARS outbreak and the 2012 MERS outbreak. “Wherever we had attended to the science, we could leverage it to streamline product development,” says Luciana Borio, vice president of technical staff at In-Q-Tel and former assistant FDA commissioner.
The Moderna mRNA vaccine was repurposed from an mRNA vaccine candidate developed during the 2012 MERS outbreak, and the Pfizer vaccine was repurposed from an adenovirus platform originally developed for Ebola. “mRNA vaccines had been in development for about 30 years, but until recently never had the business case to drive them forward,” says vaccine researcher Kathleen Neuzil, of the University of Maryland School of Medicine.
Vaccine developers can use proven platform technologies like these to quickly respond to emerging threats. For example, mRNA vaccines can easily be ‘recoded’ to produce antigens from emerging variants of both SARS-CoV-2 and influenza. It helps that a great deal is known about influenza virus variants and the type of immune response needed to prevent serious disease, says Gregory Poland, a vaccinologist at the Mayo Clinic. Nevertheless, “influenza is more complicated than coronavirus, and there’s a lot of discovery that needs to happen,” Neuzil cautions.
To quickly scale up of COVID-19 vaccine production, wealthy nations simultaneously funded development, testing and manufacturing.Credit: Andriy Onufriyenko/Getty Images
Embrace the power of partnerships. The world might still be waiting for COVID-19 vaccines were it not for cross-sector partnerships forged amidst the pandemic. In addition to the NIH-Moderna and Oxford-AstraZeneca partnerships, Merck agreed to manufacture the newly approved vaccine of Johnson & Johnson, its direct competitor, and the NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program brought together manufacturers, the NIH, and academic experts to harmonize vaccine development efforts and speed up clinical trials. “Even if a mistake was made, we learned from each other's mistakes,” says Neuzil, who was a member of ACTIV.
Meanwhile, a new partnership could address global inequities in vaccine access. As of late June, the African continent had fully vaccinated less than 1% of its population. “We are striving to get to at least 60%,” says John Nkengasong, director of the Africa Centres for Disease Control and Prevention (Africa CDC). To remedy the situation, Africa CDC and the Coalition for Epidemic Preparedness Innovations (CEPI), teamed up in spring 2021 to dramatically boost African vaccine research, development and manufacturing. “It was a historic meeting that has the potential to enhance capacity on the continent,” Nkengasong says. Similar partnerships, spanning discovery to distribution, could prove crucial in advancing universal influenza vaccines.
Make the most of trials. To accelerate vaccine testing, researchers agreed on a set of clinical endpoints and design principles for COVID-19 vaccine trials. This common ground helped them compare the safety and efficacy of different vaccine candidates across multiple studies. ACTIV and other public-private partnerships also established a network for the rapid recruitment of volunteers to multiple trials simultaneously.
The severity of the pandemic actually accelerated development of candidate vaccines by making it easier to find patients. But to prevent future pandemics before they begin, influenza vaccine researchers can draw instead on ‘challenge trials.’ In these tests, researchers vaccinate young, healthy adults, then deliberately expose them to strains of interest, with ready access to medical countermeasures like Tamiflu if needed. “There's a lot of risk in a field trial,” says Neuzil, noting that naturally circulating strains often do not match the vaccine design, and thus may elude the resulting immune response. “Challenge studies are very useful for these strain changes and measuring durability of protection and correlates of immunity,” Neuzil says.
Scale and speed both matter, as does diversity. For its international phase 3 trial, Pfizer recruited nearly 44,000 subjects on five continents to represent diverse racial and ethnic backgrounds. “These viruses and their variants arise differentially by geography, and efficacy can differ among different ethnic and racial groups,” Poland says.
Invest now or pay more later. Fighting a pandemic is costly — a recent government report states that by late 2020 the US had invested $13.8 billion just for vaccine-related funding. But the havoc wrought by COVID-19 cost orders of magnitude more: One study from the University of Sydney estimates US$3.8 trillion in global economic losses in 2020.
Governments also drove progress by underwriting at-risk private-sector R&D. “The pharmaceutical industry has tended to work in a linear fashion, where you go from step to step and make a decision at each step going forward,” says Gerald Keusch, a Boston University infectious-disease researcher. This minimizes exposure to risk, but delays progress. During the COVID-19 pandemic, in contrast, wealthy nations simultaneously funded development, testing and manufacturing for multiple vaccine programs. “It became not only acceptable but necessary to take those risks,” Borio says.
For future pandemics, it would be invaluable to have resources already set aside to support parallel R&D and mobilize manufacturing for rapid vaccine production. Increased public funding is one element of this process, as are multi-lateral initiatives like the Access to COVID-19 Tools (ACT) Accelerator. But other innovative strategies could also underwrite these efforts, such as a proposal by MIT researcher, Andrew Lo, to assemble diversified multibillion-dollar investment portfolios to support vaccine research.
Keusch cautions against being alarmed by billion-dollar price tags. “The investment that’s required globally is puny compared to the losses when something happens,” he says. “And all the evidence says that this will happen again.”