THE COVID-19 PANDEMIC BROUGHT A VAST MOBILIZATION of scientific ingenuity. At the same time, work on other medical threats continued to push forward. This week, Proto looks at the most transformational non-COVID-19 research of 2020.

As COVID-19 first captured the world’s attention, one question frequently surfaced: How does the new virus compare to the flu? The influenza virus kills tens of thousands per year in the United States even when the annual strain is mild. A more serious strain, like the one that spread in 1918, can be globally devastating.

The toll of COVID-19 will be much higher in the short term than the regular seasonal flu, but new COVID-19 vaccines promise to dramatically reduce those deaths in years to come. Flu vaccines, on the other hand, still leave many unprotected. Different strains of the influenza virus circulate from year to year, and the ones that dominate in any one year may not be the ones that year’s vaccine targets. Ideas for how to create more complete protection—a universal flu vaccine—hit a number of milestones in 2020.

The influenza virus has been hard to target because it can “drift” and “shift,” two mechanisms that can result in strains that won’t respond to a previously effective vaccine. An antigenic drift happens when the virus’s primary surface proteins—hemagglutinin (HA) and neuraminidase (NA), which the immune system recognizes and responds to—appear in new configurations. An antigenic shift, on the other hand, results in completely new HA and/or NA proteins. The last time this occurred was in 2009 when a new H1N1 virus emerged, causing the first global flu pandemic in 40 years.

Today’s flu shots are mainly designed to target the top, or head, of these HA antigens. Some of the new vaccine candidates have focused instead on the HA stalk, the bottom portion of the antigen that, as a whole, varies less than the HA head.

“The COVID-19 pandemic impacted our influenza work quite a bit,” says Florian Krammer, a microbiologist and professor of vaccinology at the Icahn School of Medicine at Mount Sinai in New York. “We also had a lot of COVID-19 projects to manage and had to ensure that proper safety protocols were being followed.” Despite this, Krammer co-authored a paper published in December in Nature Medicine—in collaboration with others at Mount Sinai, pharmaceutical company GlaxoSmithKline and Duke University—that showed promising results from their phase 1 vaccine effort, the first study to show that stalk-reactive antibodies can be produced in humans using a vaccine.

Stalk-reactive antibodies have been difficult to produce because the body reacts so strongly to the preserved part of the HA’s head that it overrides the production of antibodies against the stalk. So Krammer and his colleagues created chimeric HAs, which link the stalks to heads that are entirely new to the immune system—thereby prompting it to only produce low levels of antibodies in reaction to the heads and allowing the stalks to take center stage.

Several other strategies also moved forward in 2020. In March, biotech company Novavax announced results for its phase 3 clinical trial that used a recombinant HA vaccine, NanoFlu, formulated using four influenza strains that were predicted to circulate in the 2019–2020 Northern Hemisphere flu season. The company is now seeking regulatory approval from the U.S. Food and Drug Administration.

Another effort currently under regulatory review manufactures antigens using plants instead of genetic material, cells or eggs, giving it the potential to quickly respond to emerging viral infections. (A similar process was used last year to produce a COVID-19 vaccine candidate in just 20 days).

All of this progress is promising, but it may be years before viable vaccines are widely available. “While our trial was an important first step, it will likely take another two years to develop a chimeric HA vaccine that is truly universal,” Krammer says. “But now, with the experience of this past year, people better understand the importance of developing universal flu vaccines that protect against an emerging pandemic.”