Between 1918 and 1920, the ‘Spanish flu’ infected a third of the world’s population, and caused an astronomical 17 million deaths. A century later, we have yet to develop defenses against an equally devastating influenza pandemic, says Stacey Knobler, senior director at the Sabin Vaccine Institute.

Annual flu vaccines offer only partial protection against circulating strains that cause seasonal flu. Even in a good year, the vaccine reduces the risk of infection only 50-60 percent, and in a bad year, that number has dwindled to 20 percent. And the annual vaccines offer almost no protection from a novel influenza strain that could cause a pandemic.

“Continuing to rely on vaccines that respond to circulating strains from year to year is clearly not going to get us the protection we need,” Knobler says.

What’s needed instead are universal influenza vaccines (UIV) — vaccines that offer broad and long-lasting protection from both seasonal and pandemic flu. Now, thanks to advances in fields from basic immunology to vaccine design, universal influenza vaccines may finally be on the horizon.    

These advances have persuaded funders and philanthropists to step up, and momentum toward a UIV is building. In 2018 funding organizations from around the world joined forces to form the Global Funders Consortium for Universal Influenza Vaccine Development, to better coordinate and optimize their investment  strategies. In 2019, the National Institute of Allergy and Infectious Diseases (NIAID) launched a network of ‘Collaborative Influenza Vaccine Innovation Centers’ (CIVICs) with a $51 million investment for its first year. The network is part of a seven-year program to advance a universal vaccine.

To push UIVs further and faster, the Sabin Vaccine Institute’s Influenzer Initiative is enlisting prominent scientists, technology experts, and industry leaders to drive a new agenda to foster innovation and spur progress toward a universal influenza vaccine. “There's a sense that broader and better influenza vaccines are definitely within striking distance,” says Neil King, a biochemist and vaccine developer at the University of Washington.

Seeking common targets

Designing more powerful influenza vaccines means overcoming a wily foe. Influenza is remarkably diverse, with many genetically distinct virus strains that evolve quickly and often remain a step ahead of the human immune system.

Achieving more universal immunity therefore requires deep understanding of influenza’s variability, particularly the variability of the hemagglutinin (HA) protein, which mediates virus binding and entry into host cells. A well-matched antibody against HA can stop the virus in its tracks, but HA varies enough across influenza strains that an immune response against one strain will not necessarily protect from another.

Researchers are now finding pockets of consistency within HA, raising hopes of broad immune protection. University of Chicago immunologist, Patrick Wilson, discovered this by examining patients’ antibody responses to the strain that caused the 2009 swine flu pandemic, which is an H1N1 strain and a distant cousin to the 1918 pandemic strain. Wilson found that a subset of people who mounted a robust response to the virus had a particular subset of antibodies in common. “The antibodies zeroed in on very rare, but highly conserved, portions of the virus,” Wilson says.

Now Wilson is profiling antibodies from large numbers of influenza patients to identify other conserved portions of the virus, known as antigens. An engineered version of the HA protein with a mosaic of these antigens could induce broad protection from both seasonal and pandemic influenza.

Algorithms at work

Computational biology offers another powerful tool to help pinpoint influenza’s vulnerabilities. For example, University of Chicago computational biologist Sarah Cobey collaborates with Wilson, using sophisticated modeling to reconstruct the immunological responses that give rise to broad antibody protection against influenza.

And Ted Ross, who heads a CIVIC site based at the University of Georgia, is using algorithms to examine HA protein sequences from influenza isolates worldwide. He aims to identify and then combine these conserved features into a vaccine. This approach has already yielded vaccine designs that can protect against entire flu subtypes, including the H1N1 viruses that caused the 2009 and 1918 pandemics.

Another essential viral surface protein, neuraminidase (NA), is much less variable than HA and could be targeted for broad protection. But using it is difficult because it’s hard to manufacture for influenza vaccine production. King and his University of Washington colleague, David Baker, are engineering more stable NA variants using a computational protein-design tool called Rosetta, which lets researchers modify and manipulate protein sequences. These variants could be coupled with HA to generate dual-antigen vaccines that provide more extensive protection than either protein would provide alone.

An emergency hospital at Camp Funston, Kansas, in 1918, the first year of the devastating “Spanish flu” pandemic, which killed more than 17 million people worldwide. Credit: (NCP 1603) Historical Archives, National Museum of Health and Medicine. 

Custom-built vaccines

No matter how good a vaccine is, it must be produced quickly and at scale to combat a pandemic in progress. Yet large-scale manufacture of each year’s season influenza vaccine now takes up to six months — far too slow to respond in real time to an outbreak.

RNA-based vaccines offer one promising approach to speeding production, one that’s proving effective with COVID-19. These vaccines encase messenger RNA (mRNA) molecules in an oily coat, then deliver it to human cells. The cells then take up the mRNAs and decode them to produce viral proteins that elicit a robust immune response.

A vaccine with mRNA encoding several potent antigens could establish broad immune protection. RNA vaccines are also fast and easy to design and produce, which could help scientists update vaccine designs quickly based on new findings in viral immunology. “You can plug and play right into the system,” Ross says. This approach is also faster and cheaper than current manufacturing methods.

No single vaccine design will likely offer one-size-fits-all protection. The immune response declines as we age, depends on our history of encounters with a pathogen, and varies from one person to the next. But understanding immune variation could lay the groundwork for a series of vaccines, each tailored to best protect a certain population, says Galit Alter, a systems biologist at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard.

To develop tailored vaccines, Alter is using a strategy she developed called “systems serology” to reveal factors that shape an individual’s response to infection and vaccination. “We have to accept that flu is a complicated pathogen, and come up with better solutions that use the diversity and the complexity of human immunology to design vaccines in a smarter, rational way,” she says.

The first victories in the campaign for a universal influenza vaccine may be limited in scope, King says—for example, super-seasonal vaccines that can replace annual flu shots for several years or more. But that would set the stage for improved versions that fight off more influenza subtypes and provide a durable shield against new outbreaks.

In the wake of COVID-19, the world cannot wait any longer for such a shield, and must harness the full power of science and technology to develop universal vaccines, Knobler says. Only then will it be possible to prevent the next pandemic, rather than respond to it.

Explore Sabin Vaccine Institute’s efforts to accelerate the development of a universal influenza vaccine here.