Towards a universal flu vaccine 流感通用疫苗

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A better understanding of the immune response to influenza is driving development of vaccines that protect against many strains of the virus.

Flu shots can be hard to sell to the public. Even a run-of-the-mill influenza infection can be debilitating to otherwise healthy people, and lethal to those who are elderly or frail, so vaccinations are important. The problem is that flu vaccines deliver inconsistent performance. “In a good season, we’re up to 60% effectiveness, but in bad, mismatched years it can be as low as 10% or 20%,” says Barney Graham, deputy director of the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

Current flu vaccines provide protection only against the strains they have been matched to, so a ‘universal’ flu vaccine that provides broader protection against most influenza viruses has been a long-standing dream. The 2009 swine-flu pandemic, which caught the public-health community off guard and claimed the lives of as many as half-a-million people worldwide, gave the issue new urgency.


Part of Nature Outlook: Influenza
“The 2009 pandemic made it obvious and clear that we didn’t have good enough solutions for influenza vaccines,” says Graham. “We knew the virus, but we weren’t able to make enough vaccine quickly enough.” More-effective manufacturing is one solution but a single inoculation that protects against both seasonal and emerging strains would have much greater impact.

Fortunately, the timing of the pandemic coincided with great progress in the development of technologies for investigating the human response to influenza. “Around 2008 or 2009, people started finding a few broadly neutralizing antibodies against the influenza virus,” says Ian Wilson, a structural biologist specializing in vaccine development at Scripps Research Institute in La Jolla, California. “Once people started looking, many more were discovered.”

Now, around 100 years after the ‘Spanish flu’ pandemic of 1918 that killed about 50 million people, multiple universal-vaccine programmes are demonstrating promise in both preclinical and clinical testing. But it remains to be seen whether any will ultimately deliver the broad protection that clinicians seek.

A variable virus
Peter Palese, a microbiologist at the Icahn School of Medicine at Mount Sinai in New York City, believes that today’s flu vaccines come in for too much criticism. “They are fairly good vaccines but they’re not perfect,” he says. The main problem, he adds, is that they elicit a focused immune response against a moving target.

Humans are affected by two main types of influenza. Influenza A and B can both contribute to seasonal flu, but some influenza A subtypes preferentially infect animal hosts. Sometimes these subtypes abruptly acquire the ability to infect humans, leading to pandemics such as the one in 2009. Each year the seasonal flu vaccine is designed to cover two strains each of influenza A and B, based on the public-health community’s best informed guess about which strains will be dominant that year.

Every influenza virus is studded with hundreds of molecular structures formed by a multifunctional protein called haemagglutinin. Haemagglutinin helps the virus to bind and penetrate host cells. It comprises a bulky head attached to the virus by a slender stalk. Most of the immune response is targeted at the head because it is highly exposed, but there is also evidence that the head contains features that preferentially elicit a strong antibody response. “There are structured loops, and antibodies easily recognize loops that stick out like that,” explains James Crowe, director of the Vanderbilt Vaccine Center in Nashville, Tennessee. Unfortunately, these immunodominant elements are also highly variable between strains.

Influenza A viruses are particularly diverse. They are classified by numbers based on the subtype of haemagglutinin (H) protein and a second viral protein known as neuraminidase (N), with even greater strain variation observed among those subtypes. For example, the 2009 pandemic arose from a new strain of the H1N1 subtype. The extent of haemagglutinin variability means that poor strain selection can leave recipients largely unprotected — and even a good vaccine offers limited protection against future strains. “In two years, the virus can change again so we can get re-infected and get disease,” says Palese.

Further complicating the quest for a universal flu vaccine is the fact that our immune system is strongly biased by its earliest encounters with influenza through a phenomenon called imprinting — or, as it has been dubbed, ‘original antigenic sin’. This means that individuals have a strong antibody response to viruses with molecular features shared by the strain encountered during their first exposure, but they essentially start from scratch when exposed to distantly related strains for the first time. “It’s not that you cannot see the second virus — it’s just like you’re a baby and you’re seeing it for the first time,” says Crowe.

Imprinting is a double-edged sword because early exposure to the right strain could theoretically produce far-reaching and vigorous protection in response to vaccination. But if a child’s first influenza encounter is with a relatively unusual or atypical strain, vaccination might prove less effective in terms of rousing broadly protective immunity.

Stalking stability
A vaccine that focuses the immune response on a more stable target on the virus could overcome the problem of viral diversity. Researchers have known that such targets existed for decades. In 1983, Palese and his colleagues determined that the haemagglutinin stalk domain is so similar between strains that antibodies can recognize specific physical features, known as epitopes, of haemagglutinin proteins from multiple influenza subtypes. Unfortunately, the stalk is something of an immunological wallflower, overshadowed by the influence of the head. “We have engineered epitopes into the stalk and the same epitopes into the head, and we get a much better response to epitopes in the head,” says Palese. But immunity can still emerge naturally in some cases, and a series of stalk-specific antibodies were isolated from human donors in 2008 and 2009.

https://www.nature.com/articles/d41586-019-02751-w