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Universal Flu Vaccines: Beyond the Seasonal Jab

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Sore throat? Stuffy nose? Influenza, or flu, is a nuisance for many every year, causing unwelcome respiratory discomfort that goes away after a few days for most. In some, it can cause more severe disease and even death. Every year, we can get a seasonal flu vaccine to protect ourselves against the virus. But there are some problems with the current flu vaccine—namely, we’re only protected from the flu strains that circulate during a single year. To address these issues, scientists across the country are working on a better, ‘universal’ flu vaccine that can shield against the flu across multiple seasons and variants.

Our history with the flu

Influenza has plagued humanity for over a century, across all regions of the world. The Spanish Flu pandemic of 1918, first reported by military personnel, led to one-third of the world’s population getting infected and at least 50 million people dying from the disease. In 1957, the Asian pandemic occurred, killing about 1.1 million people. About a decade later, in 1968, the Hong Kong pandemic led to another one million deaths worldwide, and one of the current, circulating flu strains can be traced from this outbreak. The most recent 2009 swine flu pandemic led to 151,700-575,400 deaths globally (estimates are variable based on differing reports across countries), and one of the most recent flu strains is also highly similar to this pandemic strain. History tells us that flu pandemics have occurred frequently, and there’s no reason to think that they should go away anytime soon, at least with our current measures.

Where we are with the seasonal vaccine

Typically, influenza viruses circulate every year between October and May and can cause infections. The current solution is the seasonal vaccine, which is meant to prevent infection. There are a number of formulations, which include either inactivated (killed) or live-attenuated (intact, but weakened) viruses. The former is offered as an injection, as in the Fluzone vaccine, and the latter as a spray, FluMist. This vaccine is quadrivalent, containing four flu strains that experts predict will be circulating during a particular season based on WHO and CDC guidelines. Vaccine production typically takes six months from identifying flu strains through to vaccine filling and distribution and is estimated to cost $3 billion every season. In addition, vaccine effectiveness can vary significantly from around 40 to 60 percent, based on how well circulating and vaccine strains match, as well as other factors like age and health

So why is immunity against flu from the seasonal vaccine so short-lived? One reason is that flu is a moving target, evolving rapidly to evade our body’s defenses. Specifically, immunity is dependent on proteins our bodies produce called antibodies, which can bind to targets on the flu virus, called antigens, and prevent or ameliorate infection. One such antigen is called hemagglutinin (HA). HA is needed for the virus to infect us, acting as a key that lets it into our cells. The seasonal vaccine contains this HA protein, causing certain immune cells in our bodies, called B cells, to produce antibodies that target it. A subset of these B cells that remember this HA, memory B cells, can later produce more of these HA-targeting antibodies if the same strain is encountered again. However, the flu’s HA protein can accumulate changes in its structure. These changes, called antigenic drift or shift, prevent antibodies from binding this new HA variant, thereby letting it infect us in the next season. Therefore, every season, we encounter flu viruses with new variant HA proteins, which are reflected in the annually updated seasonal vaccine.

Getting longer-lasting protection: universal flu vaccines

So how can we get longer-lived immunity against flu? Enter universal flu vaccines, which aim to provide protection against most flu strains for long periods of time. In fact, there are multiple strategies that several groups are testing across the country. Three of them—COBRA, chimeric, and mosaic HA vaccines—employ distinct methods to produce immunity against multiple flu strains, all targeting certain parts of the HA protein.

These universal vaccines use engineered versions of the HA protein. To understand how they work, we have to understand their structure. HA has two parts: the head and the stem, also called the stalk. Most antibodies target the head, which also happens to vary across flu strains. In contrast, only a small fraction of antibodies bind the stem, which varies less frequently compared to the head.  

The COBRA HA merges multiple viral HA proteins into a single protein, producing antibodies that predominantly recognize the head and (to some extent) the stem. Image credit: Kaito Nagashima. Used with permission.

One approach, the computationally optimized broadly reactive antigen (COBRA) HA approach, uses a single, engineered HA protein that comes from merging multiple viral HA proteins. This resulting COBRA HA protein contains multiple regions where antibodies can bind from across several viruses. By doing so, it increases the number of flu strains we are protected from compared to the seasonal vaccine. Importantly, this approach can theoretically target strains that we haven’t yet encountered by incorporating several antibody targets across viruses. 

The chimeric HA has the head from a virus subtype we haven’t encountered before fused to the stem from the virus to be targeted. Antibodies recognize the stem portion of the chimeric HA. Image credit: Kaito Nagashima. Used with permission.

Another strategy is called the chimeric HA approach, where HAs from two different flu strains are fused together into a single, ‘chimeric’ HA with the head from one strain and the stem from another. In this strategy, experts focus on making antibodies that target the stem portion of the HA protein instead of the head. Why is this important? As mentioned before, the stem is less variable across viruses. Thus, if we can target this part of the HA protein, then we might be able to target a larger number of virus strains within a subtype (which groups multiple strains together) with a single vaccine. This chimeric HA vaccine contains a head from a virus where we don’t have much immunity, fused to a stem from a virus type that we want to target. It needs an intact head to stabilize the structure of the stem, which allows antibodies to still bind the same way as to a regular HA. The chimeric HA has shown promising preliminary results in a recent clinical trial against the viral strain that caused the 2009 swine flu pandemic.

The mosaic HA includes parts of both the head and the stem of the virus subtype of interest mixed with variable parts of the head from a virus to which we haven’t been exposed. This design produces antibodies that recognize conserved parts of the head and the stem. Image credit: Kaito Nagashima. Used with permission.

The third strategy, called the mosaic HA approach, is similar to the chimeric HA approach, but it contains conserved parts in the head portion in addition to the stem for the virus type we want to target with antibodies. It’s possible that by targeting both of these parts of the hemagglutinin protein,  we could prevent the evolution of variants that evade just the head or the stem.

All of these strategies would allow people to get a vaccine that could produce protection that lasts for several years by overcoming variation in HA across strains. Seasonal vaccine effectiveness generally wanes because flu mutates and accumulates mutations, so the antibodies against the HA antigen from one season aren’t effective for the next. A universal vaccine could overcome this inherent problem with the seasonal vaccine.

Our future with the flu

Influenza is estimated to cost the healthcare sector $10.4 billion every year in hospitalizations and outpatient visits. Clearly, it still poses a major burden across the country even with our current vaccine. The seasonal vaccine certainly works, but it’s clear that it has its drawbacks: it’s costly and time-consuming to make, and it typically only protects us for a single season. By using universal flu vaccines, we could change our relationship with the virus, eliminating our need to annually produce a vaccine, reducing both human and economic costs. Current universal flu vaccines are moving along the pipeline, with the chimeric HA already shown to be safe in a Phase I clinical trial (which tests for vaccine safety in people), and the COBRA HA in late preclinical studies. It’s unclear when a universal vaccine will be ready for distribution, but within a decade one could be available. It’s time that we control the flu, given how it’s plagued us for so long—and say goodbye to it for a long time.

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