Influenza is a complex, unpredictable virus that has kept scientists searching for more universal vaccinations and treatments to the deadly disease. Two mechanisms render the immune system ineffective in fighting the influenza virus: antigenic drift and antigenic shift.

Antigenic Drift: Due to the lack of RNA proofreading enzymes, influenza virus genomes can accumulate mutations through successive replication, leading to alterations in viral antigens and new strains of influenza virus that the immune system has never encountered.

Antigenic Shift: This reassortment of genomic segments enables the Influenza A  Virus (IAV) from other species, such as avian or swine, to infect humans. Antigenic shift is thought to be the cause of most flu pandemics.

Despite the known risks, fewer than 50% of Americans received the flu shot during the 2016–2017 flu season. And even when vaccinated, sometimes the vaccine is a “miss” and the flu can become widespread. Take these examples of deadly outbreaks that spread after the creation of the flu vaccine:

  • 1956–1958 “Asian Flu” caused by the H2N2 strain, leading to more than 2 million deaths, including nearly 70,000 in the U.S.
  • 1968 “Hong Kong Flu” caused by the H3N2 strain, leading to more than 1 million deaths, including nearly 34,000 in the U.S.
  • 2009–2010 “Swine Flu” caused by the H1N1 strain, leading to over 575,000 deaths, including over 12,000 in the U.S.

A Primer on the Influenza Virus

Strains and Subtypes

The influenza virus is categorized into four strains — A, B, C, and D — abbreviated as IAV, IBV, ICV, and IDV. IAV strains are the primary cause of influenza infections in humans, making them the focus of most vaccine research.
IAV strains are further categorized into subtypes to classify the two proteins found on the surface of the virus: hemagglutinin (HA) and neuraminidase (NA). Scientists have identified 18 HA subtypes (HA1–HA18) and 11 NA subtypes (NA1–NA11), which combine to form specific subtypes of the IAV strain.

IAV can infect pigs, birds, horses, bats, and dogs in addition to humans.

Current vaccines are strain-specific and new immunizations must be administered each season.

Cytokine Storm

The overproduction of the host’s immune response is a problem encountered in all areas of immunology and virology, especially in cancer therapies. In the case of the flu, the cytokine and chemokine response can send an overabundance of monocytes and neutrophils to the lungs, for example, resulting in life-threatening inflammation and fluid build-up.

To prevent deadly cytokine storms, researchers are developing treatments to inhibit the immune response to the flu. Read more about these efforts below.

Current Flu Treatments and Limitations

While we await a universal vaccine that would protect against all strains of the virus, scientists are searching for new treatments to influenza infections. Neuraminidase inhibitors (NAIs) are currently the only antivirals recommended to treat influenza virus infection; however, they do have limitations.

To be effective, NAIs should be administered within 48 hours of the onset of flu symptoms. Additionally, mutations have been discovered that can lead to NAI resistance and spread throughout the population.

These limitations have spurred the development of alternative anti-influenza virus drugs that are more effective, can be administered later in the disease progression, and will not be as susceptible to viral resistance.

New Treatments in Development

Monoclonal Antibodies Targeting the Stem Region of the HA Molecule

Several of these antibodies are currently in clinical trials, with demonstrated high-affinity binding of MHAA4549A and MEDI8852 to 16 IAV HA subtypes and confirmed binding of VIS410 to 7 subtypes.

These antibodies have demonstrated abilities to inhibit pulmonary viral load in animal models, control viral shedding in humans, and lower patient symptom scores and inflammatory levels.

While they have not been shown to offer better protection than NAIs, HA stem antibodies do have stronger pharmacokinetics and a longer therapeutic window than NAIs.

Influenza Virus RNA Polymerase Inhibitors

Favipiravir (T705 or Avigan) is an antiviral drug that has completed phase III trials in the U.S. This ribonucleotide analog works by inhibiting viral RNA-dependent RNA polymerase (RdRp).

Studies have shown Favipiravir effective in reducing lung viral titers and host mortality when administered up to 72 hours post-infection in mice models. The antiviral also has a high barrier for drug resistance and is a promising candidate for a broad acting anti-influenza virus therapy.

Favipiravir is also active against West Nile virus, yellow fever, foot-and-mouth disease, flaviviruses, arenaviruses, bunyaviruses, and alphaviruses.

Epithelial Cell Therapies

Because damage to the lung epithelium has a substantial impact on the patient’s respiratory function and overall health outcome following influenza infection, several therapies focus on preventing epithelial cell death.

One therapy, Fludase, which targets the virus’ entry point into epithelial cells, has been shown to remove 90% of sialic acid receptors within 15 minutes of treatment. A phase II trial spanning three flu seasons demonstrated that patients tolerated the therapy well and experienced decreased viral load and shedding.

Inhalers have been shown to be an effective method to deliver therapeutics directly to the epithelial cells for improved treatment with minimal side effects.


Influenza viruses (IVs) are a continual threat to global health.

For a more in-depth and technical discussion of influenza virus and treatments, and to see the original sources referenced in this blog post, read Treating Influenza Infection, From Now and Into the Future from Frontiers in Immunology.

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