Influenza Virus: The Concern of a Century

The 1918 influenza pandemic infected an estimated 500 million people or one third of the global population. This led to at least 50 million deaths, all by a single virus. Although the 1918 pandemic was the most severe outbreak in recent history, the influenza virus has been responsible for additional pandemics since. What made these flu viruses so deadly compared to the seasonal flu that they became pandemics?  

According to the World Health Organization (WHO), there are 3-5 million severe cases and 290,000 – 650,000 deaths due to seasonal flu every year worldwide. The seasonal flu primarily affects people with a weakened immune system as the differences in seasonal influenza strains are enough that they require a new vaccine but are still recognized by our immune system. This occurs because the virus’ main job is to spread. As our immune system becomes better adapted at recognizing the virus, the evolutionary pressure forces the virus to mutate its surface proteins to evade the immune system in a process known as antigenic drift. This is one of the reasons the influenza virus vaccine has to be updated on an annual basis as with each successful mutation vaccine efficacy decreases significantly. 

Pandemic flus, however, are different and are much more lethal. Through a process known as antigenic shift, the virus adopts modifications that changes viral surface proteins to versions that have never been encountered by humans before. One way this occurs is that some genetic information from animal virus strains can recombine with human flu viruses. As a result, people do not have any immunity and are not prepared to fight it. With its rapid spread, these viruses can quickly become a pandemic.  

For example, in 2009, the first influenza pandemic of the 21st century was caused by a novel H1N1 influenza A virus that was previously circulating in pigs. Vaccines were not available in time to prevent the first wave of infections, and viral resistance against antiviral drugs allowed the rapid spread of the virus. The constant risk of the emergence of a new flu pandemic means that there is an urgent need for a universal flu vaccine or newer antiviral drugs.  

Influenza Virus: A Global Concern 

Pandemic and seasonal influenza is caused in humans mainly by influenza A and B viruses, though influenza C and D viruses are able to cause minor disease in humans. Haemagluttinin (HA) and neuraminidase (NA) are proteins found on the virus’ surface that facilitate viral entry and viral release, respectively. In addition, they are the most variable proteins on the viral surface as they are constantly being altered, allowing them to evade the host’s immune system.  

Changes on HA and NA mean that our immune response, which involves the development of HA- and NA-specific antibodies, proteins produced by the immune system that bind and neutralize pathogens, will not be able to bind the proteins to prevent viral spread anymore. The immune system also recruits immune cells like cytotoxic T cells and T helper 1 cells to promote the elimination of influenza virus-infected cells. These responses are promoted by innate sensors on antigen presenting cells and B cells. However, while our antibodies are able to recognize small variations that come with the seasonal influenza viruses, pandemic influenza viruses are much more deadly as antibodies are not always capable of recognizing the mutated viruses.  

The HA and sometimes the NA protein in pandemic viruses are derived from diverse zoonotic strains with the potential to spread to the human population via reassortment. As a result, pre-existing antibodies offer little protection. One of the greatest concerns is the avian H7N9 virus that affects poultry. Even though no cases of sustained human-to-human transmission has been associated with this virus, the potential is there due to the amount of poultry consumed worldwide.  

The Quest for the Universal Flu Vaccine: Where are we now? 

Twice a year, the WHO meets to develop the next seasonal vaccine that aims to match, as best as possible, the HA and NA molecules of the next circulating influenza virus. However, they cannot always predict this, which means that the new vaccine will not be as effective as it could be.  

Influenza vaccines fall into 2 broad groups: those made from a protein or small pieces taken from the virus (inactivated) and those made from a weakened form of the virus (live-attenuated). Several variations are found within the inactivated vaccines group. For example, different methods are used to propagate the vaccine strains (egg-based versus cell-based culture), presence and quantity of adjuvants (a substance used in some vaccines that helps to boost the host immune response) can differ, and route of administration can vary (skin versus muscle injection). Some of the disadvantages of growing influenza viruses in eggs are that it can introduce mutations that can cause differences between the viruses in the vaccine and the ones in circulation and may also lead to the development of allergies. Newer approaches for vaccine development include recombinant vaccines, where HA genes have been combined with viruses that grow well in insects to avoid the need for egg-based propagation. 

Another difference is that antibody responses to vaccinations can vary. Antibody responses to vaccination can be so short-lived where antibody titers wean within a season. For example, a comparison made between the inactivated and live-attenuated vaccine in children demonstrated that antibody responses persist much longer in the live-attenuated vaccine. In addition, the live-attenuated vaccine induces antibody responses against HA and NA, local mucosal antibody production, and influenza specific resident memory immune cells, like CD8⁺ and CD4⁺ T cells, which the inactivated vaccine fails to do.  

One challenge for vaccine development is the concept of “original antigenic sin”. This principle suggests that exposure to a new virus strain might induce our immune system to generate antibodies against similar viruses encountered earlier in life depending on the relatedness of the viruses. Therefore, an antibody response against a novel virus variant in adults might be heavily biased by the individual’s exposure history and dampen the immune response to the new virus strain.   

Another challenge for vaccine development involves understanding the way influenza virus manipulates the inflammatory signals in our body such as the interferon system. By using new techniques in genetics, regions in the influenza A genome that affect interferon sensitivity have been discovered. This allows for the construction of vaccines containing viruses with interferon-sensitive mutations that ideally will induce a robust immune response to viral challenge. 

Although great progress has been achieved in vaccine design, major efforts are still underway for the development of a universal flu vaccine that induces sterilizing immunity, which refers to complete protection from infection by a pathogen, against seasonal influenza virus strains. This vaccine would abolish the need of annual reformulations and re-administration of seasonal vaccines. It should also aim to reduce severity of the infection, accelerate recovery, lessen complications, and reduce spread of diverse influenza virus strains.  

Several antibody targets have been identified, such as the stalk domain of the HA protein as well as regions not prone to mutations in the head of HA and NA. Even though an anti-NA immune response does not prevent infection, it has been shown to interfere with viral exit, ameliorating the clinical symptoms of the disease by limiting the amount of virus in our body. As a result, NA has become a possible vaccine target. Finally, to enhance T cell immunity, novel vaccination strategies such as vaccines containing short single-stranded synthetic DNA molecules that act as immunostimulants are being studied to generate specific types of immune responses that quickly respond and clear influenza virus infections.   

The ‘Arms Race’ Between Influenza Virus and Antiviral Drugs 

Together with vaccines, antiviral drugs play an essential role in prevention and treatment of flu infections. In the case of antiviral drugs, one key factor to take into consideration is timing. Early intervention greatly reduces severity of the infection. However, symptoms rarely appear before day 4 post-infection and by this time, antiviral efficacy is reduced. Two classes of drugs are approved to treat influenza virus infection: neuraminidase inhibitors (NAI) and adamantanes. NAIs, such as oseltamivir, are the drug of choice due to the development of antiviral resistance and side effects of adamantanes. 

Adamantane resistance was first observed in influenza A H3N2 viruses in 2003 and in influenza A H1N1 in 2009. However, oseltamivir resistance is also a current concern, especially since resistant strains have been found in the past. There is an urgent need for new antiviral drugs, especially for susceptible individuals like children and immunocompromised patients who are the most vulnerable, especially to resistant strains. Ideally, influenza virus treatment should comprise of a cocktail of drugs that target different aspects of viral replication. With a large pool of candidate drugs in preclinical development, we could see a vast array of treatment options for the flu in the future.  

Conclusion 

Even though more than one hundred years have passed since the 1918 pandemic, influenza virus still remains the major leading cause of viral respiratory disease. Even with vaccines and antiviral drugs, we have not been fully able to prevent and treat influenza. Nonetheless, substantial scientific advances in the last century have provided us with a greater understanding of its immunology, virology, molecular biology and physiology, bringing us one step closer towards the creation of a universal vaccine and better drugs. 

References  

1. Krammer, F., Smith, G., Fouchier, R., Peiris, M., Kedzierska, K., & Doherty, P. et al. (2018). Influenza. Nature Reviews Disease Primers, 4(1), 1-21. https://doi.org/10.1038/s41572-018-0002-y 

2. Dunning, J., Thwaites, R., & Openshaw, P. (2020). Seasonal and pandemic influenza: 100 years of progress, still much to learn. Mucosal Immunology, 1-8. https://doi.org/10.1038/s41385-020-0287-5 

3. Wei, C., Crank, M., Shiver, J., Graham, B., Mascola, J., & Nabel, G. (2020). Next-generation influenza vaccines: opportunities and challenges. Nature Reviews Drug Discovery, 19(4), 239-252. https://doi.org/10.1038/s41573-019-0056-x 

4. Krammer, F. (2019). The human antibody response to influenza A virus infection and vaccination. Nature Reviews Immunology, 19(6), 383-397. https://doi.org/10.1038/s41577-019-0143-6