Challenges in designing a long-lasting universal influenza vaccine

By Yeji Hong

The influenza virus causes up to 1 billion infections and over half a million mortalities each year worldwide (Clayville, 2011). This induces a significant economic and healthcare burden, therefore prioritizing the need for a vaccination. 

Vaccination is the best method for preventing and controlling the virus, and it can also lessen the severity of infection. However, although most vaccines last for several years, vaccinations for the influenza virus are only effective for a short period of time and therefore need to be redesigned biannually. The redesigning process is reliant on a screening process that is carried out after each hemisphere’s annual winter epidemic, which determines the composition of the vaccine to prepare for the next strain of influenza. 

There are three main types of influenza viruses – influenza A, B and C, which are classified based on their antigenic differences in the viral nucleoprotein and the matrix protein. Influenza A and B each contain 8 gene segments in the genomes, which are composed of single-stranded RNA. Influenza A is associated most with mortality, and this virus particle has surface proteins hemagglutinin (HA) and neuraminidase (NA) which are responsible for viral entry into epithelial host cells and are targets of B-cell immunity (Houser & Subbarao, 2015). 

The influenza vaccines that are designed seasonally have their limitations due to the ever-changing nature of the influenza virus. The rapid evolution of the virus renders the vaccines ineffective if the composition of the vaccine is not monitored to sufficiently match the novel viruses that emerge. There are two main mechanisms by which viruses transform and evade B-cell immunity. One method is through ‘antigenic drift’ which describes the ability of viruses to mutate rapidly. This mechanism is a result of inaccurate RNA polymerases, which causes the alteration HA and NA antigenic proteins through substantial amino acid substitutions. Another process is named ‘antigenic shift’ which describes the ability of the virus to undergo recombination of its segmented genome. This is possible when more than one virus infects a single host cell (Lofgren et.al., 2007). Through antigenic drift and antigenic shift, the virus constantly changing its structure to find new ways of evading the human immune system. 

Another limiting factor of influenza vaccines is the short lifespan of the bone marrow plasma cells (BMPCs). The influenza virus vaccine elicits a response from BMPCs, which are responsible for producing the B cells that secrete antibodies specific for the influenza virus. A recent study conducted by the Emory Vaccine Centre investigated the production and maintenance of BMPCs in healthy adults after influenza vaccination (Davis et. al., 2020). The researchers measured the percentage of antibody secreting BMPCs specific for the influenza virus in 53 human volunteers through ELISpot on the day of vaccination and one month after vaccination with the influenza vaccine. They found that there was an increase in the percentage of BMPCs specific for the virus after one month; however, they also found that a year after vaccination, the level of these cells had returned to baseline. Similarly, it was found that antibodies specific for the influenza virus increased one month after vaccination but declined to baseline levels after one year. This study indicated that although BMPCs specific for the virus were newly generated after vaccination, these cells only survived for a short period. From this study, the researchers concluded that the bone marrow was not an appropriate enough niche to provide longevity for the influenza specific BMPCs. This poses a challenge to creating a long-lasting vaccination for influenza, as a more suitable environment for the BMPCs need to be established to ensure that the survival of BMPCs and production of influenza-specific antibodies is long-lasting.

In recent years, the idea of devising a long-lasting universal influenza vaccine has been explored after it was discovered that the human immune system has the ability to direct antibody responses against broadly conserved epitopes on the influenza HA and NA proteins. There are two ideas that have been explored – the recombinant stalk-specific HA and chimeric recombinant HA (Corona, 2020). The stalk is the domain of the HA that anchors the globular head to the membrane of the virus, and its structure is conserved across many influenza A virus strains, making it a potential target for a universal vaccine. A proposed strategy of targeting the stalk involves forming a recombinant HA protein that lacks the globular head and contains only the stalk, which would elicit an immune response against a broader spectrum of viruses. Another strategy to target the stalk is to construct chimeric HA proteins which have the native stalk, but a chimeric globular head which is fused with non-human influenza A virus strains, which would provide universal protection. There are currently several universal flu vaccine candidates that are in Phase 2 and Phase 3 clinical trials in companies such as GlaxoSmithKline and Nanoflu which use these strategies to provide broader and longer-lasting protection from the virus (Corona, 2020).

Taking into account these new findings about the capabilities of currently existing influenza virus vaccines and advances in vaccine design, constructing a long-lasting universal flu vaccine seems plausible in the future. Many researchers believe that the chimeric recombinant HA strategy will ultimately be the most protective, but as to whether these will confer against novel influenza virus strains will have to be investigated closely. More research will also need to be conducted to find an appropriate niche that will elicit longevity of BMPCs in the human body.

References:

Clayville, L.R. (2011) Influenza Update – A Review of Currently Available Vaccines. P&T. 36(10): 659-684. Available from: doi:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278149/pdf/ptj3610659.pdf 

[Accessed 4th September 2020]

Corona, A. (2020) A Universal Influenza Vaccine: How Close Are We? American Society for Microbiology. Available from: https://asm.org/Articles/2019/August/A-Universal-Influenza-Vaccine-How-Close-Are-We [Accessed 5th September 2020]

Davis, C.W., Jackson, K.J.L., McCausland, M.M., Darce, J. et. al. (2020) Influenza vaccine-induced human bone marrow cells decline within a year after vaccination. Science. Available from: doi: 10.1126/science.aaz8432 [Accessed 3rd September 2020]

Houser, K., Subbarao, K. (2015) Influenza Vaccines: Challenges and Solutions. Cell Host Microbe. 17(3): 295-300. Available from: doi: 10.1016/j.chom.2015.02.012 [Accessed September 5th 2020]
Lofgren, E., Fefferman, N.H., Naumov, Y.N., Gorski, J. et. al. (2007) Influenza Seasonality: Underlying Causes and Modeling Theories. Journal of Virology. 81(11): 5427-5436. Available from: doi: 10.1128/JVI.01680-06 [Accessed 6th September 2020]

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