• Triple Helix

Flu Lineage Mysteriously Vanishes after COVID-19

Written by Andrew Ni ‘26

Edited by Lizzy Zhang '24

COVID-19’s appearance on the world stage unleashed universal havoc—not even its fellow ally, influenza, was spared from its spillover effects. Heavy travel restrictions, quarantining, masking, physical distancing, and countless measures designed to combat COVID-19 also inadvertently canceled the 2020-2021 flu season. In fact, since the pandemic started, influenza virus detections at one point dropped ~99% compared to previous years [2]. This meant not only an unprecedented decrease in flu cases but also a dramatic collapse in the genetic diversity of flu strains. Most notably, an entire lineage—one of four groups targeted by flu vaccines—seemingly vanished out of thin air [3].


While a lot of focus has recently been put on COVID-19, the flu has been silently killing mankind for far longer. The familiar symptoms of fever, chills, and muscle aches are something we’ve all experienced at some point in our lives. Indeed, every year around 30 million people contract the flu, and up to 36,000 people die from it. Even worse, influenza has been the culprit of some of history’s deadliest pandemics, such as the Spanish Flu, which infected a third of the global population and killed close to 50 million people in just two years’ time (8 times more than COVID-19).


Thankfully, by 1945 the first flu vaccine was licensed for use in the United States, and fast forward to today, around 500 million doses per year are distributed around the world. As part of the vaccine development process, every year health experts choose four strains of the virus to include in the vaccine—two types of influenza A and two types of influenza B—creating what is known as a quadrivalent influenza vaccine (QIV). These two types of flu have different antigens (surface molecules) and thus different characteristics. While influenza A can spread in both animals and humans to create global pandemics, influenza B only spreads in humans [4]. However, both types can cause seasonal flu pandemics and are thus candidate targets for the annual flu vaccine. Specifically, scientists select two strains of each type of flu based on what is expected to be dominant for the season by modeling historical trends and collecting data around the world [5]. However, despite years of intense vaccination efforts, the flu virus has been nearly impossible to eradicate due to its uncanny ability to mutate.


Indeed, more than 5000 strains of influenza have been genetically sequenced since 2004. Of particular interest this season is strains of flu in the lineage B/Yamagata, which was first identified in Japan around 100 years ago. Although seasonal flu vaccines have included B/Yamagata since 2010, this might change very soon. During the COVID-19 pandemic, behavioral changes and movement restrictions resulted in an overall reduction in flu cases and other common respiratory infections like respiratory syncytial virus [6]. The genetic diversity of influenza viruses also dramatically diminished. In fact, the number of strains detected has decreased for both Influenza A subtypes (H3N4 and H1N1), and also for the B/Victoria lineage. Most importantly, since April 2020, the B/Yamagata lineage has not been isolated or genetically sequenced anywhere in the world, suggesting that this influenza lineage may have gone extinct.


As of July 28, 2021, only 31 cases of B/Yamagata have been reported, compared to over 51,000 detections in 2018 [7][8]. However, in reality, the small number of cases may actually be erroneous detections from individuals who got the flu vaccine resulting in residual B/Yamagata contamination. This isn't just a hypothetical either. In the U.S. and Scotland, a couple of B/Yamagata cases were later determined to be caused by vaccine contamination and not real circulating virus [8].

Overall, this recent reduction in global B/Yamagata viruses in comparison to other lineages may signify an inherent weakness of the strain itself. Indeed, B/Yamagata viruses replicate in the body at lower rates, and those who are infected pass the virus to fewer people on average [9]. This makes B/Yamagata very susceptible to social distancing measures. Furthermore, the high frequency of B/Yamagata strains that go extinct suggests intrinsic volatility in its circulation patterns [10][11].


More importantly, the potential extinction of B/Yamagata creates opportunities for new and improved vaccines. Since one of the four components of the vaccines may be gone for good, vaccine producers may be able to return to trivalent vaccinations containing only two influenza A strains and one B/Victoria strain. Researchers estimate this would boost doses accessible for worldwide distribution from 500 to 700 million [12]. Alternatively, vaccine manufacturers could include two A(H3N2) candidate viruses in a QIV instead of just one. Since multiple A(H3N2) strains tend to circulate together, the inclusion of two A(H3N2) strains would provide greater coverage and theoretically boost vaccine effectiveness.

Because sampling and sequencing are not comprehensive, it is impossible to distinguish with 100% certainty between lack of detection and true extinction. While only time will tell if the B/Yamagata lineage has been fully eradicated, eliminating one of the four current vaccine targets may improve annual flu vaccine effectiveness and present opportunities to further reduce flu cases worldwide. In the meantime, scientists are constantly monitoring the flu and developing seasonal vaccines to create our best line of defense.

 

References

[1] [IMAGE CITATION] Graphical Representations of a Generic Influenza Virus. Images of Influenza Viruses. [Internet]. Images of Influenza Viruses. Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases (NCIRD); 2009. Available from: https://www.cdc.gov/flu/resource-center/freeresources/graphics/images.htm

[2] Laurie KL, Rockman S. Which influenza viruses will emerge following the sars‐cov‐2 pandemic? Influenza and Other Respiratory Viruses. 2021;15(5):573–6.

[3] Koutsakos M, Wheatley AK, Laurie K, Kent SJ, Rockman S. Influenza lineage extinction during the covid-19 pandemic? Nature Reviews Microbiology. 2021;19(12):741–2.

[4] Koutsakos M, Nguyen THO, Barclay WS, Kedzierska K. Knowns and Unknowns of Influenza B viruses. Future Microbiology. 2021;11(1):119–35.

[5] Agor JK, Özaltın OY. Models for predicting the evolution of influenza to inform vaccine strain selection. Human Vaccines & Immunotherapeutics. 2018;14(3):678–83.

[6] Huang QS, Wood T, Jelley L, Jennings T, Jefferies S, Daniells K, et al. Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand. Nature Communications. 2021;12(1).

[7] Merced-Morales A, Daly P, Abd Elal AI, Ajayi N, Annan E, Budd A, et al. Influenza activity and composition of the 2022–23 influenza vaccine — United States, 2021–22 season. MMWR Morbidity and Mortality Weekly Report. 2022;71(29):913–9.

[8] Paget J, Caini S, Del Riccio M, van Waarden W, Meijer A. Has influenza B/yamagata become extinct and what implications might this have for quadrivalent influenza vaccines? Eurosurveillance. 2022;27(39).

[9] Vijaykrishna D, Holmes EC, Joseph U, Fourment M, Su YCF, Halpin R, et al. The contrasting phylodynamics of human influenza B viruses. eLife. 2015;4.

[10] Langat P, Raghwani J, Dudas G, Bowden TA, Edwards S, Gall A, et al. Genome-wide evolutionary dynamics of influenza B viruses on a global scale. PLOS Pathogens. 2017;13(12).

[11] Virk RK, Jayakumar J, Mendenhall IH, Moorthy M, Lam P, Linster M, et al. Divergent evolutionary trajectories of influenza B viruses underlie their contemporaneous epidemic activity. Proceedings of the National Academy of Sciences. 2019;117(1):619–28.

[12] Palache A, Rockman S, Taylor B, Akcay M, Billington JK, Barbosa P. Vaccine complacency and dose distribution inequities limit the benefits of seasonal influenza vaccination, despite a positive trend in use. Vaccine. 2021;39(41):6081–7.


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