Influenza: History, Evolution, and the Future - An Interview with Virologist Prof. Alexandrova

Science continues to study influenza viruses, which are connected to our past and present. The latest flu season has officially opened, and as every year, questions about it do not cease from the beginning of autumn, said in an interview for BTA Prof. Dr. Radostina Alexandrova from the Institute of Experimental Morphology, Pathology and Anthropology with a Museum at the Bulgarian Academy of Sciences (BAS), who is a virologist and biologist.

She explained that the history of the influenza virus is closely linked to our past and present. This is a fairy tale about a continuous game of cat and mouse, and co-occurring evolution; a story marked by periodic flu outbreaks and its subsequent withdrawal until the next time, but also by devastating pandemics. Like the one from 1918-1920 (Spanish flu), which took the lives of over 50 million people, significantly more than the victims (over 20 million military and civilians) in the First World War. 

It is difficult to say exactly when this virus originated, but it is not excluded that this happened during the Neolithic. Epidemics of flu-like diseases have been documented in the fifth century BC. The name influenza was first documented in 1357 in Italy. In those days, people believed that epidemics occurred under the influence of the Moon. The name flu comes from the French verb gripper (to grab) and it is no coincidence, as the disease starts suddenly, literally grabs us, explained Prof. Alexandrova.

She said that for many years it was mistakenly believed that the cause of the flu was a bacterium. This confusion continued until the isolation of the influenza virus in 1933.

Influenza viruses are of four types

Today we know that influenza viruses are of four types (A, B, C and D), of which A and B are of main importance for humans. Representatives of influenza A are highly variable, causing epidemics and pandemics. Their main reservoir is waterfowl, but they affect a wide range of hosts, including domestic birds, pigs, horses and many other mammals. It is precisely these viruses that are designated by the formula HN, and the letters H and N come from hemagglutinin and neuraminidase - growths on the surface of the virus, necessary for its attachment and penetration into the cell (hemagglutinin) and for the exit of newly formed viruses from the infected cell (neuraminidase). The number after these letters specifies which type of hemagglutinin and neuraminidase is in question, said Prof. Radostina Alexandrova.

According to her, in recent decades, two types of influenza viruses of type A have been responsible for seasonal flu outbreaks: H3N2 and H1N1. It seems that people exposed to the H1N1 strain for the first time in childhood are less likely to need hospital treatment if they encounter H1N1 again later in their lives than people who have encountered H3N2 for the first time. And conversely, people exposed to H3N2 for the first time have received something like additional protection against it.

Influenza viruses of type B only cause epidemics, but they are also not to be ignored. According to data from the US and Europe, influenza B was responsible for up to 82% of the total number of laboratory-confirmed cases of influenza between 2001 and 2018, and their average seasonal manifestation was 25%. They have a lower mutation rate compared to those of type A and cause diseases mainly in humans. It has been reported that they can sometimes infect seals, but their animal reservoirs are not well studied. Type B viruses were first isolated in 1940 and were divided into two antigenically different lineages in the 1970s: B/Victoria and B/Yamagata. B/Victoria dominated from the mid to late 1980s, while B/Yamagata took over in the 90s. Since 2000, both lines have been circulating worldwide. Until the spring of 2020, when B/Yamagata disappeared, said the virologist.

Influenza viruses, especially those of type A, are experts in mutations

What is the secret power of influenza viruses, what makes them the engines of annual epidemics and periodic pandemics, and why scientists joke that there is nothing older than last year's flu vaccine - Prof. Radostina Alexandrova commented on these topics.

She explained that influenza viruses, especially those of type A, are experts in mutations.

“Like a clever criminal pursued by the law, influenza viruses are constantly changing their camouflage - i.e. their own genetic and, accordingly, antigenic composition (the so-called antigenic drift). This is a continuous process of small genetic mutations, leading to new versions of the virus. It explains why we can get the flu repeatedly and every year there is a need for an updated new vaccine. Another scenario is also possible (the so-called antigenic shift or antigenic shift), when two different influenza viruses infect the same cell, and by exchanging genetic information, they give rise to a “hybrid” new virus. The phenomenon is called reassortment and occurs in pigs, which can be infected not only with swine, but also with human and avian influenza viruses. The genome of the influenza virus is segmented, represented by eight separate fragments, which can be “shuffled and mixed” with those of the “other” virus. Fortunately, such “hybrid” viruses rarely survive,” explained the virologist.

Pandemics of flu-like diseases were described in 1510, 1580, 1688, 1693, and the one in 1580 was particularly severe. At the beginning of the 21st century, the virus that caused the Spanish flu was restored. Its genetic material was isolated from samples preserved for almost a century, including from the bodies of residents of a small village in Alaska who died from the disease, remaining in the embrace of eternal frost. The recovery operation took place under exceptional security measures in a laboratory at the Centers for Disease Control and Prevention in Atlanta, USA, and was entrusted to one researcher, warned that if something went wrong and he got infected, he would remain completely isolated from the world until he recovered completely. This is one of the first synthetic viruses in the history of biomedicine. It is the fruit not of a random whim, but in response to the question of what is the secret of the Spanish flu, what made its cause so deadly, how to recognize similar threats in the future and, most importantly, how to prepare for them. After the studies were completed, the virus was destroyed, again for security reasons, said Prof. Radostina Alexandrova.

About influenza viruses and their interactions with their hosts 

We know a lot about influenza viruses and their interactions with their hosts, but not everything. Specialists are constantly discovering new and new pieces of the mosaic, said Prof. Alexandrova.

She explained that influenza viruses can cause epigenetic changes (i.e. changes in the activity of genes without affecting the DNA molecule itself) in the cellular layer that covers the alveoli - small bubble-like formations in the lungs, where the exchange of gases takes place during breathing. The changes continue long after the virus is eliminated, and the result is the inability of the body to react adequately to bacterial pathogens in the event of a subsequent infection with pneumococci. This is because some of the affected cells have a key function in immune defense and tissue regeneration. 

“We have all heard of the challenges of long COVID, but other viruses (and not only viruses), including the influenza virus, can also leave a similar “tail” behind. So don't be surprised if you come across the term “long flu”. Long-term effects include prolonged symptoms of the respiratory system and are most often observed in people who have needed hospital treatment in connection with the influenza infection. And is the flu to blame for the development of long-term neurological and other systemic disorders” - this question was asked by Prof. Radostina Alexandrova.

According to her, an interesting hypothesis is also associated with influenza viruses. It is assumed that in the last hours before the sudden onset of symptoms, when the infected person is already contagious to others, but still does not suspect that he is getting sick, his desire for social activity increases. Let's imagine the situation from the point of view of the virus - this is the moment in which it can spread to the next hosts, because very soon “his” person will feel bad and will voluntarily or involuntarily limit his contacts, the virologist added.

What led to the disappearance of B/Yamagata? 

It turns out that the virus limited its circulation even before the onset of the COVID-19 pandemic. The reason is a major outbreak of B/Yamagata in 2017/2018, which increased the level of population immunity against it. The low variability of the virus further improved the effectiveness of this immunity, by narrowing the range of people sensitive to B/Yamagata. All this, together with the strict barriers to transmission of the virus, imposed by the restrictive measures during the pandemic, contributed to its withdrawal from the stage. Let's not forget that type B viruses have no known reservoirs in nature, said Prof. Radostina Alexandrova.

She explained that the spread and “fate” of influenza viruses is monitored throughout the year by a network specifically created to the World Health Organization (WHO) for surveillance (Global influenza Surveillance and Response System - GISRS). It has been operating since 1952 and unites representative institutions of 123 countries. 

Twice a year, the WHO reviews the collected data and, based on the analysis made, prepares recommendations for the composition of influenza vaccines for the next season - in February for the Northern Hemisphere and in September for the Southern Hemisphere.

“Special attention is paid to the highly pathogenic for birds strain A (H5N1). While the COVID-19 pandemic was raging in people's lives, A(H5N1) caused the largest panzooty (pandemic in animals) of avian flu in the animal world, which has not yet ended. The virus has caused devastating damage to poultry farming and has taken the lives of millions of wild animals. More than 500 different species of wild birds and more than 80 species of wild mammals, including rare and endemic species, have been affected. It has reached all points on the planet, including Antarctica. Once again, it reminded us that we all - people, animals and the environment, are one whole, we are destined to be together and to depend on each other,” noted the virologist.

The risk of avian flu H5N1 to humans is currently low, but the development of the virus is not out of the researchers' sight. As it should be, because the best way to deal with a potential problem is not to deny and downplay it, but to prepare for solving it, said Prof. Radostina Alexandrova.

Professor Dr. Radostina Alexandrova graduated as the top of the class with a degree in “Biochemistry and Microbiology” (today “Molecular Biology”) at the Faculty of Biology of Sofia University “St. Kliment Ohridski” with a specialization “Virology”. She is a doctor of virology and a professor of morphology. She works at the Institute of Experimental Morphology, Pathology and Anthropology with a museum at the BAS. She has specialized in Slovakia, Hungary and Denmark.

She has more than 200 publications in Bulgarian and international scientific journals and conference proceedings, has 13 chapters in books and textbooks, over 650 participations in scientific forums, over 140 popular science articles and more than 700 media appearances related to the popularization of knowledge in the field of biomedicine. She is a member of the editorial boards of several Bulgarian and international scientific journals, of the Union of Scientists in Bulgaria and of the Bulgarian Anatomical Society.

She is a honorary lecturer at the Faculty of Biology (since 1998) and at the Faculty of Medicine (2011-2014) of SU “St. Kliment Ohridski”, at the New Bulgarian University (since 2023). She leads courses for doctoral students to the Training Center of BAS. Since 2005, she has been a member of the management of the Immunology Society at SUB. She is the head of seven research projects, funded by the “Scientific Research” Fund at the Ministry of Education and Science (MES), as well as of more than ten bilateral cooperation agreements between the BAS and similar organizations abroad. She is the supervisor of 40 diploma students and ten doctoral students, as well as dozens of post-doctoral students and specialists from the country and abroad. From May 2025, she is a member of the Permanent Scientific and Expert Commission to the “Scientific Research” Fund of the MES.