**1. Introduction**

Humanity has acquired knowledge to control most anthroponotic infections, such as measles, poliomyelitis, smallpox, and mumps. However, recently, problems related to zoonotic human infections have emerged. Since the natural reservoirs of these pathogens are unlimited, they are difficult or often impossible to control.

Influenza A virus belongs to the genus *Alphainfluenzaviruses* of the *Orthomyxoviridae* family and has a segmented genome consisting of single-stranded RNA segments of negative polarity [1]. Influenza A viruses are divided into subtypes (serotypes) based on the genetic and antigenic characteristics of its two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). The nomenclature of these viruses is based on a combination of the HA (H1–H18) and NA (N1–N11) subtypes. Wild waterfowl are a natural reservoir for all influenza A subtypes [2], except for H17N10 and H18N11, which were recently found in bats [3,4]. Influenza A viruses can also be detected in a wide variety of hosts including humans, swine, horses, dogs, cats, and sea mammals.

Pandemic influenza A virus appears in the human population every 10–30 years. There is currently no immunity to these viruses; therefore, the resultant pandemics cause

**Citation:** Ilyicheva, T.; Marchenko, V.; Pyankova, O.; Moiseeva, A.; Nhai, T.T.; Lan Anh, B.T.; Sau, T.K.; Kuznetsov, A.; Ryzhikov, A.; Maksyutov, R. Antibodies to Highly Pathogenic A/H5Nx (Clade 2.3.4.4) Influenza Viruses in the Sera of Vietnamese Residents. *Pathogens* **2021**, *10*, 394. https://doi.org/10.3390/ pathogens10040394

Academic Editors: Philipp A. Ilinykh, Kai Huang and Xuguang Li

Received: 9 February 2021 Accepted: 23 March 2021 Published: 25 March 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

high morbidity and often high mortality. It is supposed that pandemic influenza A viruses emerge because of the reassortment of viruses in humans and animals or the adaptation of zoonotic viruses to humans [5].

Reassortment occurs when two strains of influenza A virus coinfect one cell and can cause procreation of the new reassortant virus, which contains a new set of genes [6]. The influenza pandemics in 1957 and 1968 were caused by reassortant viruses containing genes of influenza A viruses of humans and birds [7]. The first pandemic of the 21st century was caused by a virus that emerged after multiple reassortments of human-, avian-, and swine-origin influenza A viruses [8].

The views on the cause of the 1918 pandemic (the so-called "Spanish flu") differ among experts. Some support the idea that the virus was directly introduced into the human population (without reassortment), while others believe that the pandemic virus emerged after multiple genome reassortments of avian and mammalian, and possibly swine and/or human, viruses that had emerged during the years preceding the pandemic of 1918 [9].

Regardless of the exact mechanism of the emergence of a new virus variant, there may be a certain period before the pandemic begins that is needed by the virus for optimal adaptation to the human host [10].

If this assumption is correct, then an understanding of whether the adaptation process is ongoing is possible by analyzing antibody levels in the sera of human populations inhabiting regions where the emergence of pandemic virus variants is most likely.

The objective of this research was to analyze the sera of Vietnamese residents using the hemagglutinin inhibition (HI) test and virus microneutralization (MN) with avian influenza viruses isolated in Vietnam and the Russian Federation in 2017–2018.
