Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Oct 21:12:713408.
doi: 10.3389/fmicb.2021.713408. eCollection 2021.

A Comprehensive Molecular and Epidemiological Characterization of Influenza Viruses Circulating 2016-2020 in North Macedonia

Maja Kuzmanovska  1 , Golubinka Boshevska  1 , Elizabeta Janchevska  1 , Teodora Buzharova  1 , Milica Simova  1 , Aneta Peshnacka  1 , Gordana Nikolovska  1 , Dragan Kochinski  1 , Radica Stoleska Ilioska  1 , Kristina Stavridis  1 , Vladimir Mikikj  1 , Gordana Kuzmanovska  1 , Shaban Memeti  1 , Icko Gjorgoski  2
Affiliations

A Comprehensive Molecular and Epidemiological Characterization of Influenza Viruses Circulating 2016-2020 in North Macedonia

Maja Kuzmanovska et al. Front Microbiol. .

Abstract

Influenza viruses know no boundaries, representing an example of rapid virus evolution combined with pressure exerted by the host's immune system. Seasonal influenza causes 4-50 million symptomatic cases in the EU/EEA each year, with a global death toll reaching 650,000 deaths. That being the case, in 2014 North Macedonia introduced the sentinel surveillance in addition to the existing influenza surveillance in order to obtain more precise data on the burden of disease, circulating viruses and to implement timely preventive measures. The aims of this study were to give a comprehensive virological and epidemiological overview of four influenza seasons (2016-2020), assess the frequency and distribution of influenza circulating in North Macedonia and to carry out molecular and phylogenetic analyses of the hemagglutinin (HA) and neuraminidase (NA) genes of influenza A(H1N1)pdm09, A(H3N2) from ILI and SARI patients. Our results showed that out of 1,632 tested samples, 46.4% were influenza positive, with influenza A(H1N1)pdm09 accounting for the majority of cases (44%), followed by influenza B (32%) and A(H3N2) (17%). By comparing the sentinel surveillance system to the routine surveillance system, we showed that the newly applied system works efficiently and gives great results in the selection of cases. Statistically significant differences (p = < 0.0000001) were observed when comparing the number of reported ILI cases among patients aged 0-4, 5-14, 15-29, and 30-64 years to the reference age group. The phylogenetic analysis of the HA sequences unveiled the resemblance of mutations circulating seasonally worldwide, with a vast majority of circulating viruses belonging to subclade 6B.1A. The PROVEAN analysis showed that the D187A substitution in the receptor binding site (RBS) of the A(H1N1)pdm09 HA has a deleterious effect on the its function. The A(H3N2) viruses fell into the 3C.2a and 3C.3a throughout the analyzed seasons. Molecular characterization revealed that various substitutions in the A(H3N2) viruses gradually replaced the parental variant in subsequent seasons before becoming the dominant variant. With the introduction of sentinel surveillance, accompanied by the advances made in whole-genome sequencing and vaccine therapeutics, public health officials can now modify their approach in disease management and intervene effectively and in a timely manner to prevent major morbidity and mortality from influenza.

Keywords: A(H1N1)pdm09; A(H3N2); ILI sentinel surveillance system; SARI sentinel surveillance system; influenza; molecular evolution; phylogeny.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Percentage of influenza types and subtypes from ILI and SARI surveillance (2016–2020). (B) The total number of influenza positive samples per year is presented by blue bars. Annual percentages of reported positive cases for influenza A subtypes H1N1pdm09 (orange), H3N2 (gray) and influenza B/Victoria (green) and B/Yamagata (blue) are also presented.
FIGURE 2
FIGURE 2
Graphical representation of ILI and SARI positive cases divided by week and subtype.
FIGURE 3
FIGURE 3
A(H1N1)pdm09 HA phylogenetic tree.
FIGURE 4
FIGURE 4
A(H3N2) HA phylogenetic tree.
See this image and copyright information in PMC

References

    1. Al Khatib H. A., Al Thani A. A., Gallouzi I., Yassine H. M. (2019). Epidemiological and genetic characterization of pH1N1 and H3N2 influenza viruses circulated in MENA region during 2009–2017. BMC Infect. Dis. 19:314. 10.1186/s12879-019-3930-6 - DOI - PMC - PubMed
    1. Baranovich T., Vongphrachanh P., Ketmayoon P., Sisouk T., Chomlasack K., Khanthamaly V., et al. (2017). Antiviral drug–resistant influenza B viruses carrying H134N substitution in neuraminidase, Laos, February 2016. Emerg. Infect. Dis. 23 686–690. 10.3201/eid2304.161876 - DOI - PMC - PubMed
    1. Bedford T., Riley S., Barr I. G., Broor S., Chadha M., Cox N. J., et al. (2015). Global circulation patterns of seasonal influenza viruses vary with antigenic drift. Nature 523 217–220. 10.1038/nature14460 - DOI - PMC - PubMed
    1. Bragstad K., Nielsen L. P., Fomsgaard A. (2008). The evolution of human influenza A viruses from 1999 to 2006: a complete genome study. Virol, J. 5 1–19. 10.1186/1743-422X-5-40 - DOI - PMC - PubMed
    1. Broberg E., Melidou A., Prosenc K., Bragstad K., Hungnes O., and WHO European Region and the European Influenza Surveillance Network members of the reporting countries., et al. (2016). Predominance of influenza A (H1N1) pdm09 virus genetic subclade 6B. 1 and influenza B/Victoria lineage viruses at the start of the 2015/16 influenza season in Europe. Euro Surveill 21:30184. 10.2807/1560-7917.ES.2016.21.13.30184 - DOI - PubMed

LinkOut - more resources