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

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.

Is influenza B/Yamagata extinct and what public health implications could this have? An updated literature review and comprehensive assessment of global surveillance databases

“…Of the remaining 587 articles, 547 were discarded for not matching the inclusion criteria (of these, 62 were not further considered since no reported influenza cases were type B), 7 for being based on the WHO FluNet and/or GISAID database, 3 for being previous reports from the GIHSN, and 4 because of overlap with more recent and/or larger articles based on the same data sources. A total of 26 articles were included in the systematic review: their main characteristics are reported in Table 1 [ Soldevila 2022, Murillo-Zamora 2021, Korsun 2021, Panatto 2021, Pablo-Marcos 2020, Miron 2021, Hu 2021, Omer 2022, Olson 2022, Auvinen 2022, Kuzmanovska 2021, Wagatsuma 2022, Heinzinger 2021, Rios-Silva 2022, Suntronwong 2021, da Costa 2022, Melidou 2020, Huang 2022, O’Neill 2022, Kolosova 2022, Peck 2023, Chon 2023, Merced-Morales 2022, Melidou 2022, Sominina 2022, Song 2022 ]. Europe was the most represented area (12 articles, of which 2 reported findings from multiple countries in the WHO European Region), followed by Asia (n=6), North America (n=5), and Oceania and South America (n=1 each).…”

Phylogenetic analysis of HA and NA genes of influenza A viruses in immunosuppressed inpatients in Beijing during the 2018–2020 influenza seasons

“…The previous literatures and surveillances of the Centers for Disease Control and Prevention (CDC) of influenza at the molecular level were mainly from immunocompetent patients [ 8 , 9 ]. With the progress of medical technology, immunosuppressed patients who have undergone haemopoietic stem cell transplantation (HSCT) or solid-organ transplantation (SOT), patients on chronic haemodialysis, and patients receiving systemic corticosteroids, immunosuppressants and biological reagents have increased each year [ 10 – 12 ].…”