Genetic and Antigenic Characterization of an Influenza A(H3N2) Outbreak in Cambodia and the Greater Mekong Subregion during the COVID-19 Pandemic, 2020

Abstract

Introduction of non-pharmaceutical interventions to control COVID-19 in early 2020 coincided with a global decrease in active influenza circulation. However, between July and November 2020, an influenza A(H3N2) epidemic occurred in Cambodia and in other neighboring countries in the Greater Mekong Subregion in Southeast Asia. We characterized the genetic and antigenic evolution of A(H3N2) in Cambodia and found that the 2020 epidemic comprised genetically and antigenically similar viruses of Clade3C2a1b/131K/94N, but they were distinct from the WHO recommended influenza A(H3N2) vaccine virus components for 2020-2021 Northern Hemisphere season. Phylogenetic analysis revealed multiple virus migration events between Cambodia and bordering countries, with Laos PDR and Vietnam also reporting similar A(H3N2) epidemics immediately following the Cambodia outbreak: however, there was limited circulation of these viruses elsewhere globally. In February 2021, a virus from the Cambodian outbreak was recommended by WHO as the prototype virus for inclusion in the 2021-2022 Northern Hemisphere influenza vaccine. IMPORTANCE The 2019 coronavirus disease (COVID-19) pandemic has significantly altered the circulation patterns of respiratory diseases worldwide and disrupted continued surveillance in many countries. Introduction of control measures in early 2020 against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection has resulted in a remarkable reduction in the circulation of many respiratory diseases. Influenza activity has remained at historically low levels globally since March 2020, even when increased influenza testing was performed in some countries. Maintenance of the influenza surveillance system in Cambodia in 2020 allowed for the detection and response to an influenza A(H3N2) outbreak in late 2020, resulting in the inclusion of this virus in the 2021-2022 Northern Hemisphere influenza vaccine.

Keywords: A(H3N2); COVID-19; Cambodia; Influenza; Laos; Vietnam; influenza; outbreak; vaccine.

FIG 1

Influenza detection by week in Cambodia, Laos PDR, Thailand, and Vietnam in 2020 compared to pandemic response stringency. Influenza detection in Cambodia (A), Laos PDR (B), Thailand (C), and Vietnam (D) compared to average weekly stringency (19) of public health policies enacted in accordance with the COVID-19 pandemic (blue line).

FIG 2

Dated phylogeny of HA gene of A(H3N2) virus showing an apparent global bottleneck in 2020. The analysis was based on 1,387 globally representative samples using the best-fit nucleotide substitution model (GTR+F3+R4). Cambodia viruses are colored in red, and reference strains and recent vaccine strains are highlighted along the tips.

FIG 3

Evolutionary relationships of the A(H3N2) viruses in Southeast Asia, late 2020–2021. Maximum likelihood phylogeny with branch lengths in substitutions per site (scale bar) generated using the best-fit nucleotide substitution model (K3Pu+F). Viruses collected from Southeast Asia from Jun 2020 are colored by country.

FIG 4

Location of antigenic mismatches between the 2020/2021 H3N2 vaccine virus and recent Cambodian viruses. (A) Influenza HA subunits and antigen sites A–E mapped on the crystal structure of the A/Brisbane/10/2007 (H3N2) influenza virus HA in complex with NeuAcα2-6Gal (PDB: 6AOV). (B) Antigenic mismatches between the 2020/2021 H3N2 vaccine seed strains and recent Cambodian viruses. The 2020/2021 vaccine seed strains included both the egg-based (A/Hong Kong/2671/2019) and cell-based (A/Hong Kong/45/2019) vaccine. Egg -and cell-based specific antigenic mismatches are indicated by * and #, respectively.