Background As a new epi-center of COVID-19 in Asia and a densely populated developing country, Indonesia is facing unprecedented challenges in public health. SARS-CoV-2 lineage B.1.466.2 was reported to be an indigenous dominant strain in Indonesia (once second only to the Delta variant). However, it remains unclear how this variant evolved and spread within such an archipelagic nation. Methods For statistical description, the spatiotemporal distributions of the B.1.466.2 variant were plotted using the publicly accessible metadata in GISAID. A total of 1302 complete genome sequences of Indonesian B.1.466.2 strains with high coverage were downloaded from the GISAID’s EpiCoV database on 28 August 2021. To determine the molecular evolutionary characteristics, we performed a time-scaled phylogenetic analysis using the maximum likelihood algorithm and called the single nucleotide variants taking the Wuhan-Hu-1 sequence as reference. To investigate the spatiotemporal transmission patterns, we estimated two dynamic parameters (effective population size and effective reproduction number) and reconstructed the phylogeography among different islands. Results As of the end of August 2021, nearly 85% of the global SARS-CoV-2 lineage B.1.466.2 sequences (including the first one) were obtained from Indonesia. This variant was estimated to account for over 50% of Indonesia’s daily infections during the period of March–May 2021. The time-scaled phylogeny suggested that SARS-CoV-2 lineage B.1.466.2 circulating in Indonesia might have originated from Java Island in mid-June 2020 and had evolved into two disproportional and distinct sub-lineages. High-frequency non-synonymous mutations were mostly found in the spike and NSP3; the S-D614G/N439K/P681R co-mutations were identified in its larger sub-lineage. The demographic history was inferred to have experienced four phases, with an exponential growth from October 2020 to February 2021. The effective reproduction number was estimated to have reached its peak (11.18) in late December 2020 and dropped to be less than one after early May 2021. The relevant phylogeography showed that Java and Sumatra might successively act as epi-centers and form a stable transmission loop. Additionally, several long-distance transmission links across seas were revealed. Conclusions SARS-CoV-2 variants circulating in the tropical archipelago may follow unique patterns of evolution and transmission. Continuous, extensive and targeted genomic surveillance is essential.

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