Simulations of R52I variant showed slight lowering of interaction affinity between ORF8 monomers compared to wildtype strain. mutations in the S protein might lead to higher affinity with host receptors and resistance against antibodies, but not all are due to different antibody binding (epitope) regions. Mutations may, however, result in NPI64 diagnostic tests failures and possible interference with binding of newly identified anti-viral candidates against SARS-CoV-2, likely necessitating roll out of recurring flu-like shots annually for tackling COVID-19. The functional relevance of these mutations has been described in terms of modulation of host tropism, antibody resistance, diagnostic sensitivity and therapeutic candidates. Besides global economic losses, post-vaccine reinfections with emerging variants can have significant clinical, therapeutic and public health impacts. Keywords: B.1.1.7, B.1.351, B.1.1.28.1, 501Y.V1, 501Y.V2, P.1, Clade G, COVID-19 vaccines, D614G variant, furin cleavage site, immune escape, ORF8, spike protein, public health strategies, vaccine delivery 1. Background Since the initial outbreak of COVID-19, the Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) virus has claimed more than 2.4 million lives out of 100 million affected individuals. The SARS-CoV-2 genome codes for non-structural (nsp) and Vegfb structural proteins including the spike (S), nucleocapsid (N), membrane (M), and envelope (E) proteins [1,2]. The S protein mediates initial contact with human hosts while the E and M proteins function in viral assembly and budding. The recent temporal analyses of SARS-CoV-2 epidemics highlighted selective global sweep of the D614G variant S protein (Clade G) over G251V in ORF3a (Clade V) and L84S in ORF 8 (Clade S) NPI64 variants [2,3,4,5]. The ubiquitous D614G variant of SARS-CoV-2 exhibits efficient replication in upper respiratory tract epithelial cells and higher transmissibility among humans, thereby conferring enhanced fitness [6,7]. As per the latest global reports on COVID-19, three new strains assigned to lineages 501Y.V1, 501Y.V2 and P.1 have been NPI64 identified (Figure 1ACC) (cov-lineages.org). The former, referred to as SARS-CoV-2 VOC 202012/01 (Variant Of Concern, year 2020, month 12, variant 01), was identified as a part of virological and epidemiological analysis, due to a sudden rise in COVID-19 cases detected in south-east England (Figure 1A) [8,9]. For week 51 of 2020, hospital and/or intensive care unit (ICU) occupancy and/or new admissions due to COVID-19 were high (at least 25% of the peak level during the pandemic) or had increased compared with the previous week in the UK and other 30 countries [10]. For week 51 of 2020, hospital and/or ICU occupancy as well as new admissions due to COVID-19 had increased compared with the previous week in the UK and other 30 countries [10]. For week 52/2020, all-cause excess mortality data from the UK and EU/EEA countries reported to the EuroMOMO network NPI64 identified a recent substantial increase in mortality, mainly affecting those aged 45 years and above and likely attributed to the 501Y.V1 variant. Preliminary reports from the UK suggested higher transmissibility (increase by 40C70%) of this strain, escalating the Ro (basic reproduction number) of the virus to 1 1.5C1.7 [8,11]. This apparent fast spreading variant shows twenty three mutationsthirteen non-synonymous, six synonymous and four amino acid deletions and is reported by forty-five nations [8]. The 501Y.V2 lineage emerged in the Nelson Mandela Bay area of Eastern Cape Province, South Africa, followed by its steep spread to Eastern and Western Cape Provinces (Figure 1B) [12]. In mid-October after gradual weakening on first epidemic wave, the Nelson Mandela Bay area showed 20% PCR positivity rate followed by resurgence of a second wave in both Eastern and Western cape provinces, resulting in Ro > 1 [12]. The identified mutant strain (501Y.V2) displays nine non-synonymous mutations along with three amino acid deletions and is reported by twenty-four countries till date. Another variant from Brazil (known as VOC202101/02 in UK), identified first in Japanese travelers from Brazil, shows seventeen unique mutations including the N501Y and E484K mutations [13]. As of 23 January NPI64 2021, the P.1 lineage has been reported by six countries, including Germany, Italy, Brazil, Japan and South Korea (Figure 1C) [14,15]. Open in a separate window Figure 1 Emergence of new B.1.1.7, B.1.351 and P.1 variant lineages. (ACC) Global distribution of sequences arising from various nations reporting 501Y.V1 (B.1.1.7), 501Y.V2 (B.1.351) and P.1 (B.1.1.28.1) variants, respectively. Pinned colored shapes on the map indicate major vaccine trials in various regions around the globe. Geographical pinning of vaccines in regions with rising frequency of variant population indicate the need to re-assess these candidates against new variants. Single (Light Blue), More.