Imprinting has been beneficial up to Delta, but the completely different Omicron lineages evade antibodies and T-cells elicited by prior immunogens [2,3,24,68,75,76,77]. underscoring qualitative differences in antibodies elicited by contamination or vaccination. Together, these findings spotlight the importance of vaccination to trigger highly cross-reactive antibodies that neutralize phylogenetically and antigenically distant strains, and suggest that immune imprinting by first generation vaccines may restrict, but not abolish, cross-neutralization. Keywords: SARS-CoV-2, neutralization, vaccination, hybrid immunity, breakthrough contamination, Omicron BA.1 BA.2 BA.4 BA.5 1. Introduction The Omicron lineage of SARS-CoV-2 comprises several sublineages. BA.1, BA.2 and BA.3 were first identifed in South Africa in November 2021. Between December 2021 and early January 2022, Omicron BA.1 rapidly outcompeted the Delta variant, which dominated the COVID-19 scenery across all continents at the time [1]. BA.1 was rapidly followed by the genetically distinct BA.2 sublineage, generating two overlapping peaks in most countries, including Luxembourg, in the winter and early spring 2022. BA.1 and BA.2 harbor 29 and 34 mutations, insertions and deletions in Spike, respectively, of which 21 are shared by the two sublineages. BA.3 shares mutations with both BA.1 and BA.2 but spread poorly compared to BA.1 and BA.2. Within a few months, other BA.2-derived sublineages, such as BA.4, BA.5 and BA.2.12.1 displaced BA.1 and BA.2. BA.4 and BA.5 have identical Spike sequences and differ by only three mutations in ORF7b, M (Membrane protein) and N (Nucleocapsid). Nevertheless, BA.5 has become the dominant variant in most countries. Penthiopyrad Since summer time 2022, the Omicron scenery has expanded further. BA.2 sublineages BA.2.12.1, BA.2.75, BA.2.75.2, as well as BA.4, BA.5 and their offspring BA.4.6, BQ.1.1 and XBB.1 are gaining ground. These FBL1 strains carry additional mutations which further increase their infectivity and antibody escape compared to the parental BA.2 [2,3,4,5,6,7,8,9,10]. While Omicron strains are less pathogenic and associated with lower fatality rates than Delta, the later strains BA.2.75 and BA.5 seem to gain pathogenicity compared to the early BA.1 and BA.2 [6,11,12,13,14,15,16,17,18,19,20,21,22]. The Omicron lineage typically features strongly enhanced transmissibility compared to Delta and pre-Omicron variants [3,4,5,6,23,24]. Increased transmissibility is due to its stronger docking to the receptor ACE2, and to its endocytosis-mediated, TMPRSS-2 impartial entry into target cells, which also favors immune evasion [5,14,19,25,26,27,28,29,30,31,32,33], although BA.5 can also use the TMPRSS-2 route [24]. Furthermore, compensatory mutations have appeared in several Penthiopyrad strains to balance the replicative cost imposed by immune escape mutations (e.g., R493Q for F486V in BA.4/5 [2,34,35]). The Omicron Spike also adopts a distinct, more compact conformation and glycosylation patterns which shield it from type 1, 2 and 3 Neutralizing antibodies (NAbs) [33,36,37]. Typically, BA.1 and BA.2 show a dramatic drop in susceptibility to neutralization compared to the ancestral B.1 strain containing the Spike D614G mutation [25,26,27,28,38,39,40,41,42,43,44,45,46,47,48]. Sera from vaccinees who have received 2 vaccine doses do not cross-neutralize Omicron Penthiopyrad sublineages BA.1 and BA.2 [4,25,26,27,28,34,37,41,42,46,47,49,50]. Vaccination-induced and infection-induced NAbs wane after a few months. Booster vaccination (3rd and 4th doses) effectively restore NAbs and cellular responses against Omicron variants and protect against severe COVID-19 and death [28,29,34,42,45,46,50,51,52,53,54,55,56,57,58,59,60,61,62,63], but their durability is usually short [19,37,62,63]. BA.2 offspring BA.2.12.1 and BA.2.75 are modestly more resistant to NAbs than BA.2, while BA.2.75.2, BA.4 and BA.5 are typically more resistant to vaccine-elicited antibodies than BA.2 due Penthiopyrad to mutations such as R346T, L542R and F486V/S [2,4,8,9,10,19,34,35,52,63,64,65,66]. BA.2.75, BA.4 and BA.5 also resist antibodies elicited by Omicron BA.1 and BA.2 contamination [2,3,19,34,35,52,65,66,67,68]. The emergence of antigenically unique variants with increased infectivity and ability to evade immune responses elicited by prior contamination or vaccination designs both the pandemic scenery and clinical burden [2,65,69]. With the exponential increase in breakthrough infections due to Omicron, numerous studies have investigated cross-protection between Omicron sublineages. Epidemiological studies suggest that breakthrough contamination with BA.1 and BA.2 confers some degree of cross-protection against contamination with other Omicron sublineages like BA.2-offspring [70,71]. This increased protection may reflect better cross-neutralization due to antigenically closer strains, or the shorter time elapsed since contamination [23,66,71,72,73,74]. Aside.