Patient Samples Serum from 70 unvaccinated patients (hereafter convalescent sera) who were infected between March and July 2020 and serum from 16 vaccinated patients with breakthrough contamination (2 Gamma and 14 Delta) (hereafter BTI sera) who were infected between 15 July and 20 September 2021 were analyzed

Patient Samples Serum from 70 unvaccinated patients (hereafter convalescent sera) who were infected between March and July 2020 and serum from 16 vaccinated patients with breakthrough contamination (2 Gamma and 14 Delta) (hereafter BTI sera) who were infected between 15 July and 20 September 2021 were analyzed. Spike protein and the RBD. All but one convalescent serum failed to neutralize Omicron BA.1. Overall, convalescent sera from patients with moderate disease experienced higher antibody levels and displayed a higher neutralizing ability against all strains than patients with moderate or severe forms of the disease. The sera from BTI cases fell into one of two groups: half the sera experienced a high neutralizing activity against the ancestral B.1 strain as well as against the infecting strain, while the other half had no or a very low neutralizing activity against all strains. Although antibody levels against the spike protein and the RBD were lower in BTI sera than in unvaccinated convalescent sera, most neutralizing sera also retained partial neutralizing activity against Omicron BA.1, suggestive of a better cross-neutralization and higher affinity of vaccine-elicited antibodies over virus-induced antibodies. Accordingly, the IC50: antibody level ratios were comparable for BTI and convalescent sera, but remained lower in the neutralizing convalescent sera from patients with moderate disease than in BTI sera. The neutralizing activity of BTI sera was strongly correlated with antibodies against the Spike protein and the RBD. Together, these findings spotlight qualitative differences in antibody responses elicited by contamination in vaccinated and unvaccinated individuals. They further indicate that breakthrough infection with a pre-Omicron variant boosts immunity and induces cross-neutralizing antibodies against different strains, including Omicron BA.1. Keywords: SARS-CoV-2, variants of concern Pyrithioxin (VOCs), neutralizing antibodies, convalescent sera, breakthrough contamination, Delta, Omicron BA.1 Pyrithioxin 1. Introduction Two years into the COVID-19 pandemic which originated in Wuhan, China, in December 2019, SARS-CoV-2 has officially infected over 551 million individuals and claimed more than 6. 34 million lives as of 3 July 2022. SARS-CoV-2 variants constantly mold the pandemic scenery. Variants that spread faster or elude immunity conferred by prior contamination or by vaccines readily outcompete established strains. The first evolution of the Wuhan strain (B.1) emerged between mid-February and mid-March 2020 [1,2,3]. It harbors the D614G mutation in the Spike protein (S-D614G), which favors viral infectivity and transmission by positioning the Spike protein in an up position prone to bind ACE-2 [4]. Numerous other lineages have since stemmed from B.1, including the main variants of concern (VOCs) Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.1.529). Aside from an increased transmission, Pyrithioxin contamination with the Alpha and Delta variants is usually associated with higher disease severity and fatality rates [5,6,7,8,9,10,11,12,13,14], including in children and adolescents [15,16]. The recent Omicron variants BA.1 and BA.2, which were first identified in sub-Saharan Africa in November 2021, have supplanted Delta within a few weeks, causing two twin peaks in most countries [17]. Their infectivity and transmissibility are much higher than Delta and yet more transmissible sublineages are now blossoming. These variants are in turn being outgrown by BA.2 sublineages (notably BA.2.12.1) and by BA.4 and BA.5 [18,19]. The large number of deletions and mutations (>60 across the genome, including 37 in the viral Spike protein and R203K in the Nucleocapsid N), improve its affinity for the viral receptor ACE2 on target cells [20,21,22,23] and thereby its transmissibility, accelerate viral assembly and enable immune evasion [24,25,26,27,28]. Omicron variants cause less severe forms of COVID-19 (~60% lower risk of hospitalization or death compared to Delta) [20,29,30,31,32], reflecting the combined effects of intrinsic lower viral pathogenicity and prior immunity [14,33,34,35,36]. Encapsulated mRNA-based vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) as well as CSF1R adenovector-based vaccines ChAdOx1 (Astra Zeneca, AZ) and Ad26.Cov2.S (Janssen) confer effective protection against severe forms of COVID-19 [10,37,38,39,40,41]. Protection against contamination and transmission is usually less striking, particularly for the two latest VOCs Delta and Omicron [10,39,40,41,42,43,44,45,46,47,48,49,50], as testified by increasing numbers of reinfections and breakthrough infections [25,36,38,51,52,53,54,55,56,57,58]. The waning of immune responses and the emergence of variants with mutations in the Spike protein [25,26,27,37,38,39,40,43,48,49,51,52,59,60,61,62,63,64,65,66,67,68,69,70,71] are the main reasons of vaccine escape and reinfections. Convalescent individual sera and sera from individuals vaccinated.