WH1 RBD-specific IgG levels were consistently lower in ChAdOx1 recipients, irrespective of their age (Fig.1E). proportion of WH1-specific IgG was 26% and 17%, respectively. All donors generated resting Dichlorisone acetate RBD-specific Bmem, which were boosted after the second dose of ChAdOx1 and were similar in number to those produced by BNT162b2. The second dose of ChAdOx1 boosted Bmem that recognized VoC, and 37% and 39% of WH1-specific Bmem recognized BA.2 and BA.5, respectively. These data uncover mechanisms by which ChAdOx1 elicits immune memory to confer effective protection against severe COVID-19. == Supplementary Information == The online version contains supplementary material available at 10.1007/s10875-023-01527-2. Keywords:COVID-19 vaccine, memory B cells, variant of concern, adenoviral vector vaccine, neutralizing antibodies == Introduction == The coronavirus disease 2019 (COVID-19) pandemic is an ongoing worldwide health threat that has caused over 757 million cases and over 6.8 million deaths, as of February 2022 [1]. The virus causing COVID-19, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has a positive-sense single-stranded RNA genome which encodes four main structural proteins: Spike, Nucleocapsid (NCP), Envelope, and Membrane [2]. Viral fusion is mediated by the receptor-binding domain (RBD) of the Spike protein, which binds the human angiotensin converting enzyme 2 (ACE2) receptor, initiating entry into host cells [3,4]. In efforts to control the pandemic, there has been rapid global uptake of new mRNA and adenoviral vector vaccines, which are both over 90% effective against severe disease and hospitalization with COVID-19 [5,6]. These COVID-19 vaccines use the Spike protein as the main immunogen, as the RBD is the major target for neutralizing antibodies (NAb) [711]. In Australia, the Pfizer-BioNTech BNT162b2 mRNA vaccine (BNT162b2) and Dichlorisone acetate the AstraZeneca ChAdOx1 nCoV-19 adenoviral vector vaccine (ChAdOx1) were first approved for two-dose primary schedules [12,13]. As evidence arose that protection against infection decreased over 46 months following two-dose vaccination, mRNA booster vaccines (3rd and 4th doses) were recommended [14,15]. Despite this, ChAdOx1 is the most widely distributed COVID-19 vaccine globally, meaning that a large proportion of the global population received this vaccine for their primary doses [1,16,17]. It has been well-characterized that the levels of NAb, Spike-specific, and RBD-specific IgG detected after two doses of ChAdOx1 were all significantly lower than those elicited by mRNA vaccines such as BNT162b2 [1821]. After either vaccine type, the RBD-specific antibody levels significantly declined after 1-month post-vaccination; however, IgG remained detectable at least 6 months post-dose two [2224]. The Spike RBD-specific Bmem elicited by two doses BNT162b2 have been studied comprehensively [2227]. These Bmem are boosted by the second dose and show increased affinity of their surface Ig [23]. Spike- and RBD-specific Bmem displayed a resting phenotype with the majority expressing surface CD27 and most lacking surface CD71, a Dichlorisone acetate marker of recent activation [22,26]. Spike-specific Bmem have also been detected in all individuals after two doses of ChAdOx1 [28]. However, it remains unclear how these Bmem compared to those elicited by mRNA vaccination with regards to their phenotype, durability, and kinetics. Multiple SARS-CoV-2 variants of concern (VoC) have arisen, which evade the humoral immune response to differing degrees, mostly due to mutations in the RBD [25,2933]. Following emergence of the Alpha, Beta, Gamma, and Delta variants, the currently designated VoC (as of January 2022) is the Omicron variant, with multiple sublineages Rabbit Polyclonal to PIAS2 including BA.1, BA.2, BA.4, and BA.5 [3436]. Omicron demonstrates enhanced transmissibility and has been found to escape vaccine-elicited NAb to a far greater degree than any of the past VoC. The original Omicron sublineage BA.1 carries 35 Spike mutations, 15 of which are in the RBD [3740]. The BA.2 sublineage has 16 RBD mutations, with six differences from BA.1, and became the predominant SARS-CoV-2 variant around March 2022 [38,39]. BA.4 and BA.5 have the same RBD sequence with 17 mutations and share all BA.2 RBD mutations except for Q493R while having acquired L452R, shared with Delta, and F486V [38,39]. BA.5 overtook BA.2 as the prevalent circulating strain worldwide around Dichlorisone acetate August 2022. Two doses of either an mRNA or adenoviral vector vaccine elicit very weak NAb against all Omicron sublineages, with levels 10100-fold lower than those against the WH1 strain [32,4152]. However, mRNA vaccines have been found to elicit substantial frequencies of Omicron-specific Bmem [26,27,53]. Higher somatic hypermutation (SHM) levels were found in variant-binding Bmem than in.