key: cord-0977076-xqte49qb
authors: Fang, Zhenhao; Peng, Lei; Lin, Qianqian; Zhou, Liqun; Yang, Luojia; Feng, Yanzhi; Ren, Ping; Renauer, Paul A.; Park, Jonathan J.; Zhou, Xiaoyu; Wilen, Craig B.; Chen, Sidi
title: Heterotypic vaccination responses against SARS-CoV-2 Omicron BA.2
date: 2022-03-23
journal: bioRxiv
DOI: 10.1101/2022.03.22.485418
sha: 8e80f9c7ffe996e5e96890273a3175ba1483876e
doc_id: 977076
cord_uid: xqte49qb

The Omicron sub-lineage BA.2 of SARS-CoV-2 has recently become dominant across many areas in the world in the on-going waves of COVID-19. Compared to the ancestral/wild-type (WT) virus, Omicron lineage variants, both BA.1 and BA.2, contain high number of mutations, especially in the spike protein, causing significant immune escape that leads to substantial reduction of vaccine and antibody efficacy. Because of this antigenic drift, BA.2 exhibited differential resistance profile to monoclonal antibodies than BA.1. Thus, it is important to understand whether the immunity elicited by currently available vaccines are effective against the BA.2 subvariant. We directly tested the heterotypic vaccination responses against Omicron BA.2, using vaccinated serum from animals receiving WT- and variant-specific mRNA vaccine in lipid nanoparticle (LNP) formulations. Omicron BA.1 and BA.2 antigen showed similar reactivity to serum antibodies elicited by two doses of WT, B.1.351 and B.1.617 LNP-mRNAs. Neutralizing antibody titers of B.1.351 and B.1.617 LNP-mRNA were ~2-fold higher than that of WT LNP-mRNA. Both homologous boosting with WT LNP-mRNA and heterologous boosting with BA.1 LNP-mRNA substantially increased waning immunity of WT vaccinated mice against both BA.1 and BA.2 subvariants. The BA.1 LNP-mRNA booster was ~3-fold more efficient than WT LNP-mRNA at elevating neutralizing antibody titers of BA.2. Together, these data provided a direct preclinical evaluation of WT and variant-specific LNP-mRNAs in standard two-dose and as boosters against BA.1 and BA.2 subvariants.

BA.1 and BA.2 subvariants share 21 mutations, but differ in 25 sites ( Fig. 1a-1b) Fig. 1c-1d) why the antibody response to BA.2 was higher in these two variants LNP-mRNA groups compared 99 to WT LNP-mRNA (Fig. 1a) . In all three vaccination groups, antibody response to BA.2 was 100 similar to that of BA.1 (Fig. 1c) RBD  S2  NTD   69del  L212I  S371L  Q493R  N764K N856K  N969K  P681H  G446S  A67V  T95I G142D 211del G339D  N440K  N679K  D796Y  Q954H  T547K   T19I  L24S  25-27del   V213G  S371F  T376A   D405N  R408S   143-145del  T478K Q498R  S375F  ins214EPE  70del  S477N G496S  L981F  S373P   K417N 

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