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[Preprint]. 2024 Jul 16:2024.07.15.602781.
doi: 10.1101/2024.07.15.602781.

Dissecting human monoclonal antibody responses from mRNA- and protein-based XBB.1.5 COVID-19 monovalent vaccines

Raianna F Fantin  1   2 , Jordan J Clark  1   2 , Hallie Cohn  1   2 , Deepika Jaiswal  1 , Bailey Bozarth  1   2 , Alesandro Civljak  1 , Vishal Rao  1   2   3 , Igor Lobo  1   2 , Jessica R Nardulli  1   2 , Komal Srivastava  1   2 , Jeremy Yong  1   2 , Robert Andreata-Santos  1   2   4 , Kaitlyn Bushfield  1   2 , Edward S Lee  5   6 , Gagandeep Singh  1   2 ; PVI Study Group; Steven H Kleinstein  5   7 , Florian Krammer  1   2   8   9 , Viviana Simon  1   2   8   10   11 , Goran Bajic  1 , Camila H Coelho  1   2   12
Affiliations

Dissecting human monoclonal antibody responses from mRNA- and protein-based XBB.1.5 COVID-19 monovalent vaccines

Raianna F Fantin et al. bioRxiv. .

Update in

Abstract

The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicit de novo B-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was a de novo, antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs' specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms.\.

Keywords: Novavax; SARS-CoV-2 mAbs; cryo-EM; mRNA vaccines; monovalent XBB.1.5.

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Conflict of interest statement

Competing interests The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARSCoV-2 serological assays, NDV-based SARS-CoV-2 vaccines influenza virus vaccines and influenza virus therapeutics which list Florian Krammer as co-inventor. Viviana Simon is listed on the SARS-CoV-2 serological assay patent application as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, CastleVax, to develop SARS-CoV-2 vaccines. Florian Krammer is co-founder and scientific advisory board member of CastleVax. Florian Krammer has consulted for Merck, Curevac, GSK, Seqirus and Pfizer and is currently consulting for 3rd Rock Ventures, Gritstone and Avimex. The Krammer laboratory is collaborating with Dynavax on influenza vaccine development and with VIR on influenza virus therapeutics.

Figures

Figure 1.
Figure 1.. SARS-CoV-2 Immune history of enrolled participants.
Participants 1, 2, and 3 received XBB.1.5 mRNA vaccination, while 4 and 5 received the recombinant protein XBB.1.5 vaccine. Delta and Omicron variant’s timeline reflects the United States of America. Created with BioRender.com.
Figure 2.
Figure 2.. Binding and neutralizing capacity of monoclonal antibodies isolated from participants vaccinated with either mRNA or protein-based SARS-CoV-2 XBB.1.5 vaccines
(a – c) Binding activity of the 21 selected mAbs against ancestral, XBB.1.5 and JN.1 spike protein and (d -f) ancestral, XBB.1.5 and JN.1 RBD. Neutralizing capacity of binding mAbs against (g) ancestral, (h) XBB.1.5, and (k) JN.1 SARS-CoV-2. Antibodies from the mRNA group are represented by the letter M and protein-based by the letter P. Antibodies that did not bind any antigen are not shown. Only mAbs binding to at least one antigen were selected for the in vitro neutralization assays. The dashed line represents the limit of detection (LOD), which is set at the starting dilution of 30 μg/mL. Binding is defined by minimum binding concentration (μg/mL) and neutralization is determined by half-maximal inhibitory concentration (IC50). Negatives were assigned half the LOD.
Figure 3:
Figure 3:. In vivo protection by prophylactic treatment with mAbs M2, M27 and M39.
(a – c) Weight loss in mice treated with 10 mg/kg (intraperitoneally) of M2, M27, or M39 mAbs two hours before challenge with a 3xLD50 dose of (a) WA1/2020, (b) XBB.1.5 and (c) JN.1. (d – f) Survival curves of mice treated with M2, M27, or M39 mAbs and infected with (d) WA1/2020, (e) XBB.1.5, and (c) JN.1. An influenza virus anti-hemagglutinin mAb, CR9114, was utilized as a negative control. Antibodies from the mRNA group are represented by the letter M and protein-based by the letter P.
Figure 4.
Figure 4.. Cryo-EM structures of M2 and M39 Fabs in complex with XBB.1.5 spike.
(a) Surface regions of the SARS-CoV-2 spike contacted by the two antibodies M2 and M39. The global composite cryo-EM map is shown as a transparent surface, with the NTD:M2 Fab and RBD:M39 Fab complexes docked and shown in cartoon representation. (b) The M2 Fab defines an epitope on the “top” side of the NTD. M2 creates an extensive surface contact area and engages NTD with both its heavy and light chains. (d) and (e) are two 180° views along the y-axis that show details of the intermolecular interactions between the M2 Fab and NTD with numerous polar and non-polar interactions. p-GLU designates pyroglutamate. (c) The M39 Fab defines an epitope on RBD engaged by numerous published “class 3” antibodies. M39 (f) and (g) are two 180° views along the y-axis that show details of the M39 Fab:RBD molecular interface with very few interacting residues forming salt bridges.
Figure 5.
Figure 5.. Usage of antibody V gene in heavy and light chain of monoclonal antibodies targeting SARSCoV-2 spike protein epitopes.
(a) V gene pairings for monoclonal antibodies targeting the entire ancestral spike protein, as well as the RBD, NTD, and S1 and S2 subunits. (b) V gene pairings for monoclonal antibodies targeting the entire ancestral spike protein, XBB.1.5, and JN.1 variants, along with their respective RBD domains. The size of each circle indicates the number of monoclonal antibodies that use the corresponding V gene pair and bind to the specified epitope. The definition of positive binding was determined based on the cutoffs from Figure 2 and Supplementary Figure S3.
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