Scholars@Duke publication: Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human VH1-2-rearranging mouse models.

Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human VH1-2-rearranging mouse models.

Publication , Journal Article

Batra, H; Luo, S; Saunders, KO; Higgins, JS; Jian, F; Zhang, J; Kibria, MG; Jonaid, GM; Zhou, QJ; Eaton, A; Cronin, K; Mallory, ML; Parks, R ...

Published in: Proc Natl Acad Sci U S A

March 31, 2026

Published version (DOI) Link to item

During V(D)J recombination, antibody diversity is enhanced by nontemplated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human VH1-2 and Vκ1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a related mouse model in which a single VH1-2 rearranges to human D3-3 and JH6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4/.5 spike-ferritin nanoparticle-immunization of the new model elicited four highly related humanized antibodies that potently neutralize downstream Omicron subvariants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early Omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are related in their epitope recognition to recently described antibodies from Omicron-infected humans. These studies validate the utility of single human VH- and Vκ-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens.

Duke Scholars

Author Barton Ford Haynes Medicine, Duke Human Vaccine Institute

Author Kevin O'Neil Saunders Surgery, Surgical Sciences

Author David Charles Montefiori Surgery, Surgical Sciences

Published In

Proc Natl Acad Sci U S A

DOI

10.1073/pnas.2537053123

EISSN

1091-6490

Publication Date

March 31, 2026

Volume

123

Issue

Start / End Page

e2537053123

Location

United States

Related Subject Headings

Spike Glycoprotein, Coronavirus
SARS-CoV-2
Mice
Humans
Disease Models, Animal
Complementarity Determining Regions
COVID-19
Broadly Neutralizing Antibodies
Antibodies, Viral
Antibodies, Neutralizing

Citation

APA

Chicago

ICMJE

MLA

NLM

Batra, H., Luo, S., Saunders, K. O., Higgins, J. S., Jian, F., Zhang, J., … Alt, F. W. (2026). Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human VH1-2-rearranging mouse models. Proc Natl Acad Sci U S A, 123(13), e2537053123. https://doi.org/10.1073/pnas.2537053123

Batra, Himanshu, Sai Luo, Kevin O. Saunders, Jaclyn S. Higgins, Fanchong Jian, Jun Zhang, Md Golam Kibria, et al. “Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human VH1-2-rearranging mouse models.” Proc Natl Acad Sci U S A 123, no. 13 (March 31, 2026): e2537053123. https://doi.org/10.1073/pnas.2537053123.

Batra H, Luo S, Saunders KO, Higgins JS, Jian F, Zhang J, et al. Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human VH1-2-rearranging mouse models. Proc Natl Acad Sci U S A. 2026 Mar 31;123(13):e2537053123.

Batra, Himanshu, et al. “Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human VH1-2-rearranging mouse models.” Proc Natl Acad Sci U S A, vol. 123, no. 13, Mar. 2026, p. e2537053123. Pubmed, doi:10.1073/pnas.2537053123.

Batra H, Luo S, Saunders KO, Higgins JS, Jian F, Zhang J, Kibria MG, Jonaid GM, Zhou QJ, Eaton A, Cronin K, Mallory ML, Mattocks M, Edwards RJ, Parks R, Lee EM, Ye AY, Williams AC, Jung G, Mansouri K, Alam SM, Montefiori DC, Tian M, Baric RS, Cao Y, Haynes BF, Chen B, Alt FW. Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human VH1-2-rearranging mouse models. Proc Natl Acad Sci U S A. 2026 Mar 31;123(13):e2537053123.

Published In

Proc Natl Acad Sci U S A

DOI

10.1073/pnas.2537053123

EISSN

1091-6490

Publication Date

March 31, 2026

Volume

123

Issue

Start / End Page

e2537053123

Location

United States

Related Subject Headings

Spike Glycoprotein, Coronavirus
SARS-CoV-2
Mice
Humans
Disease Models, Animal
Complementarity Determining Regions
COVID-19
Broadly Neutralizing Antibodies
Antibodies, Viral
Antibodies, Neutralizing