Breast milk delivery of an engineered dimeric IgA protects neonates against rotavirus

Stephanie N Langel; Claire E Otero; Justin T Steppe; Caitlin A Williams; Tatiana Travieso; Jerry Chang; Helen Webster; Lauren E Williamson; James E Crowe Jr; Harry B Greenberg; Huali Wu; Christoph P Hornik; Katayoun Mansouri; Robert J Edwards; Victoria Stalls; Priyamvada Acharya; Maria Blasi; Sallie R Permar

doi:10.1016/j.mucimm.2025.01.002

Breast milk delivery of an engineered dimeric IgA protects neonates against rotavirus

Mucosal Immunol. 2025 Jan 20:S1933-0219(25)00002-9. doi: 10.1016/j.mucimm.2025.01.002. Online ahead of print.

Authors

Stephanie N Langel¹, Claire E Otero², Justin T Steppe², Caitlin A Williams³, Tatiana Travieso⁴, Jerry Chang⁴, Helen Webster⁴, Lauren E Williamson⁵, James E Crowe Jr⁵, Harry B Greenberg⁶, Huali Wu⁷, Christoph P Hornik⁸, Katayoun Mansouri⁴, Robert J Edwards⁹, Victoria Stalls⁴, Priyamvada Acharya¹⁰, Maria Blasi¹¹, Sallie R Permar¹²

Affiliations

¹ Department of Pathology, Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
² Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
³ Weill Cornell Medicine Department of Pediatrics, Division of Infectious Disease, New York, NY, USA.
⁴ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
⁵ Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pediatrics, Vanderbilt University Medical Center, Vanderbilt, TN, USA.
⁶ Departments of Medicine and Microbiology and Immunology, Stanford University School of Medicine, Stanford CA, USA; The VA Palo Alto Health Care System, Department of Veterans Affairs, Palo Alto, CA, USA.
⁷ Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
⁸ Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
⁹ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA; Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
¹⁰ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA; Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
¹¹ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA; Department of Medicine, Duke University School of Medicine, Durham, NC, USA. Electronic address: maria.blasi@duke.edu.
¹² Weill Cornell Medicine Department of Pediatrics, Division of Infectious Disease, New York, NY, USA. Electronic address: sallie.permar@med.cornell.edu.

PMID: 39842610
DOI: 10.1016/j.mucimm.2025.01.002

Abstract

Dimeric IgA (dIgA) is the dominant antibody in many mucosal tissues. It is actively transported onto mucosal surfaces as secretory IgA (sIgA) which plays an integral role in protection against enteric pathogens, particularly in young children. Therapeutic strategies that deliver engineered, potently neutralizing antibodies directly into the infant intestine through breast milk could provide enhanced antimicrobial protection for neonates. Here, we developed a murine model of maternal protective transfer against human rotavirus (RV) using systemic administration of a dimeric IgA monoclonal antibody (mAb). First, we showed that systemically administered dIgA passively transferred into breast milk and the stomach of suckling pups in a dose-dependent manner. Next, we optimized the recombinant production of a potently RV-neutralizing, VP4-specific dIgA (mAb41) antibody. We then demonstrated that systemic administration of dIgA and IgG mAb41 in lactating dams conferred protection from RV-induced diarrhea in suckling pups, with dIgA resulting in lower diarrhea incidence from IgG. Systemic delivery of engineered antimicrobial dIgA mAbs should be considered as an effective strategy for sIgA delivery to the infant gastrointestinal tract via breast milk to increase protection against enteric pathogens.

Keywords: Breast milk; Dimeric IgA; Maternal immunity; Neonatal immunity; Passive transfer; Rotavirus.