Germline-encoded antibodies

The National Institute of Allergy and Infectious Diseases awarded the Trustees of Boston University $815,378 on May 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to identify and characterize high-affinity germline-encoded antibodies targeting viral pathogens that cause significant disease in infants and newborns.

The recipient will immortalize naive B cell antibody repertoires from umbilical cord blood using yeast display technology and screen the resulting libraries to identify naive antibodies that bind to viral surface antigens from twelve different viruses. The work includes binding affinity analysis, epitope mapping, identification of antibody determinants of binding, and evaluation of human immune system mice as a model for high-affinity germline-encoded antibody responses. The research addresses the hypothesis that germline-encoded antibodies serve as a pathogen-specific bridge between innate and adaptive immune responses, particularly for newborns and infants at greater risk during the first week of infection.

Place of performance is Roxbury, Massachusetts. The period of performance runs from May 1, 2026 through April 30, 2031. This is a Project Grant, classified as assistance funding to a nonprofit research institution.

Abstract

The human immune system has evolved to provide rapid and long-term immunity to pathogens that humans are likely to encounter during their lifetime. Innate immunity encompasses a broad range of nonspecific immediate responses that recognize common features of pathogens. Adaptive immunity provides pathogen-specific responses that take a week or longer to develop and improve with each subsequent infection. Antibodies are derived from pools of naïve b cells that canonically have little to no affinity for pathogen-specific antigens. After initial selection based on low affinity, naïve b cells enter germinal centers where somatic hypermutation increases the average affinity of antibodies over time. Our recent studies show that the naïve b cell pool includes high- affinity germline-encoded antibodies that can neutralize RSV. RSV is a common viral infection that hospitalizes millions and kills thousands of infants worldwide, including in the united states. We hypothesize that germline- encoded antibodies serve as a pathogen-specific bridge between classical innate and adaptive immune responses, particularly for newborns and infants who are at greater risk of death in the first week of infection due to respiratory failure and sepsis. This study will focus on identifying high-affinity germline-encoded antibodies targeting viral pathogens that cause significant morbidity and mortality in infants and newborns. We will immortalize naïve b cell antibody repertoires from umbilical cord blood using yeast display technology. We will use the libraries to identify naïve antibodies that bind to viral surface antigens from twelve different viruses that cause infection in infants and newborns. We will then analyze their binding affinities, map their epitopes, and identify antibody determinants of binding. Finally, we will determine whether human immune system mice can serve are a model for high-affinity germline-encoded antibody responses to vaccination. This research has the potential to reorient and widen our understanding of the role unmutated antibodies play in pathogen control prior to the induction of adaptive immunity. These antibodies could play an important role in the protection of infants who are at higher risk of respiratory failure, sepsis, and death.