Biology subjects

Abbott, R. K.

Publications and source records attributed to Abbott, R. K..

3 recordsLinked to original sources

bioRxiv2025

Antigen avidity drives the durability of the vaccine immune response.

One challenge in vaccine development is designing immunogens that elicit durable immunity. We hypothesized that antigen avidity regulates the magnitude, diversity, and durability of the vaccine immune response. We tested this in multiple preclinical HIV vaccine models using a neoteric mosaic nanoparticle platform. This allowed us to precisely modulate antigen avidity by varying multivalency and affinity independently, whilst keeping other variables constant. Antigen avidity drove seeding, interclonal competition, and immunodominance within germinal centers. High-valency immunogens promoted durable germinal center, memory B cell, serum antibody, and long-lived plasma cell responses. Restricting interclonal competition rescued B cell responses to low-valency immunogens. B cell receptor sequencing revealed that antigen valency had minimal impact on individual somatic hypermutations but promoted clonal diversity. Affinity worked in concert with valency in driving productive B cell responses, with multivalency having dominant influences. The results underscore the importance of antigen avidity in driving durable and diverse vaccine responses.

immunology↗

bioRxiv2020

Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model

The development of countermeasures to prevent and treat COVID-19 is a global health priority. In under 7 weeks, we enrolled a cohort of SARS-CoV-2-recovered participants, developed neutralization assays to interrogate serum and monoclonal antibody responses, adapted our high throughput antibody isolation, production and characterization pipeline to rapidly screen over 1000 antigen-specific antibodies, and established an animal model to test protection. We report multiple highly potent neutralizing antibodies (nAbs) and show that passive transfer of a nAb provides protection against high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs define protective epitopes to guide vaccine design.

immunology↗

bioRxiv2020

B cells expressing authentic naive human VRC01-class BCRs can be primed and recruited to germinal centers in multiple independent mouse models

Animal models of human antigen-specific B cell receptors (BCR) generally depend on "inferred germline" sequences, and thus their relationship to authentic naive human B cell BCR sequences and affinities is unclear. Here, BCR sequences from authentic naive human VRC01-class B cells from healthy human donors were selected for the generation of three new BCR knock-in mice. The BCRs span the physiological range of affinities found in humans, and use three different light chains (VK3-20, VK1-5, and VK1-33) found among subclasses of naive human VRC01-class B cells and HIV broadly neutralizing antibodies (bnAbs). The germline-targeting HIV immunogen eOD-GT8 60mer is currently in clinical trial as a candidate bnAb vaccine priming immunogen. To attempt to model human immune responses to the eOD-GT8 60mer, we tested each authentic naive human VRC01-class BCR mouse model under rare human physiological B cell precursor frequency conditions. B cells with high (HuGL18HL) or medium (HuGL17HL) affinity BCRs were primed, recruited to germinal centers, accrued substantial somatic hypermutation, and formed memory B cells. Precursor frequency and affinity interdependently influenced responses. Taken together, these experiments utilizing authentic naive human VRC01-class BCRs validate a central tenet of germline-targeting vaccine design and extend the overall concept of the reverse vaccinology approach to vaccine development.

immunology↗