On Immunological Imprinting

Immunological memory is considered the hallmark of the adaptive immune system, where primary exposure to an antigen establishes a population of memory cells capable of responding to future encounters to the same antigen with increased speed and magnitude. For rapidly mutating respiratory pathogens such as influenza viruses and SARS-CoV-2, subsequent encounters are not to the same antigen, but rather one that has mutated and formed new epitopes. Immunological imprinting (formerly known as original antigenic sin) describes the propensity for memory B responses elicited after primary exposure to dominate secondary responses to mutated virus variants as opposed to eliciting new responses against new epitopes. Though the phenomenon of immunological imprinting has been repeatedly observed, the underlying mechanisms of how secondary responses are shaped, and the extent to which this phenomenon influences clinical outcome, remain unclear. To assess how immunological imprinting shapes the specificity of responses to mutating virus, antibody and B cell responses were investigated in imprinted humans and nonhuman primates after SARS-CoV-2 variant exposures. Although variant responses predominantly arose from imprinted memory, de novo variant type-specific responses were identified in several individuals. As a primary exposure, variants were discovered to elicit distinct antibody and B cell repertoires, owing to differences in antigen conformation and immunodominance. Finally, in a rhesus macaque challenge model, imprinted and heterologous variant-boosted animals were not at a protective disadvantage compared to variant-primed animals. Collectively, this work suggests that though immunological memory significantly shapes future variant responses at the B cell repertoire level, it is not necessarily an impedance to protective variant responses.

Author dc:creator

• Johnston, Timothy, Stuart

Advisor dc:contributor.advisor

• Douek, Daniel, C.

• Immunology and Infectious Disease

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62787

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62787