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Original antigenic sin describes the phenomenon in which immunity against pathogens or antigens is shaped by the host’s first exposure to a related pathogen or antigen. When primary immunity is boosted not by the homologous but by a cross-reacting vaccine, the newly formed antibodies may react better with the primary antigen than with the antigen actually eliciting the response. This form of immune imprinting, which has been observed with influenza, dengue, human immunodeficiency virus, and other pathogens, has profound implications for the approach to seasonal vaccination against a variety of diseases, including COVID-19. Public health agencies and regulatory bodies have consistently recommended repeated vaccinations every few months as a way to protect against COVID-19. However, the risks and benefits of this approach require scrutiny given the concern for original antigenic sin in response to SARS-CoV-2. This manuscript examines what is known about immune imprinting and looks ahead to explore how this phenomenon may impact seasonal vaccination against emerging SARS-CoV-2 subvariants such as BA.4, BA.5, and BA.5.1, which have been associated with increased transmissibility due to enhanced immune escape.

Original antigen sin and COVID-19: implications for seasonal vaccination