Impact of antigenic evolution and original antigenic sin on SARS-CoV-2 immunity

Abstract

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccinations targeting the spike protein (S) offer protective immunity against coronavirus disease 2019 (COVID-19). This immunity may further be shaped by cross-reactivity with common cold coronaviruses. Mutations arising in S that are associated with altered intrinsic virus properties and immune escape result in the continued circulation of SARS-CoV-2 variants. Potentially, vaccine updates will be required to protect against future variants of concern, as for influenza. To offer potent protection against future variants, these second-generation vaccines may need to redirect immunity to epitopes associated with immune escape and not merely boost immunity toward conserved domains in preimmune individuals. For influenza, efficacy of repeated vaccination is hampered by original antigenic sin, an attribute of immune memory that leads to greater induction of antibodies specific to the first-encountered variant of an immunogen compared with subsequent variants. In this Review, recent findings on original antigenic sin are discussed in the context of SARS-CoV-2 evolution. Unanswered questions and future directions are highlighted, with an emphasis on the impact on disease outcome and vaccine design.

Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting

“…mRNA vaccine platforms can quickly adapt to new SARS-CoV-2 variants [13][14][15][16] . However, since the majority of the population was vaccinated with the ancestral SARS-CoV-2 strain, immune imprinting induced by WT vaccination presents a major challenge to the performance of updated boosters 17,18 . This is because boosting with a variant antigenically distinct from WT would majorly recall memory B cells induced by WT vaccination and masks the de novo generation of variantspecific B cells, which would hinder the generation of satisfying humoral immune responses toward new variants 6,7, [19][20][21][22][23] .…”

COVID-19, post-acute COVID-19 syndrome (PACS, “long COVID”) and post-COVID-19 vaccination syndrome (PCVS, “post-COVIDvac-syndrome”): Similarities and differences

“…The protection gained from a COVID-19 vaccination booster dose diminishes with increasing number of booster doses received, as recently found [37] . Repeated vaccination and confrontation with novel antigen variants are associated with the immune memory phenomenon of “original antigenic sin” (leading to less efficient immune responses in comparison to the original antigen variant) and “immune imprinting” (leading to a progressively narrowed immune response towards a new antigen variant) [38] . That the “vaccine-induced immune imprinting against the S [spike] protein partially inhibits the response against the N [nucleocapsid] protein after SARS-CoV-2 infection” has been shown already [39] , and a recent study came to the conclusion that “protective effects from the humoral immunity and cellular immunity established by the conventional immunization were both profoundly impaired during the extended vaccination course.” [40] .…”

Repeated Omicron infection alleviates SARS-CoV-2 immune imprinting

“…mRNA vaccine platforms can quickly adapt to new SARS-CoV-2 variants [14][15][16][17] . However, since the majority of the population was vaccinated with the ancestral SARS-CoV-2 strain, immune imprinting induced by WT vaccination presents a major challenge to the performance of updated boosters 18,19 . This is because boosting with a variant antigenically distinct from WT would majorly recall memory B cells induced by WT vaccination and masks the de novo generation of variantspecific B cells, which would hinder the generation of satisfying humoral immune responses toward new variants 6,7,9,[20][21][22][23] .…”