Impact of antigenic evolution and original antigenic sin on SARS-CoV-2 immunity
Muriel Aguilar-Bretones, … , Marion P.G. Koopmans, Gijsbert P. van Nierop
Muriel Aguilar-Bretones, … , Marion P.G. Koopmans, Gijsbert P. van Nierop
Published January 3, 2023
Citation Information: J Clin Invest. 2023;133(1):e162192. https://doi.org/10.1172/JCI162192.
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Review

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.

Authors

Muriel Aguilar-Bretones, Ron A.M. Fouchier, Marion P.G. Koopmans, Gijsbert P. van Nierop

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Figure 1

Antigenic changes of spike and hemagglutinin result in boost of non-neutralizing antibodies.

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Antigenic changes of spike and hemagglutinin result in boost of non-neut...
(A) The SARS-CoV-2 spike trimer (S) consists of the S2 and S1 subdomains. S1 contains the N-terminal domain (NTD) and receptor-binding domain (RBD). Influenza hemagglutinin (HA) consists of a stalk domain and a head domain, which contains the receptor-binding site (RBS). (B) The S2 and HA stalk are highly conserved between virus variants, while the S1 and HA head are more variable. Antibodies that target S1 or HA head domains, especially NTD, RBD, and RBS, have the highest neutralization potential, while antibodies targeting S2 or HA stalk have lower neutralization potential. (C) Neutralizing (green color family; c and d) and non-neutralizing antibodies (orange color family; a and b) are induced after primary exposure. After exposure with the same virus variant (homologous re-exposure), both antibody classes are boosted from immune memory and undergo similar affinity maturation, from moderate (±) to high affinity (+). The kinetics of these responses is shown as a stacked plot in the right panel. (D) Infection with a heterologous virus strain that carries immune escape mutations in the S1 domain (light green and yellow) boosts cross-reactive antibodies. Those targeting shared epitopes will mature into high-affinity antibodies (+), and those that target mutated epitopes will bind with low affinity (–). Because of higher similarity in epitopes of non-neutralizing antibodies (orange; a), they are preferentially boosted over neutralizing antibodies (green; c). Neoepitopes are targeted with moderate affinity, and these antibodies represent a minor fraction of the total response (±; e and f). The kinetics of the response is shown in the right panel. Owing to original antigenic sin, the breadth and magnitude of the neoepitope-specific response (non-neutralizing: yellow, e; neutralizing: light green, f) are lower than those of the initial response.