key: cord-0794315-g9rs9cx8 authors: Bachmann, Martin F.; Mohsen, Mona O.; Speiser, Daniel E. title: Increased receptor affinity of SARS-CoV-2: a new immune escape mechanism date: 2022-05-25 journal: NPJ Vaccines DOI: 10.1038/s41541-022-00479-9 sha: e019b7e7e2796c97a2b841543735d6079fa69040 doc_id: 794315 cord_uid: g9rs9cx8 ‘Affinity escape’: Novel SARS-CoV-2 variants may escape immunity by raising the RBD-ACE2 affinity high enough to outcompete the avidity of neutralizing antibodies. SARS-CoV-2 has proven to be a rapidly evolving RNA virus with steadily emerging new viral variants. Several of them show enhanced infectivity and/or escape from neutralization by monoclonal antibodies (mAbs), and some were termed variants of concern (VoC). Extended escape from protective antibodies is well described in virology as so-called serotype formation 1 . Serotypes avoid recognition by previously generated anti-viral antibodies because they differ in neutralizing epitopes due to viral mutation and selection. Typical examples of such serotype-forming viruses are Polio and Dengue viruses, forming 3 and 4 distinct and stable serotypes, respectively 1 . For the Beta and Gamma variants of SARS-CoV-2, it has recently been shown that the E484K mutation within the receptor binding domain (RBD) of the spike protein strongly reduces recognition by convalescent sera from individuals after infection with the original Wuhan strain 2,3 . While this observation suggests development of viral serotypes, it has been difficult to make the reverse observation, i.e., to find or induce sera that neutralize variants with the E484K mutation better than the Wuhan strain [3] [4] [5] . Thus, the current data do not fully demonstrate the existence of different SARS-CoV-2 serotypes. Generally, the demonstration of mAbs capable of distinguishing distinct variants is not sufficient to declare new serotypes, as serotypes are defined by polyclonal anti-sera. In contrast, we have recently demonstrated that viral strains can escape neutralizing antibodies despite essentially preserved recognition specificity: by ways of increased receptor affinity. While RBD of the Wuhan strain binds ACE2 with an affinity of 2-10 −8 M, RBD with the L452R and E484Q mutations (such as in the Delta and Kappa variants) shows a 4-5 fold higher affinity for the receptor 3 . This not only causes the well-known increased infectivity but also shifts the virus-receptor equilibrium to the right, i.e., the virus binds more strongly to the ACE2 receptor. Indeed, neutralizing antibodies after infection and vaccination have difficulties in competing with RBD-ACE2 binding, suggesting that neutralization is reduced despite that the epitopes of the mutated RBD maintained essentially the same specificity for these antibodies (Fig. 1) . Thus, increasing receptor affinity may constitute a new pathway for viruses to escape neutralizing antibodies and may be called affinity escape 6 . Differences in assay setups (e.g., plate coating of ACE2 7 versus coating of RBD on sensor chips 3 ) may lead to different affinities measured in specific cases. Nevertheless, it is well documented that some VoCs exhibit clearly higher affinities for ACE2 3,7-9 , supporting the notion that the above-described affinity type escape is a general phenomenon of SARS-CoV-2. Consequently, vaccine optimization should aim at inducing higher avidity antibodies, rather than altered epitope specificity as would be required for new serotypes 10 . Indeed, Wuhan strain-based vaccines that induce high avidity antibodies also protect from severe disease caused by prominent VoCs 3 . Even protection from the Omicron variant is achieved to a relatively high degree after three vaccinations 11 , likely because this induces high titers of antibodies with increased avidity. The latter is promoted by the well-known mechanism of antibody avidity maturation which is enhanced by booster vaccination and with time 12 . Interestingly, booster vaccination after a prolonged interval to the first vaccine dose resulted in enhanced antibody responses 13 . Importantly, a longer vaccination-infection interval was found to be associated with increased neutralization potency to Omicron after breakthrough infection 14 , an observation consistent with the notion that protection from variants may be favored by progressive affinity maturation during the intervals. Re-infection by VoCs and SARS-CoV-2 in general is favored by the fact that the avidity of antibodies induced by natural infection is relatively low 15, 16 , probably related to the low capability of SARS-CoV-2 to induce neutralizing antibodies 17 and the poor formation of germinal centers required for antibody avidity maturation 12, 18 . mAb therapy of infection with viral variants is improved by coadministration of multiple neutralizing mAbs with several different relevant specificities 19 , reflecting the superiority of polyclonal as opposed to monoclonal antibodies and the presence of multiple neutralizing epitopes on the spike protein and its RBD 20 . In comparison to mAb therapy that can only be done with a low number of different antibodies, serum antibodies have the advantage of being highly polyclonal and multi-specific. Evolutionary, novel serotypes are unlikely to emerge from viruses that are inefficient at inducing neutralizing antibodies 17 . Instead, such viruses may get bigger selective advantage by increasing receptor affinity. These observations imply that the current large efforts to identify correlates of protection 21 should include the assessment of antibody avidity 22 which is often not done 23 . It will be interesting to determine whether Coronaviruses are unique in this regard, or whether similar observations may be made for other viruses with well-known receptors, such as Adenoviruses. Updates on immunologic correlates of vaccine-induced protection Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant In vitro data suggest that Indian delta variant B.1.617 of SARS-CoV-2 escapes neutralization by both receptor affinity and immune evasion Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis The future of SARS-CoV-2 vaccination. Defining affinity escape. Letter to the editor Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants Molecular definition of severe acute respiratory syndrome coronavirus 2 receptor-binding domain mutations: receptor affinity versus neutralization of receptor interaction Structural basis of receptor recognition by SARS-CoV-2 SARS-CoV-2 variants and vaccines mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant Germinal centers Delayed-interval BNT162b2 mRNA COVID-19 vaccination enhances humoral immunity and induces robust T cell responses Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies Vaccination versus infection with SARS-CoV-2: establishment of a high avidity IgG response versus incomplete avidity maturation SARS-CoV-2 structural features may explain limited neutralizing-antibody responses Immune imprinting, breadth of variant recognition and germinal center response in human SARS-CoV-2 infection and vaccination Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies Targeting multiple epitopes on the spike protein: a new hope for COVID-19 antibody therapy A government-led effort to identify correlates of protection for COVID-19 vaccines Laboratory correlates of protection against Haemophilus influenzae type b disease. Importance of assessment of antibody avidity and immunologic memory Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection We thank our team members for their numerous contributions. The work was supported by the Swiss National Science Foundation (SNF grants 31003A 149925 and 310030-179459) and Inselspital Bern, Switzerland. Correspondence and requests for materials should be addressed to Martin F. Bachmann or Daniel E. Speiser.Reprints and permission information is available at http://www.nature.com/ reprintsPublisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Fig. 1 Serotype escape or Affinity escape. Top: Neutralization of wildtype virus by pre-existing antibodies that block RBD binding to the receptor on the surface of susceptible host cells. Bottom left: RBD mutations may alter B cell epitopes such that pre-existing antibodies can no longer neutralize ("Serotype escape"). Bottom right: Alternatively, immune escape may occur because RBD affinity has increased to the extent that the binding of pre-existing antibodies is too weak for competing with RBD-receptor binding. Therefore, the antibodies are unable to neutralize the virus ("Affinity escape"). RBD, receptor binding domain.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. 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