key: cord-0875742-nif9i27x
authors: Chang, Xinyue; Augusto, Gilles Sousa; Liu, Xuelan; Kündig, Thomas M.; Vogel, Monique; Mohsen, Mona O.; Bachmann, Martin F.
title: BNT162b2 mRNA COVID‐19 vaccine induces antibodies of broader cross‐reactivity than natural infection, but recognition of mutant viruses is up to 10‐fold reduced
date: 2021-05-20
journal: Allergy
DOI: 10.1111/all.14893
sha: 3573f8132ddfdfabe7afd93f88e11f63653498eb
doc_id: 875742
cord_uid: nif9i27x

nan

To the Editor,

The receptor binding domain (RBD) of SARS-CoV-2 spike (S) glycoprotein, which is involved in virus attachment and cell entry, is the primary target for neutralizing antibodies. 1 Immunization against full-length S or parts of it may result in more potent and longerlasting antibody responses than natural viral infection. 2 Therefore, global vaccination programs based on induction of neutralizing antibodies are the most promising strategy for controlling the COVID-19

A worrying factor, however, has been the emerging variants capable to escape immunity produced by vaccination or infection. A study has shown that E484 K mutation is associated with reduced neutralization, by SARS-CoV-2 infection or BNT162b2elicited sera. 3 Whether reduced neutralization was due to impaired binding was, however, not analyzed. Here, we assessed the presence of such cross-reactive antibodies in convalescent sera and sera from individuals immunized with mRNA-based BNT162b2

To this end, we generated four mutant RBDs:K417 N (RBD 417 ), E484 K (RBD 484 ), N501Y (RBD 501 ), and one triple mutated version with all three mutations (RBD trip ) ( Figure 1A) . Two of these mutations, E484 K and N501Y, are localized within the receptor binding motif, 4 directly interacting with ACE2. Our ELISA results show that binding of convalescent sera was strongly reduced for RBD 417 and RBD 501 and, however, essentially abolished for RBD 484 and RBD trip ( Figure 1B, left) . In contrast, BNT162b2-elicited antibodies exhibited only weakly reduced binding to RBD 417 and RBD 501 (2.5-3-fold), but 10-fold reduced binding to RBD 484 and RBD trip ( Figure 1B, right) . Figure 1C summarizes the antibody titers and Figure 1D quantifies the reduced binding of vaccine-induced sera to the mutant RBDs compared to RBD wt (wild-type RBD). Interestingly, the E484 K mutation was equally potent at reducing antibody binding as in RBD trip , indicating that the mutation E484 K is particularly problematic, perhaps because it involves a change from positive to negative charge. This is consistent with recent data showing less neutralization titer against a variant containing E484 K mutation, however, only with 1.41-fold reduction. 5 We performed assays to estimate the antibodies' avidity for RBD and mutants. Interestingly, virus-induced antibodies were of limited avidity for RBD wt , and binding to mutant RBDs was essentially abolished with 7 M urea wash, indicating that the antibodies binding to mutant RBDs were all of low avidity (Figure 2A shows results for RBD wt ). In contrast, BNT162b2-induced antibodies were of significantly higher avidity ( Figure 2B ). In addition, there was some residual binding to mutant RBDs, indicating, however, overall low avidity as well ( Figure 2C ). The avidity index allows to quantify the loss in binding caused by the 7 M urea wash and therefore reflects the "quality" of the antibodies. Indeed, the avidity index of vaccine-induced antibodies is much higher for RBD wt and mutants than those induced by infection. This reduced affinity of antibodies induced by infection is consistent with the notion that individual RBDs are spaced by 25 nm on SARS-CoV-2, too large for inducing optimal antibodies. 6 In conclusion, BNT162b2-induced antibodies recognize mutant RBDs better than those by natural infection. Recognition may, however, be 10-fold reduced for the variants B.1.351/P.1, suggesting that development of a new vaccine may be warranted.

E484 K mutation is shown here to be a key hurdle for immune recognition. Hence, monoclonal antibody therapy and serological assays based on wildtype sequence may therefore be seriously impaired.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 

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