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Wratil, P.R.* ; Stern, M.* ; Priller, A.* ; Willmann, A. ; Almanzar, G.* ; Vogel, E. ; Feuerherd, M. ; Cheng, C.-C. ; Yazici, S.* ; Christa, C. ; Jeske, S. ; Lupoli, G.* ; Vogt, T.* ; Albanese, M.* ; Mejias-Perez, E.* ; Bauernfried, S.* ; Graf, N. ; Mijočević, H. ; Vu, M. ; Tinnefeld, K. ; Wettengel, J.M. ; Hoffmann, D. ; Muenchhoff, M.* ; Daechert, C.* ; Mairhofer, H.* ; Krebs, S.* ; Fingerle, V.* ; Graf, A.* ; Steininger, P.* ; Blum, H.* ; Hornung, V.* ; Liebl, B.* ; Überla, K.* ; Prelog, M.* ; Knolle, P.* ; Keppler, O.T.* ; Protzer, U.

Three exposures to the spike protein of SARS-CoV-2 by either infection or vaccination elicit superior neutralizing immunity to all variants of concern.

Nat. Med. 28, 496–503 (2022)

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Infection-neutralizing antibody responses after SARS-CoV-2 infection or COVID-19 vaccination are an essential component of antiviral immunity. Antibody-mediated protection is challenged by the emergence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529) that is rapidly spreading worldwide. Here, we report neutralizing antibody dynamics in a longitudinal cohort of COVID-19 convalescent and infection-naive individuals vaccinated with mRNA BNT162b2 by quantifying anti-SARS-CoV-2-spike antibodies and determining their avidity and neutralization capacity in serum. Using live-virus neutralization assays, we show that a superior infection-neutralizing capacity against all VoCs, including omicron, developed after either two vaccinations in convalescents or after a third vaccination or breakthrough infection of twice-vaccinated, naive individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. We conclude that an infection-plus-vaccination-induced hybrid immunity or a triple immunization can induce high-quality antibodies with superior neutralization capacity against VoCs, including omicron.

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