key: cord-0995166-qucdv4p8 authors: Bauer, Georg title: Comment to the manuscript by William P. Hausdorff and Jorge Flores: Low-dose and oral exposure to SARS-CoV-2 may help us understand and prevent severe COVID-19, IJID 103 (2021) 37–41 date: 2021-04-02 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.03.084 sha: b2c7d396a44dc4b47aca59cb468bed262b2d09f1 doc_id: 995166 cord_uid: qucdv4p8 nan New data and concepts related to protective immunity towards SARS-CoV-2 infection oblige me to comment on the manuscript by Hausdorff and Flores. An essential point in their manuscript is the assumption that low-dose or oral SARS-CoV-2 may lead to immunization. Several lines of evidence (most of them established after submission of the manuscript by Hausdorff and Flores) indicate, however, that natural infection with SARS-CoV-2 does not necessarily lead to protective immunity. 1) Khatri et al., 2020 reported on the high affinity between SARS-CoV-2 surface protein and its cellular receptor ACE2. They therefore concluded that only IgG with high affinity for the S protein can efficiently interfere with infection. 2) Recent findings show frequent incomplete avidity maturation of IgG towards SARS-CoV-2 nucleoprotein (NP), surface protein-1 (S1) and receptor-binding domain (RBD) [Strömer et al., 2020; Liu et al., 2020; Bauer et al., 2020 Bauer et al., , 2021 . Avidity (i. e. the strength of binding between IgG and epitope) matures in parallel to affinity. More than 70 percent of Covid-19 outpatients do not generate high avidity IgG at five monts after the onset of disease [Bauer et al., 2020 [Bauer et al., , 2021 . Kinetic analysis revealed that avidity maturation stopped in parallel to the break in IgG production [Bauer et al., 2020 [Bauer et al., , 2021 which seems to be leading to waning antibody levels [Seow et al., 2020] . Therefore, in the majority of cases, IgG directed towards SARS-CoV-2 RBD can be predicted not to be efficient with respect to interference with the high affinity interaction between ACE2 and RBD. 3) In many viral systems, the failure to achieve complete avidity maturation leads to a failure in protection towards infection and disease [reviewed in Bauer, 2021] . 4) The immature avidity of the IgG response towards seasonal coronaviruses [Bauer et al., 2020 [Bauer et al., , 2021 might be the biological basis for the observed repeated cycles of reinfections by these viruses [Edrige et al. 2020; Galanti and Shaman, 2020] . These findings indicate that vaccination, leading to a neutralizing IgG response towards RBD/S1, characterized by high avidity, seems to be the only chance to stop the present pandemic [Bauer, 2021] . This goal seems to be achievable, as vaccination is not hampered by the negative effect of SARS-CoV-2 infection on germinal centers of secondary lymphoid organs, the site of B cell maturation [Kaneko et al., 2020] . In the line of these novel findings, I feel that it is appropriate to reevaluate the potential risk for participants in the study proposed by Hausdorff and Flores. Publication costs will be sponsored by the Medical Faculty of the University of Freiburg. No other funding was obtained. No ethical approval was required for this work. The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. J o u r n a l P r e -p r o o f The potential significance of high avidity IgG for protective immunity towards SARS CoV-2 The serological response to SARS corona virus-2 is characterized by frequent incomplete maturation of functional affinity (avidity) The challenge of avidity determination in SARS-CoV-2 serology Seasonal corona virus protective immunity is short-lasting Direct observation of repeated infections with endemic coronaviruses Pillai, S,& the Massachusetts Consortium on Pathogen Readiness Specimen Working Group Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19 Blocking of the high-affinity interaction-synapse between SARS CoV-2 spike and human ACE2 proteins likely requires multiple highaffinity antibodies: an immune perspective Quantification of antibody avidities and accurate detection of SARS-CoV-2 antibodies in serum and saliva on plasmonic substrates following SARS-CoV-2 infection in humans Kinetics of nucleo-and spike protein-specific immunoglobulin G and of virusneutralizing antibodies after SARS-CoV-2 infection