key: cord-0945040-zxmz0r2g authors: Gorgoulis, V. G. title: SARS-CoV-2 antigenemia/viremia masks seroconversion in a COVID-19 patient date: 2021-01-29 journal: nan DOI: 10.1101/2021.01.26.21250561 sha: bccd7ae21bacc2ba4a3f8846ef97c68198377999 doc_id: 945040 cord_uid: zxmz0r2g Immune responses against SARS-CoV-2 have been vigorously analyzed. It has been proposed that a subset of mild or asymptomatic cases with undetectable antibodies may clear the virus in a T-cell cytotoxic-dependent manner, albeit recent data revealed the importance of B-cells in that regard. We hypothesized that underdiagnosed antigenemia/viremia may conceal humoral response possibly through immunocomplex formation. We report the first case of late-onset seroconversion detected following decline in antigenemia/viremia levels. Consequently, classification of at least a subset of COVID-19 cases as non-responders might not represent a true immunobiological phenomenon, rather reflect antibody masking due to prolonged antigenemia/viremia. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 14 . This phenomenon of undetectable antibody titers following convalescence constitutes a 79 paradox which has neither been studied nor satisfactorily explained. To explain this paradox in COVID-19, we sought to examine the hypothesis that the 81 presence of the virus and/or viral fragments (viremia and/or antigenemia) in the serum may 82 mask seroconversion. If this is true, then two conditions should be met: 1) viral RNA should 83 be detected in the blood stream, and 2) if the absence of seroconversion is due to 84 antigen/viral-mediated saturation of circulating antibodies (i.e immunocomplexes formation), 85 then the progressive decrease of antigenemia/viremia should be followed by increasingly 86 detectable antibody titers 15 . Herein, we report to the best of our knowledge, the first case as a 87 proof-of-concept supporting the proposed scenario. Case presentation 90 We report the case of a young male in his 20's who presented with a 24-hour history 91 of fever up to 38.4˚C, without any additional signs or symptoms (Figure 2A ). Due to a recent 92 history of close contact with a confirmed COVID-19 case, nasopharyngeal swab from the 93 patient was obtained and tested for SARS-CoV-2 with reverse transcription polymerase chain 94 reaction (RT-PCR) on day 2 p.s.o, confirming the diagnosis (Cycle threshold value (Ct)=15). Subsequently, the patient self-isolated at home for two weeks, as per national infection 96 control protocols. His fever subsided within a few days. Besides antipyretics, the patient did 97 not receive any other medications. However, upon completion of the two-weeks' isolation, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101/2021.01.26.21250561 doi: medRxiv preprint appropriate steps using Phosphate Buffer Saline/0.1% Tween (PBSTx5). Following testing 126 on 150 negative pre-COVID-19 and 250 RT-PCR positive samples, validation data revealed 127 90.5% sensitivity and 95% specificity (Suppl. Figure 1i) . 128 Our 'in house' method was cross-referenced to an FDA-approved and independently 129 validated enzyme linked immunosorbent assay (ELISA) (Euroimmun, Luebeck, GmBH, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101/2021.01.26.21250561 doi: medRxiv preprint pre-COVID-19 samples), revealing a sensitivity of 93% and specificity of 99% (Suppl. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101/2021.01.26.21250561 doi: medRxiv preprint was confirmed by 1) omitting the primary antibody and 2) performing competition with the is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101/2021.01.26.21250561 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101/2021.01.26.21250561 doi: medRxiv preprint ( Figure 3F, Supplementary Figure 3B ) and in contrast to RT-PCR testing, which was 422 repeatedly negative ( Figure 3A) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. see Figure 2 iii ? Long COVID-19 C. P. ?L.C. : Long COVID-19 haulers (up to 18 weeks) Figure 1 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted January 29, 2021. 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