Vaccines 2023, 11, 5. https://doi.org/10.3390/vaccines11010005 www.mdpi.com/journal/vaccines Article Reinfection with SARS‐CoV‐2 and Waning Humoral Immunity: A Case Report Jason D. Goldman 1,2,3 , Kai Wang 4 , Katharina Röltgen 5 , Sandra C. A. Nielsen 5 , Jared C. Roach 4, *, Samia N. Naccache 6 , Fan Yang 5 , Oliver F. Wirz 5 , Kathryn E. Yost 5 , Ji‐Yeun Lee 5 , Kelly Chun 7 , Terri Wrin 8 , Christos J. Petropoulos 8 , Inyoul Lee 4 , Shannon Fallen 4 , Paula M. Manner 2,9 , Julie A. Wallick 2,9 , Heather A. Algren 2,9 , Kim M. Murray 4 , Jennifer Hadlock 2,4 , Daniel Chen 4 , Chengzhen L. Dai 4 , Dan Yuan 4 , Yapeng Su 4 , Joshua Jeharajah 10 , William R. Berrington 1,2 , George P. Pappas 11 , Sonam T. Nyatsatsang 1,2 , Alexander L. Greninger 12,13 , Ansuman T. Satpathy 5 , John S. Pauk 1,2 , Scott D. Boyd 5,14 and James R. Heath 4 1 Division of Infectious Diseases, Swedish Medical Center, Seattle, WA 98122, USA 2 Providence St. Joseph Health, Renton, WA 98057, USA 3 Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195, USA 4 Institute for Systems Biology, Seattle, WA 98103, USA 5 Department of Pathology, Stanford University, Stanford, CA 94305, USA 6 Department of Microbiology, LabCorp, Seattle, WA 98104, USA 7 LabCorp Esoterix, Calabasas, CA 91301, USA 8 Monogram Biosciences, South San Francisco, CA 94080, USA 9 Swedish Center for Research and Innovation, Swedish Medical Center, Seattle, WA 98104, USA 10 Division of Infectious Diseases, Polyclinic, Seattle, WA 98104, USA 11 Division of Pulmonology and Critical Care Medicine, Swedish Medical Center, Seattle, WA 98104, USA 12 Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA 13 Vaccine and Infectious Disease Division, Fred Hutch, Seattle, DC 98109, USA 14 Sean N. Parker Center for Allergy and Asthma Research, Stanford, CA 94304, USA * Correspondence: jared.roach@isbscience.org Abstract: Recovery from COVID‐19 is associated with production of anti‐SARS‐CoV‐2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID‐19 separated by 144 days in a single patient, to con‐ clusively describe reinfection with a different strain harboring the spike variant D614G. This case of reinfection was one of the first cases of reinfection reported in 2020. With antibody, B cell and T cell analytics, we show correlates of adaptive immunity at reinfection, including a differential response in neutralizing antibodies to a D614G pseudovirus. Finally, we discuss implications for vaccine pro‐ grams and begin to define benchmarks for protection against reinfection from SARS‐CoV‐2. Keywords: SARS‐CoV‐2; COVID‐19; reinfection; humoral immunity 1. Introduction The risk of reinfection with SARS‐CoV‐2 after primary infection had not been con‐ sistently demonstrated until late in 2020 [1]. Multiple reports documented prolonged viral RNA shedding [2], though virus is not likely to be transmissible after 10 days [3,4], or possibly up to 20 days in immunocompromised patients [5]. These data suggested pro‐ longed shedding of viral remnants, as opposed to ongoing shedding of replication‐com‐ petent virus. A large case series from the Korean CDC [6] found lack of transmission events from symptomatic patients repeatedly positive for SARS‐CoV‐2 after negative test‐ ing. Most case reports did not distinguish between prolonged shedding and reinfection [7–9]. Without viral sequencing analysis, one could not exclude the possibility that Citation: Goldman, J.D.; Wang, K.; Röltgen, K.; Nielsen, S.C.A.; Roach, J.C.; Naccache, S.N.; Yang, F.; Wirz, O.F.; Yost, K.E.; Lee, J.‐Y.; et al. Reinfection with SARS‐CoV‐2 and Waning Humoral Immunity: A Case Report. Vaccines 2023, 11, 5. https://doi.org/10.3390/ vaccines11010005 Academic Editors: Velmurugan Balaraman and Jayme Souza‐Neto Received: 17 November 2022 Revised: 15 December 2022 Accepted: 15 December 2022 Published: 20 December 2022 Copyright: © 2022 by the authors. Li‐ censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con‐ ditions of the Creative Commons At‐ tribution (CC BY) license (https://cre‐ ativecommons.org/licenses/by/4.0/).