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Immunoglobulin (IG) replacement products are used routinely in patients with immune deficiency and other immune dysregulation disorders who have poor responses to vaccination and require passive immunity conferred by commercial antibody products. The binding, neutralizing, and protective activity of intravenously administered IG against SARS-CoV-2 emerging variants remains unknown. Here, we tested 198 different IG products manufactured from December 2019 to August 2022. We show that prepandemic IG had no appreciable cross-reactivity or neutralizing activity against SARS-CoV-2. Anti-spike antibody titers and neutralizing activity against SARS-CoV-2 WA1/2020 D614G increased gradually after the pandemic started and reached levels comparable to vaccinated healthy donors 18 months after the diagnosis of the first COVID-19 case in the United States in January 2020. The average time between production to infusion of IG products was 8 months, which resulted in poor neutralization of the variant strain circulating at the time of infusion. Despite limited neutralizing activity, IG prophylaxis with clinically relevant dosing protected susceptible K18-hACE2-transgenic mice against clinical disease, lung infection, and lung inflammation caused by the XBB.1.5 Omicron variant. Moreover, following IG prophylaxis, levels of XBB.1.5 infection in the lung were higher in FcγR-KO mice than in WT mice. Thus, IG replacement products with poor neutralizing activity against evolving SARS-CoV-2 variants likely confer protection to patients with immune deficiency disorders through Fc effector function mechanisms.

Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including a similar deletion, but the addition of an anti-RBD mAb prevents such escape. Thus, our study highlights a common strategy of immune evasion by SARS-CoV-2 variants and how targeting spatially distinct epitopes, including those in the NTD, may limit such escape., Competing Interests: Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, Ocugen, Topspin Therapeutics, GlaxoSmithKline, Moderna, and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions, and Moderna. Some of the mAbs described in this study have been licensed by Washington University to Bio X Cell. D.H.F. is a founder of Courier Therapeutics and has received funding support in a sponsored research agreement from Emergent BioSolutions. J.E.C. has served as a consultant for Eli Lilly and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines, and is the founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from AstraZeneca and IDBiologics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Although SARS-CoV-2 vaccines have proven effective in eliciting a protective immune response in healthy individuals, their ability to induce a durable immune response in immunocompromised individuals remains poorly understood. Primary antibody deficiency (PAD) syndromes are among the most common primary immunodeficiency disorders in adults and are characterized by hypogammaglobulinemia and impaired ability to mount robust antibody responses following infection or vaccination., Methods: Here, we present an analysis of both the B and T cell response in a prospective cohort of 30 individuals with PAD up to 150 days following initial COVID-19 vaccination and 150 days post mRNA booster vaccination., Results: After the primary vaccination series, many of the individuals with PAD syndromes mounted SARS-CoV-2 specific memory B and CD4 + T cell responses that overall were comparable to healthy individuals. Nonetheless, individuals with PAD syndromes had reduced IgG1 + and CD11c + memory B cell responses following the primary vaccination series, with the defect in IgG1 class-switching rescued following mRNA booster doses. Boosting also elicited an increase in the SARS-CoV-2-specific B and T cell response and the development of Omicron-specific memory B cells in COVID-19-naïve PAD patients. Individuals that lacked detectable B cell responses following primary vaccination did not benefit from booster vaccination., Conclusion: Together, these data indicate that SARS-CoV-2 vaccines elicit memory B and T cells in most PAD patients and highlights the importance of booster vaccination in immunodeficient individuals., Competing Interests: MD is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, Moderna, and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, Immunome, and Emergent BioSolutions. OZ and family own Moderna stock. The Ellebedy laboratory received unrelated funding support from Emergent BioSolutions and AbbVie. AE is a consultant for Mubadala Investment Company and the founder of ImmuneBio Consulting. JT is a consultant for Gerson Lehrman Group. JT and AE are recipients of a licensing agreement with Abbvie that is unrelated to this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Doss, Davis-Adams, Adams, Hanson, VanBlargan, Liang, Chen, Monroy, Wedner, Kulczycki, Mantia, O’Shaughnessy, Raju, Zhao, Rizzi, Rigell, Dy, Kau, Ren, Turner, O’Halloran, Presti, Fremont, Kendall, Ellebedy, Mudd, Diamond, Zimmerman and Laidlaw.)

We designed a protein biosensor that uses thermodynamic coupling for sensitive and rapid detection of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in serum. The biosensor is a switchable, caged luciferase-receptor-binding domain (RBD) construct that detects serum-antibody interference with the binding of virus RBD to angiotensin-converting enzyme 2 (ACE-2) as a proxy for neutralization. Our coupling approach does not require target modification and can better distinguish sample-to-sample differences in analyte binding affinity and abundance than traditional competition-based assays., (© 2022. The Author(s).)

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited by various vaccine platforms against VOCs, compared with non-human primates or humans, suggesting caution should be exercised when interpreting data obtained with this animal model., Competing Interests: Declaration of interests A.C.W., N.P.K., and D.V. are named as inventors on patent applications filed by the University of Washington based on the RBD-NP presented in this paper. N.P.K. is a co-founder, shareholder, paid consultant, and chair of the scientific advisory board of Icosavax, Inc., and the King lab has received an unrelated sponsored research agreement from Pfizer. M.S.D. is a consultant for Inbios, Vir Biotechnology, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Kaleido, and Emergent BioSolutions and past support from Moderna not related to these studies. K.W., A.C., and D.K.E are employees of Moderna and hold stock/stock options in the company. D.H.F. has equity interest in HDT Bio., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Individuals with primary antibody deficiency (PAD) syndromes have poor humoral immune responses requiring immunoglobulin replacement therapy. We followed individuals with PAD after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination by evaluating their immunoglobulin replacement products and serum for anti-spike binding, Fcγ receptor (FcγR) binding, and neutralizing activities. The immunoglobulin replacement products tested have low anti-spike and receptor-binding domain (RBD) titers and neutralizing activity. In coronavirus disease 2019 (COVID-19)-naive individuals with PAD, anti-spike and RBD titers increase after mRNA vaccination but wane by 90 days. Those vaccinated after SARS-CoV-2 infection develop higher and more sustained responses comparable with healthy donors. Most vaccinated individuals with PAD have serum-neutralizing antibody titers above an estimated correlate of protection against ancestral SARS-CoV-2 and Delta virus but not against Omicron virus, although this is improved by boosting. Thus, some immunoglobulin replacement products likely have limited protective activity, and immunization and boosting of individuals with PAD with mRNA vaccines should confer at least short-term immunity against SARS-CoV-2 variants, including Omicron., Competing Interests: Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, Immunome, and Emergent BioSolutions. O.Z. and family own Moderna stock. G.A. is a founder and equity holder for Seromyx Systems Inc. and an equity holder for Leyden Labs. The Ellebedy laboratory received unrelated funding support from Emergent BioSolutions and AbbVie. A.H.E. is a consultant for Mubadala Investment Company and the founder of ImmuneBio Consulting. J.S.T. is a consultant for Gerson Lehrman Group. J.S.T. and A.H.E. are recipients of a licensing agreement with Abbvie that is unrelated to this manuscript., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope ("supersite") on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2-neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2-transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy was achieved with a homotrimeric version of the 75-residue angiotensin-converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. Consistent with the design model, in the cryo-electron microscopy structure TRI2-2 forms a tripod at the apex of the spike protein that engaged all three receptor binding domains simultaneously. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than the monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies in greater resistance to viral escape and antigenic drift, and advantages over native receptor traps in lower chances of autoimmune responses.

Background: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, viral variants with greater transmissibility or immune-evasion properties have arisen, which could jeopardize recently deployed vaccine- and antibody-based countermeasures., Methods: Here, we evaluated in mice and hamsters the efficacy of a pre-clinical version of the Moderna mRNA vaccine (mRNA-1273) and the Johnson & Johnson recombinant adenoviral-vectored vaccine (Ad26.COV2.S) against the B.1.621 (Mu) variant of SARS-CoV-2, which contains spike mutations T95I, Y144S, Y145N, R346K, E484K, N501Y, D614G, P681H, and D950N., Findings: Immunization of 129S2 and K18-human ACE2 transgenic mice with the mRNA-1273 vaccine protected against weight loss, lung infection, and lung pathology after challenge with the B.1.621 or WA1/2020 N501Y/D614G SARS-CoV-2 strain. Similarly, immunization of 129S2 mice and Syrian hamsters with a high dose of Ad26.COV2.S reduced lung infection after B.1.621 virus challenge., Conclusions: Thus, immunity induced by the mRNA-1273 or Ad26.COV2.S vaccine can protect against the B.1.621 variant of SARS-CoV-2 in multiple animal models., Funding: This study was supported by the NIH (R01 AI157155 and U01 AI151810), NIAID Centers of Excellence for Influenza Research and Response [CEIRR] contracts 75N93021C00014 and 75N93021C00016, and the Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051. It was also supported, in part, by the National Institutes of Allergy and Infectious Diseases Center for Research on Influenza Pathogenesis (HHSN272201400008C) and the Japan Program for Infectious Diseases Research and Infrastructure (JP21wm0125002) from the Japan Agency for Medical Research and Development (AMED)., Competing Interests: Declaration of interests The A.C.M.B. laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, GreenLight Biosciences, Inc., and Nano Targeting & Therapy Biopharma, Inc. The A.C.M.B. laboratory has received funding support from AbbVie, Inc., for the commercial development of SARS-CoV-2 mAbs. M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Kaleido, and Emergent BioSolutions and past support from Moderna not related to these studies. S.M.E. and D.K.E. are employees of and shareholders in Moderna, Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures., (© 2022. Springer Nature Limited.)

Background: Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention or therapy. The pre-exposure prophylactic efficacy of neutralizing antibodies that are engineered with mutations to extend their persistence in human serum and the neutralizing antibody titer in serum required for protection against SARS-CoV-2 infection remain poorly characterized., Methods: The Fc region of two neutralizing mAbs (COV2-2130 and COV2-2381) targeting non-overlapping epitopes on the receptor binding domain of SARS-CoV-2 spike protein was engineered to extend their persistence in humans and reduce interactions with Fc gamma receptors. We assessed protection by individual antibodies or a combination of the two antibodies (designated ADM03820) given prophylactically by an intravenous or intramuscular route in a non-human primate (NHP) model of SARS-CoV-2 infection., Findings: Passive transfer of individual mAbs or ADM03820 conferred virological protection in the NHP respiratory tract in a dose-dependent manner, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro . We defined a protective serum-neutralizing antibody titer and concentration in NHPs for passively transferred human antibodies that acted by direct viral neutralization., Conclusions: In summary, we demonstrate that neutralizing antibodies with extended half-life and lacking Fc-mediated effector functions are efficient for pre-exposure prophylaxis of SARS-CoV-2 infection in NHPs. These results support clinical development of ADM03820 for COVID-19 prevention., Funding: This research was supported by a contract from the JPEO-CBRND (W911QY-20-9-003, 20-05); the Joint Sciences and Technology Office and Joint Program Executive Office (MCDC-16-01-002 JSTO, JPEO); a DARPA grant (HR0011-18-2-0001); an NIH grant (R01 AI157155); and the 2019 Future Insight Prize from Merck KGaA., Competing Interests: R.R.C., R.V.H., D.M.S., M.H., B.H., L.C., G.H.N., M.T.T., and K.H. are employees of Ology Bioservices. C.G.E. and N.M.D. are employees of the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense for the US Department of Defense (JPEO-CBRND). S.A.H. is an employee of Logistics Management Institute (LMI), performing technical contract support for JPEO-CBRND. J.E.C. has served as a consultant for Luna Innovations, is a member of the scientific advisory board of Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from Takeda, IDBiologics, and AstraZeneca. Vanderbilt University has applied for patents related to antibodies studied in this paper. M.S.D. is a consultant for InBios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and is on the scientific advisory boards of Moderna and Immunome. The laboratory of M.S.D. has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions., (© 2022 Elsevier Inc.)

Although mRNA vaccines encoding the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevent COVID-19, the emergence of new viral variants jeopardizes their efficacy. Here, we assessed the immunogenicity and protective activity of historical (mRNA-1273, designed for Wuhan-1 spike protein) or modified (mRNA-1273.351, designed for B.1.351 spike protein) Moderna mRNA vaccines in 129S2 and K18-hACE2 mice. Mice were immunized with either high-dose or low-dose formulations of the mRNA vaccines, where low-dose vaccination modeled suboptimal immune responses. Immunization with formulations at either dose induced neutralizing antibodies in serum against ancestral SARS-CoV-2 WA1/2020 and several virus variants, although serum titers were lower against the B.1.617.2 (Delta) virus. Protection against weight loss and lung pathology was observed with all high-dose vaccines against all viruses. However, low-dose formulations of the vaccines, which produced lower magnitude antibody and T cell responses, showed breakthrough lung infections with B.1.617.2 and development of pneumonia in K18-hACE2 mice. Thus, in individuals with reduced immunity after mRNA vaccination, breakthrough infection and disease may occur with some SARS-CoV-2 variants.

The emergence of SARS-CoV-2 antigenic variants with increased transmissibility is a public health threat. Some variants show substantial resistance to neutralization by SARS-CoV-2 infection- or vaccination-induced antibodies. Here, we analyzed receptor binding domain-binding monoclonal antibodies derived from SARS-CoV-2 mRNA vaccine-elicited germinal center B cells for neutralizing activity against the WA1/2020 D614G SARS-CoV-2 strain and variants of concern. Of five monoclonal antibodies that potently neutralized the WA1/2020 D614G strain, all retained neutralizing capacity against the B.1.617.2 variant, four also neutralized the B.1.1.7 variant, and only one, 2C08, also neutralized the B.1.351 and B.1.1.28 variants. 2C08 reduced lung viral load and morbidity in hamsters challenged with the WA1/2020 D614G, B.1.351, or B.1.617.2 strains. Clonal analysis identified 2C08-like public clonotypes among B cells responding to SARS-CoV-2 infection or vaccination in 41 out of 181 individuals. Thus, 2C08-like antibodies can be induced by SARS-CoV-2 vaccines and mitigate resistance by circulating variants of concern., Competing Interests: Declaration of interests The Ellebedy laboratory received funding under sponsored research agreements that are unrelated to the data presented in the current study from Emergent BioSolutions and from AbbVie. A.H.E. is a consultant for Mubadala Investment Company and the founder of ImmuneBio Consulting LLC. M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, Carnival Corporation and on the Scientific Advisory Board of Moderna and Immunome. The Diamond laboratory has received unrelated sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. The Boon laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, GreenLight Biosciences Inc., and Nano targeting & Therapy Biopharma Inc. The Boon laboratory has received funding support from AbbVie Inc., for the commercial development of a SARS-CoV-2 mAb. A.J.S., J.S.T., W.B.A., J.B.C., S.P.J.W., M.S.D., A.C.M.B., and A.H.E. are recipients of a licensing agreement with Abbvie Inc., for commercial development of a SARS-CoV-2 mAb. A patent application related to this work has been filed by Washington University School of Medicine. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines, which list Florian Krammer as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. Florian Krammer has consulted for Merck and Pfizer (before 2020) and is currently consulting for Pfizer, Seqirus, and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2. The Shi laboratory has received sponsored research agreements from Pfizer, Gilead, Merck, and IGM Sciences Inc. The Whelan laboratory has received unrelated funding support in sponsored research agreements with Vir Biotechnology, AbbVie, and sAB therapeutics. All other authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures. Although cell culture experiments have demonstrated a loss of potency of several anti-spike neutralizing antibodies against variant strains of SARS-CoV-2 1-3 , the in vivo importance of these results remains uncertain. Here we report the in vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which correspond to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with mutations at residue E484 of the spike protein, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016 combination therapy, both of which lost all protective activity, and the combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity. When administered after infection, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but not all-of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing variant strains of SARS-CoV-2., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis., Competing Interests: Declaration of interests S.P.J.W., P.W.R., and Washington University have filed a patent application for uses of VSV-SARS-CoV-2. S.P.J.W. has received unrelated funding support in sponsored research agreements with Vir Biotechnology, Abbvie, and SAB therapeutics. M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation, and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Boards of Meissa Vaccines, and is Founder of IDBiologics. The Crowe laboratory has received sponsored research agreements from Takeda, AstraZeneca, and IDBiologics. Vanderbilt University has applied for patents related to antibodies described in this paper. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)