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Current vaccines against COVID-19 elicit immune responses that are overall strong but wane rapidly. As a consequence, the necessary booster shots have contributed to vaccine fatigue. Hence, vaccines that would provide lasting protection against COVID-19 are needed, but are still unavailable. Cytomegaloviruses (CMVs) elicit lasting and uniquely strong immune responses. Used as vaccine vectors, they may be attractive tools that obviate the need for boosters. Therefore, we tested the murine CMV (MCMV) as a vaccine vector against COVID-19 in relevant preclinical models of immunization and challenge. We have previously developed a recombinant MCMV vaccine vector expressing the spike protein of the ancestral SARS-CoV-2 (MCMV S ). In this study, we show that the MCMV S elicits a robust and lasting protection in young and aged mice. Notably, spike-specific humoral and cellular immunity was not only maintained but also even increased over a period of at least 6 months. During that time, antibody avidity continuously increased and expanded in breadth, resulting in neutralization of genetically distant variants, like Omicron BA.1. A single dose of MCMV S conferred rapid virus clearance upon challenge. Moreover, MCMV S vaccination controlled two variants of concern (VOCs), the Beta (B.1.135) and the Omicron (BA.1) variants. Thus, CMV vectors provide unique advantages over other vaccine technologies, eliciting broadly reactive and long-lasting immune responses against COVID-19., Competing Interests: LČ-Š, SJ, and YK are applicants for a patent based on MCMV as a vaccine vector. LČ-Š served as advisor to SANOFI for COVID vaccines, unrelated to this study. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Metzdorf, Jacobsen, Kim, Teixeira Alves, Kulkarni, Brdovčak, Materljan, Eschke, Chaudhry, Hoffmann, Bertoglio, Ruschig, Hust, Šustić, Krmpotić, Jonjić, Widera, Ciesek, Pöhlmann, Landthaler and Čičin-Šain.)

BA.2.86, a recently identified descendant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sublineage, contains ∼35 mutations in the spike (S) protein and spreads in multiple countries. Here, we investigated whether the virus exhibits altered biological traits, focusing on S protein-driven viral entry. Employing pseudotyped particles, we show that BA.2.86, unlike other Omicron sublineages, enters Calu-3 lung cells with high efficiency and in a serine- but not cysteine-protease-dependent manner. Robust lung cell infection was confirmed with authentic BA.2.86, but the virus exhibited low specific infectivity. Further, BA.2.86 was highly resistant against all therapeutic antibodies tested, efficiently evading neutralization by antibodies induced by non-adapted vaccines. In contrast, BA.2.86 and the currently circulating EG.5.1 sublineage were appreciably neutralized by antibodies induced by the XBB.1.5-adapted vaccine. Collectively, BA.2.86 has regained a trait characteristic of early SARS-CoV-2 lineages, robust lung cell entry, and evades neutralizing antibodies. However, BA.2.86 exhibits low specific infectivity, which might limit transmissibility., Competing Interests: Declaration of interests A.K., I.N., S.P. and M.H. conducted contract research (testing of vaccinee sera for neutralizing activity against SARS-CoV-2) for Valneva unrelated to this work. G.M.N.B. served as advisor for Moderna, and S.P. served as advisor for BioNTech, unrelated to this work. A.D-J. served as advisor for Pfizer, unrelated to this work. The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The novel betacoronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a form of severe pneumonia disease called coronavirus disease 2019 (COVID-19). To develop human neutralizing anti-SARS-CoV-2 antibodies, antibody gene libraries from convalescent COVID-19 patients were constructed and recombinant antibody fragments (scFv) against the receptor-binding domain (RBD) of the spike protein were selected by phage display. The antibody STE90-C11 shows a subnanometer IC 50 in a plaque-based live SARS-CoV-2 neutralization assay. The in vivo efficacy of the antibody is demonstrated in the Syrian hamster and in the human angiotensin-converting enzyme 2 (hACE2) mice model. The crystal structure of STE90-C11 Fab in complex with SARS-CoV-2-RBD is solved at 2.0 Å resolution showing that the antibody binds at the same region as ACE2 to RBD. The binding and inhibition of STE90-C11 is not blocked by many known emerging RBD mutations. STE90-C11-derived human IgG1 with FcγR-silenced Fc (COR-101) is undergoing Phase Ib/II clinical trials for the treatment of moderate to severe COVID-19., Competing Interests: Declaration of interests F.B., D.M., N.L., S. Steinke, P.A.H., R.B., M.R., K.-T.S., K.D.R.R., S.Z.-E., M.B., V.F., S.D., M. Schubert, and M.H. are inventors on a patent application on blocking antibodies against SARS-CoV-2. A.H., A.F., and T.S. are officers of CORAT Therapeutics GmbH, a company founded by YUMAB GmbH for the clinical and regulatory development of STE90-C11 (development name COR-101) (ClinicalTrials.gov ID: NCT04674566 for safety and efficacy of COR-101 in hospitalized patients with moderate to severe COVID-19). A.H. is a shareholder of CORAT Therapeutics GmbH. S.D. and M.H. are advisors to Corat Therapeutics GmbH. A.F., T.S., S.D., and M.H. are shareholders of YUMAB GmbH., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

COVID-19 is a severe acute respiratory disease caused by SARS-CoV-2, a new recently emerged sarbecovirus. This virus uses the human ACE2 enzyme as receptor for cell entry, recognizing it with the receptor binding domain (RBD) of the S1 subunit of the viral spike protein. We present the use of phage display to select anti-SARS-CoV-2 spike antibodies from the human naïve antibody gene libraries HAL9/10 and subsequent identification of 309 unique fully human antibodies against S1. 17 antibodies are binding to the RBD, showing inhibition of spike binding to cells expressing ACE2 as scFv-Fc and neutralize active SARS-CoV-2 virus infection of VeroE6 cells. The antibody STE73-2E9 is showing neutralization of active SARS-CoV-2 as IgG and is binding to the ACE2-RBD interface. Thus, universal libraries from healthy human donors offer the advantage that antibodies can be generated quickly and independent from the availability of material from recovering patients in a pandemic situation.

Poor immune protection upon vaccination is a critical determinant of immunosenescence. Latent Cytomegalovirus (CMV) infection has been associated with poor antibody responses to vaccination, but a causative role for CMV in the poor immune response requires experimental evidence and thus could not be confirmed in clinical studies. To test the hypothesis that latent CMV infection causes poor antibody responses, we infected young or adult mice with mouse CMV and challenged them with Vesicular stomatitis virus (VSV) at 15 or 18months of age. Latent, but not primary infection with mouse CMV resulted in diminished neutralizing titers of the serum IgG fraction at day 7 post challenge, which recovered by day 14 post challenge. This phenomenon was specific for mice infected with mouse CMV, but not mice infected with other herpesviruses, like murine herpesvirus-68 or herpes simplex virus type 1, or mice infected with non-persistent viruses, such as influenza or Vaccinia virus. Hence, our data indicate a delay in IgG class-switch that was specific for the CMV infection. Herpesviral infections did not change the B-cell memory compartment, and increased the size of the effector-memory subset of blood CD4 T-cells only when administered in combination. Furthermore, CD4 T-cell response to VSV infection was maintained in latently infected mice. Therefore, our results argue that latent CMV infection impairs B-cell, but not T-cell responses to a challenge with VSV and delays antibody class-switch by a mechanism which may be independent of T-cell help., (Copyright © 2014 Elsevier Inc. All rights reserved.)