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Immunization with mosaic-8b (nanoparticles presenting 8 SARS-like betacoronavirus [sarbecovirus] receptor-binding domains [RBDs]) elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated the effects of prior COVID-19 vaccinations in non-human primates and mice on anti-sarbecovirus responses elicited by mosaic-8b, admix-8b (8 homotypics), or homotypic SARS-CoV-2 immunizations, finding the greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate mapping, in which antibodies from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced by mosaic-8b, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19-vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential., Competing Interests: Declaration of interests P.J.B. and A.A.C. are inventors on U.S. Patent Application 17/523,813 filed by the California Institute of Technology that covers the mosaic nanoparticles described in this work. A.I.R. and J.D.P. are inventors on U.S. Patent Application 11,780,888 that covers the chimeric sequence of RBD fused to the HA2 stem of influenza hemagglutinin. A.J.G. is an inventor on a Fred Hutchinson Cancer Center-optioned technology related to DMS of the RBD of SARS-CoV-2 spike protein. L.M., S.B., R.C., C.S.-A., and I.G.F. are inventors on U.S. Patent Applications 16/952,983 and 17/651,476 filed by Ingenza Ltd. that cover Bacillus and Pichia strains established to manufacture endotoxin-free vaccine products. J.H.E. is an employee of HDT Bio that provided the repRNA-LION vaccine. D.H.F. is a co-founder of Orlance, Inc. that is developing gene gun delivery of DNA and repRNA vaccines. S.B., R.C., M.Q.-A., E.R., C.S.-A., L.M., and I.G.F. are employees of Ingenza Ltd. P.J.B. and G.D.V. are scientific advisors for Vaccine Company, Inc., and P.J.B. is a scientific advisor for Vir Biotechnology. N.P. is named on patents describing the use of nucleoside-modified mRNA in LNPs as a vaccine platform. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022 and the mRNA technology advisory board of Pfizer in 2023 and is a member of the scientific advisory board of AldexChem and Bionet-Asia. P.J.C.L. is an employee of Acuitas Therapeutics, a company developing LNP delivery systems for RNA therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7-100 ng ml -1 . These antibodies target an hACE2 epitope that binds to the SARS-CoV-2 spike, but they do not inhibit hACE2 enzymatic activity nor do they induce cell-surface depletion of hACE2. They have favourable pharmacology, protect hACE2 knock-in mice against SARS-CoV-2 infection and should present a high genetic barrier to the acquisition of resistance. These antibodies should be useful prophylactic and treatment agents against any current or future SARS-CoV-2 variants and might be useful to treat infection with any hACE2-binding sarbecoviruses that emerge in the future., (© 2023. The Author(s).)

Efficient mouse models to study SARS-CoV-2 infection are critical for the development and assessment of vaccines and therapeutic approaches to mitigate the current pandemic and prevent reemergence of COVID-19. While the first generation of mouse models allowed SARS-CoV-2 infection and pathogenesis, they relied on ectopic expression and non-physiological levels of human angiotensin-converting enzyme 2 (hACE2). Here we generated a mouse model carrying the minimal set of modifications necessary for productive infection with multiple strains of SARS-CoV-2. Substitution of only three amino acids in the otherwise native mouse Ace2 locus ( Ace2 TripleMutant or Ace2 ™ mice exhibited weight loss and lung damage and inflammation, similar to COVID-19 patients. Previous exposure to USA-WA1/2020 or mRNA vaccination generated memory B cells that participated in plasmablast responses during breakthrough B.1.1.529 infection. Thus, the Ace2 ™ mice exhibited weight loss and lung damage and inflammation, similar to COVID-19 patients. Previous exposure to USA-WA1/2020 or mRNA vaccination generated memory B cells that participated in plasmablast responses during breakthrough B.1.1.529 infection. Thus, the Ace2 ™ mouse replicates human disease after SARS-CoV-2 infection and provides a tool to study immune responses to sequential infections in mice., Competing Interests: NP is named on a patent describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. He has disclosed those interests fully to the University of Pennsylvania and has an approved plan in place for managing any potential conflicts arising from the licensing of that patent. PJCL is an employee of Acuitas Therapeutics, a company involved in the development of mRNA-LNP therapeutics. GDV is a scientific advisor for Vaccine Company, Inc. 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 Nakandakari-Higa, Parsa, Reis, de Carvalho, Mesin, Hoffmann, Bortolatto, Muramatsu, Lin, Bilate, Rice, Pardi, Mucida, Victora and Canesso.)

Objective: To describe the evolution of seropositivity in the State of Rio Grande do Sul, Brazil, through 10 consecutive surveys conducted between April 2020 and April 2021., Methods: Nine cities covering all regions of the State were studied, 500 households in each city. One resident in each household was randomly selected for testing. In survey rounds 1-8 we used the rapid WONDFO SARS-CoV-2 Antibody Test (Wondfo Biotech Co., Guangzhou, China). In rounds 9-10, we used a direct ELISA test that identifies IgG to the viral S protein (S-UFRJ). In terms of social distancing, individuals were asked three questions, from which we generated an exposure score using principal components analysis., Results: Antibody prevalence in early April 2020 was 0.07%, increasing to 10.0% in February 2021, and to 18.2% in April 2021. In round 10, self-reported whites showed the lowest seroprevalence (17.3%), while indigenous individuals presented the highest (44.4%). Seropositivity increased by 40% when comparing the most with the least exposed., Conclusions: The proportion of the population already infected by SARS-Cov-2 in the state is still far from any perspective of herd immunity and the infection affects population groups in very different levels.

Objectives. To evaluate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) over 6 months in the Brazilian State of Rio Grande do Sul (population 11.3 million), based on 8 serological surveys. Methods. In each survey, 4151 participants in round 1 and 4460 participants in round 2 were randomly sampled from all state regions. We assessed presence of antibodies against SARS-CoV-2 using a validated lateral flow point-of-care test; we adjusted figures for the time-dependent decay of antibodies. Results. The SARS-CoV-2 antibody prevalence increased from 0.03% (95% confidence interval [CI] = 0.00%, 0.34%; 1 in every 3333 individuals) in mid-April to 1.89% (95% CI = 1.36%, 2.54%; 1 in every 53 individuals) in early September. Prevalence was similar across gender and skin color categories. Older adults were less likely to be infected than younger participants. The proportion of the population who reported leaving home daily increased from 21.4% (95% CI = 20.2%, 22.7%) to 33.2% (95% CI = 31.8%, 34.5%). Conclusions. SARS-CoV-2 infection increased slowly during the first 6 months in the state, differently from what was observed in other Brazilian regions. Future survey rounds will continue to document the spread of the pandemic.

Background: Large-scale epidemiological studies of seroprevalence of antibodies against SARS-CoV-2 often rely on point-of-care tests that provide immediate results to participants. Yet, little is known on how long rapid tests remain positive after the COVID-19 episode, or how much variability exists across different brands and even among batches of the same test., Methods: In November 2020, we assessed the sensitivity of three tests applied to 133 individuals with a previous positive PCR result between April and October. All subjects provided finger prick blood samples for two batches (A and B) of the Wondfo lateral-flow IgG/IgM test, and dried blood spot samples for the S-UFRJ ELISA test., Results: Overall sensitivity levels were 92.5% (95% CI 86.6-96.3), 63.2% (95% CI 54.4-71.4) and 33.8% (95% CI 25.9-42.5) for the S-UFRJ test, Wondfo A and Wondfo B tests, respectively. There was no evidence of a decline in the positivity of S-UFRJ with time since the diagnosis, but the two Wondfo batches showed sharp reductions to as low as 41.9% and 19.4%, respectively, for subjects with a positive PCR in June or earlier. Positive results for batch B of the rapid test were 35% to 54% lower than for batch A at any given month of diagnosis., Interpretation: Whereas the ELISA test showed high sensitivity and stability of results over the five months of the study, both batches of the rapid test showed substantial declines, with one of the batches consistently showing lower sensitivity levels than the other. ELISA tests based on dried-blood spots are an inexpensive alternative to rapid lateral-flow tests in large-scale epidemiological studies., Funding: The study was funded by the "Todos Pela Saúde" initiative, Instituto Serrapilheira, Brazilian Ministry of Health, Brazilian Collective Health Association (ABRASCO) and the JBS S.A. initiative 'Fazer o Bem Faz Bem'., Competing Interests: Conflicts of interest None., (Copyright © 2021 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)