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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.)

With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice., Competing Interests: Declaration of interests M.M., V.S., M.P.S., and V.N.G. have filed patents on measuring aging. C.H. is affiliated with the Institute for Biomedical Aging Research, Universität Innsbruck, Austria and an honorary research fellow at the Department of Women’s Cancer, EGA Institute for Women’s Health, University College London, United Kingdom. C.H. and M.W. are shareholders of Sola Diagnostics GmbH and named as inventors on a patent on an epigenetic clock indicative of breast cancer risk. J.N.J. is affiliated with the Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA and the XPRIZE Foundation, Culver City, CA, USA. J.N.J. also serves on the advisory board for the American Federation for Aging Research (AFAR)’s Finding Aging biomarkers by Searching existing Trials (FAST) Initiative and the editorial board of Journals of Gerontology Series A Biological Sciences, eLife, and Experimental Gerontology. D.W.B. is affiliated with the Child Brain Development Network, Canadian Institute for Advanced Research and SocioMed Research Nucleus, Universidad Mayor, Santiago, Chile. D.W.B. also serves on the advisory board for the American Federation for Aging Research (AFAR)’s Finding Aging biomarkers by Searching existing Trials (FAST) Initiative and the editorial board of Journals of Gerontology Series A Biological Sciences and is an inventor of DunedinPACE, a Duke University and University of Otago invention licensed to TruDiagnostic. A.A.C. is a founder, president, and majority shareholder at Oken Health. I.B. is affiliated with the SOMT University of Physiotherapy, Amersfoort, The Netherlands and is a member of the clinical advisory board of Rejuvenate Biomed. M.W. is affiliated with the Institute for Biomedical Aging Research, Universität Innsbruck, Austria. N.B. is the Scientific Director of the American Federation for Aging Research (AFAR), on the board of the executive committee of the Longevity Biotech Association, and advisor on the Board of the Academy for Health and Lifespan Research. M.K. is an employee and shareholder of Optispan Inc., a company developing tools to enable science-based personalized and preventative geromedicine. The Regents of the University of California is the sole owner of a patent application directed at GrimAge and other epigenetic clocks for which S.H. is a named inventor. S.H. is also a founder and paid consultant of the nonprofit Epigenetic Clock Development Foundation that licenses patents surrounding epigenetic clocks. A.B.M. is the Chief Medical Officer of NU. V.N.G. is a scientific advisor to Retro and Dior. M.P.S. is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, Protos, RTHM, Iollo, Marble Therapeutics, Crosshair Therapeutics, and Mirvie. M.P.S. is also a scientific advisor of Jupiter, Neuvivo, Swaza, and Mitrix. V.S. is co-founder, SAB chair, and head of research of Turn Biotechnologies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8 + T cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared with conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for 3 months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses., Competing Interests: Declaration of interests M.A.G.H. and P.J.B. are inventors on a US patent application filed by the California Institute of Technology that covers the EABR technology described in this work. W.J.M. and P.J.C.L. are employees of Acuitas Therapeutics, a company developing LNP delivery technology; P.J.C.L. holds equity in Acuitas Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses., Competing Interests: Declaration of interests A provisional patent for the novel SARS-CoV-2 mAbs described in this study has been filed. The authors listed on that application are R.J.X., J.F.S., C.O.B., P.J.B., and B.E. The Broad Institute has filed multiple patents in the area of single cell RNA-seq on which A.R. and O.R.-R. are named inventors. Rockefeller University has applied for a patent relating to the replication competent VSV/SARS-CoV-2 chimeric virus on which Y.W., T.H., and P.D.B. are listed as inventors (US patent 63/036,124). R.J.X. is co-founder and equity holder of Jnana Therapeutics. R.J.X. and A.R. are co-founders and equity holders of Celsius Therapeutics. A.R. is an equity holder in Immunitas and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov. A.R. and O.R.-R. are employees of Genentech (member of the Roche Group) since August and October 2020, respectively. These companies did not provide support for this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Drugs and drug combinations have complex biological effects on cells and organisms. Little is known about how drugs affect protein dynamics that determine these effects. Here, we use a dynamic proteomics approach to accurately follow 15 protein levels in human cells in response to 13 different drugs. We find that protein dynamics in response to combinations of drugs are described accurately by a linear superposition (weighted sum) of their response to individual drugs. The weights in this superposition describe the relative impact of each drug on each protein. Using these weights, we show that one can predict the dynamics in a three-drug or four-drug combination on the basis of the dynamics in drug pairs. Our approach might eliminate the need to increase the number of experiments exponentially with the number of drugs and suggests that it might be possible to rationally control protein dynamics with specific drug combinations., ((c) 2010 Elsevier Inc. All rights reserved.)