Biology subjects

Aldis, M.

Publications and source records attributed to Aldis, M..

3 recordsLinked to original sources

bioRxiv2026

Multivalent Anti-ACE2 Nanobodies Confer Broad Pan-Sarbecovirus Protection

The continual emergence of SARS-CoV-2 variants that rapidly evade conventional spike-directed neutralizing antibodies, together with the ongoing risk of cross-species spillover and new sarbecovirus outbreaks, underscores the need to develop broadly acting, escape-resistant therapeutic agents. Here, we optimized a nanobody discovery pipeline incorporating competition-based yeast surface display assays to isolate single-chain variable heavy chain-only antibody domains (VHHs or nanobodies) that bind human ACE2 and inhibit SARS-CoV-2 entry. Dimeric VHHs, as well as bivalent and tetravalent Fc-fusion proteins exhibited markedly increased antiviral activity, blocking a broad panel of SARS-CoV-2 variants and diverse sarbecoviruses at low-nanomolar to picomolar concentrations. These agents did not affect ACE2 enzymatic function or cell surface expression. The VHH-Fc fusion proteins had favorable pharmacokinetics and conferred prophylactic protection in mouse models of both SARS-CoV-2 and SARS-CoV infection, showcasing their potential as broadly acting receptor-targeted biologics against pandemic-threat viruses.

immunology↗

bioRxiv2026

Genetic innovation in coronaviruses driven by a viral nuclease

Genetic variation in viruses is well known to arise from polymerase-driven nucleotide misincorporation. However, insertion and deletion (indel) mutations that occur at lower, largely unknown, frequencies can underly more dramatic phenotypic changes that emerge when advantageous. Using a human coronavirus (HCoV-OC43) construct that reports rare indel mutations, we show that non-structural protein-15 (NSP15), a nuclease encoded by coronaviruses, can drive the acquisition of a class of insertion mutations. Ultra-deep sequencing of both HCoV-OC43 and SARS-CoV-2 populations reveals a similar requirement for NSP15 during insertion mutant generation. Overall, the insertional mutation frequency exceeded 10-3/genome in these two coronaviruses. Analysis of thousands of HCoV-OC43 and SARS-CoV-2 insertion mutants reveals a mutational process in which NSP15 cuts viral RNA, yielding oligonucleotides that correspond to inserts that are acquired at distal genomic locations. The presence of an insertion mutation at the S1/S2 junction in the SARS-CoV-2 spike protein that generates a furin cleavage site and enhances viral transmissibility, may have been necessary for enabling the COVID19 pandemic. We found numerous examples of potential furin cleavage site acquisition and replacement through insertion mutation during the normal course of coronavirus replication. Such events are, therefore, likely commonplace in coronavirus populations of a size that occurs in nature.

microbiology↗

bioRxiv2026

A designed overlapping variant immunogen pool elicits broad sarbecovirus neutralization

A central problem in achieving vaccine-based protection against viral infections is eliciting antibodies that are resilient to viral variation. Successive waves of SARS-CoV-2 infection during the COVID19 pandemic were driven by variants that acquired resistance to neutralizing antibodies elicited by prior SARS-CoV-2 variants. To the extent that serum neutralization breadth occurs in individuals with multiple exposures to SARS-CoV-2 antigens, we and others find that it is largely comprised of antibodies that target the variable receptor binding domain (RBD), rather than more conserved spike protein domains. By designing synthetic dimeric RBD immunogens we show that limiting divergence in heterodimeric components favors the generation of cross-reactive B cells and antibodies. We thus devised a vaccine approach based on a two-dose immunization with a pool of five overlapping heterodimeric synthetic RBD variants. Collectively, the RBD heterodimer pool was designed to cover 10% sequence variation and elicited greater antibody cross-reactivity and neutralization breadth than homodimers or heterodimers with highly divergent components. Using an unconventional prospective challenge model in mice, we demonstrate the effectiveness of the RBD heterodimer pool in inducing antibody responses that attenuate infection by future SARS-CoV-2 variants, as well as protection in a challenge model based on a chimeric vesicular stomatitis virus bearing a spike protein from SARS-CoV-1. Significance statementViral antigenic escape undermines both vaccination efforts and the development of herd immunity, resulting in an enormous viral disease burden. A central problem in eliciting vaccine-based protection against some viral infections is achieving antibody neutralization breadth. To elicit collections of antibodies that overcome the problem of limited antibody tolerance of viral variation, we designed a novel strategy based on an overlapping series of immunogens. This immunogen pool conferred at least partial protection against subsequently prevalent SARS-CoV-2 variants as well as a chimeric SARS-CoV-1 based model virus.

microbiology↗