Biology subjects

Schommers, P.

Publications and source records attributed to Schommers, P..

11 recordsLinked to original sources

bioRxiv2026

Durable suppression of viremia by lipid nanoparticle-formulated RNA encoding for a highly potent HIV-1 neutralizing antibody

Recombinant broadly neutralizing antibodies (bNAbs) are promising tools to treat and prevent HIV-1 infection but are associated with manufacturing challenges. To overcome this limitation, we encoded the potent bNAb 1-18-LS on RNA (1-18-LS RibobNAb) for delivery via lipid nanoparticles (LNPs). Indicating high in vivo antibody expression, a 30 ug RNA-LNP intravenous injection resulted in an average peak 1-18-LS RibobNAb serum concentration of 1,061 ug/mL in human neonatal Fc receptor-transgenic mice. Notably, weekly 30 ug RNA-LNP doses maintained higher trough bNAb levels than 500 ug protein injections. Highlighting potent antiviral activity, RNA-LNP-mediated 1-18-LS RibobNAb monotherapy of viremic HIV-1YU2-infected humanized mice resulted in durable HIV-1 suppression without emerging viral escape. Importantly, 1-18-LS RNA-LNP treatment also fully controlled infection after interruption of antiretroviral therapy in humanized mice infected with different patient-derived polyclonal HIV-1 isolates. Our findings provide a proof-of-principle for effective RNA-mediated bNAb immunotherapy of HIV-1 infection.

immunology↗

bioRxiv2025

Geno2pheno: Interpretable and accurate HIV antibody resistance prediction

BackgroundAntiretroviral therapy (ART) is a life saving option for people living with HIV-1 (PLWH) and is effective against many viral strains. The most common ARTs involve combinations of drugs targeting viral or cellular proteins. Most of these drugs have to be taken daily. An alternative to ARTs with established inhibitors comprises broadly neutralizing antibodies (bNAbs). However, bNAbs share the problem of viral resistance with protein inhibitors. We developed a web service geno2pheno[bNAbs] that allows users to upload viral genotypes and estimates the respective resistance to many common bNAbs. The service uses trained statistical models to classify the virus into sensitive and resistant, respectively or to regress the IC50. MethodsWe used two linear models as well as two neural nets for each task and multi-task (MT) learning to train both models for IC50 prediction and classification simultaneously. During multi-task learning we penalize divergence of class and IC50 score in addition to the loss individual to each of the models. FindingsWe compared the linear models of geno2pheno[bNAbs] to other state-of-the-art methods like recurrent neural nets and self-attention, and found them to be competitive in regard to accuracy and have the benefit of fast computation and being easily interpretable in regard to features, i.e., positions on the envelope. InterpretationWe developed a web service for the prediction of antibody resistance (geno2pheno[bNAbs]) to HIV-1, which is free to use and can be extended to other viruses, like Sars-Cov2, in the future.

bioinformatics↗

bioRxiv2025

Identification of a broad and potent V3 glycan site bNAb targeting anN332gp120 glycan-independent epitope

Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here, we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels1-3 (GeoMean IC50 = 0.012 {micro}g/mL, breadth = 69%, 217 virus strains) by targeting a N332gp120 glycan-independent V3 epitope, a site of Env vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryo-EM structure revealed contacts with the V3 324GD/NIR327 motif and interactions with N156gp120 and N301gp120 glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332gp120 glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs, and bivalent 007 IgG was up to [~]300-fold more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1ADA-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007s potential for HIV-1 prevention, therapy, functional cure, and vaccine design.

immunology↗

bioRxiv2025

Profiling a large HIV-1 elite neutralizer cohort reveals remarkable CD4bs bNAb for HIV-1 prevention and therapy

Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by broad envelope sequence diversity and rapid emergence of viral escape1-9. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies (bNAbs) with highest potency and breadth for clinical application. From 831 expressed monoclonal antibodies, we identified 04_A06, a new VH1-2-encoded CD4 binding site bNAb with remarkable breadth and potency against extended multiclade pseudovirus panels (GeoMean IC50 = 0.059 {micro}g/ml, breadth = 98.5%, 332 virus strains). Moreover, 04_A06 was not susceptible to classic viral CD4bs escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed that antiviral activity is mediated by an unusually long 11-amino acid heavy chain insertion. This insertion facilitates inter-protomer contacts and interactions with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody Mediated Prevention (AMP) trials (GeoMean IC50 = 0.082 {micro}g/ml, breadth = 98.4%, 191 virus strains) and in silico modeling for 04_A06LS predicted HIV-1 prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention strategies of HIV-1 infection.

immunology↗

bioRxiv2023

Mapping the neutralizing specificity of human anti-HIV serum by deep mutational scanning

Understanding the specificities of human serum antibodies that broadly neutralize HIV can inform prevention and treatment strategies. Here we describe a deep mutational scanning system that can measure the effects of combinations of mutations to HIV envelope (Env) on neutralization by antibodies and polyclonal serum. We first show that this system can accurately map how all functionally tolerated mutations to Env affect neutralization by monoclonal antibodies. We then comprehensively map Env mutations that affect neutralization by a set of human polyclonal sera known to target the CD4-binding site that neutralize diverse strains of HIV. The neutralizing activities of these sera target different epitopes, with most sera having specificities reminiscent of individual characterized monoclonal antibodies, but one sera targeting two epitopes within the CD4 binding site. Mapping the specificity of the neutralizing activity in polyclonal human serum will aid in assessing anti-HIV immune responses to inform prevention strategies.

immunology↗

bioRxiv2022

Determining probabilities of HIV-1 bNAb development in healthy and chronically infected individuals

HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs frequently carry uncommon molecular characteristics that might prevent their induction. Here, we performed unbiased sequence analyses of B cell receptor repertoires from 57 healthy and 46 chronically HIV-1- or HCV-infected individuals and learned probabilistic models to predict the likelihood of bNAb development. We formally show that lower probabilities for bNAbs are predictive of higher HIV-1 neutralization activity. Moreover, ranking of bNAbs by their probabilities allowed to identify highly potent antibodies with superior generation probabilities as preferential targets for vaccination approaches. Importantly, we found equal bNAb probabilities across infected and healthy donors. This implies that chronic infection is not a prerequisite for the generation of bNAbs, fostering the hope that HIV-1 vaccines can induce bNAb development in healthy individuals. Significance StatementWhile HIV-1 broadly neutralizing antibodies (bNAbs) can develop in chronically HIV-1-infected individuals, they could not yet be elicited by active vaccination. Here, we computationally demonstrate that HIV-1 bNAbs carry distinct sequence features making them unlikely outcomes of the antibody evolution. However, our approach allowed us to identify bNAbs with higher probabilities of being generated. These candidates can now serve as the most promising targets to be induced by vaccination. Moreover, we show that chronic infection has no influence on the probabilities of finding typical bNAb sequence features in the memory B cell compartment. Both findings are critical to design effective vaccination strategies.

immunology↗

bioRxiv2022

Delineating antibody escape from Omicron variants

SARS-CoV-2 neutralizing antibodies play a critical role in prevention and treatment of COVID-19 but are challenged by viral evolution and antibody evasion, exemplified by the highly resistant Omicron BA.1 sublineage.1-12 Importantly, the recently identified Omicron sublineages BA.2.12.1 and BA.4/5 with differing spike mutations are rapidly emerging in various countries. By determining polyclonal serum activity of 50 convalescent or vaccinated individuals against BA.1, BA.1.1, BA.2, BA.2.12.1, and BA.4/5, we reveal a further reduction of BA.4/5 susceptibility to vaccinee sera. Most notably, delineation of the sensitivity to an extended panel of 163 antibodies demonstrates pronounced antigenic differences of individual sublineages with distinct escape patterns and increased antibody resistance of BA.4/5 compared to the most prevalent BA.2 sublineage. These results suggest that the antigenic distance from BA.1 and the increased resistance compared to BA.2 may favor immune escape-mediated expansion of BA.4/5 after the first Omicron wave. Finally, while most monoclonal antibodies in clinical stages are inactive against all Omicron sublineages, we identify promising novel antibodies with high pan-Omicron neutralizing potency. Our study provides a detailed understanding of the antibody escape from the most recently emerging Omicron sublineages that can inform on effective strategies to prevent and treat COVID-19.

immunology↗

bioRxiv2022

A naturally arising broad and potent CD4-binding site antibody with low somatic mutation

The induction of broadly neutralizing antibodies (bNAbs) is a potential strategy for a vaccine against HIV-1. However, most bNAbs exhibit features such as unusually high somatic hypermutation, including insertions and deletions, which make their induction challenging. VRC01-class bNAbs exhibit extraordinary breadth and potency, but also rank among the most highly somatically-mutated bNAbs. Here we describe a VRC01-class antibody isolated from a viremic controller, BG24, that has less than half the mutations of most other relatives of its class, while achieving comparable breadth and potency. A 3.8 [A] X-ray crystal structure of a BG24-BG505 Env trimer complex revealed conserved contacts at the gp120 interface characteristic of the VRC01-class Abs, despite lacking common CDR3 sequence motifs. The existence of moderately-mutated CD4-binding site (CD4bs) bNAbs such as BG24 provides a simpler blueprint for CD4bs antibody induction by a vaccine, raising the prospect that such an induction might be feasible with a germline-targeting approach. TeaserAn anti-HIV-1 antibody with comparable neutralization breadth and potency to similarly-classed antibodies, with half as many mutations.

immunology↗

bioRxiv2021

Kinetics and correlates of the neutralizing antibody response to SARS-CoV-2

A detailed understanding of antibody-based SARS-CoV-2 immunity has critical implications for overcoming the COVID-19 pandemic and for informing on vaccination strategies. In this study, we evaluated the dynamics of the SARS-CoV-2 antibody response in a cohort of 963 recovered individuals over a period of 10 months. Investigating a total of 2,146 samples, we detected an initial SARS-CoV-2 antibody response in 94.4% of individuals, with 82% and 79% exhibiting serum and IgG neutralization, respectively. Approximately 3% of recovered patients demonstrated exceptional SARS-CoV-2 neutralizing activity, defining them as elite neutralizers. These individuals also possessed effective cross-neutralizing IgG antibodies to SARS-CoV-1 without any known prior exposure to this virus. By applying multivariate statistical modeling, we found that sero-reactivity, age, time since disease onset, and fever are key factors predicting SARS-CoV-2 neutralizing activity in mild courses of COVID-19. Investigating longevity of the antibody response, we detected loss of anti-spike reactivity in 13% of individuals 10 months after infection. Moreover, neutralizing activity had an initial half-life of 6.7 weeks in serum versus 30.8 weeks in purified IgG samples indicating the presence of a more stable and long-term memory IgG B cell repertoire in the majority of individuals recovered from COVID-19. Our results demonstrate a broad spectrum of the initial SARS-CoV-2 neutralizing antibody response depending on clinical characteristics, with antibodies being maintained in the majority of individuals for the first 10 months after mild course of COVID-19.

immunology↗

bioRxiv2020

Longitudinal isolation of potent near-germline SARS-CoV-2-neutralizing antibodies from COVID-19 patients

The SARS-CoV-2 pandemic has unprecedented implications for public health, social life, and world economy. Since approved drugs and vaccines are not available, new options for COVID-19 treatment and prevention are highly demanded. To identify SARS-CoV-2 neutralizing antibodies, we analysed the antibody response of 12 COVID-19 patients from 8 to 69 days post diagnosis. By screening 4,313 SARS-CoV-2-reactive B cells, we isolated 255 antibodies from different time points as early as 8 days post diagnosis. Among these, 28 potently neutralized authentic SARS-CoV-2 (IC100 as low as 0.04 g/ml), showing a broad spectrum of V genes and low levels of somatic mutations. Interestingly, potential precursors were identified in naive B cell repertoires from 48 healthy individuals that were sampled before the COVID-19 pandemic. Our results demonstrate that SARS-CoV-2 neutralizing antibodies are readily generated from a diverse pool of precursors, fostering the hope of rapid induction of a protective immune response upon vaccination.

immunology↗

bioRxiv2019

openPrimeR for multiplex amplification of highly diverse templates

To study the diversity of immune receptors and pathogens, multiplex PCR has become a central approach in research and diagnostics. However, insufficient primer design against highly diverse templates often prevents amplification and therefore limits the correct understanding of biological processes. Here, we present openPrimeR, an R-based tool for evaluating and designing multiplex PCR primers. openPrimeR provides a functional and intuitive interface and uses either a greedy algorithm or an integer linear program to compute the minimal set of primers that performs full target coverage. As proof of concept, we used openPrimeR to find optimal primer sets for the amplification of highly mutated immunoglobulins. Comprehensive analyses on specifically generated immunoglobulin variable gene segment libraries resulted in the composition of highly effective primer sets (oPR-IGHV, oPR-IGKV and oPR-IGLV) that demonstrated to be particularly suitable for the isolation of novel human antibodies.

immunology↗