Biology subjects

Lore, K.

Publications and source records attributed to Lore, K..

6 recordsLinked to original sources

bioRxiv2026

Distinct mechanisms of neutralization by antibodies targeting a conserved pneumovirus F epitope

Pneumoviruses cause seasonal outbreaks leading to hospitalizations of vulnerable populations such as infants and the elderly. Cross-neutralizing antibodies targeting viral fusion have been isolated from infected individuals, but their elicitation and mechanisms of action remain understudied. Here, we describe two vaccine-elicited antibody classes, LOR24 and LOR69, that bind an overlapping epitope, and identify the somatic mutations that endow their breadth and potency, respectively. Cryo-electron microscopy structures of both antibodies bound to the HRSV fusion (F) protein show binding modes distinct from each other and from the previously described cross-neutralizing antibody MPE8, yet they all use similar motifs for binding. Complementary in vitro and electron microscopy experiments show that these antibodies either lock prefusion F as a trimer, arrest F in a monomeric or intermediate state, or promote the transition to the postfusion conformation. This work sheds light on mechanisms of pneumovirus neutralization and the elicitation of cross-neutralizing antibody responses.

immunology↗

bioRxiv2024

A genetically engineered therapeutic lectin inhibits human influenza A virus infection and sustains robust virus-specific CD8 T cell expansion

Native banana lectin (BanLec) is antiviral but highly mitogenic, which limits its therapeutic value. In contrast, the genetically engineered H84T BanLec (H84T) is not mitogenic but remains effective against influenza A virus (IAV) infection in mouse models. However, the potency and effect of H84T on human immune cells and IAV-specific immune responses is undetermined. We found that H84T efficiently inhibited IAV replication in human dendritic cells (DCs) from blood and tonsils, which preserved DC viability and allowed acquisition and presentation of viral antigen. Consequently, H84T-treated DCs initiated effective expansion of IAV-specific CD8 T cells. Furthermore, H84T preserved the capacity of IAV-exposed DCs to present a second non-IAV antigen and induce robust CD8 T cell expansion. This supports H84T as a potent antiviral in humans as it effectively inhibits IAV infection without disrupting DC function, and preserves induction of antigen-specific adaptive immune responses against diverse antigens, which likely is clinically beneficial.

immunology↗

bioRxiv2023

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has a remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signaling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

immunology↗

bioRxiv2023

Cell targeting and immunostimulatory properties of a novel Fcγ-receptor independent agonistic anti-CD40 antibody in rhesus macaques

Targeting CD40 by agonistic antibodies used as vaccine adjuvants or for cancer immunotherapy is a strategy to stimulate immune responses. The majority of studied agonistic anti-human CD40 antibodies require crosslinking of their Fc region to inhibitory Fc{gamma}RIIb to induce immune stimulation although this has been associated with toxicity in previous studies. Here we introduce an agonistic anti-human CD40 monoclonal IgG1 antibody (MAB273) unique in its specificity to the CD40L binding site of CD40 but devoid of Fc{gamma}-receptor binding, we demonstrate rapid binding of MAB273 to B cells and dendritic cells resulting in strong activation in vitro on human cells and in vivo in rhesus macaques. Dissemination of fluorescently labeled MAB273 after subcutaneous administration was found predominantly at the site of injection and specific draining lymph nodes. Phenotypic cell differentiation and upregulation of genes associated with immune activation were found in the targeted tissues. Antigen-specific T cell responses were enhanced by MAB273 when given in a prime-boost regimen and for boosting low preexisting responses. MAB273 may therefore be a promising immunostimulatory adjuvant that warrants future testing for therapeutic and prophylactic vaccination strategies.

immunology↗

bioRxiv2020

Single cell transcriptomics of primate sensory neurons identifies cell types associated with human chronic pain

Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of human chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

neuroscience↗

bioRxiv2020

SARS-CoV-2 protein subunit vaccination elicits potent neutralizing antibody responses

The outbreak and spread of SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19), is a current global health emergency and a prophylactic vaccine is needed urgently. The spike glycoprotein of SARS-CoV-2 mediates entry into host cells, and thus is a target for neutralizing antibodies and vaccine design. Here we show that adjuvanted protein immunization with SARS-CoV-2 spike trimers, stabilized in prefusion conformation 1, results in potent antibody responses in mice and rhesus macaques with neutralizing antibody titers orders of magnitude greater than those typically measured in serum from SARS-CoV-2 seropositive humans. Neutralizing antibody responses were observed after a single dose, with exceptionally high titers achieved after boosting. Furthermore, neutralizing antibody titers elicited by a dose-sparing regimen in mice were similar to those obtained from a high dose regimen. Taken together, these data strongly support the development of adjuvanted SARS-CoV-2 prefusion-stabilized spike protein subunit vaccines.

immunology↗