Biology subjects

Mandolesi, M.

Publications and source records attributed to Mandolesi, M..

4 recordsLinked to original sources

bioRxiv2025

HIV Env trimers elicit NHP apex cross-neutralizing antibodies mimicking human bNAbs

As a chronically replicating virus, HIV has evolved extreme sequence variability and effective shielding of functionally constrained spike protein determinants by host-derived glycans. Broadly neutralizing antibodies (bNAbs), though rare, can be isolated from people living with HIV, revealing conserved Env sites as key targets for vaccine development. One such target is the apex of the envelope glycoprotein (Env) spike. Here, we identified a vaccination strategy using heterologous HIV Env trimers covalently coupled to liposomes for multivalent display that resulted in the elicitation of cross-neutralizing HIV serum antibody responses in all immunized non-human primates (NHPs). Critically, we isolated a set of monoclonal antibodies (mAbs) that cross-neutralized multiple divergent HIV clinical isolates. High-resolution cryoEM structural analysis of mAbs from three different NHPs demonstrated that they targeted the Env trimer apex in a manner remarkably similar to that of the human infection-elicited, apex-directed bNAb PG9, representing a substantial advance in HIV vaccine development.

immunology↗

bioRxiv2022

Archaic humans have contributed to large-scale variation in modern human T cell receptor genes

The human T cell receptor (TCR) genes are critical for mediating immune responses to pathogens, tumors and regulating self-antigen recognition. A detailed analysis and validation of expressed TCR alpha, beta, gamma, and delta genes in 45 donors from 4 human populations: African, East Asian, South Asian, and European, revealed a total of 175 novel TCR variable and junctional alleles. The majority of novel alleles contained coding changes and were present at widely differing frequencies in the populations, a finding confirmed using DNA samples and sequences from the 1000 Genomes Project. Importantly, we identified three Neanderthal-derived, introgressed TCR regions, including a highly divergent novel TRGV4 variant, present in all archaic assemblies, that was frequent in all modern Eurasian population groups. Our results demonstrate significant variation in TCR genes at both individual and population levels, providing a strong incentive for including allelic variation in studies of TCR function in human biology.

immunology↗

bioRxiv2021

Driving potent neutralization of a SARS-CoV-2 Variant of Concern with a heterotypic boost

The emergence of SARS-CoV-2 Variants of Concern (VOCs) with mutations in key neutralizing antibody epitopes threatens to undermine vaccines developed against the pandemic founder variant (Wu-Hu-1). Widespread vaccine rollout and continued transmission are creating a population that has antibody responses of varying potency to Wu-Hu-1. Against this background, it is critical to assess the outcomes of subsequent immunization with variant antigens. It is not yet known whether heterotypic vaccine boosts would be compromised by original antigenic sin, where pre-existing responses to a prior variant dampen responses to a new one, or whether the primed memory B cell repertoire would bridge the gap between Wu-Hu-1 and VOCs. Here, we show that a single adjuvanted dose of receptor binding domain (RBD) protein from VOC 501Y.V2 (B.1.351) drives an extremely potent neutralizing antibody response capable of cross-neutralizing both Wu-Hu-1 and 501Y.V2 in rhesus macaques previously immunized with Wu-Hu-1 spike protein. Passive immunization with plasma sampled following this boost protected K18-hACE2 mice from lethal challenge with a 501Y.V2 clinical isolate, whereas only partial protection was afforded by plasma sampled after two Wu-Hu-1 spike immunizations.

immunology↗

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↗