Potently neutralizing and protective anti-human metapneumovirus antibodies target diverse sites on the fusion glycoprotein

Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or treatment of hMPV-associated disease. Here, we used a high-throughput single-cell technology to interrogate memory B cell responses to the hMPV fusion (F) glycoprotein in young adult and elderly donors. Across all donors, the neutralizing antibody response was primarily directed to epitopes expressed on both pre- and post-fusion F conformations. However, we identified rare, highly potent broadly neutralizing antibodies that recognize pre-fusion-specific epitopes and structurally characterized an antibody that targets a site of vulnerability at the pre-fusion F trimer apex. Additionally, monotherapy with neutralizing antibodies targeting three distinct antigenic sites provided robust protection against lower respiratory tract infection in a small animal model. This study provides promising monoclonal antibody candidates for passive immunoprophylaxis and informs the rational design of hMPV vaccine immunogens.We acknowledge the Immune Monitoring and Flow Cytometry Resource (IMFCSR) at the Norris Cotton Cancer Center at Dartmouth supported by NCI Cancer Center Support Grant 5P30CA023108-41. This work was funded in part by Welch Foundation grant number F-0003-19620604.S

Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-Ebolavirus Protection.

Passive administration of monoclonal antibodies (mAbs) is a promising therapeutic approach for Ebola virus disease (EVD). However, all mAbs and mAb cocktails that have entered clinical development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against outbreak-causing Bundibugyo virus (BDBV) and Sudan virus (SUDV). Here, we advance MBP134, a cocktail of two broadly neutralizing human mAbs, ADI-15878 from an EVD survivor and ADI-23774 from the same survivor but specificity-matured for SUDV GP binding affinity, as a candidate pan-ebolavirus therapeutic. MBP134 potently neutralized all ebolaviruses and demonstrated greater protective efficacy than ADI-15878 alone in EBOV-challenged guinea pigs. A second-generation cocktail, MBP134AF, engineered to effectively harness natural killer (NK) cells afforded additional improvement relative to its precursor in protective efficacy against EBOV and SUDV in guinea pigs. MBP134AF is an optimized mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates

Broad neutralization of SARS-related viruses by human monoclonal antibodies

Broadly protective vaccines against known and preemergent human coronaviruses (HCoVs) are urgently needed. To gain a deeper understanding of cross-neutralizing antibody responses, we mined the memory B cell repertoire of a convalescent severe acute respiratory syndrome (SARS) donor and identified 200 SARS coronavirus 2 (SARS-CoV-2) binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the non-neutralizing antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of preexisting memory B cells elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a target for the rational design of pan-sarbecovirus vaccines

Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine

A comprehensive understanding of the development and evolution of human B cell responses duced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a gh-throughput single B cell cloning technology to longitudinally track the human B cell response to the llow fever virus 17D (YFV-17D) vaccine. The earlymemory B cell (MBC) response was mediated by both assical immunoglobulin M (IgM) (IgM(+)CD27(+)) and switched immunoglobulin (swIg(+)) MBC pulations; however, classical IgM MBCs waned rapidly, whereas swIg(+) and atypical IgM(+) and IgD(+) MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination

Genotype-specific features reduce the susceptibility of South American yellow fever virus strains to vaccine-induced antibodies

The resurgence of yellow fever in South America has prompted vaccination against the etiologic agent, yellow fever virus (YFV). Current vaccines are based on a live-attenuated YF-17D virus derived from a virulent African isolate. The capacity of these vaccines to induce neutralizing antibodies against the vaccine strain is used as a surrogate for protection. However, the sensitivity of genetically distinct South American strains to vaccine-induced antibodies is unknown. We show that antiviral potency of the polyclonal antibody response in vaccinees is attenuated against an emergent Brazilian strain. This reduction was attributable to amino acid changes at two sites in central domain II of the glycoprotein E, including multiple changes at the domain I-domain II hinge, which are unique to and shared among most South American YFV strains. Our findings call for a reevaluation of current approaches to YFV immunological surveillance in South America and suggest approaches for updating vaccines

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

International audienceThe rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the “capping loop” of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines

Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody

International audienceEmerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic

Las alfareras rebeldes: una mirada desde la arqueología ecuatoriana a las relaciones de género, la opresión femenina y el patriarcado

In the light of Engels' proposal on the origin and consolidation of patriarchy, this article proposes a re-reading of some iconographic elements of the period of Regional Development of the coast of Ecuador. The anthropomorphic figurines of the Tolita/Tumaco, Bahia, and Jama Coaque cultures, famous for their aesthetic value, present evidence of asymmetrical gender relations that have so far not been observed or thematized in literature. Methodology: The article is based on the iconographic analysis that the author has been conducting for over a decade. The iconography is contrasted with Engels' theory from a feminist approach. It includes a reflection on different historical and contemporary episodes that reveal a patriarchal and machista system prevailing in Ecuador, about which the author also presents an introspective vision from her own experience as an academic. Conclusions: The early iconography of the Ecuadorian coast shows a substantial change between the Formative and Regional Development periods. The increase in social stratification and the accumulation of wealth probably led to the establishment of a patriarchal ideology, justified through iconography as a means of mass transmission of messages. Originality: This article provides in-depth coverage, for the first time, of the discussion on inequality in gender relations in pre-Hispanic Ecuador and material evidence of an ideological discourse tending to naturalize such inequality, through an ideal of subordination of female characters to male ones.Propõe-se uma releitura de alguns elementos iconográficos do período de Desenvolvimento Regional da costa do Equador, à luz da proposta de Engels sobre a origem e consolidação do patriarcado. As figuras antropomorfas das culturas Tolita/Tumaco, Bahía e Jama Coaque, famosas por seu valor estético, apresentam evidências sobre relações de gênero assimétricas que até o momento não têm sido observadas nem tematizadas na literatura. Metodologia: O artigo parte da análise iconográfica que a autora vem realizando há mais de uma década. A iconografia é contrastada com a teoria de Engels desde um enfoque feminista. Inclui uma reflexão sobre diferentes episódios históricos e contemporâneos que deixam em evidência um sistema patriarcal e machista imperante no Equador, sobre o que a autora apresenta também uma visão introspectiva desde sua própria experiência como acadêmica. Conclusões: A iconografia precoce da costa equatoriana deixa ver uma mudança substancial entre os períodos Formativo e de Desenvolvimento Regional. O aumento na estratificação social e a acumulação de riqueza provavelmente implicaram o estabelecimento de uma ideologia patriarcal, justificada através da iconografia como meio em massa de transmissão de mensagens. Originalidade: este artigo põe sobre a mesa e com profundidade, pela primeira vez, a discussão sobre a desigualdade nas relações de gênero no Equador pré-hispânico e a evidência material sobre um discurso ideológico tendente a naturalizar dita desigualdade, através de um ideal de subordinação das personagens femininos frente às masculinas.Se propone una relectura de algunos elementos iconográficos del periodo de Desarrollo Regional de la costa del Ecuador, a la luz de la propuesta de Engels sobre el origen y consolidación del patriarcado. Las figurillas antropomorfas de las culturas Tolita/Tumaco, Bahía y Jama Coaque, famosas por su valor estético, presentan evidencias sobre relaciones de género asimétricas que hasta el momento no han sido observadas ni tematizadas en la literatura. Metodología: El artículo parte del análisis iconográfico que la autora viene realizando desde hace más de una década. La iconografía es contrastada con la teoría de Engels desde un enfoque feminista. Incluye una reflexión sobre diferentes episodios históricos y contemporáneos que dejan en evidencia un sistema patriarcal y machista imperante en el Ecuador, sobre el que la autora presenta también una visión introspectiva desde su propia experiencia como académica. Conclusiones: La iconografía temprana de la costa ecuatoriana deja ver un cambio sustancial entre los periodos Formativo y de Desarrollo Regional. El aumento en la estratificación social y la acumulación de riqueza probablemente conllevaron el establecimiento de una ideología patriarcal, justificada a través de la iconografía como medio masivo de transmisión de mensajes. Originalidad: Este artículo pone sobre el tapete a profundidad, por primera vez, la discusión sobre la desigualdad en las relaciones de género en el Ecuador prehispánico y la evidencia material sobre un discurso ideológico tendiente a naturalizar dicha desigualdad, a través de un ideal de subordinación de los personajes femeninos frente a los masculinos

Analysis of Technological Portfolios for CO2 Stabilizations and Effects of Technological Changes

In this study, cost-effective technological options to stabilize CO2 concentrations at 550, 500, and 450 ppmv are evaluated using a world energy systems model of linear programming with a high regional resolution. This model treats technological change endogenously for wind power, photovoltaics, and fuel-cell vehicles, which are technologies of mass production and are considered to follow the learning by doing process. Technological changes induced by climate policies are evaluated by maintaining the technological changes at the levels of the base case wherein there is no climate policy. The results achieved through model analyses include 1) cost-effective technological portfolios, including carbon capture and storage, marginal CO2 reduction costs, and increases in energy system cost for three levels of stabilization and 2) the effect of the induced technological change on the above mentioned factors. A sensitivity analysis is conducted with respect to the learning rate

Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site

Summary: Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp™ is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses. By replacing one of the ZMapp™ components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross-protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails. : Howell et al. examine a mAb, FVM04, that binds the ebolavirus receptor-binding site and find that FVM04 protects against EBOV and SUDV. When combined with two ZMapp™ components, the antibody cocktail retains EBOV protection similar to that of ZMapp™ and extends protection against SUDV. Specific glycoprotein mutations that enhance the exposure of cross-neutralizing epitopes are described