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1.
N Engl J Med ; 390(12): 1105-1117, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38507753

RESUMO

BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).


Assuntos
Autoanticorpos , Síndromes de Imunodeficiência , Interleucina-23 , Infecções Oportunistas , Adulto , Humanos , Autoanticorpos/imunologia , Síndromes de Imunodeficiência/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/imunologia , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Micoses/imunologia , Infecções Oportunistas/imunologia , Timoma/imunologia , Neoplasias do Timo/imunologia , Anticorpos Neutralizantes/imunologia , Infecções Bacterianas/imunologia
2.
Am J Physiol Heart Circ Physiol ; 326(5): H1080-H1093, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38426866

RESUMO

Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating disease progression. The literature suggests an important role for the activation of interleukin-13 or interleukin-4 signaling in improving ischemic heart failure outcomes after myocardial infarction in mice. Dupilumab, a neutralizing antibody that inhibits the shared IL13/IL4 receptor subunit IL4Rα, is widely used for conditions such as ectopic dermatitis in humans. If global depletion of IL4Rα influences ischemic heart failure, either in mice or in humans taking dupilumab, is unknown. Here, we investigated the pathophysiological effects of global IL4Rα genetic deletion in adult mice after surgically induced myocardial infarction (MI). We also determined heart failure risk in patients with ischemic heart disease and concomitant usage of dupilumab using the collaborative patient data network TriNetX. Global deletion of IL4Rα results in exacerbated cardiac dysfunction associated with reduced capillary size after myocardial infarction in mice. In agreement with our findings in mice, dupilumab treatment significantly increased the risk of heart failure development in patients with preexisting diagnosis of ischemic heart disease. Our results indicate that systemic IL4Rα signaling is protective against heart failure development in adult mice and human patients specifically following an ischemic event. Thus, the compelling evidence presented hereby advocates for the development of a randomized clinical trial specifically investigating heart failure development after myocardial ischemia in patients taking dupilumab for another underlying condition.NEW & NOTEWORTHY A body of literature suggests a protective role for IL4Rα signaling postmyocardial infarction in mice. Here, our observational study demonstrates that humans taking the IL4Rα neutralizing antibody, dupilumab, have increased incidence of heart failure following an ischemic event. Similarly, global IL4Rα deletion in mice exacerbates heart failure postinfarct. To our knowledge, this is the first study reporting an adverse association in humans of dupilumab use with heart failure following a cardiac ischemic event.


Assuntos
Cardiopatias , Insuficiência Cardíaca , Infarto do Miocárdio , Isquemia Miocárdica , Animais , Humanos , Camundongos , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/imunologia , Infarto do Miocárdio/genética , Isquemia Miocárdica/genética
4.
J Virol ; 98(3): e0120623, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38305154

RESUMO

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with greater transmissibility or immune evasion properties has jeopardized the existing vaccine and antibody-based countermeasures. Here, we evaluated the efficacy of boosting pre-immune hamsters with protein nanoparticle vaccines (Novavax, Inc.) containing recombinant Prototype (Wuhan-1) or BA.5 S proteins against a challenge with the Omicron BA.5 variant of SARS-CoV-2. Serum antibody binding and neutralization titers were quantified before challenge, and viral loads were measured 3 days after challenge. Boosting with Prototype or BA.5 vaccine induced similar antibody binding responses against ancestral Wuhan-1 or BA.5 S proteins, and neutralizing activity of Omicron BA.1 and BA.5 variants. One and three months after vaccine boosting, hamsters were challenged with the Omicron BA.5 variant. Prototype and BA.5 vaccine-boosted hamsters had reduced viral infection in the nasal washes, nasal turbinates, and lungs compared to unvaccinated animals. Although no significant differences in virus load were detected between the Prototype and BA.5 vaccine-boosted animals, fewer breakthrough infections were detected in the BA.5-vaccinated hamsters. Thus, immunity induced by Prototype or BA.5 S protein nanoparticle vaccine boosting can protect against the Omicron BA.5 variant in the Syrian hamster model. IMPORTANCE: As SARS-CoV-2 continues to evolve, there may be a need to update the vaccines to match the newly emerging variants. Here, we compared the protective efficacy of the updated BA.5 and the original Wuhan-1 COVID-19 vaccine against a challenge with the BA.5 Omicron variant of SARS-CoV-2 in hamsters. Both vaccines induced similar levels of neutralizing antibodies against multiple variants of SARS-CoV-2. One and three months after the final immunization, hamsters were challenged with BA.5. No differences in protection against the BA.5 variant virus were observed between the two vaccines, although fewer breakthrough infections were detected in the BA.5-vaccinated hamsters. Together, our data show that both protein nanoparticle vaccines are effective against the BA.5 variant of SARS-CoV-2 but given the increased number of breakthrough infections and continued evolution, it is important to update the COVID-19 vaccine for long-term protection.


Assuntos
Vacinas contra COVID-19 , 60547 , SARS-CoV-2 , Animais , Cricetinae , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Infecções Irruptivas/imunologia , Infecções Irruptivas/prevenção & controle , Infecções Irruptivas/virologia , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Mesocricetus/imunologia , Mesocricetus/virologia , 60547/imunologia , SARS-CoV-2/imunologia , Imunização Secundária , Carga Viral
5.
J Virol ; 98(3): e0199523, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38323813

RESUMO

Historically, antibody reactivity to pathogens and vaccine antigens has been evaluated using serological measurements of antigen-specific antibodies. However, it is difficult to evaluate all antibodies that contribute to various functions in a single assay, such as the measurement of the neutralizing antibody titer. Bulk antibody repertoire analysis using next-generation sequencing is a comprehensive method for analyzing the overall antibody response; however, it is unreliable for estimating antigen-specific antibodies due to individual variation. To address this issue, we propose a method to subtract the background signal from the repertoire of data of interest. In this study, we analyzed changes in antibody diversity and inferred the heavy-chain complementarity-determining region 3 (CDRH3) sequences of antibody clones that were selected upon influenza virus infection in a mouse model using bulk repertoire analysis. A decrease in the diversity of the antibody repertoire was observed upon viral infection, along with an increase in neutralizing antibody titers. Using kernel density estimation of sequences in a high-dimensional sequence space with background signal subtraction, we identified several clusters of CDRH3 sequences induced upon influenza virus infection. Most of these repertoires were detected more frequently in infected mice than in uninfected control mice, suggesting that infection-specific antibody sequences can be extracted using this method. Such an accurate extraction of antigen- or infection-specific repertoire information will be a useful tool for vaccine evaluation in the future. IMPORTANCE: As specific interactions between antigens and cell-surface antibodies trigger the proliferation of B-cell clones, the frequency of each antibody sequence in the samples reflects the size of each clonal population. Nevertheless, it is extremely difficult to extract antigen-specific antibody sequences from the comprehensive bulk antibody sequences obtained from blood samples due to repertoire bias influenced by exposure to dietary antigens and other infectious agents. This issue can be addressed by subtracting the background noise from the post-immunization or post-infection repertoire data. In the present study, we propose a method to quantify repertoire data from comprehensive repertoire data. This method allowed subtraction of the background repertoire, resulting in more accurate extraction of expanded antibody repertoires upon influenza virus infection. This accurate extraction of antigen- or infection-specific repertoire information is a useful tool for vaccine evaluation.


Assuntos
Anticorpos Antivirais , Infecções por Orthomyxoviridae , Orthomyxoviridae , Animais , Camundongos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Células Clonais/citologia , Células Clonais/imunologia , Regiões Determinantes de Complementaridade/imunologia , Vacinas contra Influenza/imunologia , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/sangue , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia
6.
J Virol ; 98(1): e0155823, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38174926

RESUMO

Enterovirus A71 (EV-A71) can induce severe neurological complications and even fatal encephalitis in children, and it has caused several large outbreaks in Taiwan since 1998. We previously generated VP1 codon-deoptimized (VP1-CD) reverse genetics (rg) EV-A71 viruses (rgEV-A71s) that harbor a high-fidelity (HF) 3D polymerase. These VP1-CD-HF rgEV-A71s showed lower replication kinetics in vitro and decreased virulence in an Institute of Cancer Research (ICR) mouse model of EV-A71 infection, while still retaining their antigenicity in comparison to the wild-type virus. In this study, we aimed to further investigate the humoral and cellular immune responses elicited by VP1-CD-HF rgEV-A71s to assess the potential efficacy of these EV-A71 vaccine candidates. Following intraperitoneal (i.p.) injection of VP1-CD-HF rgEV-A71s in mice, we observed a robust induction of EV-A71-specific neutralizing IgG antibodies in the antisera after 21 days. Splenocytes isolated from VP1-CD-HF rgEV-A71s-immunized mice exhibited enhanced proliferative activities and cytokine production (IL-2, IFN-γ, IL-4, IL-6, and TNF-α) upon re-stimulation with VP1-CD-HF rgEV-A71, as compared to control mice treated with adjuvant only. Importantly, administration of antisera from VP1-CD-HF rgEV-A71s-immunized mice protected against lethal EV-A71 challenge in neonatal mice. These findings highlight that our generated VP1-CD-HF rgEV-A71 viruses are capable of inducing both cellular and humoral immune responses, supporting their potential as next-generation EV-A71 vaccines for combating EV-A71 infection.IMPORTANCEEV-A71 can cause severe neurological diseases and cause death in young children. Here, we report the development of synthetic rgEV-A71s with the combination of codon deoptimization and high-fidelity (HF) substitutions that generate genetically stable reverse genetics (rg) viruses as potential attenuated vaccine candidates. Our work provides insight into the development of low-virulence candidate vaccines through a series of viral genetic editing for maintaining antigenicity and genome stability and suggests a strategy for the development of an innovative next-generation vaccine against EV-A71.


Assuntos
Proteínas do Capsídeo , Enterovirus Humano A , Infecções por Enterovirus , RNA Polimerase Dependente de RNA , Animais , Camundongos , Anticorpos Antivirais/imunologia , Códon , Enterovirus Humano A/genética , Infecções por Enterovirus/imunologia , Vacinas Atenuadas , Proteínas do Capsídeo/genética , Imunidade Humoral , Imunidade Celular , Anticorpos Neutralizantes/imunologia , Vacinas Virais , Camundongos Endogâmicos ICR , Camundongos Endogâmicos BALB C , RNA Polimerase Dependente de RNA/genética
7.
J Virol ; 98(1): e0084923, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38174935

RESUMO

Hepatitis C virus (HCV) is a member of the Flaviviridae family; however, unlike other family members, the HCV virion has an unusually high lipid content. HCV has two envelope glycoproteins, E1 and E2. E2 contributes to receptor binding, cell membrane attachment, and immune evasion. In contrast, the functions of E1 are poorly characterized due, in part, to challenges in producing the protein. This manuscript describes the expression and purification of a soluble E1 ectodomain (eE1) that is recognized by conformational, human monoclonal antibodies. eE1 forms a complex with apolipoproteins AI and AII, cholesterol, and phospholipids by recruiting high-density lipoprotein (HDL) from the extracellular media. We show that HDL binding is a function specific to eE1 and HDL hinders recognition of E1 by a neutralizing monoclonal antibody. Either low-density lipoprotein or HDL increases the production and infectivity of cell culture-produced HCV, but E1 preferentially selects HDL, influencing both viral life cycle and antibody evasion.IMPORTANCEHepatitis C virus (HCV) infection is a significant burden on human health, but vaccine candidates have yet to provide broad protection against this infection. We have developed a method to produce high quantities of soluble E1 or E2, the viral proteins located on the surface of HCV. HCV has an unusually high lipid content due to the recruitment of apolipoproteins. We found that E1 (and not E2) preferentially recruits host high-density lipoprotein (HDL) extracellularly. This recruitment of HDL by E1 prevents binding of E1 by a neutralizing antibody and furthermore prevents antibody-mediated neutralization of the virus. By comparison, low-density lipoprotein does not protect the virus from antibody-mediated neutralization. Our findings provide mechanistic insight into apolipoprotein recruitment, which may be critical for vaccine development.


Assuntos
Hepacivirus , Hepatite C , Evasão da Resposta Imune , Lipoproteínas HDL , Proteínas do Envelope Viral , Humanos , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Apolipoproteínas/metabolismo , Hepacivirus/patogenicidade , Hepatite C/imunologia , Hepatite C/virologia , Anticorpos Anti-Hepatite C/imunologia , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Proteínas do Envelope Viral/metabolismo , Células HEK293
8.
Nature ; 625(7993): 148-156, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37993710

RESUMO

The continuing emergence of SARS-CoV-2 variants highlights the need to update COVID-19 vaccine compositions. However, immune imprinting induced by vaccination based on the ancestral (hereafter referred to as WT) strain would compromise the antibody response to Omicron-based boosters1-5. Vaccination strategies to counter immune imprinting are critically needed. Here we investigated the degree and dynamics of immune imprinting in mouse models and human cohorts, especially focusing on the role of repeated Omicron stimulation. In mice, the efficacy of single Omicron boosting is heavily limited when using variants that are antigenically distinct from WT-such as the XBB variant-and this concerning situation could be mitigated by a second Omicron booster. Similarly, in humans, repeated Omicron infections could alleviate WT vaccination-induced immune imprinting and generate broad neutralization responses in both plasma and nasal mucosa. Notably, deep mutational scanning-based epitope characterization of 781 receptor-binding domain (RBD)-targeting monoclonal antibodies isolated from repeated Omicron infection revealed that double Omicron exposure could induce a large proportion of matured Omicron-specific antibodies that have distinct RBD epitopes to WT-induced antibodies. Consequently, immune imprinting was largely mitigated, and the bias towards non-neutralizing epitopes observed in single Omicron exposures was restored. On the basis of the deep mutational scanning profiles, we identified evolution hotspots of XBB.1.5 RBD and demonstrated that these mutations could further boost the immune-evasion capability of XBB.1.5 while maintaining high ACE2-binding affinity. Our findings suggest that the WT component should be abandoned when updating COVID-19 vaccines, and individuals without prior Omicron exposure should receive two updated vaccine boosters.


Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Imunização Secundária , Memória Imunológica , SARS-CoV-2 , Animais , Humanos , Camundongos , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Epitopos de Linfócito B/imunologia , Memória Imunológica/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Mutação
9.
Nature ; 625(7995): 578-584, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38123677

RESUMO

The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex1, containing PfRH5 (refs. 2,3), PfCyRPA, PfRIPR, PfCSS and PfPTRAMP, is essential for erythrocyte invasion by the deadliest human malaria parasite, Plasmodium falciparum. Invasion can be prevented by antibodies3-6 or nanobodies1 against each of these conserved proteins, making them the leading blood-stage malaria vaccine candidates. However, little is known about how PfPCRCR functions during invasion. Here we present the structure of the PfRCR complex7,8, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. We test the hypothesis that PfRH5 opens to insert into the membrane9, instead showing that a rigid, disulfide-locked PfRH5 can mediate efficient erythrocyte invasion. We show, through modelling and an erythrocyte-binding assay, that PfCyRPA-binding antibodies5 neutralize invasion through a steric mechanism. We determine the structure of PfRIPR, showing that it consists of an ordered, multidomain core flexibly linked to an elongated tail. We also show that the elongated tail of PfRIPR, which is the target of growth-neutralizing antibodies6, binds to the PfCSS-PfPTRAMP complex on the parasite membrane. A modular PfRIPR is therefore linked to the merozoite membrane through an elongated tail, and its structured core presents PfCyRPA and PfRH5 to interact with erythrocyte receptors. This provides fresh insight into the molecular mechanism of erythrocyte invasion and opens the way to new approaches in rational vaccine design.


Assuntos
Eritrócitos , Malária Falciparum , Complexos Multiproteicos , Parasitos , Plasmodium falciparum , Proteínas de Protozoários , Animais , Humanos , Anticorpos Neutralizantes/imunologia , Antígenos de Protozoários/química , Antígenos de Protozoários/imunologia , Microscopia Crioeletrônica , Dissulfetos/química , Dissulfetos/metabolismo , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Merozoítos/metabolismo , Complexos Multiproteicos/química , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Parasitos/metabolismo , Parasitos/patogenicidade , Plasmodium falciparum/metabolismo , Plasmodium falciparum/patogenicidade , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/ultraestrutura
10.
Nature ; 626(7998): 385-391, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38096903

RESUMO

A limitation of current SARS-CoV-2 vaccines is that they provide minimal protection against infection with current Omicron subvariants1,2, although they still provide protection against severe disease. Enhanced mucosal immunity may be required to block infection and onward transmission. Intranasal administration of current vaccines has proven inconsistent3-7, suggesting that alternative immunization strategies may be required. Here we show that intratracheal boosting with a bivalent Ad26-based SARS-CoV-2 vaccine results in substantial induction of mucosal humoral and cellular immunity and near-complete protection against SARS-CoV-2 BQ.1.1 challenge. A total of 40 previously immunized rhesus macaques were boosted with a bivalent Ad26 vaccine by the intramuscular, intranasal and intratracheal routes, or with a bivalent mRNA vaccine by the intranasal route. Ad26 boosting by the intratracheal route led to a substantial expansion of mucosal neutralizing antibodies, IgG and IgA binding antibodies, and CD8+ and CD4+ T cell responses, which exceeded those induced by Ad26 boosting by the intramuscular and intranasal routes. Intratracheal Ad26 boosting also led to robust upregulation of cytokine, natural killer, and T and B cell pathways in the lungs. After challenge with a high dose of SARS-CoV-2 BQ.1.1, intratracheal Ad26 boosting provided near-complete protection, whereas the other boosting strategies proved less effective. Protective efficacy correlated best with mucosal humoral and cellular immune responses. These data demonstrate that these immunization strategies induce robust mucosal immunity, suggesting the feasibility of developing vaccines that block respiratory viral infections.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunidade nas Mucosas , Imunização Secundária , Macaca mulatta , SARS-CoV-2 , Animais , Humanos , Administração Intranasal , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Citocinas/imunologia , Imunidade nas Mucosas/imunologia , Imunização Secundária/métodos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Injeções Intramusculares , Células Matadoras Naturais/imunologia , Pulmão/imunologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Vacinas de mRNA/administração & dosagem , Vacinas de mRNA/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/imunologia , Traqueia/imunologia , Traqueia/virologia
11.
J Virol ; 97(12): e0107023, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38019013

RESUMO

IMPORTANCE: Multiple SARS-CoV-2 variants of concern have emerged and caused a significant number of infections and deaths worldwide. These variants of concern contain mutations that might significantly affect antigen-targeting by antibodies. It is therefore important to further understand how antibody binding and neutralization are affected by the mutations in SARS-CoV-2 variants. We highlighted how antibody epitope specificity can influence antibody binding to SARS-CoV-2 spike protein variants and neutralization of SARS-CoV-2 variants. We showed that weakened spike binding and neutralization of Beta (B.1.351) and Omicron (BA.1) variants compared to wildtype are not universal among the panel of antibodies and identified antibodies of a specific binding footprint exhibiting consistent enhancement of spike binding and retained neutralization to Beta variant. These data and analysis can inform how antigen-targeting by antibodies might evolve during a pandemic and prepare for potential future sarbecovirus outbreaks.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , COVID-19 , SARS-CoV-2/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
12.
J Virol ; 97(11): e0113723, 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-37855619

RESUMO

IMPORTANCE: The ongoing COVID-19 pandemic has been characterized by the emergence of new SARS-CoV-2 variants including the highly transmissible Omicron XBB sublineages, which have shown significant resistance to neutralizing antibodies (nAbs). This resistance has led to decreased vaccine effectiveness and therefore result in breakthrough infections and reinfections, which continuously threaten public health. To date, almost all available therapeutic nAbs, including those authorized under Emergency Use Authorization nAbs that were previously clinically useful against early strains, have recently been found to be ineffective against newly emerging variants. In this study, we provide a comprehensive structural basis about how the Class 3 nAbs, including 1G11 in this study and noted LY-CoV1404, are evaded by the newly emerged SARS-CoV-2 variants.


Assuntos
Anticorpos Neutralizantes , COVID-19 , Pandemias , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais , Infecções Irruptivas , COVID-19/imunologia , COVID-19/virologia
13.
N Engl J Med ; 389(17): 1590-1600, 2023 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-37889107

RESUMO

BACKGROUND: Passive immunization with plasma collected from convalescent patients has been regularly used to treat coronavirus disease 2019 (Covid-19). Minimal data are available regarding the use of convalescent plasma in patients with Covid-19-induced acute respiratory distress syndrome (ARDS). METHODS: In this open-label trial, we randomly assigned adult patients with Covid-19-induced ARDS who had been receiving invasive mechanical ventilation for less than 5 days in a 1:1 ratio to receive either convalescent plasma with a neutralizing antibody titer of at least 1:320 or standard care alone. Randomization was stratified according to the time from tracheal intubation to inclusion. The primary outcome was death by day 28. RESULTS: A total of 475 patients underwent randomization from September 2020 through March 2022. Overall, 237 patients were assigned to receive convalescent plasma and 238 to receive standard care. Owing to a shortage of convalescent plasma, a neutralizing antibody titer of 1:160 was administered to 17.7% of the patients in the convalescent-plasma group. Glucocorticoids were administered to 466 patients (98.1%). At day 28, mortality was 35.4% in the convalescent-plasma group and 45.0% in the standard-care group (P = 0.03). In a prespecified analysis, this effect was observed mainly in patients who underwent randomization 48 hours or less after the initiation of invasive mechanical ventilation. Serious adverse events did not differ substantially between the two groups. CONCLUSIONS: The administration of plasma collected from convalescent donors with a neutralizing antibody titer of at least 1:160 to patients with Covid-19-induced ARDS within 5 days after the initiation of invasive mechanical ventilation significantly reduced mortality at day 28. This effect was mainly observed in patients who underwent randomization 48 hours or less after ventilation initiation. (Funded by the Belgian Health Care Knowledge Center; ClinicalTrials.gov number, NCT04558476.).


Assuntos
Soroterapia para COVID-19 , COVID-19 , Síndrome do Desconforto Respiratório , Adulto , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , COVID-19/complicações , COVID-19/imunologia , COVID-19/terapia , Respiração Artificial , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/terapia , SARS-CoV-2 , Resultado do Tratamento
14.
Nature ; 624(7992): 639-644, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37871613

RESUMO

A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant, BA.2.86, has emerged and spread to numerous countries worldwide, raising alarm because its spike protein contains 34 additional mutations compared with its BA.2 predecessor1. We examined its antigenicity using human sera and monoclonal antibodies (mAbs). Reassuringly, BA.2.86 was no more resistant to human sera than the currently dominant XBB.1.5 and EG.5.1, indicating that the new subvariant would not have a growth advantage in this regard. Importantly, sera from people who had XBB breakthrough infection exhibited robust neutralizing activity against all viruses tested, suggesting that upcoming XBB.1.5 monovalent vaccines could confer added protection. Although BA.2.86 showed greater resistance to mAbs to subdomain 1 (SD1) and receptor-binding domain (RBD) class 2 and 3 epitopes, it was more sensitive to mAbs to class 1 and 4/1 epitopes in the 'inner face' of the RBD that is exposed only when this domain is in the 'up' position. We also identified six new spike mutations that mediate antibody resistance, including E554K that threatens SD1 mAbs in clinical development. The BA.2.86 spike also had a remarkably high receptor affinity. The ultimate trajectory of this new SARS-CoV-2 variant will soon be revealed by continuing surveillance, but its worldwide spread is worrisome.


Assuntos
Epitopos de Linfócito B , Receptores Virais , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Epitopos de Linfócito B/imunologia , Imunogenicidade da Vacina , Mutação , Receptores Virais/metabolismo , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Soros Imunes/imunologia
15.
J Virol ; 97(10): e0069623, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37796129

RESUMO

IMPORTANCE: Human cytomegalovirus (HCMV) infection is the leading cause of non-heritable birth defects worldwide. HCMV readily infects the early progenitor cell population of the developing brain, and we have found that infection leads to significantly downregulated expression of key neurodevelopmental transcripts. Currently, there are no approved therapies to prevent or mitigate the effects of congenital HCMV infection. Therefore, we used human-induced pluripotent stem cell-derived organoids and neural progenitor cells to elucidate the glycoproteins and receptors used in the viral entry process and whether antibody neutralization was sufficient to block viral entry and prevent disruption of neurodevelopmental gene expression. We found that blocking viral entry alone was insufficient to maintain the expression of key neurodevelopmental genes, but neutralization combined with neurotrophic factor treatment provided robust protection. Together, these studies offer novel insight into mechanisms of HCMV infection in neural tissues, which may aid future therapeutic development.


Assuntos
Anticorpos Neutralizantes , Infecções por Citomegalovirus , Citomegalovirus , Expressão Gênica , Fatores de Crescimento Neural , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Células-Tronco Pluripotentes Induzidas/citologia , Fatores de Crescimento Neural/farmacologia , Fatores de Crescimento Neural/uso terapêutico , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Organoides/citologia , Organoides/metabolismo , Organoides/virologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , Proteínas do Envelope Viral/antagonistas & inibidores , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus/efeitos dos fármacos
16.
Science ; 382(6666): eadj0070, 2023 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-37797027

RESUMO

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, multiple variants escaping preexisting immunity emerged, causing reinfections of previously exposed individuals. Here, we used antigenic cartography to analyze patterns of cross-reactivity among 21 variants and 15 groups of human sera obtained after primary infection with 10 different variants or after messenger RNA (mRNA)-1273 or mRNA-1273.351 vaccination. We found antigenic differences among pre-Omicron variants caused by substitutions at spike-protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and >3 months after a second dose. We found changes in immunodominance of different spike regions, depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine-strain selection.


Assuntos
Antígenos Virais , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vacinas de mRNA , Humanos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Reações Cruzadas , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Vacinas de mRNA/imunologia , Vacinação , Substituição de Aminoácidos
17.
Int J Mol Sci ; 24(19)2023 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-37834322

RESUMO

Analytical ultracentrifugation (AUC) analysis shows that the SARS-CoV-2 trimeric Spike (S) protein adopts different quaternary conformations in solution. The relative abundance of the "open" and "close" conformations is temperature-dependent, and samples with different storage temperature history have different open/close distributions. Neutralizing antibodies (NAbs) targeting the S receptor binding domain (RBD) do not alter the conformer populations; by contrast, a NAb targeting a cryptic conformational epitope skews the Spike trimer toward an open conformation. The results highlight AUC, which is typically applied for molecular mass determination of biomolecules as a powerful tool for detecting functionally relevant quaternary protein conformations.


Assuntos
SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Epitopos/química , Epitopos/imunologia , SARS-CoV-2/química , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Ultracentrifugação , Domínios Proteicos
18.
BMC Infect Dis ; 23(1): 676, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37821853

RESUMO

BACKGROUND: Virginia is a large state in the USA, yet it remains unclear what percentage of the population has had natural COVID-19 infection and whether risk factors for infection have changed over time. METHODS: Using a longitudinal cohort, from December 2021-July 2022 we performed follow up serology and a questionnaire on 784 individuals from across Virginia who had previously participated in a statewide COVID-19 seroepidemiology study in 2020. Children were also invited to participate and an additional 62 children also completed the study. Serology was performed using Roche nucleocapsid and spike serological assays. RESULTS: The majority of participants were white (78.6%), over 50 years old (60.9%), and reported having received COVID-19 vaccine (93.4%). 28.6% had evidence of prior COVID-19 infection (nucleocapsid positive). Reweighted by region, age, and sex to match the Virginia census data, the seroprevalence of nucleocapsid antibodies was estimated to be 30.6% (95% CI: 24.7, 36.6). We estimated that 25-53% of COVID-19 infections were asymptomatic. Infection rates were lower in individuals > 60 years old and were higher in Blacks and Hispanics. Infection rates were also higher in those without health insurance, in those with greater numbers of household children, and in those that reported a close contact or having undergone quarantine for COVID-19. Participants from Southwest Virginia had lower seropositivity (16.2%, 95% CI 6.5, 26.0) than other geographic regions. Boosted vaccinees had lower infection rates than non-boosted vaccinees. Frequenting indoor bars was a risk factor for infection, while frequently wearing an N95 mask was protective, though the estimates of association were imprecise. Infection rates were higher in children than adults (56.5% vs. 28.6%). Infection in the parent was a risk factor for child infection. Spike antibody levels declined with time since last vaccination, particularly in those that were vaccinated but not previously infected. Neutralizing antibody positivity was high (97-99%) for wild type, alpha, beta, gamma, delta, and omicron variants. Neutralizing antibody levels were higher in the follow-up survey compared to the first survey in 2020 and among individuals with evidence of natural infection compared to those without. CONCLUSIONS: In this longitudinal statewide cohort we observed a lower-than-expected COVID-19 infection rate as of August 2022. Boosted vaccinees had lower infection rates. Children had higher infection rates and infections tracked within households. Previously identified demographic risk factors for infection tended to persist. Even after the omicron peak, a large number of Virginians remain uninfected with COVID-19, underscoring the need for ongoing vaccination strategies.


Assuntos
Anticorpos Neutralizantes , COVID-19 , Adulto , Criança , Humanos , Pessoa de Meia-Idade , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Estudos Longitudinais , Fatores de Risco , SARS-CoV-2/imunologia , Estudos Soroepidemiológicos , Virginia/epidemiologia
19.
J Virol ; 97(10): e0092923, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37737588

RESUMO

IMPORTANCE: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants, infecting all children by age 5. RSV also causes substantial morbidity and mortality in older adults, and a vaccine for older adults based on a prefusion-stabilized form of the viral F glycoprotein was recently approved by the FDA. Here, we investigate a set of antibodies that belong to the same public clonotype and were isolated from individuals vaccinated with a prefusion-stabilized RSV F protein. Our results reveal that these antibodies are highly potent and recognize a previously uncharacterized antigenic site on the prefusion F protein. Vaccination with prefusion RSV F proteins appears to boost the elicitation of these neutralizing antibodies, which are not commonly elicited by natural infection.


Assuntos
Anticorpos Antivirais , Epitopos de Linfócito B , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Vacinação , Proteínas Virais de Fusão , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Virais de Fusão/química , Proteínas Virais de Fusão/imunologia , Proteínas Virais de Fusão/metabolismo
20.
Front Immunol ; 14: 1231276, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37600825

RESUMO

The kinetics of Fc-mediated functions following SARS-CoV-2 infection or vaccination in people living with HIV (PLWH) are not known. We compared SARS-CoV-2 spike-specific Fc functions, binding, and neutralization in PLWH and people without HIV (PWOH) during acute infection (without prior vaccination) with either the D614G or Beta variants of SARS-CoV-2, or vaccination with ChAdOx1 nCoV-19. Antiretroviral treatment (ART)-naïve PLWH had significantly lower levels of IgG binding, neutralization, and antibody-dependent cellular phagocytosis (ADCP) compared with PLWH on ART. The magnitude of antibody-dependent cellular cytotoxicity (ADCC), complement deposition (ADCD), and cellular trogocytosis (ADCT) was differentially triggered by D614G and Beta. The kinetics of spike IgG-binding antibodies, ADCC, and ADCD were similar, irrespective of the infecting variant between PWOH and PLWH overall. However, compared with PWOH, PLWH infected with D614G had delayed neutralization and ADCP. Furthermore, Beta infection resulted in delayed ADCT, regardless of HIV status. Despite these delays, we observed improved coordination between binding and neutralizing responses and Fc functions in PLWH. In contrast to D614G infection, binding responses in PLWH following ChAdOx-1 nCoV-19 vaccination were delayed, while neutralization and ADCP had similar timing of onset, but lower magnitude, and ADCC was significantly higher than in PWOH. Overall, despite delayed and differential kinetics, PLWH on ART develop comparable responses to PWOH, supporting the prioritization of ART rollout and SARS-CoV-2 vaccination in PLWH.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Citotoxicidade Celular Dependente de Anticorpos , COVID-19 , Infecções por HIV , Fragmentos Fc das Imunoglobulinas , Glicoproteína da Espícula de Coronavírus , Infecções por HIV/sangue , Infecções por HIV/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Fragmentos Fc das Imunoglobulinas/sangue , Fragmentos Fc das Imunoglobulinas/imunologia , ChAdOx1 nCoV-19/imunologia , ChAdOx1 nCoV-19/uso terapêutico , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Vacinação , Glicoproteína da Espícula de Coronavírus/imunologia , Células HEK293 , Humanos , Imunidade Humoral , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade
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