RESUMO
Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.
Assuntos
Infecções por Coronavirus/imunologia , Centro Germinativo/imunologia , Pneumonia Viral/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , COVID-19 , Feminino , Centro Germinativo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Baço/imunologia , Baço/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis (Mtb). Intravenous (i.v.) vaccination with Bacille Calmette-Guérin (BCG) provides nearly complete protection against TB in rhesus macaques, but the antibody response it elicits remains incompletely defined. Here we show that i.v. BCG drives superior antibody responses in the plasma and the lungs of rhesus macaques compared to traditional intradermal BCG administration. While i.v. BCG broadly expands antibody titers and functions, IgM titers in the plasma and lungs of immunized macaques are among the strongest markers of reduced bacterial burden. IgM was also enriched in macaques that received protective vaccination with an attenuated strain of Mtb. Finally, an Mtb-specific IgM monoclonal antibody reduced Mtb survival in vitro. Collectively, these data highlight the potential importance of IgM responses as a marker and mediator of protection against TB.
Assuntos
Anticorpos Antibacterianos/sangue , Vacina BCG/administração & dosagem , Imunogenicidade da Vacina , Imunoglobulina M/sangue , Mycobacterium tuberculosis/imunologia , Tuberculose/prevenção & controle , Vacinação , Administração Intravenosa , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Macaca mulatta , Mycobacterium tuberculosis/patogenicidade , Fatores de Tempo , Tuberculose/imunologia , Tuberculose/microbiologiaRESUMO
SARS-CoV-2 mRNA vaccines confer robust protection against COVID-19, but the emergence of variants has generated concerns regarding the protective efficacy of the currently approved vaccines, which lose neutralizing potency against some variants. Emerging data suggest that antibody functions beyond neutralization may contribute to protection from the disease, but little is known about SARS-CoV-2 antibody effector functions. Here, we profiled the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOCs). Although the neutralizing responses to VOCs decreased in both groups, the Fc-mediated responses were distinct. In convalescent individuals, although antibodies exhibited robust binding to VOCs, they showed compromised interactions with Fc-receptors. Conversely, vaccine-induced antibodies also bound robustly to VOCs but continued to interact with Fc-receptors and mediate antibody effector functions. These data point to a resilience in the mRNA-vaccine-induced humoral immune response that may continue to offer protection from SARS-CoV-2 VOCs independent of neutralization.
Assuntos
Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Anticorpos Antivirais/imunologia , COVID-19/metabolismo , COVID-19/prevenção & controle , Receptores Fc/metabolismo , SARS-CoV-2/imunologia , Vacina de mRNA-1273 contra 2019-nCoV/administração & dosagem , Adulto , Anticorpos Neutralizantes/imunologia , Reações Cruzadas/imunologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Adulto JovemRESUMO
A combination of vaccination approaches will likely be necessary to fully control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Here, we show that modified vaccinia Ankara (MVA) vectors expressing membrane-anchored pre-fusion stabilized spike (MVA/S) but not secreted S1 induced strong neutralizing antibody responses against SARS-CoV-2 in mice. In macaques, the MVA/S vaccination induced strong neutralizing antibodies and CD8+ T cell responses, and conferred protection from SARS-CoV-2 infection and virus replication in the lungs as early as day 2 following intranasal and intratracheal challenge. Single-cell RNA sequencing analysis of lung cells on day 4 after infection revealed that MVA/S vaccination also protected macaques from infection-induced inflammation and B cell abnormalities and lowered induction of interferon-stimulated genes. These results demonstrate that MVA/S vaccination induces neutralizing antibodies and CD8+ T cells in the blood and lungs and is a potential vaccine candidate for SARS-CoV-2.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Vetores Genéticos/genética , SARS-CoV-2/imunologia , Vacinas de DNA/imunologia , Vaccinia virus/genética , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Vacinas contra COVID-19/genética , Modelos Animais de Doenças , Expressão Gênica , Ordem dos Genes , Imunofenotipagem , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Vacinação/métodos , Vacinas de DNA/genéticaRESUMO
The Ad26.COV2.S vaccine1-3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies1. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Ad26COVS1 , Adolescente , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Humanos , Imunidade Celular , Imunidade Humoral , Pessoa de Meia-Idade , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto JovemRESUMO
The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).
Assuntos
Adjuvantes Imunológicos , Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Compostos de Alúmen , Animais , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , COVID-19/virologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Modelos Animais de Doenças , Imunidade Celular , Imunidade Humoral , Macaca mulatta/imunologia , Masculino , Oligodesoxirribonucleotídeos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , EsqualenoRESUMO
While Epstein-Barr virus causes mostly asymptomatic infection, associated malignancies, and autoimmune and lymphoproliferative diseases occur. To dissect the evolution of humoral immune responses over the course of EBV infection and to gain a better understanding of the potential contribution of antibody (Ab) function to viral control, we comprehensively profiled Ab specificities and Fc-functionalities using systems serology and VirScan. Ab functions against latent (EBNA1), early (p47/54) and two late (gp350/220 and VCA-p18) EBV proteins were overall modest and/or short-lived, differing from humoral responses induced during acute infection by other viruses such as HIV. In the first year post infection, only p18 elicited robust IgM-driven complement deposition and IgG-driven neutrophil phagocytosis while responses against EBNA-1 were largely Fc-functionally silent and only matured during chronic infection to drive phagocytosis. In contrast, Abs against Influenza virus readily mediated broad Fc-activity in all participants. These data suggest that EBV evades the induction of robust Fc-functional Abs, potentially due to the virus' life cycle, switching from lytic to latent stages during infection.
Assuntos
Infecções por Vírus Epstein-Barr , Anticorpos Antivirais , Antígenos Nucleares do Vírus Epstein-Barr , Herpesvirus Humano 4 , Humanos , Imunoglobulina G , Imunoglobulina MRESUMO
The central nervous system (CNS) has emerged as a critical HIV reservoir. Thus, interventions aimed at controlling and eliminating HIV must include CNS-targeted strategies. Given the inaccessibility of the brain, efforts have focused on cerebrospinal fluid (CSF), aimed at defining biomarkers of HIV-disease in the CNS, including HIV-specific antibodies. However, how antibodies traffic between the blood and CNS, and whether specific antibody profiles track with HIV-associated neurocognitive disorders (HAND) remains unclear. Here, we comprehensively profiled HIV-specific antibodies across plasma and CSF from 20 antiretroviral therapy (ART) naive or treated persons with HIV. CSF was populated by IgG1 and IgG3 antibodies, with reduced Fc-effector profiles. While ART improved plasma antibody functional coordination, CSF profiles were unaffected by ART and were unrelated to HAND severity. These data point to a functional sieving of antibodies across the blood-brain barrier, providing previously unappreciated insights for the development of next-generation therapeutics targeting the CNS reservoir.
Assuntos
Infecções por HIV , HIV-1 , Sistema Nervoso Central , Anticorpos Anti-HIV , Humanos , Transtornos Neurocognitivos/complicaçõesRESUMO
Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB.
Assuntos
Anticorpos Antibacterianos , Fragmentos Fc das Imunoglobulinas , Mycobacterium tuberculosis , Neutrófilos , Tuberculose , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/genética , Neutrófilos/imunologia , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/genética , Tuberculose/imunologia , Tuberculose/microbiologia , Anticorpos Antibacterianos/imunologia , Engenharia de Proteínas , Animais , Receptores Fc/imunologia , Receptores Fc/metabolismo , Receptores Fc/genética , CamundongosRESUMO
Despite the success of existing COVID-19 vaccine platforms, the persistent limitations in global deployment of vaccines and waning immunity exhibited by many of the currently deployed vaccine platforms have led to perpetual outbreaks of SARS-CoV-2 variants of concern. Thus, there is an urgent need to develop new durable vaccine candidates, to expand the global vaccine pipeline, and provide safe and effective solutions for every country worldwide. Here we deeply profiled the functional humoral response induced by two doses of AS03-adjuvanted and non-adjuvanted plant-derived Coronavirus-like particle (CoVLP) vaccine candidate from the phase 1 clinical trial, at peak immunogenicity and six months post-vaccination. AS03-adjuvanted CoVLP induced robust and durable SARS-CoV-2 specific humoral immunity, marked by strong IgG1antibody responses, potent FcγR binding, and antibody effector function. Contrary to a decline in neutralizing antibody titers, the FcγR2A-receptor binding capacity and antibody-mediated effector functions, such as opsonophagocytosis, remained readily detectable for at least six months.
RESUMO
People with HIV (PWH) appear to be at higher risk for suboptimal pathogen responses and for worse COVID-19 outcomes, but the effects of host factors and COVID-19 on the humoral repertoire remain unclear. We assessed the antibody isotype/subclass and Fc-receptor binding Luminex arrays of non-SARS-CoV-2 and SARS-CoV-2 humoral responses among antiretroviral therapy-treated (ART-treated) PWH. Among the entire cohort, COVID-19 infection was associated with higher cytomegalovirus (CMV) responses (vs. the COVID- cohort ), potentially signifying increased susceptibility or a consequence of persistent inflammation. Among the COVID+ participants, (a) higher BMI was associated with a striking amplification of SARS-CoV-2 responses, suggesting exaggerated inflammatory responses, and (b) lower nadir CD4 was associated with higher SARS-CoV-2 IgM and FcγRIIB binding capacity, indicating poorly functioning extrafollicular and inhibitory responses. Among the COVID-19- participants, female sex, older age, and lower nadir CD4 were associated with unique repertoire shifts. In this first comprehensive assessment of the humoral repertoire in a global cohort of PWH, we identify distinct SARS-CoV-2-specific humoral immune profiles among PWH with obesity or lower nadir CD4+ T cell count, underlining plausible mechanisms associated with worse COVID-19-related outcomes in this setting. Host factors associated with the humoral repertoire in the COVID-19- cohort enhance our understanding of these important shifts among PWH.
Assuntos
COVID-19 , Feminino , Humanos , Antirretrovirais , Anticorpos Antivirais , Linfócitos T CD4-Positivos , SARS-CoV-2 , Infecções por HIV/tratamento farmacológicoRESUMO
Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data have revealed enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced COVID-19, pointing to a hybrid immune advantage with infection-associated immune priming. Beyond neutralizing antibodies and T cell immunity, mounting data point to a potential role for additional antibody effector functions, including opsinophagocytic activity, in the resolution of symptomatic COVID-19. Whether hybrid immunity modifies the Fc-effector profile of the mRNA vaccine-induced immune response remains incompletely understood. Thus, here we profiled the SARS-CoV-2 specific humoral immune response in a group of individuals with and without prior COVID-19. As expected, hybrid Spike-specific antibody titers were enhanced following the primary dose of the mRNA vaccine but were similar to those achieved by naive vaccinees after the second mRNA vaccine dose. Conversely, Spike-specific vaccine-induced Fc-receptor binding antibody levels were higher after the primary immunization in individuals with prior COVID-19 and remained higher following the second dose compared to those in naive individuals, suggestive of a selective improvement in the quality, rather than the quantity, of the hybrid humoral immune response. Thus, while the magnitude of antibody titers alone may suggest that any two antigen exposures-either hybrid immunity or two doses of vaccine alone-represent a comparable prime/boost immunologic education, we find that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc-effector functions against conserved regions of the virus. IMPORTANCE Recent data indicates improved immunity to SARS-CoV-2 in individuals who experience a combination of two mRNA vaccine doses and infection, "hybrid immunity," compared to individuals who receive vaccination or experience infection alone. While previous infection accelerates the vaccine-induced immune response following the first dose of mRNA vaccination, subsequent doses demonstrate negligible increases in antibody titers or T cell immunity. Here, using systems serology, we observed a unique antibody profile induced by hybrid immunity, marked by the unique induction of robust Fc-recruiting antibodies directed at the conserved region of the viral Spike antigen, the S2-domain, induced at lower levels in individuals who only received mRNA vaccination. Thus, hybrid immunity clearly redirects vaccine-induced immunodominance, resulting in the induction of a robust functional humoral immune response to the most highly conserved region of the SARS-CoV-2 Spike antigen, which may be key to protection against existing and emerging variants of concern. Thus, next-generation vaccines able to mimic hybrid immunity and drive a balanced response to conserved regions of the Spike antigen may confer enhanced protection against disease.
Assuntos
COVID-19 , Vacinas Virais , Humanos , Vacinas contra COVID-19 , SARS-CoV-2 , COVID-19/prevenção & controle , Anticorpos Antivirais , Anticorpos Neutralizantes , Vacinação , RNA Mensageiro , Glicoproteína da Espícula de Coronavírus/genética , Imunidade Humoral , Vacinas de mRNARESUMO
Preterm newborns are more likely to suffer from infectious diseases at birth compared to children delivered at term. Whether this is due to compromised cellular, humoral, or organ-specific development remains unclear. To begin to define whether maternal-fetal antibody transfer profiles differ across preterm (PT) and fullterm (FT) infants, the overall quantity and functional quality of an array of 24 vaccine-, endemic pathogen-, and common antigen-specific antibodies were assessed across a cohort of 11 PT and 12 term-delivered maternal:infant pairs from birth through week 12. While total IgG levels to influenza, pneumo, measles, rubella, EBV, and RSV were higher in FT newborns, selective Fc-receptor binding antibodies was noted in PT newborns. In fact, near equivalent antibody-effector functions were observed across PT and FT infants, despite significant quantitative differences in transferred antibody levels. Moreover, temporal transfer analysis revealed the selective early transfer of FcRn, FcγR2, and FcγR3 binding antibodies, pointing to differential placental sieving mechanisms across gestation. These data point to selectivity in placental transfer at distinct gestational ages, to ensure that children are endowed with the most robust humoral immunity even if born preterm.
Assuntos
Recém-Nascido Prematuro , Rubéola (Sarampo Alemão) , Anticorpos Antivirais/metabolismo , Criança , Feminino , Idade Gestacional , Humanos , Imunoglobulina G/metabolismo , Lactente , Recém-Nascido , Placenta/metabolismo , GravidezRESUMO
Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov: NCT04397757), we find that the clinical benefits of CCP are associated with a shift toward reduced inflammatory Spike (S) responses and enhanced nucleocapsid (N) humoral responses. We find that CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and that CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least 2 months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for development of a different class of COVID-19 hyperinflammation-targeting antibody therapeutic agents.
Assuntos
COVID-19 , Humanos , COVID-19/terapia , SARS-CoV-2 , Imunização Passiva/métodos , Anticorpos Antivirais/uso terapêutico , Nucleocapsídeo , Soroterapia para COVID-19RESUMO
South Africa has the highest prevalence of HIV and tuberculosis (TB) co-infection globally. Recurrent TB, caused by relapse or reinfection, makes up the majority of TB cases in South Africa, and HIV infected individuals have a greater likelihood of developing recurrent TB. Given that TB remains a leading cause of death for HIV infected individuals, and correlates of TB recurrence protection/risk have yet to be defined, here we sought to understand the antibody associated mechanisms of recurrent TB by investigating the humoral response in a longitudinal cohort of HIV co-infected individuals previously treated for TB with and without recurrent disease during follow-up, in order to identify antibody correlates of protection between individuals who do not have recurrent TB and individuals who do. We used a high-throughput, "systems serology" approach to profile biophysical and functional characteristics of antibodies targeting antigens from Mycobacterium tuberculosis (Mtb). Differences in antibody profiles were noted between individuals with and without recurrent TB, albeit these differences were largely observed close to the time of re-diagnosis. Individuals with recurrent TB had decreased Mtb-antigen specific IgG3 titers, but not other IgG subclasses or IgA, compared to control individuals. These data point to a potential role for Mtb-specific IgG3 responses as biomarkers or direct mediators of protective immunity against Mtb recurrence.
Assuntos
Anticorpos Antibacterianos/sangue , Imunidade Humoral , Imunoglobulina G/sangue , Mycobacterium tuberculosis/imunologia , Reinfecção , Tuberculose Pulmonar/microbiologia , Biomarcadores/sangue , Coinfecção , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno , Humanos , Mycobacterium tuberculosis/patogenicidade , Valor Preditivo dos Testes , Testes Sorológicos , África do Sul/epidemiologia , Células THP-1 , Fatores de Tempo , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/imunologiaRESUMO
The establishment of a long-lived viral reservoir is the key obstacle for achieving an HIV-1 cure. However, the anatomic, virologic, and immunologic features of the viral reservoir in tissues during antiretroviral therapy (ART) remain poorly understood. Here we present a comprehensive necroscopic analysis of the SIV/SHIV viral reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Viral DNA is observed broadly in multiple tissues and is comparable in animals that had initiated ART at week 1 or week 52 of infection. In contrast, viral RNA is restricted primarily to lymph nodes. Ongoing viral RNA transcription is not the result of unsuppressed viral replication, as single-genome amplification and subsequent phylogenetic analysis do not show evidence of viral evolution. Gag-specific CD8+ T cell responses are predominantly observed in secondary lymphoid organs in animals chronically infected prior to ART and these responses are dominated by CD69+ populations. Overall, we observe that the viral reservoir in rhesus macaques is widely distributed across multiple tissue sites and that lymphoid tissues act as a site of persistent viral RNA transcription under conditions of long-term ART suppression.
Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/virologia , Linfonodos/virologia , RNA Viral/genética , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Linfócitos T CD8-Positivos , DNA Viral , Modelos Animais de Doenças , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Linfonodos/imunologia , Tecido Linfoide/virologia , Macaca mulatta , Filogenia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética , Carga Viral , Replicação ViralRESUMO
There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1µg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Ácidos Esteáricos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Vacinas contra COVID-19/administração & dosagem , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/imunologia , Humanos , Macaca mulatta , Camundongos , Ligação Proteica , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/imunologia , Ácidos Esteáricos/imunologiaRESUMO
Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike trimers (preS dTM) from the severe acute respiratory syndrome coronavirus (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHP). Binding and functional neutralization assays and systems serology revealed that NHP developed AS03-dependent multi-functional humoral responses that targeted multiple spike domains and bound to a variety of antibody FC receptors mediating effector functions in vitro. Pseudovirus and live virus neutralizing IC50 titers were on average greater than 1000 and significantly higher than a panel of human convalescent sera. NHP were challenged intranasally and intratracheally with a high dose (3×106 PFU) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days post-challenge, vaccinated NHP showed rapid control of viral replication in both the upper and lower airways. Notably, vaccinated NHP also had increased spike-specific IgG antibody responses in the lung as early as 2 days post challenge. Moreover, vaccine-induced IgG mediated protection from SARS-CoV-2 challenge following passive transfer to hamsters. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine are sufficient to mediate protection against SARS-CoV-2 and support the evaluation of this vaccine in human clinical trials.
RESUMO
Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike protein trimers (preS dTM) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHPs). Binding and functional neutralization assays and systems serology revealed that the vaccinated NHP developed AS03-dependent multifunctional humoral responses that targeted distinct domains of the spike protein and bound to a variety of Fc receptors mediating immune cell effector functions in vitro. The neutralizing 50% inhibitory concentration titers for pseudovirus and live SARS-CoV-2 were higher than titers for a panel of human convalescent serum samples. NHPs were challenged intranasally and intratracheally with a high dose (3 × 106 plaque forming units) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days after challenge, vaccinated NHPs showed rapid control of viral replication in both the upper and lower airways. Vaccinated NHPs also had increased spike protein-specific immunoglobulin G (IgG) antibody responses in the lung as early as 2 days after challenge. Moreover, passive transfer of vaccine-induced IgG to hamsters mediated protection from subsequent SARS-CoV-2 challenge. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine were sufficient to mediate protection against SARS-CoV-2 in NHPs and that rapid anamnestic antibody responses in the lung may be a key mechanism for protection.
Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/terapia , Cricetinae , Imunização Passiva , Pulmão , Primatas , SARS-CoV-2 , Vacinação , Soroterapia para COVID-19RESUMO
The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor-binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.