RESUMO
Respiratory syncytial virus (RSV) infection is a major cause of severe lower respiratory tract infection and death in young infants and the elderly. With no effective prophylactic treatment available, current vaccine candidates aim to elicit neutralizing antibodies. However, binding and neutralization have poorly predicted protection in the past, and accumulating data across epidemiologic cohorts and animal models collectively point to a role for additional antibody Fc-effector functions. To begin to define the humoral correlates of immunity against RSV, here we profiled an adenovirus 26 RSV-preF vaccine-induced humoral immune response in a group of healthy adults that were ultimately challenged with RSV. Protection from infection was linked to opsonophagocytic functions, driven by IgA and differentially glycosylated RSV-specific IgG profiles, marking a functional humoral immune signature of protection against RSV. Furthermore, Fc-modified monoclonal antibodies able to selectively recruit effector functions demonstrated significant antiviral control in a murine model of RSV.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Camundongos , Animais , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Anticorpos Neutralizantes , Anticorpos Antivirais , Imunoglobulina G , Fragmentos Fc das Imunoglobulinas , Proteínas Virais de FusãoRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease in older adults, but no licensed RSV vaccine currently exists. An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with RSV preF protein was previously shown to elicit humoral and cellular immunogenicity. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b, proof-of-concept trial to evaluate the efficacy, immunogenicity, and safety of an Ad26.RSV.preF-RSV preF protein vaccine. Adults who were 65 years of age or older were randomly assigned in a 1:1 ratio to receive vaccine or placebo. The primary end point was the first occurrence of RSV-mediated lower respiratory tract disease that met one of three case definitions: three or more symptoms of lower respiratory tract infection (definition 1), two or more symptoms of lower respiratory tract infection (definition 2), and either two or more symptoms of lower respiratory tract infection or one or more symptoms of lower respiratory tract infection plus at least one systemic symptom (definition 3). RESULTS: Overall, 5782 participants were enrolled and received an injection. RSV-mediated lower respiratory tract disease meeting case definitions 1, 2, and 3 occurred in 6, 10, and 13 vaccine recipients and in 30, 40, and 43 placebo recipients, respectively. Vaccine efficacy was 80.0% (94.2% confidence interval [CI], 52.2 to 92.9), 75.0% (94.2% CI, 50.1 to 88.5), and 69.8% (94.2% CI, 43.7 to 84.7) for case definitions 1, 2, and 3, respectively. After vaccination, RSV A2 neutralizing antibody titers increased by a factor of 12.1 from baseline to day 15, a finding consistent with other immunogenicity measures. Percentages of participants with solicited local and systemic adverse events were higher in the vaccine group than in the placebo group (local, 37.9% vs. 8.4%; systemic, 41.4% vs. 16.4%); most adverse events were mild to moderate in severity. The frequency of serious adverse events was similar in the vaccine group and the placebo group (4.6% and 4.7%, respectively). CONCLUSIONS: In adults 65 years of age or older, Ad26.RSV.preF-RSV preF protein vaccine was immunogenic and prevented RSV-mediated lower respiratory tract disease. (Funded by Janssen Vaccines and Prevention; CYPRESS ClinicalTrials.gov number, NCT03982199.).
Assuntos
Anticorpos Neutralizantes , Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Infecções Respiratórias , Idoso , Humanos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Método Duplo-Cego , Infecções por Vírus Respiratório Sincicial/sangue , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/uso terapêutico , Vírus Sincicial Respiratório Humano/imunologia , Infecções Respiratórias/sangue , Infecções Respiratórias/imunologia , Infecções Respiratórias/prevenção & controle , Eficácia de Vacinas , Imunogenicidade da Vacina/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: Since influenza and respiratory syncytial virus (RSV) carry significant burden in older adults with overlapping seasonality, vaccines for both pathogens would ideally be coadministered in this population. Here we evaluate the immunogenicity and safety of concomitant administration of Ad26.RSV.preF/RSV preF protein and high-dose seasonal influenza vaccine (Fluzone-HD) in adults ≥65 years old. METHODS: Participants were randomized 1:1 to the Coadministration or Control group. The Coadministration group received concomitant Ad26.RSV.preF/RSV preF protein and Fluzone-HD on day 1 and placebo on day 29, while the Control group received Fluzone-HD and placebo on day 1 and Ad26.RSV.preF/RSV preF protein on day 29. Influenza hemagglutination-inhibiting and RSV preF-binding antibody titers were measured postvaccination and tested for noninferiority between both groups. Safety data were collected throughout the study and analyzed descriptively. RESULTS: Coadministered Ad26.RSV.preF/RSV preF protein and Fluzone-HD vaccines induced noninferior immune responses compared to each vaccine administered alone. Seroconversion and seroprotection rates against influenza were similar between groups. Both vaccines remained well tolerated upon concomitant administration. CONCLUSIONS: Coadministration of Ad26.RSV.preF/RSV preF protein and Fluzone-HD showed an acceptable safety profile and did not hamper the immunogenicity of either vaccine, thus supporting that both vaccines can be concomitantly administered in adults ≥65 years old.
Assuntos
Anticorpos Antivirais , Vacinas contra Influenza , Influenza Humana , Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Humanos , Idoso , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Feminino , Masculino , Anticorpos Antivirais/sangue , Influenza Humana/prevenção & controle , Influenza Humana/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/imunologia , Idoso de 80 Anos ou mais , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vírus Sincicial Respiratório Humano/imunologia , Testes de Inibição da Hemaglutinação , Imunogenicidade da Vacina , Método Duplo-Cego , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/imunologiaRESUMO
BACKGROUND: Ad26.RSV.preF is an adenovirus serotype 26 vector-based respiratory syncytial virus (RSV) vaccine encoding a prefusion conformation-stabilized RSV fusion protein (preF) that demonstrated robust humoral and cellular immunogenicity and showed promising efficacy in a human challenge study in younger adults. Addition of recombinant RSV preF protein might enhance RSV-specific humoral immune responses, especially in older populations. METHODS: This randomized, double-blind, placebo-controlled, phase 1/2a study compared the safety and immunogenicity of Ad26.RSV.preF alone and varying doses of Ad26.RSV.preF-RSV preF protein combinations in adults aged ≥60 years. This report includes data from cohort 1 (initial safety, n = 64) and cohort 2 (regimen selection, n = 288). Primary immunogenicity and safety analyses were performed 28 days postvaccination (cohort 2) for regimen selection. RESULTS: All vaccine regimens were well tolerated, with similar reactogenicity profiles among them. Combination regimens induced greater humoral immune responses (virus-neutralizing and preF-specific binding antibodies) and similar cellular ones (RSV-F-specific T cells) as compared with Ad26.RSV.preF alone. Vaccine-induced immune responses remained above baseline up to 1.5 years postvaccination. CONCLUSIONS: All Ad26.RSV.preF-based regimens were well tolerated. A combination regimen comprising Ad26.RSV.preF, which elicits strong humoral and cellular responses, and RSV preF protein, which increases humoral responses, was selected for further development. Clinical Trials Registration. NCT03502707.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Idoso , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Imunidade Humoral , Imunogenicidade da Vacina , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Pessoa de Meia-IdadeRESUMO
IMPORTANCE: Respiratory syncytial virus (RSV) can cause serious illness in older adults (i.e., those aged ≥60 years). Because options for RSV prophylaxis and treatment are limited, the prevention of RSV-mediated illness in older adults remains an important unmet medical need. Data from prior studies suggest that Fc-effector functions are important for protection against RSV infection. In this work, we show that the investigational Ad26.RSV.preF/RSV preF protein vaccine induced Fc-effector functional immune responses in adults aged ≥60 years who were enrolled in a phase 1/2a regimen selection study of Ad26.RSV.preF/RSV preF protein. These results demonstrate the breadth of the immune responses induced by the Ad26.RSV.preF/RSV preF protein vaccine.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Idoso , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Fragmentos Fc das Imunoglobulinas , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano , Proteínas Virais de Fusão/imunologiaRESUMO
BACKGROUND: This phase 1 placebo-controlled study assessed the safety and immunogenicity of 2-dose regimens of Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) and MVA-BN-Filo (modified vaccinia Ankara [MVA]) vaccines with booster vaccination at day 360. METHODS: Healthy US adults (Nâ =â 164) randomized into 10 groups received saline placebo or standard or high doses of Ad26 or MVA in 2-dose regimens at 7-, 14-, 28-, or 56-day intervals; 8 groups received booster Ad26 or MVA vaccinations on day 360. Participants reported solicited and unsolicited reactogenicity; we measured immunoglobulin G binding, neutralizing antibodies and cellular immune responses to Ebola virus glycoprotein. RESULTS: All regimens were well tolerated with no serious vaccine-related adverse events. Heterologous (Ad26,MVA [dose 1, dose 2] or MVA,Ad26) and homologous (Ad26,Ad26) regimens induced humoral and cellular immune responses 21 days after dose 2; responses were higher after heterologous regimens. Booster vaccination elicited anamnestic responses in all participants. CONCLUSIONS: Both heterologous and homologous Ad26,MVA Ebola vaccine regimens are well tolerated in healthy adults, regardless of interval or dose level. Heterologous 2-dose Ad26,MVA regimens containing an Ebola virus insert induce strong, durable humoral and cellular immune responses. Immunological memory was rapidly recalled by booster vaccination, suggesting that Ad26 booster doses could be considered for individuals at risk of Ebola infection, who previously received the 2-dose regimen.
Assuntos
Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Vacínia , Adenoviridae , Adulto , Anticorpos Antivirais , Humanos , Sorogrupo , Vacínia/induzido quimicamente , Vaccinia virus/genéticaRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) remains a leading cause of pediatric morbidity, with no approved vaccine. We assessed the safety and immunogenicity of the Ad26.RSV.preF vaccine candidate in adults and children. METHODS: In this randomized, double-blind, phase 1/2a, placebo-controlled study, 12 adults (18-50 years) and 36 RSV-seropositive children (12-24 months) were randomized 2:1 to Ad26.RSV.preF (1 × 1011 viral particles [vp] for adults, 5 × 1010 vp for children) or placebo, at day 1 and 29, with 6-month immunogenicity and 1-year safety follow-up. Respiratory syncytial virus infection was an exploratory outcome in children. RESULTS: In adults, solicited adverse events (AEs) were generally mild to moderate, with no serious AEs. In children, no vaccination-related serious AEs were reported; fever was reported in 14 (58.3%) Ad26.RSV.preF recipients. Baseline pediatric geometric mean titers for RSV A2 neutralization increased from 121 (95% confidence interval [CI], 76-191) to 1608 (95% CI, 730-3544) at day 29, and 2235 (95% CI, 1586-3150) at day 57, remaining elevated over 7 months. Respiratory syncytial virus infection was confirmed in fewer children receiving Ad26.RSV.preF (1, 4.2%) than placebo (5, 41.7%). CONCLUSIONS: Ad26.RSV.preF demonstrated immunogenicity in healthy adults and toddlers, with no safety concerns raised. Evaluations in RSV-seronegative children are underway.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Humanos , Adulto , Criança , Anticorpos Neutralizantes , Anticorpos Antivirais , Vírus Sincicial Respiratório Humano/genética , Adenoviridae/genética , Imunogenicidade da VacinaRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) is a significant cause of severe lower respiratory tract disease in children and older adults, but has no approved vaccine. This study assessed the potential of Ad26.RSV.preF to protect against RSV infection and disease in an RSV human challenge model. METHODS: In this double-blind, placebo-controlled study, healthy adults aged 18-50 years were randomized 1:1 to receive 1 × 1011 vp Ad26.RSV.preF or placebo intramuscularly. Twenty-eight days postimmunization, volunteers were challenged intranasally with RSV-A (Memphis 37b). Assessments included viral load (VL), RSV infections, clinical symptom score (CSS), safety, and immunogenicity. RESULTS: Postchallenge, VL, RSV infections, and disease severity were lower in Ad26.RSV.preF (n = 27) vs placebo (n = 26) recipients: median VL area under the curve (AUC) quantitative real-time polymerase chain reaction: 0.0 vs 236.0 (P = .012; predefined primary endpoint); median VL-AUC quantitative culture: 0.0 vs 109; RSV infections 11 (40.7%) vs 17 (65.4%); median RSV AUC-CSS 35 vs 167, respectively. From baseline to 28 days postimmunization, geometric mean fold increases in RSV A2 neutralizing antibody titers of 5.8 and 0.9 were observed in Ad26.RSV.preF and placebo, respectively. Ad26.RSV.preF was well tolerated. CONCLUSIONS: Ad26.RSV.preF demonstrated protection from RSV infection through immunization in a human challenge model, and therefore could potentially protect against natural RSV infection and disease. CLINICAL TRIALS REGISTRATION: NCT03334695; CR108398, 2017-003194-33 (EudraCT); VAC18193RSV2002.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Idoso , Anticorpos Neutralizantes , Anticorpos Antivirais , Criança , Humanos , Imunização , Proteínas Virais de FusãoRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) and influenza cause significant disease burden in older adults. Overlapping RSV and influenza seasonality presents the opportunity to coadminister vaccines for both infections. This study assessed coadministration of the investigational vaccine, Ad26.RSV.preF, an adenovirus serotype 26 (Ad26) vector encoding RSV F protein stabilized in its prefusion conformation (pre-F), with a seasonal influenza vaccine in older adults. METHODS: In this phase 2a, double-blind, placebo-controlled study, 180 adults aged ≥60 years received Ad26.RSV.preF plus Fluarix on day 1 and placebo on day 29, or placebo plus Fluarix on day 1 and Ad26.RSV.preF on day 29 (control). RESULTS: The coadministration regimen had an acceptable tolerability profile. Reactogenicity was generally higher after Ad26.RSV.preF versus Fluarix, but symptoms were generally transient and mild or moderate. At 28 days after the first vaccination, the upper confidence intervals of the hemagglutination inhibition antibody geometric mean ratio (control/coadministration) for all influenza strains were <2, demonstrating noninferiority. Robust neutralizing and binding antibody responses to RSV A2 were observed in both groups. CONCLUSIONS: Coadministration of Fluarix with Ad26.RSV.preF vaccine had an acceptable safety profile and showed no evidence of interference in immune response. The results are compatible with simultaneous seasonal vaccination with both vaccines. CLINICAL TRIALS REGISTRATION: NCT03339713.
Assuntos
Imunogenicidade da Vacina , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Método Duplo-Cego , Feminino , Humanos , Esquemas de Imunização , Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/efeitos adversos , Masculino , Pessoa de Meia-Idade , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vírus Sinciciais Respiratórios/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/imunologiaRESUMO
BACKGROUND: Despite the high disease burden of respiratory syncytial virus (RSV) in older adults, there is no approved vaccine. We evaluated the experimental RSV vaccine, Ad26.RSV.preF, a replication-incompetent adenovirus 26 vector encoding the F protein stabilized in prefusion conformation. METHODS: This phase 1 clinical trial was performed in healthy adults agedâ ≥60 years. Seventy-two participants received 1 or 2 intramuscular injections of low-dose (LD; 5 × 1010 vector particles) or high-dose (HD; 1 × 1011 vector particles) Ad26.RSV.preF vaccine or placebo, with approximately 12 months between doses and 2-year follow-up for safety and immunogenicity outcomes. RESULTS: Solicited adverse events were reported by 44% of vaccine recipients and were transient and mild or moderate in intensity. No serious adverse events were related to vaccination. After the first vaccination, geometric mean titers for RSV-A2 neutralization increased from baseline (432 for LD and 512 for HD vaccine) to day 29 (1031 for LD and 1617 for HD). Pre-F-specific antibody geometric mean titers and median frequencies of F-specific interferon γ-secreting T cells also increased substantially from baseline. These immune responses were still maintained above baseline levels 2 years after immunization and could be boosted with a second immunization at 1 year. CONCLUSIONS: Ad26.RSV.preF (LD and HD) had an acceptable safety profile and elicited sustained humoral and cellular immune responses after a single immunization in older adults.
Assuntos
Adenoviridae , Vetores Genéticos , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Virais de Fusão/imunologia , Adenoviridae/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Feminino , Vetores Genéticos/genética , Humanos , Imunidade Celular , Imunogenicidade da Vacina , Masculino , Pessoa de Meia-Idade , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/genética , Vírus Sincicial Respiratório Humano/genética , Vacinação , Proteínas Virais de Fusão/genéticaRESUMO
UNLABELLED: Exhaustion of antiviral CD8(+) T cells contributes to persistence of hepatitis C viral (HCV) infection. This immune response has proved difficult to restore by therapeutic vaccination, even when HCV replication is suppressed using antiviral regimens containing type I interferon. Because immunomodulatory effects of type I interferon may be a factor in poor T-cell priming, we undertook therapeutic vaccination in two chronically infected chimpanzees during treatment with a direct-acting antiviral (DAA) targeting the HCV NS5b polymerase protein. Immunization with genetic vaccines encoding the HCV NS3-NS5b nonstructural proteins during DAA treatment resulted in a multifunctional CD8(+) T-cell response. However, these antiviral CD8(+) T cells did not prevent persistent replication of DAA-resistant HCV variants that emerged during treatment. Most vaccine-induced CD8(+) T cells targeted class I epitopes that were not conserved in the circulating virus. Exhausted intrahepatic CD8(+) T-cell targeting-conserved epitopes did not expand after vaccination, with a notable exception. A sustained, multifunctional CD8(+) T-cell response against at least one intact class I epitope was detected in blood after vaccination. Persistence of HCV was not due to mutational escape of this epitope. Instead, failure to control HCV replication was likely caused by localized exhaustion in the liver, where CD8(+) T-cell expression of the inhibitory receptor programmed cell death 1 increased 25-fold compared with those in circulation. CONCLUSION: Treatment with a DAA during therapeutic vaccination provided transient control of HCV replication and a multifunctional T-cell response, primarily against nonconserved class I epitopes; exhaustion of liver-infiltrating CD8(+) T cells that target conserved epitopes may not be averted when DAA therapy fails prematurely due to emergence of resistant HCV variants.
Assuntos
Antivirais/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Hepacivirus/fisiologia , Hepatite C Crônica/terapia , Vacinas contra Hepatite Viral/imunologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/imunologia , Replicação Viral , Animais , Hepacivirus/imunologia , Hepatite C Crônica/virologia , Pan troglodytes , VacinaçãoRESUMO
Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited.
Assuntos
Hepatite C Crônica/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Imunoterapia , Pan troglodytes , Receptor de Morte Celular Programada 1/imunologia , Viremia/imunologia , Viremia/terapia , Replicação ViralRESUMO
IMPORTANCE: Developing effective vaccines against Ebola virus is a global priority. OBJECTIVE: To evaluate an adenovirus type 26 vector vaccine encoding Ebola glycoprotein (Ad26.ZEBOV) and a modified vaccinia Ankara vector vaccine, encoding glycoproteins from Ebola virus, Sudan virus, Marburg virus, and Tai Forest virus nucleoprotein (MVA-BN-Filo). DESIGN, SETTING, AND PARTICIPANTS: Single-center, randomized, placebo-controlled, observer-blind, phase 1 trial performed in Oxford, United Kingdom, enrolling healthy 18- to 50-year-olds from December 2014; 8-month follow-up was completed October 2015. INTERVENTIONS: Participants were randomized into 4 groups, within which they were simultaneously randomized 5:1 to receive study vaccines or placebo. Those receiving active vaccines were primed with Ad26.ZEBOV (5 × 10(10) viral particles) or MVA-BN-Filo (1 × 10(8) median tissue culture infective dose) and boosted with the alternative vaccine 28 or 56 days later. A fifth, open-label group received Ad26.ZEBOV boosted by MVA-BN-Filo 14 days later. MAIN OUTCOMES AND MEASURES: The primary outcomes were safety and tolerability. All adverse events were recorded until 21 days after each immunization; serious adverse events were recorded throughout the trial. Secondary outcomes were humoral and cellular immune responses to immunization, as assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot performed at baseline and from 7 days after each immunization until 8 months after priming immunizations. RESULTS: Among 87 study participants (median age, 38.5 years; 66.7% female), 72 were randomized into 4 groups of 18, and 15 were included in the open-label group. Four participants did not receive a booster dose; 67 of 75 study vaccine recipients were followed up at 8 months. No vaccine-related serious adverse events occurred. No participant became febrile after MVA-BN-Filo, compared with 3 of 60 participants (5%; 95% CI, 1%-14%) receiving Ad26.ZEBOV in the randomized groups. In the open-label group, 4 of 15 Ad26.ZEBOV recipients (27%; 95% CI, 8%-55%) experienced fever. In the randomized groups, 28 of 29 Ad26.ZEBOV recipients (97%; 95% CI, 82%- 99.9%) and 7 of 30 MVA-BN-Filo recipients (23%; 95% CI, 10%-42%) had detectable Ebola glycoprotein-specific IgG 28 days after primary immunization. All vaccine recipients had specific IgG detectable 21 days postboost and at 8-month follow-up. Within randomized groups, at 7 days postboost, at least 86% of vaccine recipients showed Ebola-specific T-cell responses. CONCLUSIONS AND RELEVANCE: In this phase 1 study of healthy volunteers, immunization with Ad26.ZEBOV or MVA-BN-Filo did not result in any vaccine-related serious adverse events. An immune response was observed after primary immunization with Ad26.ZEBOV; boosting by MVA-BN-Filo resulted in sustained elevation of specific immunity. These vaccines are being further assessed in phase 2 and 3 studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02313077.
Assuntos
Vacinas contra Ebola/efeitos adversos , Vacinas contra Ebola/imunologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/imunologia , Imunidade Humoral , Adulto , Vacinas contra Ebola/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Feminino , Vetores Genéticos , Voluntários Saudáveis , Humanos , Imunidade Celular , Imunização Secundária , Masculino , Marburgvirus/imunologia , Pessoa de Meia-Idade , Método Simples-Cego , Linfócitos T/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Vacínia/imunologia , Proteínas Virais/imunologiaRESUMO
UNLABELLED: Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) targeted epitopes in the E2, nonstructural (NS)5a, and NS5b proteins. A second infection to assess CD8+ T-cell responsiveness resulted in rapid suppression of HCV replication by week 2, but viremia rebounded 3 weeks later and the infection persisted. The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets after reinfection. Resurgent HCV replication was temporally associated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the first chronic infection. Two epitopes in E2 remained intact throughout both persistent infections. Intrahepatic CD8+ T cells targeting intact and escape-prone epitopes differed in expression of phenotypic markers of functional exhaustion 2 years after successful DAA therapy and in the capacity to expand in liver upon reinfection. CONCLUSIONS: The intrahepatic HCV-specific CD8+ T-cell repertoire established during chronic infection was narrowly focused, but very stable, after cure with DAA. Existing intrahepatic CD8+ T cells targeting dominant epitopes of the challenge virus failed to prevent persistence. Vaccination after DAA cure may be necessary to broaden T-cell responses and reduce the risk of a second persistent infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatite Viral Animal/imunologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Hepatite Viral Animal/tratamento farmacológico , Hepatite Viral Animal/virologia , Pan troglodytes , Recidiva , Proteínas não Estruturais Virais/imunologiaRESUMO
The Ad26.RSV.preF/RSV preF protein vaccine has previously demonstrated efficacyin protecting older adults against respiratory syncytial virus (RSV)-related lower respiratory tract disease in a phase 2b study. This study compared the immunogenicity of vaccine clinical trial material (CTM) representative of phase 2b clinical studies with CTM used in phase 3 clinical studies. A total of 248 adults aged 60-75 years, randomized in a 1:1 ratio, received one dose of either phase 3 CTM or phase 2b CTM. Solicited adverse events (AEs), unsolicited AEs, and serious AEs (SAEs) were assessed for 7-d, 28-d, and 6-month periods post-vaccination, respectively. RSV preF-ELISA antibody titers and RSV neutralizing titers were measured before and 14 d after vaccination. The phase 3 CTM-induced preF-ELISA response at Day 15, in terms of geometric mean titer, was shown to be non-inferior to that induced by phase 2b CTM. The RSV neutralizing antibody titers were also similar in the two groups at Day 15. The safety profile in terms of solicited AEs, unsolicited AEs, or SAEs was in general similar between the phase 3 CTM and phase 2b CTM groups, and solicited AEs were mostly mild to moderate in intensity. No related SAEs were reported, and no safety concerns were identified.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra Vírus Sincicial Respiratório , Humanos , Pessoa de Meia-Idade , Idoso , Masculino , Feminino , Anticorpos Antivirais/sangue , Anticorpos Neutralizantes/sangue , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/imunologia , Imunogenicidade da Vacina , Ensaio de Imunoadsorção Enzimática , Vírus Sincicial Respiratório Humano/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologiaRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) is increasingly recognized as a significant cause of lower respiratory tract disease (LRTD) in older adults. The Ad26.RSV.preF/RSV preF protein vaccine demonstrated protective efficacy against RSV related LRTD in a Phase 2b study in the United States. Hence, Ad26.RSV.preF/RSV preF protein vaccine candidate was evaluated in the Japanese older adult population. METHODS: This Phase 1 study evaluated safety, reactogenicity, and immunogenicity of Ad26.RSV.preF/RSV preF protein vaccine at dose level of 1 × 1011 vp/150 µg in Japanese healthy adult aged ≥60 years. The study included a screening Phase, vaccination, 28-day follow up Phase, a 182-day follow-up period, and final visit on Day 183. A total of 36 participants were randomized in a 2:1 ratio to receive Ad26.RSV.preF/RSV preF protein vaccine (n = 24) or placebo (n = 12). After study intervention administration, the safety and immunogenicity analysis were performed as per planned schedule. Immune responses including virus-neutralizing and preF-specific binding antibodies were measured on Days 1, 15, 29, and 183. RESULTS: There were no deaths, SAEs, or AEs leading to discontinuation reported during the study. The Ad26.RSV.preF/RSV preF protein vaccine had acceptable safety and tolerability profile with no safety concern in Japanese older adults. The Ad26.RSV.preF/RSV preF protein vaccine induced RSV-specific humoral immunity, with increase in antibody titers on Days 15 and 29 compared with baseline which was well maintained until Day 183. CONCLUSIONS: A single dose of Ad26.RSV.preF/RSV preF protein vaccine had an acceptable safety and tolerability profile and induced RSV-specific humoral immunity in Japanese healthy adults. TRIAL REGISTRATION: NCT number: NCT04354480; Clinical Registry number: CR108768.
Assuntos
Anticorpos Antivirais , Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Antivirais/sangue , Método Duplo-Cego , População do Leste Asiático , Imunogenicidade da Vacina , Japão , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/imunologiaRESUMO
This study assessed three Ad26.RSV.preF/RSV preF protein combinations, combining different Ad26.RSV.preF doses and naturally aged preF protein, representing the expected critical vaccine quality attributes close to release, around intermediate shelf-life (ISL) and near-presumed end-of-shelf-life (EoSL), as a way to evaluate the vaccine immunogenicity and safety throughout its shelf-life. A single dose of Ad26.RSV.preF/RSV preF protein vaccine was administered to adults 60-75 years of age. Solicited adverse events (AEs), unsolicited AEs, and serious AEs (SAEs) were assessed for 7-day, 28-day, and 6-month periods after vaccination, respectively. RSV preF-binding antibody concentrations and RSV neutralizing titers were measured 14 days post-vaccination as primary and secondary endpoints, respectively; binding antibodies were also measured 6 months post-vaccination. The RSV preF-binding antibody responses induced by Ad26.RSV.preF/RSV preF protein vaccine lots representing the critical quality attributes around ISL and near presumed EoSL were noninferior to the responses induced by the vaccine lot representing the critical quality attributes near release. The RSV preF-binding and RSV neutralizing antibody levels measured 14 days post-vaccination were similar across the 3 groups. RSV preF-binding antibody concentrations were also similar 6 months post-vaccination. Solicited AEs were mostly mild to moderate in intensity, and a decreased reactogenicity was observed from the Release group to the ISL and EoSL group. None of the reported SAEs were considered related to study vaccination. The study provided evidence of sustained immunogenicity and safety over the intended shelf-life of the Ad26.RSV.pref/RSV preF protein vaccine. The three vaccine lots had acceptable safety profiles.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra Vírus Sincicial Respiratório , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Imunogenicidade da Vacina , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vírus Sincicial Respiratório Humano/imunologia , Potência de Vacina , Método Duplo-CegoRESUMO
BACKGROUND: Ad26.RSV.preF-RSV preF protein showed 80·0% vaccine efficacy against respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in older adults during one RSV season. No RSV vaccines have shown three-season efficacy. We aimed to evaluate efficacy of Ad26.RSV.preF-RSV preF protein over three RSV seasons. METHODS: CYPRESS was a randomised, double-blind, placebo-controlled, phase 2b study done at 40 US clinical research centres wherein adults aged 65 years or older were centrally randomly assigned 1:1 by computer algorithm to receive Ad26.RSV.preF-RSV preF protein or placebo (one intramuscular injection) on day 1. Investigators, participants, site personnel, and the sponsor were masked to vaccine allocation, except for individuals involved in preparation of study vaccinations. The primary endpoint (first occurrence of RSV-mediated LRTD meeting one of three case definitions) was previously reported. Here, the predefined exploratory endpoint of vaccine efficacy against RSV-positive LRTD was assessed in the per-protocol efficacy set (all participants randomly assigned and vaccinated without protocol deviations affecting efficacy) through season 1 and from day 365 until the end of season 3. Humoral and cellular immunogenicity was assessed in a subset of randomly assigned and vaccinated participants. The secondary endpoint of safety through the first RSV season was previously reported; follow-up for selected safety outcomes (fatal adverse events, adverse events leading to study discontinuation, serious adverse events, and vaccine-related serious adverse events) until study completion is reported here in all randomly assigned and vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT03982199 and is complete. FINDINGS: Of 6672 adults screened, 5782 participants (2891 each receiving vaccine or placebo) were enrolled and vaccinated between Aug 5 and Nov 13, 2019. The season 2 per-protocol efficacy set included 2124 vaccine recipients and 2126 placebo recipients (season 3: 864 and 881; across three seasons: 2795 and 2803, respectively). Vaccine efficacy against RSV LRTD was 76·1% (95% CI 26·9-94·2) over seasons 2 and 3 and 78·7% (57·3-90·4) across three seasons. For those in the immunogenicity subset (vaccine n=97; placebo n=98), immune responses remained above baseline for at least 1 year. Serious adverse events occurred in 47 (2·1%) and 12 (1·3%) vaccine recipients and 45 (2·1%) and 10 (1·1%) placebo recipients during seasons 2 and 3, respectively. No treatment-related serious or fatal adverse events were reported. INTERPRETATION: Ad26.RSV.preF-RSV preF protein maintained high efficacy against RSV LRTD in older adults across three RSV seasons. FUNDING: Janssen Vaccines & Prevention.
RESUMO
RSV is divided into two antigenic subtypes, RSV A and RSV B, which is largely based on the variation in the G protein, while the fusion protein F is more conserved and a target for antibody-mediated neutralization. Here we evaluate the breadth of the protective immune responses across RSV A and RSV B subtypes, induced by vaccines based on the RSV A-based fusion protein, stabilized in the prefusion conformation (preF) in preclinical models. Immunization of naïve cotton rats with preF subunit or preF encoded by a replication incompetent Adenoviral 26, induced antibodies capable of neutralizing recent RSV A and RSV B clinical isolates, as well as protective efficacy against a challenge with RSV A and RSV B strains. Similarly, induction of cross-neutralizing antibodies was observed after immunization with Ad26-encoded preF, preF protein or a mix of both (Ad26/preF protein) in RSV pre-exposed mice and African Green Monkeys. Transfer of serum of human subjects immunized with Ad26/preF protein into cotton rats provide protection against challenges with both RSV A and RSV B, with complete protection against both strains observed in the lower respiratory tract. In contrast, almost no protection against RSV A and B infection was observed after the transfer of a human serum pool isolated pre-vaccination. These results collectively show that the RSV A-based monovalent Ad26/preF protein vaccine induced neutralizing antibodies, as well as protection against both RSV A and RSV B subtypes in animals, including by passive transfer of human antibodies alone, suggesting that clinical efficacy against both subtypes can be achieved.
RESUMO
Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease for which no licensed vaccine is available. We have previously shown that a prefusion (preF) conformation-stabilized RSV F protein antigen and an adenoviral vector encoding RSV preF protein (Ad26.RSV.preF) are immunogenic and protective in animals when administered as single components. Here, we evaluated a combination of the 2 components, administered as a single injection. Strong induction of both humoral and cellular responses was shown in RSV-naïve and pre-exposed mice and pre-exposed African green monkeys (AGMs). Both components of the combination vaccine contributed to humoral immune responses, while the Ad26.RSV.preF component was the main contributor to cellular immune responses in both mice and AGMs. Immunization with the combination elicited superior protection against RSV A2 challenge in cotton rats. These results demonstrate the advantage of a combination vaccine and support further clinical development.