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In response to the 2022 outbreak of mpox driven by unprecedented human-to-human monkeypox virus (MPXV) transmission, we designed BNT166, aiming to create a highly immunogenic, safe, accessible, and scalable next-generation vaccine against MPXV and related orthopoxviruses. To address the multiple viral forms and increase the breadth of immune response, two candidate multivalent mRNA vaccines were evaluated pre-clinically: a quadrivalent vaccine (BNT166a; encoding the MPXV antigens A35, B6, M1, H3) and a trivalent vaccine (BNT166c; without H3). Both candidates induced robust T cell responses and IgG antibodies in mice, including neutralizing antibodies to both MPXV and vaccinia virus. In challenge studies, BNT166a and BNT166c provided complete protection from vaccinia, clade I, and clade IIb MPXV. Furthermore, immunization with BNT166a was 100% effective at preventing death and at suppressing lesions in a lethal clade I MPXV challenge in cynomolgus macaques. These findings support the clinical evaluation of BNT166, now underway (NCT05988203).
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Monkeypox virus , Mpox , Vacuna contra Viruela , Animales , Humanos , Ratones , Macaca fascicularis , Monkeypox virus/genética , Mpox/inmunología , Mpox/prevención & control , Vacunas Combinadas , Virus Vaccinia/genéticaRESUMEN
Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.
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Epigenómica , Inmunidad/genética , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Análisis de la Célula Individual , Transcripción Genética , Vacunación , Adolescente , Adulto , Antibacterianos/farmacología , Antígenos CD34/metabolismo , Antivirales/farmacología , Reprogramación Celular , Cromatina/metabolismo , Citocinas/biosíntesis , Combinación de Medicamentos , Femenino , Regulación de la Expresión Génica , Histonas/metabolismo , Humanos , Inmunidad Innata/genética , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Interferón Tipo I/metabolismo , Masculino , Células Mieloides/metabolismo , Polisorbatos/farmacología , Escualeno/farmacología , Receptores Toll-Like/metabolismo , Factor de Transcripción AP-1/metabolismo , Transcriptoma/genética , Adulto Joven , alfa-Tocoferol/farmacologíaRESUMEN
Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.
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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).
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Adyuvantes Inmunológicos , Anticuerpos Neutralizantes/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas de Subunidad/inmunología , Compuestos de Alumbre , Animales , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , COVID-19/virología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Modelos Animales de Enfermedad , Inmunidad Celular , Inmunidad Humoral , Macaca mulatta/inmunología , Masculino , Oligodesoxirribonucleótidos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , EscualenoRESUMEN
BACKGROUND: Universal varicella vaccination might reduce opportunities for varicella-zoster virus (VZV) exposure and protective immunological boosting, thus increasing herpes zoster incidence in latently infected adults. We assessed humoral and cell-mediated immunity (CMI), as markers of VZV exposure, in adults aged ≥50 years. METHODS: We repurposed data from placebo recipients in a large multinational clinical trial (ZOE-50). Countries were clustered based on their varicella vaccination program characteristics, as having high, moderate, or low VZV circulation. Anti-VZV antibody geometric mean concentrations, median frequencies of VZV-specific CD4 T cells, and percentages of individuals with increases in VZV-specific CD4 T-cell frequencies were compared across countries and clusters. Sensitivity analyses using a variable number of time points and different thresholds were performed for CMI data. RESULTS: VZV-specific humoral immunity from 17 countries (12 high, 2 moderate, 3 low circulation) varied significantly between countries (Pâ <â .0001) but not by VZV circulation. No significant differences were identified in VZV-specific CMI between participants from 2 high versus 1 low circulation country. In 3/5 sensitivity analyses, increases in CMI were more frequent in high VZV circulation countries (.03â ≤â Pâ <â .05). CONCLUSIONS: We found no consistent evidence of reduced VZV exposure among older adults in countries with universal varicella vaccination. CLINICAL TRIALS REGISTRATION: NCT01165177.
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Varicela , Vacuna contra el Herpes Zóster , Herpes Zóster , Varicela/epidemiología , Varicela/prevención & control , Herpes Zóster/epidemiología , Herpes Zóster/prevención & control , Herpesvirus Humano 3 , Humanos , Inmunidad Celular , Persona de Mediana Edad , VacunaciónRESUMEN
BACKGROUND: Some vaccines elicit nonspecific immune responses that may protect against heterologous infections. We evaluated the association between recombinant adjuvanted zoster vaccine (RZV) and coronavirus disease 2019 (COVID-19) outcomes at Kaiser Permanente Southern California. METHODS: In a cohort design, adults aged ≥50 years who received ≥1 RZV dose before 1 March 2020 were matched 1:2 to unvaccinated individuals and followed until 31 December 2020. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for COVID-19 outcomes were estimated using Cox proportional hazards regression. In a test-negative design, cases had a positive severe acute respiratory syndrome coronavirus 2 test and controls had only negative tests, during 1 March-31 December 2020. Adjusted odds ratios (aORs) and 95% CIs for RZV receipt were estimated using logistic regression. RESULTS: In the cohort design, 149â 244 RZV recipients were matched to 298â 488 unvaccinated individuals. The aHRs for COVID-19 diagnosis and hospitalization were 0.84 (95% CI, .81-.87) and 0.68 (95% CI, .64-.74), respectively. In the test-negative design, 8.4% of 75â 726 test-positive cases and 13.1% of 340â 898 test-negative controls had received ≥1 RZV dose (aOR, 0.84 [95% CI, .81-.86]). CONCLUSIONS: RZV vaccination was associated with a 16% lower risk of COVID-19 diagnosis and 32% lower risk of hospitalization. Further study of vaccine-induced nonspecific immunity for potential attenuation of future pandemics is warranted.
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COVID-19 , Vacuna contra el Herpes Zóster , Herpes Zóster , Adyuvantes Inmunológicos , Adyuvantes Farmacéuticos , Anciano , COVID-19/diagnóstico , COVID-19/prevención & control , Prueba de COVID-19 , Herpes Zóster/diagnóstico , Herpes Zóster/epidemiología , Herpes Zóster/prevención & control , Hospitalización , Humanos , Vacunas SintéticasRESUMEN
RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in â¼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4+ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.
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Inmunidad Adaptativa/efectos de los fármacos , Anticuerpos Antiprotozoarios/biosíntesis , Inmunidad Innata/efectos de los fármacos , Vacunas contra la Malaria/administración & dosificación , Malaria Falciparum/inmunología , Proteínas Protozoarias/administración & dosificación , Vacunas Sintéticas/administración & dosificación , Adenoviridae/genética , Adenoviridae/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/inmunología , Humanos , Inmunización Secundaria/métodos , Inmunogenicidad Vacunal , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Malaria Falciparum/parasitología , Malaria Falciparum/prevención & control , Plasmodium falciparum/inmunología , Plasmodium falciparum/patogenicidad , Proteínas Protozoarias/genética , Proteínas Protozoarias/inmunología , Vacunación/métodosRESUMEN
To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8(+) T cells responding to the live yellow fever virus and smallpox vaccines--two highly successful human vaccines. Our results show that both vaccines generated a brisk primary effector CD8(+) T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8(+) T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8(+) T cells specific for persistent viruses. These results provide a benchmark for CD8(+) T cell responses induced by two of the most effective vaccines ever developed.
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Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Vacuna contra Viruela/inmunología , Subgrupos de Linfocitos T/inmunología , Vacuna contra la Fiebre Amarilla/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Activación de Linfocitos , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Vacunación , Virus Vaccinia/inmunología , Vacuna contra la Fiebre Amarilla/metabolismoRESUMEN
Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com.
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Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Vacunas/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Método Doble Ciego , Femenino , Anticuerpos contra la Hepatitis B/sangre , Anticuerpos contra la Hepatitis B/inmunología , Humanos , Inmunoensayo/métodos , Mediciones Luminiscentes , Masculino , Vacunación/métodos , Vacunas/administración & dosificaciónRESUMEN
BACKGROUND: Prior receipt of a trivalent seasonal influenza vaccine (TIV) can affect hemagglutination inhibition (HI) antibody responses to pandemic influenza vaccines. We investigated the effect of TIV priming on humoral responses to AS03-adjuvanted and nonadjuvanted A(H1N1)pdm09 vaccines, the role of AS03 on cell-mediated immune (CMI) responses, and vaccine safety. METHODS: Healthy adults (aged 19-40 years) were randomized 1:1:1:1 to receive TIV or saline followed 4 months later by 2 doses, 3 weeks apart, of adjuvanted or nonadjuvanted A(H1N1)pdm09 vaccine and followed up to study end (day 507). Pre- and postvaccination responses of HI and neutralizing antibody, CD4(+)/CD8(+) T cells, memory B cells, and plasmablasts were assessed. RESULTS: Ninety-nine of the 133 participants enrolled completed the study. No vaccine-related serious adverse events were recorded. In TIV-primed participants, A(H1N1)pdm09-specific antibody and CD4(+) T-cell and memory B-cell responses to the pandemic vaccine tended to be diminished. Vaccine adjuvantation led to increased responses of vaccine-homologous and -heterologous HI and neutralizing antibodies and CD4(+) T cells, homologous memory B cells, and plasmablasts. CONCLUSIONS: In healthy adults, prior TIV administration decreased humoral and CMI responses to A(H1N1)pdm09 vaccine. Adjuvantation of A(H1N1)pdm09 antigen helped to overcome immune interference between the influenza vaccines. No safety concerns were observed. REGISTRATION: Clinical Trials.gov identifier NCT00707967.
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Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/farmacología , Gripe Humana/prevención & control , Adulto , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Inmunidad Celular/inmunología , Inmunidad Humoral/inmunología , Esquemas de Inmunización , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Masculino , Método Simple Ciego , Adulto JovenRESUMEN
BACKGROUND: Previously we conducted a double-blind controlled, randomized efficacy field trial of gD-2 HSV vaccine adjuvanted with ASO4 in 8323 women. Subjects had been previously selected to be seronegative for HSV-1 and HSV-2. We found that vaccine was 82% protective against HSV-1 genital disease, but offered no significant protection against HSV-2 genital disease. METHODS: To better understand the results of the efficacy study, post-vaccination anti-gD-2 antibody concentrations from all HSV infected subjects and matched uninfected controls were measured. Three models were used to determine whether thes responses correlated with protection against HSV infection or disease. Similarly, cellular immune responses from a subset of subjects and matched controls were evaluated for a correlation with HSV protection. RESULTS: Antibodies to gD-2 correlated with protection against HSV-1 infection with higher antibody concentration associated with higher efficacy. Cellular immune responses to gD-2 did not correlate with protection. CONCLUSIONS: The protection against HSV-1 infection observed in the Herpevac Trial for Women was associated with antibodies directed against the vaccine. Clinical Trials Registration NCT00057330.
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Herpes Genital/inmunología , Herpes Genital/prevención & control , Vacunas contra el Virus del Herpes Simple/administración & dosificación , Vacunas contra el Virus del Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Estudios de Casos y Controles , Citocinas/sangre , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Femenino , Herpes Genital/sangre , Humanos , Estudios ProspectivosRESUMEN
The adjuvant AS01 plays a key role in the immunogenicity of several approved human vaccines with demonstrated high efficacy. Its adjuvant effect relies on activation of the innate immune system. However, specific effects of AS01-adjuvanted vaccines on innate cell function and epigenetic remodeling, as described for Bacille Calmette-Guérin (BCG) and influenza vaccines, are still unknown. We assessed the long-term functional and epigenetic changes in circulating monocytes and dendritic cells induced by a model vaccine containing hepatitis B surface antigen and AS01 in healthy adults (NCT01777295). The AS01-adjuvanted vaccine, but not an Alum-adjuvanted vaccine, increased the number of circulating monocytes and their expression of human leukocyte antigen (HLA)-DR, which correlated with the magnitude of the memory CD4+ T cell response. Single-cell analyses revealed epigenetic alterations in monocyte and dendritic cell subsets, affecting accessibility of transcription factors involved in cell functions including activator protein-1 (AP-1), GATA, C/EBP, and interferon regulatory factor. The functional changes were characterized by a reduced proinflammatory response to Toll-like receptor activation and an improved response to interferon-γ, a cytokine critical for the adjuvant's mode of action. Epigenetic changes were most evident shortly after the second vaccine dose in CD14+ monocytes, for which accessibility differences of some transcription factors could persist for up to 6 months postvaccination. Together, we show that reprogramming of monocyte subsets occurs after vaccination with an AS01-adjuvanted vaccine, an effect that may contribute to the impact of vaccination beyond antigen-specific protection.
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Epigénesis Genética , Monocitos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes de Vacunas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Combinación de Medicamentos , Interferón gamma/metabolismo , Lípido A/análogos & derivados , Monocitos/metabolismo , Monocitos/inmunología , Monocitos/efectos de los fármacos , Saponinas , VacunaciónRESUMEN
There is a complex interplay between the immune system and a developing tumor that is manifest in the way that the balance of T cell subsets in the local tumor environment reflects clinical outcome. Tumor infiltration by CD8(+) T cells and regulatory T cells (Treg) is associated with improved and reduced survival, respectively, in many cancer types. However, little is known of the prognostic value of immunological parameters measured in peripheral blood. In this study, peripheral CD8(+) T cells and Treg from 43 patients with malignant mesothelioma or advanced non-small-cell lung cancer scheduled to commence palliative chemotherapy were assessed by flow cytometry and evaluated for association with patient survival. Patients had a higher proportion of peripheral Treg, proliferating CD8(+) T cells and CD8(+) T cells with an activated effector phenotype compared with age-matched healthy controls. Higher proportions of Treg and proliferating CD8(+) T cells were both associated with poor survival in univariate analyses (hazard ratio [HR] 3.81, 95 % CI 1.69-8.57; p < 0.01 and HR 2.86, 95 % CI 1.26-6.50; p < 0.05, respectively). CD8(+) T cell proliferation was independently predictive of reduced survival in multivariate analysis (HR 2.58, 95 % CI 1.01-6.61; p < 0.05). These findings suggest that peripheral CD8(+) T cell proliferation can be a useful prognostic marker in patients with thoracic malignancies planned for palliative chemotherapy.
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Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/inmunología , Mesotelioma/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Proliferación Celular , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Activación de Linfocitos , Masculino , Mesotelioma/mortalidad , Persona de Mediana Edad , Pronóstico , Linfocitos T Reguladores/inmunologíaRESUMEN
The mechanisms by which antibodies confer protection vary across vaccines, ranging from simple neutralization to functions requiring innate immune recruitment via Fc-dependent mechanisms. The role of adjuvants in shaping the maturation of antibody-effector functions remains under investigated. Using systems serology, we compared adjuvants in licensed vaccines (AS01B/AS01E/AS03/AS04/Alum) combined with a model antigen. Antigen-naive adults received two adjuvanted immunizations followed by late revaccination with fractional-dosed non-adjuvanted antigen ( NCT00805389 ). A dichotomy in response quantities/qualities emerged post-dose 2 between AS01B/AS01E/AS03 and AS04/Alum, based on four features related to immunoglobulin titers or Fc-effector functions. AS01B/E and AS03 induced similar robust responses that were boosted upon revaccination, suggesting that memory B-cell programming by the adjuvanted vaccinations dictated responses post non-adjuvanted boost. AS04 and Alum induced weaker responses, that were dissimilar with enhanced functionalities for AS04. Distinct adjuvant classes can be leveraged to tune antibody-effector functions, where selective vaccine formulation using adjuvants with different immunological properties may direct antigen-specific antibody functions.
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In the wake of the A/California/7/2009 H1N1 influenza pandemic vaccination campaigns in 2009-2010, an increased incidence of the chronic sleep-wake disorder narcolepsy was detected in children and adolescents in several European countries. Over the last decade, in-depth epidemiological and immunological studies have been conducted to investigate this association, which have advanced our understanding of the events underpinning the observed risk. Narcolepsy with cataplexy (defined as type-1 narcolepsy, NT1) is characterized by an irreversible and chronic deficiency of hypocretin peptides in the hypothalamus. The multifactorial etiology is thought to include genetic predisposition, head trauma, environmental triggers, and/or infections (including influenza virus infections), and an increased risk was observed following administration of the A/California/7/2009 H1N1 vaccine Pandemrix (GSK). An autoimmune origin of NT1 is broadly assumed. This is based on its strong association with a predisposing allele (the human leucocyte antigen DQB1*0602) carried by the large majority of NT1 patients, and on links with other immune-related genetic markers affecting the risk of NT1. Presently, hypotheses on the underlying potential immunological mechanisms center on molecular mimicry between hypocretin and peptides within the A/California/7/2009 H1N1 virus antigen. This molecular mimicry may instigate a cross-reactive autoimmune response targeting hypocretin-producing neurons. Local CD4+ T-cell responses recognizing peptides from hypocretin are thought to play a central role in the response. In this model, cross-reactive DQB1*0602-restricted T cells from the periphery would be activated to cross the blood-brain barrier by rare, and possibly pathogen-instigated, inflammatory processes in the brain. Current hypotheses suggest that activation and expansion of cross-reactive T-cells by H1N1/09 influenza infection could have been amplified following the administration of the adjuvanted vaccine, giving rise to a "two-hit" hypothesis. The collective in silico, in vitro, and preclinical in vivo data from recent and ongoing research have progressively refined the hypothetical model of sequential immunological events, and filled multiple knowledge gaps. Though no definitive conclusions can be drawn, the mechanistical model plausibly explains the increased risk of NT1 observed following the 2009-2010 H1N1 pandemic and subsequent vaccination campaign, as outlined in this review.
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Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Narcolepsia , Niño , Adolescente , Humanos , Gripe Humana/epidemiología , Gripe Humana/prevención & control , Gripe Humana/complicaciones , Orexinas , Narcolepsia/etiología , Narcolepsia/genética , PéptidosRESUMEN
Transcriptional responses to adjuvanted vaccines can vary substantially among populations. Interindividual diversity in levels of pathogen exposure, and thus of cell-mediated immunological memory at baseline, may be an important determinant of population differences in vaccine responses. Adjuvant System AS01 is used in licensed or candidate vaccines for several diseases and populations, yet the impact of pre-existing immunity on its adjuvanticity remains to be elucidated. In this exploratory post-hoc analysis of clinical trial samples (clinicalTrials.gov: NCT01424501), we compared gene expression patterns elicited by two immunizations with the candidate tuberculosis (TB) vaccine M72/AS01, between three groups of individuals with different levels of memory responses to TB antigens before vaccination. Analyzed were one group of TB-disease-treated individuals, and two groups of TB-disease-naïve individuals who were (based on purified protein derivative [PPD] skin-test results) stratified into PPD-positive and PPD-negative groups. Although TB-disease-treated individuals displayed slightly stronger transcriptional responses after each vaccine dose, functional gene signatures were overall not distinctly different between groups. Considering the similarities with the signatures found previously for other AS01-adjuvanted vaccines, many features of the response appeared to be adjuvant-driven. Across groups, cell proliferation-related signals at 7 days post-dose 1 were associated with increased anti-M72 antibody response magnitudes. These early signals were stronger in the TB-disease-treated group as compared to both TB-disease-naïve groups. Interindividual homogeneity in gene expression levels was also higher for TB-disease-treated individuals post-dose 1, but increased in all groups post-dose 2 to attain similar levels between the three groups. Altogether, strong cell-mediated memory responses at baseline accelerated and amplified transcriptional responses to a single dose of this AS01-adjuvanted vaccine, resulting in more homogenous gene expression levels among the highly-primed individuals as compared to the disease-naïve individuals. However, after a second vaccination, response heterogeneity decreased and was similar across groups, irrespective of the degree of immune memory acquired at baseline. This information can support the design and analysis of future clinical trials evaluating AS01-adjuvanted vaccines.
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Vacunas contra la Tuberculosis , Tuberculosis , Humanos , Adyuvantes Inmunológicos , Tuberculina/metabolismo , Tuberculosis/prevención & control , Vacunación , Ensayos Clínicos como AsuntoRESUMEN
OBJECTIVES: We previously described the Phase I-II evaluation of SARS-CoV-2 recombinant protein candidate vaccine, CoV2-PreS-dTM, with AF03- or AS03-adjuvant systems (ClinicalTrials.gov, NCT04537208). Here, we further characterise the cellular immunogenicity profile of this vaccine candidate using a whole-blood secretion assay in parallel to intracellular cytokine staining (ICS) of cryopreserved peripheral blood mononuclear cells (PBMCs). METHODS: A randomly allocated subset of 90 healthy, SARS-CoV-2-seronegative adults aged ≥ 18 years who had received (random allocation) one or two separate injections (on study day [D]1 and D22) of saline placebo or CoV2-PreS-dTM formulated with AS03 or AF03 were included. Cytokine secretion was assessed using a TruCulture® whole-blood stimulation system in combination with multiplex bead array, and intracellular cytokine profiles were evaluated on thawed PBMCs following ex vivo stimulation with recombinant S protein at pre-vaccination (D1), post-dose 1 (D22) and post-dose 2 (D36). RESULTS: Both methods detected similar vaccine-induced responses after the first and second doses. We observed a Th1 bias (Th1/Th2 ratio > 1.0) for most treatment groups when analysed in whole blood, mainly characterised by increased IFN-γ, IL-2 and TNF-α secretion. Among participants aged ≥ 50 years, the Th1/Th2 ratio was higher for those who received vaccine candidate with AS03 versus AF03 adjuvant. ICS revealed that this higher Th1/Th2 ratio resulted from higher levels of IFN-γ expression and that the vaccine induced polyfunctional CD4+ T cells. CONCLUSIONS: The whole-blood cytokine secretion assay is a high-throughput alternative for assessing the quantity and character of vaccine-induced cellular responses.
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As the SARS-CoV-2 pandemic evolves, vaccine evaluation needs to include consideration of both durability and cross-reactivity. This report expands on previously reported results from a Phase 1 trial of an AS03-adjuvanted, plant-based coronavirus-like particle (CoVLP) displaying the spike (S) glycoprotein of the ancestral SARS-CoV-2 virus in healthy adults (NCT04450004). Humoral and cellular responses against the ancestral strain were evaluated 6 months post-second dose (D201) as secondary outcomes. Independent of dose, all vaccinated individuals retain binding antibodies, and ~95% retain neutralizing antibodies (NAb). Interferon gamma and interleukin-4 responses remain detectable in ~94% and ~92% of vaccinees respectively. In post-hoc analyses, variant-specific (Alpha, Beta, Delta, Gamma and Omicron) NAb were assessed at D42 and D201. Using a live virus neutralization assay, broad cross-reactivity is detectable against all variants at D42. At D201, cross-reactive antibodies are detectable in almost all participants against Alpha, Gamma and Delta variants (94%) and the Beta variant (83%) and in a smaller proportion against Omicron (44%). Results are similar with the pseudovirion assay. These data suggest that two doses of 3.75 µg CoVLP+AS03 elicit a durable and cross-reactive response that persists for at least 6 months post-vaccination.
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COVID-19 , Vacunas de Partículas Similares a Virus , Vacunas Virales , Adulto , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Inmunidad , SARS-CoV-2 , Glicoproteína de la Espiga del CoronavirusRESUMEN
The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and to fight variants. We report herein a pre-specified interim analysis of the phase 2 portion of a Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate, produced in plants that displays the SARS-CoV-2 spike glycoprotein, adjuvanted with AS03 (NCT04636697). A total of 753 participants were recruited between 25th November 2020 and 24th March 2021 into three groups: Healthy Adults (18-64 years: N = 306), Older Adults (≥65 years: N = 282) and Adults with Comorbidities (≥18 years: N = 165) and randomized 5:1 to receive two intramuscular doses of either vaccine (3.75 µg CoVLP/dose+AS03) or placebo, 21 days apart. This report presents safety, tolerability and immunogenicity data up to 6 months post-vaccination. The immune outcomes presented include neutralizing antibody (NAb) titres as measured by pseudovirion assay at days 21 and 42 as well as neutralizing antibody cross-reactivity to several variants of concern (VOCs): Alpha, Beta, Gamma, Delta, and Omicron (BA.1), up to 201 days post-immunization. Cellular (IFN-γ and IL-4 ELISpot) response data in day 21 and 42 peripheral blood are also presented. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults and the reactogenicity was higher after the second dose. CoVLP+AS03 induced seroconversion in >35% of participants in each group after the first dose and in ~98% of participants, 21 days after the second dose. In all cohorts, 21-days after the second dose, NAb levels in sera against the vaccine strain were ~10-times those in a panel of convalescent sera. Cross-reactivity to Alpha, Beta and Delta variants was generally retained to day 201 (>80%) while cross-reactivity to the Gamma variant was reduced but still substantial at day 201 (73%). Cross-reactivity to the Omicron variant fell from 72% at day 42 to 20% at day 201. Almost all participants in all groups (>88%) had detectable cellular responses (IFN-γ, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after the second dose. These data demonstrated that CoVLP+AS03 is well-tolerated and highly immunogenic, generating a durable (at least 6 months) immune response against different VOCs, in adults ≥18 years of age, with and without comorbidities.
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Adjuvants enhance the magnitude and the durability of the immune response to vaccines. However, there is a paucity of comparative studies on the nature of the immune responses stimulated by leading adjuvant candidates. In this study, we compared five clinically relevant adjuvants in mice-alum, AS03 (a squalene-based adjuvant supplemented with α-tocopherol), AS37 (a TLR7 ligand emulsified in alum), CpG1018 (a TLR9 ligand emulsified in alum), O/W 1849101 (a squalene-based adjuvant)-for their capacity to stimulate immune responses when combined with a subunit vaccine under clinical development. We found that all four of the adjuvant candidates surpassed alum with respect to their capacity to induce enhanced and durable antigen-specific antibody responses. The TLR-agonist-based adjuvants CpG1018 (TLR9) and AS37 (TLR7) induced Th1-skewed CD4+ T cell responses, while alum, O/W, and AS03 induced a balanced Th1/Th2 response. Consistent with this, adjuvants induced distinct patterns of early innate responses. Finally, vaccines adjuvanted with AS03, AS37, and CpG1018/alum-induced durable neutralizing-antibody responses and significant protection against the B.1.351 variant 7 months following immunization. These results, together with our recent results from an identical study in non-human primates (NHPs), provide a comparative benchmarking of five clinically relevant vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV-2 subunit vaccines to provide durable protection against the B.1.351 variant. Furthermore, these results reveal differences between the widely-used C57BL/6 mouse strain and NHP animal models, highlighting the importance of species selection for future vaccine and adjuvant studies.