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BACKGROUND: This phase 1 trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1647, an mRNA-based cytomegalovirus (CMV) vaccine, in CMV-seronegative and -seropositive adults. METHODS: Participants were randomly assigned to receive 30, 90, 180, or 300 µg of mRNA-1647 or placebo on a 0-, 2-, and 6-month schedule and followed for 12 months after the last dose. RESULTS: A total of 154 (80 CMV-seronegative and 74 CMV-seropositive) participants were enrolled; 118 participants were randomized to mRNA-1647 and 36 to placebo. Mean (SD) age was 32.5 (8.6) and 35.1 (8.9) years in the placebo and mRNA-1647 groups, respectively, in phase B (63% and 64% female) and 42.5 (6.2) and 33.3 (8.7) years, respectively, in phase C (2% and 16% female). No deaths, related serious adverse events, or adverse events of special interest were reported. Most adverse reactions were grade ≤2 severity. Increased neutralizing antibody, binding antibody, and antigen-specific cell-mediated responses were observed across mRNA-1647 treatment groups, regardless of CMV serostatus. CONCLUSIONS: This phase 1, first-in-human trial demonstrated mRNA-1647 has an acceptable safety profile in adults and elicits humoral and cellular immune responses. TRIALS REGISTRATION: NCT03382405; https://clinicaltrials.gov/ct2/show/NCT03382405.
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BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. RESULTS: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).
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Vacunas contra la COVID-19 , COVID-19/prevención & control , SARS-CoV-2 , Vacuna nCoV-2019 mRNA-1273 , Adolescente , Adulto , Anciano , COVID-19/diagnóstico , COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Gravedad del Paciente , Método Simple Ciego , Glicoproteína de la Espiga del Coronavirus , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To describe the survival outcomes of metastatic non-small cell lung cancer patients with limited access to immunotherapy and targeted therapy in a cancer reference center in Colombia. METHODS: A retrospective analysis of metastatic non-small cell lung cancer patients treated between 2013 and 2018 was performed, majority diagnosed with adenocarcinoma. It was carried out in a public cancer reference center that provides care to patients of low and middle socioeconomic status. Overall survival and progression-free survival were evaluated by Kaplan-Meier analysis and log-rank test. A Cox regression model was performed for univariate and multivariate analysis. RESULTS: 209 patients were included with majority of adenocarcinoma (79.5%). First-line treatment was cytotoxic chemotherapy (50.2%), EGFR-targeted therapy (14.8%), chemoimmunotherapy (1.9%), and ALK-targeted therapy (1.4%). 31.6% received best supportive care. Median time of follow-up was 13 months, median overall survival was 11.2 months (95% CI, 7.9-14.4), 13 months for adenocarcinoma (95% CI, 8.1-17.9), and 2.5 months for squamous cell carcinoma (95% CI, 0.6-4.4) (P < .001). Median progression-free survival was 9.3 months (95% CI, 7.9-10.7) without differences according to the type of first-line therapy. Median time-to-treatment was 55 days and only 54% of patients with a tested actionable mutation in EGFR received an EGFR-targeted therapy as the first-line treatment. Multivariate analysis showed that squamous cell carcinoma histology and receiving best supportive care were independent factors for worse overall survival ((HR:1.8, 95% CI, 1.076-3.082, P=.026) and (HR:14.6, 95% CI, 8.921-24.049, P < .001), respectively). Meanwhile, squamous cell carcinoma histology was an independent factor for worse progression-free survival (HR:3.4, 95% CI, 1.540-7.464, P=.002). CONCLUSIONS: Despite advances in precision medicine, during the study period, cytotoxic chemotherapy was the most used treatment in our patients. Furthermore, about a third of them received best supportive care. The use of targeted therapies has been restricted by access to molecular diagnosis and remained low until 2018. Access to immunotherapy should be prioritized.
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Adenocarcinoma , Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Antineoplásicos/uso terapéutico , Estudios Retrospectivos , Inmunoterapia , Adenocarcinoma/tratamiento farmacológico , Receptores ErbB/genética , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: We previously demonstrated that an intranasal dose of 108 50% tissue culture infectious dose (TCID50) M2-deficient single replication (M2SR) influenza vaccine protected against highly drifted H3N2 influenza challenge in a subset of subjects who demonstrated ≥2-fold increase in microneutralization (MN) antibodies to Belgium2015 (the challenge strain) after vaccination. Here, we describe a phase 1b, observer-blinded, dose-escalation study demonstrating an increased proportion of responders with this signal of immune protection. METHODS: Serosusceptible subjects aged 18-49 years were randomized to receive 2 doses (108-109 TCID50) of M2SR or placebo administered 28 days apart. Clinical specimens were collected before and after each dose. The primary objective was to demonstrate safety of M2SR vaccines. RESULTS: The vaccine was well tolerated at all dose levels. Against Belgium2015, ≥ 2-fold increases in MN antibodies were noted among 40% (95% confidence interval [CI], 24.9%-56.7%) of subjects following a single 108 TCID50 M2SR dose and among 80.6% (95% CI, 61.4%-92.3%) after 109 dose (P < .001). A single 109 TCID50 dose of M2SR generated ≥4-fold hemagglutination inhibition antibody seroconversion against the vaccine strain in 71% (95% CI, 52.0%-85.8%) of recipients. Mucosal and cellular immune responses were also induced. CONCLUSIONS: These results indicate that M2SR may provide substantial protection against infection with highly drifted strains of H3N2 influenza. CLINICAL TRIALS REGISTRATION: NCT03999554.
In recent years, influenza A H3N2 viruses have evolved into multiple cocirculating clades, resulting in low vaccine efficacy and highlighting the need for more effective influenza vaccines. In a previous challenge study, a single intranasal dose of the investigational vaccine M2SR demonstrated protection against a highly drifted H3N2 influenza challenge virus in a subset of vaccine recipients with a signature immune response. Increasing the dose of the M2SR vaccine in this phase1b study demonstrated a statistically significant increase in the proportion of subjects with the signature immune responses seen previously. The vaccine-induced antibodies were cross-reactive with a panel of drifted H3N2 viruses from 2007 to 2019. Additionally, M2SR generated a rise in serum hemagglutination inhibition antibody titer in 71% of subjects. In contrast, the H3N2 seroresponse rate for the licensed intranasal vaccine FluMist is 10% in seronegative adults. Moreover, M2SR elicited mucosal and cell-mediated immune responses. This study demonstrates that the intranasal M2SR generates a multifaceted immune response and has the potential to provide better efficacy against vaccine-matched strains and influenza drift variants reducing the need to update the vaccine on an annual basis. This is a noteworthy step in the development of a broadly protective influenza vaccine.
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Vacunas contra la Influenza , Gripe Humana , Humanos , Adulto , Subtipo H3N2 del Virus de la Influenza A , Anticuerpos Antivirales , Vacunación , Pruebas de Inhibición de HemaglutinaciónRESUMEN
BACKGROUND: Zika virus (ZIKV) may cause severe congenital disease after maternal-fetal transmission. No vaccine is currently available. OBJECTIVE: To assess the safety and immunogenicity of Ad26.ZIKV.001, a prophylactic ZIKV vaccine candidate. DESIGN: Phase 1 randomized, double-blind, placebo-controlled clinical study. (ClinicalTrials.gov: NCT03356561). SETTING: United States. PARTICIPANTS: 100 healthy adult volunteers. INTERVENTION: Ad26.ZIKV.001, an adenovirus serotype 26 vector encoding ZIKV M-Env, administered in 1- or 2-dose regimens of 5 × 1010 or 1 × 1011 viral particles (vp), or placebo. MEASUREMENTS: Local and systemic adverse events; neutralization titers by microneutralization assay (MN50) and T-cell responses by interferon-γ enzyme-linked immunospot and intracellular cytokine staining; and protectivity of vaccine-induced antibodies in a subset of participants through transfer in an exploratory mouse ZIKV challenge model. RESULTS: All regimens were well tolerated, with no safety concerns identified. In both 2-dose regimens, ZIKV neutralizing titers peaked 14 days after the second vaccination, with geometric mean MN50 titers (GMTs) of 1065.6 (95% CI, 494.9 to 2294.5) for 5 × 1010 vp and 956.6 (595.8 to 1535.8) for 1 × 1011 vp. Titers persisted for at least 1 year at a GMT of 68.7 (CI, 26.4-178.9) for 5 × 1010 vp and 87.0 (CI, 29.3 to 258.6) for 1 × 1011 vp. A 1-dose regimen of 1 × 1011 vp Ad26.ZIKV.001 induced seroconversion in all participants 56 days after the first vaccination (GMT, 103.4 [CI, 52.7 to 202.9]), with titers persisting for at least 1 year (GMT, 90.2 [CI, 38.4 to 212.2]). Env-specific cellular responses were induced. Protection against ZIKV challenge was observed after antibody transfer from participants into mice, and MN50 titers correlated with protection in this model. LIMITATION: The study was conducted in a nonendemic area, so it did not assess safety and immunogenicity in a flavivirus-exposed population. CONCLUSION: The safety and immunogenicity profile makes Ad26.ZIKV.001 a promising candidate for further development if the need reemerges. PRIMARY FUNDING SOURCE: Janssen Vaccines and Infectious Diseases.
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Vacunas Virales/inmunología , Infección por el Virus Zika/prevención & control , Adenoviridae/inmunología , Adulto , Animales , Método Doble Ciego , Femenino , Humanos , Masculino , Ratones , Estados Unidos , Virus Zika/inmunología , Infección por el Virus Zika/inmunologíaRESUMEN
Sporotrichosis is an emergent subcutaneous mycosis that is a threat to both humans and other animals. Sporotrichosis is acquired by the traumatic implantation of species of the Sporothrix genus. Added to the detoxification systems, pathogenic fungi possess different mechanisms that allow them to survive within the phagocytic cells of their human host during the oxidative burst. These mechanisms greatly depend from the cell wall (CW) since phagocytic cells recognize pathogens through specific receptors associated to the structure. To date, there are no studies addressing the modulation of the expression of S. schenckii CW proteins (CWP) in response to reactive oxygen species (ROS). Therefore, in this work, a proteomic analysis of the CW of S. schenckii in response to the oxidative agent menadione (O2â¢-) was performed. Proteins that modulate their expression were identified which can be related to the fungal survival mechanisms within the phagocyte. Among the up-regulated CWP in response to the oxidative agent, 13 proteins that could be involved in the mechanisms of oxidative stress response in S. schenckii were identified. The proteins identified were thioredoxin1 (Trx1), superoxide dismutase (Sod), GPI-anchored cell wall protein, ß-1,3-endoglucanase EglC, glycoside hydrolase (Gh), chitinase, CFEM domain protein, glycosidase crf1, covalently-linked cell wall protein (Ccw), 30 kDa heat shock protein (Hsp30), lipase, trehalase (Treh), fructose-bisphosphate aldolase (Fba1) and citrate synthase (Cs). The identification of CWP that modulates their expression in response to superoxide ion (O2â¢-) in S. schenckii is a useful approach to understand how the fungus defends itself against ROS, in order to evade the phagocytic cells from the host and cause the infection.
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Pared Celular/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sporothrix , Vitamina K 3/farmacología , Animales , Pared Celular/química , Enfermedades Transmisibles Emergentes/inmunología , Enfermedades Transmisibles Emergentes/microbiología , Proteínas Fúngicas/análisis , Proteínas Fúngicas/metabolismo , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Genoma Fúngico , Evasión Inmune , Oxidantes/farmacología , Estrés Oxidativo/fisiología , Fagocitos/inmunología , Fagocitos/microbiología , Proteómica , Sporothrix/efectos de los fármacos , Sporothrix/genética , Sporothrix/metabolismo , Esporotricosis/inmunologíaRESUMEN
Sporotrichosis is a fungal disease caused by the Sporothrix schenckii complex that includes species such as S. brasiliensis, S. schenckii sensu stricto, S. globosa, S. luriei, S. mexicana, and S. pallida, which exhibit different potentially antigenic molecular components. The immune response of susceptible hosts to control infection and disease caused by these fungi has been little studied. Besides, the fungus-host interaction induces the activation of different types of immune response. This mini-review analyzes and discusses existing reports on the identification and functional characterization of molecules from species of the S. schenckii complex with clinical relevance, and the mechanisms that mediate the type and magnitude of the immune response in experimental models in vivo and in vitro. This knowledge is expected to contribute to the development of protective and therapeutic strategies against sporotrichosis and other mycoses.
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Sporothrix/inmunología , Esporotricosis/inmunología , Animales , Proteínas Fúngicas/genética , Proteínas Fúngicas/inmunología , Humanos , Sporothrix/genética , Esporotricosis/microbiologíaRESUMEN
BACKGROUND: Ultrasound-guided transvaginal follicular aspiration is the standard of care in women undergoing oocyte retrieval during vitro fertilization (IVF). When this approach is inaccessible, there are alternative methods to extract the oocytes at the exact moment. One of these alternative options is the transabdominal ultrasound-guided follicular aspiration. We present a case report of a mixed follicular aspiration in a patient with ovaries of difficult access. CASE REPORT: A 36-year-old patient with primary infertility came for medical advice. Because of bilateral tubal occlusion, an in vitro fertilization cycle was started. Transvaginal sonograms revealed a normal left ovary, but the right one was completely attached to the anterior face of the uterus. After ovarian stimulation, transvaginal follicular aspiration was done on the left ovary, meanwhile, on the right ovary; transabdominal follicular aspiration was performed, retrieving 3 oocytes on metaphase II by this technique. Finally, there were no complications during the procedure and the patient got pregnant at the end of the treatment. CONCLUSIONS: Ultrasound-guided transabdominal follicular aspiration, is the safest and most effective technique when transvaginal access to the ovaries is compromised.
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Recuperación del Oocito/métodos , Abdomen , Adulto , Femenino , Fertilización In Vitro , Humanos , Ultrasonografía IntervencionalRESUMEN
The safety, reactogenicity, and immunogenicity of 3 doses of ExPEC10V (VAC52416), a vaccine candidate to prevent invasive Escherichia coli disease, were assessed in a phase 1/2a study (NCT03819049). In Cohort 1, ExPEC10V was well tolerated; the high dose was selected as optimal and further characterized in Cohort 2. Cohort 2 comprised a maximum 28-day screening, vaccination (Day 1), double-blind 181-day follow-up, and open-label long-term follow-up until Year 1. Healthy participants (≥60 years) with a history of urinary tract infection (UTI) within 5 years were randomized to receive ExPEC10V or placebo. The primary endpoint evaluated the safety and reactogenicity of ExPEC10V (solicited local and systemic AEs [until Day 15]; unsolicited AEs [until Day 30], SAEs [until Day 181], and immunogenicity [Day 30]) via multiplex electrochemiluminescent (ECL) and multiplex opsonophagocytic assay (MOPA). 416 participants (ExPEC10V, n = 278; placebo, n = 138) were included (mean age [SD], 68.8 [6.52] years; female, 79.6%; White, 96.1%). The incidence of solicited AEs was higher with ExPEC10V (local, 50.0% [n = 139]; systemic, 50.0% [n = 139]) than placebo (15.9% [n = 22]; 38.4% [n = 53]); rates of unsolicited AEs were comparable (ExPEC10V, 28.4% [n = 79]; placebo, 26.1% [n = 36]). No vaccine-related SAEs or deaths were reported. ExPEC10V elicited a robust antibody-mediated immunogenic response across all serotypes with ECL (Day 30 geometric mean fold increase, 2.33-8.18) and demonstrated functional opsonophagocytic killing activity across all measured serotypes (Day 30 geometric mean fold increase, 1.81-9.68). ExPEC10V exhibited an acceptable safety profile and a robust vaccine-induced functional immunogenic response in participants with a history of UTI. Clinical trial registration details: https://clinicaltrials.gov/study/NCT03819049 .
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BACKGROUND: Three encephalitic alphaviruses-western, eastern, and Venezuelan equine encephalitis virus (WEEV, EEEV and VEEV)-can cause severe disease and have the potential to be used as biological weapons. There are no approved vaccines for human use. A novel multivalent MVA-BN-WEV vaccine encodes the envelope surface proteins of the 3 viruses and is thereby potentially able to protect against them all, as previously demonstrated in animal models. This first-in-human study assessed the safety, tolerability, and immunogenicity of MVA-BN-WEV vaccine in healthy adult participants. METHODS: Forty-five participants were enrolled into 3 dose groups (1 × 10E7 Inf.U, 1 × 10E8 Inf.U, and 2 × 10E8 Inf.U), received 2 doses 4 weeks apart, and were then monitored for 6 months. RESULTS: The safety profile of MVA-BN-WEV was acceptable at all administered doses, with incidence of local solicited AEs increased with increasing dose and no other clinically meaningful differences between dose groups. One SAE (Grade 2 pleural effusion) was reported in the lowest dose group and assessed as possibly related. No AEs resulted in death or led to withdrawal from the second vaccination or from the trial. The most common local solicited AE was injection site pain, and general solicited AEs were headache, fatigue, and myalgia. MVA-BN-WEV induced humoral immune responses; WEEV-, EEEV- and VEEV-specific neutralizing antibody responses peaked 2 weeks following the second vaccination, and the magnitude of these responses increased with dose escalation. The highest dose resulted in seroconversion of all (100 %) participants for WEEV and VEEV and 92.9 % for EEEV, 2 weeks following second vaccination, and durability was observed for 6 months. MVA-BN-WEV induced cellular immune responses to VEEV E1 and E2 (EEEV and WEEV not tested) and a dose effect for peptide pool E2. CONCLUSION: The study demonstrated that MVA-BN-WEV is well tolerated, induces immune responses, and is suitable for further development. CLINICAL TRIAL REGISTRY NUMBER: NCT04131595.
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Alphavirus , Virus de la Encefalitis Equina Venezolana , Encefalomielitis Equina , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Encefalomielitis Equina/prevención & control , Inmunogenicidad Vacunal , Virus VacciniaRESUMEN
BACKGROUND: Despite substantial reductions in pneumococcal disease with the availability of pneumococcal conjugate vaccines, a significant burden of pneumococcal disease remains due to the diversity of serotypes combined with serotype replacement. We developed a new vaccine candidate, VAX-24 (24-valent pneumococcal conjugate vaccine), using cell-free protein synthesis to produce a variant of cross-reactive material 197 (eCRM) as the carrier protein, increasing serotype coverage while minimising carrier suppression. The aim of this clinical trial was to assess the safety, tolerability, and immunogenicity of three different doses of VAX-24 compared to pneumococcal 20-valent conjugate vaccine (PCV20). METHODS: This was a phase 1/2, randomised, double-masked study of VAX-24 versus PCV20 conducted in the USA. Key inclusion criteria included being a male or female aged 18 to 64 years in good health; key exclusion criteria included previous history of pneumococcal disease, receipt of a licensed or investigational pneumococcal vaccine, or immunosuppressive therapy. Participants were randomly allocated in a 1:1:1:1 ratio by permuted block to receive one dose of VAX-24 (1·1 µg of each antigen, 2·2 µg of each antigen, or 2·2 µg of 17 antigens mixed with 4·4 µg of seven antigens), or PCV20. The safety population included all participants with safety data. The immunogenicity population was as per-treatment in phase 2. Primary outcome measures included solicited and unsolicited adverse events. Secondary outcomes included serotype-specific opsonophagocytic activity (OPA) geometric mean titres (GMT), and IgG geometric mean concentrations (GMC) were measured 1 month postvaccination. Traditional non-inferiority criteria included OPA geometric mean ratio (GMR), with a lower bound of the two sided 95% CI of greater than 0·5 for shared serotypes. This completed trial is registered at ClinicalTrials.gov, NCT05266456. FINDINGS: Safety profiles were comparable among the treatment groups, with 170 of 209 participants (81%, 95% CI 75·2-86·2) to 178 of 207 participants (86%, 80·5-90·4) reporting at least one solicited adverse event among the three VAX-24 groups. 24 of 207 participants (12%, 7·6-16·8) to 32 of 209 of participants (15%, 10·7-20·9) experiened an unsolicited treatment emergent adverse event within 1 month postvaccination. VAX-24 2·2 µg met traditional OPA GMR non-inferiority criteria for all 20 shared serotypes; 16 serotypes elicited GMR point estimates greater than 1·0, and four reached the lower bound of the two-sided 95% CI greater than 1·0. INTERPRETATION: VAX-24 had a safety profile similar to PCV20 at all doses, with the 2·2 µg dose showing increased serotype coverage with decreased carrier suppression. FUNDING: Vaxcyte.
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Infecciones Neumocócicas , Streptococcus pneumoniae , Adulto , Humanos , Masculino , Femenino , Vacunas Conjugadas , Método Doble Ciego , Anticuerpos Antibacterianos , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas , Inmunogenicidad VacunalRESUMEN
BACKGROUND: Older adults (aged ≥65 years) show increased susceptibility to severe disease with influenza virus infection, accounting for 70-85% of annual influenza-related fatalities in the USA. Stimulating mucosal antibodies and T cells might enhance the low vaccine effectiveness seen in older adults for currently licensed inactivated influenza vaccines, which induce mainly serum antibodies. We aimed to evaluate the safety and immunogenicity of the intranasal H3N2 M2-deficient single-replication (M2SR) vaccine, alone or coadministered with a licensed inactivated influenza vaccine (Fluzone High-Dose Quadrivalent; hereafter referred to as Fluzone HD), in older adults. METHODS: In this multicentre, randomised, double-blind, double-dummy, phase 1b trial, individuals aged 65-85 years who were considered healthy or with stable chronic conditions with no recent (<6 months) influenza vaccinations were recruited from five clinical trial sites in the USA and randomly assigned (3:3:3:1) using a permuted block design to receive the H3N2 M2SR vaccine and Fluzone HD, the H3N2 M2SR vaccine and placebo, Fluzone HD and placebo, or placebo alone. All participants received a single intranasal spray and a single intramuscular injection, whether active or placebo, to maintain masking. The primary outcome was to assess the safety of H3N2 M2SR, administered alone or with Fluzone HD, in the safety analysis set, which included all participants who were randomly assigned and received treatment. Serum and mucosal antibodies were assessed as a secondary endpoint, and cell-mediated immunity as an exploratory endpoint, in participants in the per-protocol population, which included individuals in the safety analysis set without major protocol deviations. This trial is registered with ClinicalTrials.gov, NCT05163847. FINDINGS: Between June 14 and Sept 15, 2022, 305 participants were enrolled and randomly assigned to receive the H3N2 M2SR vaccine plus placebo (n=89), H3N2 M2SR vaccine plus Fluzone HD (n=94), Fluzone HD plus placebo (n=92), or placebo alone (n=30). All randomly assigned participants were included in the safety analysis set. The most frequently reported local symptoms up to day 8 in groups that received M2SR were rhinorrhoea (43% [38 of 89] in the H3N2 M2SR plus placebo group and 38% [36 of 94] in the H3N2 M2SR plus Fluzone HD group), nasal congestion (51% [45 of 89] and 35% [33 of 94]), and injection-site pain (8% [seven of 89] and 49% [46 of 94]), and the most frequently reported solicited systemic symptoms were sore throat (28% [25 of 89]) for M2SR and decreased activity (26% [24 of 94]) for the M2SR plus Fluzone HD group. In the Fluzone HD plus placebo group, the most frequently reported local symptom was injection-site pain (48% [44 of 92]) and systemic symptom was muscle aches (22% [20 of 92]). The frequency of participants with any treatment-emergent adverse event related to vaccination was low across all groups (2-5%). One serious adverse event was reported, in a participant in the Fluzone HD plus placebo group. M2SR with Fluzone HD induced seroconversion (≥four-fold increase in haemagglutination inhibition antibodies from baseline to day 29) in 44 (48%) of 91 participants, compared with 28 (31%) of 90 participants who seroconverted in the Fluzone HD plus placebo group (p=0·023). M2SR with Fluzone HD also induced mucosal and cellular immune responses. INTERPRETATION: The H3N2 M2SR vaccine coadministered with Fluzone HD in older adults was well tolerated and provided enhanced immunogenicity compared with Fluzone HD administered alone, suggesting potential for improved efficacy of influenza vaccination in this age group. Additional studies are planned to assess efficacy. FUNDING: US Department of Defense.
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Background: ExPEC10V is a bioconjugate vaccine containing O-antigen polysaccharides of 10 extraintestinal pathogenic Escherichia coli (ExPEC) serotypes. This phase 1/2a study (NCT03819049) assessed the safety, reactogenicity, and immunogenicity of ExPEC10V (VAC52416) to prevent invasive E coli disease in elderly adults. Methods: The observer-blind, active-controlled design included a 28-day screening, vaccination, 181-day follow-up, and 1-year follow-up. Participants (60-85 years of age) were randomized to ExPEC10V low dose (antigen dose range, 4-8â µg), ExPEC10V medium dose (4-16â µg), or ExPEC10V high dose (8-16â µg); 4-valent ExPEC vaccine (ExPEC4V); or 13-valent pneumococcal conjugate vaccine (PCV13). The incidence of adverse events (AEs; solicited, day 15; unsolicited, day 30; serious AEs, day 181) and immunogenicity (electrochemiluminescent-based assay [ECL] and multiplex opsonophagocytic assay [MOPA]) were assessed. Optimal ExPEC10V dose was determined from safety data through day 30 and an immunogenicity dose selection algorithm based on day 15 ECL and MOPA results. Results: A total of 416 participants were included (median age, 64.0 years; 54.8% female). The incidences of solicited local and systemic AEs were, respectively, 44.2% and 39.4% for low-dose, 52.9% and 46.1% for medium-dose, 57.7% and 45.2% for high-dose ExPEC10V, and 74.1% and 48.1% for PCV13. Five serious AEs, not vaccine related, were reported. The ECL revealed a robust antibody response to ExPEC10V through year 1. Opsonophagocytic killing activity was detected against all but serotype O8; this lack of response against serotype O8 was linked to low assay sensitivity. Based on the totality of data, high-dose ExPEC10V was considered optimal. Conclusions: ExPEC10V was well tolerated and immunogenic in elderly adults against all but serotype O8.
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Sporothrix schenckii modulates the expression of its cell wall proteins (CWPs) in response to reactive oxygen species (ROS) generated by the phagocytic cells of the human host, which allows it to evade and escape the immune system. In this study, we performed a comparative proteomic analysis of the CW of S. schenckii after exposure and nonexposure to H2O2. Several CWPs involved in CW remodeling and fungal pathogenesis that modulated their expression in response to this oxidizing agent were identified, as were a number of antioxidant enzymes and atypical CWPs, called moonlighting proteins, such as the Hsp70-5, lipase 1 (Lip1), enolase (Eno), and pyruvate kinase (Pk). Moreover, RT-qPCR assays demonstrated that the transcription of genes HSP70-5, LIP1, ENO, and PK is regulated in response to the oxidant. The results indicated that S. schenckii differentially expressed CWPs to confer protection against ROS upon this fungus. Furthermore, among these proteins, antioxidant enzymes and interestingly, moonlighting-like CWPs play a role in protecting the fungus from oxidative stress (OS), allowing it to infect human host cells.
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Purpose: Latin America is one of the regions with the highest incidence of gastric cancer. Even though, there are not reports about the patterns of pleuro-pulmonary metastases in patients with gastric adenocarcinoma treated with curative intent and the prognosis according to each dissemination pattern. Material and methods: We conducted a retrospective analysis of patients with gastric adenocarcinoma treated with curative intent at the National Cancer Institute (INC) between 2010 and 2017. Demographic variables, variables associated with the primary disease and variables associated with the presence of pleuro-pulmonary opacities and metastases were collected. A univariate and multivariate logistic regression analysis was performed and survival curves were presented using the Kaplan Meier method and compared using the log-rank test. A Cox regression model was performed for multivariate analysis for overall survival. Results: The study included 450 patients, 51.3% were male and the median age was 63 years. Intestinal adenocarcinoma was the most frequent histological subtype, in 261 cases (58.0%). Gastric cancer initial pathological stage was stage I in 23.3% of the patients, stage II in 19.3% and stage III in 53.6%. During a median follow-up of 31.9 months, 37 (8.2%) patients developed pleuro-pulmonary opacities; among those, 14 (3.1%) met the criteria for pleuro-pulmonary metastases: 6 (1.3%) had lymphangitic metastasis, 4 (0.9%) had a mixed pattern of pleural and lung nodules, 3 (0.7%) had pleural metastasis, and only one (0.2%) had hematogenous metastasis. The median OS was 114.5 months for the entire cohort and 38.2 (95%CI, 19.2-57.2) months for patients with pleuro-pulmonary metastases. Patients with pleural metastasis and lymphangitic carcinomatosis had median survival of 24.3 (95%CI, 0.01-51.0) and 26.4 (95%CI, 18.2-34.7) months, respectively. Conclusions: incidence of pleuro-pulmonary metastases in patients with gastric adenocarcinoma treated with curative intention was low. In our series, lymphangitic carcinomatosis was the main pattern of dissemination; meanwhile, hematogenous metastasis was rare and patients with pleural carcinomatosis had the lowest median survival.
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BACKGROUND The occurrence of metastasis from one neoplasm to another is known as tumor-to-tumor metastasis (TTM). It is a rare phenomenon in the natural history of any neoplasm, with approximately 100 cases reported in the literature to date. The lungs are the most frequent metastatic tumor donors and kidney cancer is the most common recipient. However, the opposite phenomenon (lung adenocarcinoma as a recipient of metastasis from renal carcinoma) has not been previously reported in the literature. CASE REPORT We present the case of a man with a history of multiple neoplasms. He had a diffuse large B-cell lymphoma in 2006, a left papillary renal cell carcinoma (RCC) type 2 in 2006, and an acinar adenocarcinoma of the prostate in 2011. A follow-up computed tomography scan in July 2019 showed a suspicious lung nodule on the left upper lobe and a retroperitoneal hypermetabolic mass on the positron emission tomography scan. The lung nodule and retroperitoneal mass biopsies were consistent with a primary lung adenocarcinoma with a lepidic pattern and a metastatic RCC, respectively. In January 2020, he underwent a thoracoscopic left upper lobectomy and a mediastinal lymph node dissection. Histopathological evaluation revealed a 2-cm nodule composed of a lung adenocarcinoma with an intratumoral metastasis from a papillary RCC. To date, the patient has stable renal neoplastic metastatic disease and no locoregional recurrences of the lung adenocarcinoma. CONCLUSIONS Metastasis from one primary tumor to another primary tumor is an extremely unusual event. We report one of the first cases of an RCC metastasis to a primary lung adenocarcinoma.
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Adenocarcinoma del Pulmón , Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Pulmonares , Humanos , Masculino , Recurrencia Local de NeoplasiaRESUMEN
M2SR (M2-deficient single replication) is an investigational live intranasal vaccine that protects against multiple influenza A subtypes in influenza-naïve and previously infected ferrets. We conducted a phase 1, first-in-human, randomized, dose-escalation, placebo-controlled study of M2SR safety and immunogenicity. Adult subjects received a single intranasal administration with either placebo or one of three M2SR dose levels (106, 107 or 108 tissue culture infectious dose (TCID50)) expressing hemagglutinin and neuraminidase from A/Brisbane/10/2007 (H3N2) (24 subjects per group). Subjects were evaluated for virus replication, local and systemic reactions, adverse events (AE), and immune responses post-vaccination. Infectious virus was not detected in nasal swabs from vaccinated subjects. At least one AE (most commonly mild nasal rhinorrhea/congestion) was reported among 29%, 58%, and 83% of M2SR subjects administered a low, medium or high dose, respectively, and among 46% of placebo subjects. No subject had fever or a severe reaction to the vaccine. Influenza-specific serum and mucosal antibody responses and B- and T-cell responses were significantly more frequent among vaccinated subjects vs. placebo recipients. The M2SR vaccine was safe and well tolerated and generated dose-dependent durable serum antibody responses against diverse H3N2 influenza strains. M2SR demonstrated a multi-faceted immune response in seronegative and seropositive subjects.
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The role of immune cells associated with sporotrichosis caused by Sporothrix schenckii is not yet fully clarified. Macrophages through pattern recognition receptors (PRRs) can recognize pathogen-associated molecular patterns (PAMPs) of Sporothrix, engulf it, activate respiratory burst, and secrete pro-inflammatory or anti-inflammatory biological mediators to control infection. It is important to consider that the characteristics associated with S. schenckii and/or the host may influence macrophage polarization (M1/M2), cell recruitment, and the type of immune response (1, 2, and 17). Currently, with the use of new monocyte-macrophage cell lines, it is possible to evaluate different host-pathogen interaction processes, which allows for the proposal of new mechanisms in human sporotrichosis. Therefore, in order to contribute to the understanding of these host-pathogen interactions, the aim of this review is to summarize and discuss the immune responses induced by macrophage-S. schenckii interactions, as well as the PRRs and PAMPs involved during the recognition of S. schenckii that favor the immune evasion by the fungus.
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PURPOSE: Mediastinal germ cell tumors (GCT) are rare neoplasms associated with poor survival prognosis. Due to their low incidence, limited information is available about this disease in South America. The objective of this study is to report the clinical characteristics and outcomes of patients with mediastinal GCT in a cancer center in Colombia. MATERIALS AND METHODS: We conducted a retrospective analysis of patients with mediastinal GCT treated at the National Cancer Institute at Bogota (Colombia) between 2008 and 2020. Survival curves were presented using the Kaplan-Meier method. Chi-square and Cox proportional hazard model tests were used for data analysis. RESULTS: Sixty-one patients were included in the study. Of them, 60 were male and 51 (83.6%) of whom had non-seminomatous germ cell tumors (NSGCT). Twenty-nine patients (47.5%) presented with superior vena cava syndrome, and 18 (29.5%) patients had extrapulmonary metastatic involvement. The three-year overall survival (OS) of NSGCT patients was 26%. The 3-year OS of NSGCT patients who underwent surgical resection of residual mediastinal mass after chemotherapy was 59%. Non-surgical management after first-line chemotherapy was associated with a worse survival prognosis in NSGCT patients (p = 0.002). Ten patients with mediastinal seminomatous germ cell tumors (SCGT) achieved a 3-year OS of 100%. CONCLUSION: Mediastinal NSGCT had poor outcomes. Surgery of the residual mass after first-line chemotherapy seems to improve the outcome of NSGCT patients. Advanced disease at presentation may reflect inadequate access to reference cancer centers in Colombia and potentially explain poor survival outcomes in this cohort. On the other hand, mediastinal SCGT is a biologically different disease; most patients will achieve disease remission and long-term survival with first-line chemotherapy.
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OBJECTIVE: Evaluate whether adjuvanted quadrivalent influenza vaccine (aQIV) elicits a noninferior immune response compared with a licensed adjuvanted trivalent influenza vaccine (aTIV-1; Fluad™) and aTIV-2 containing an alternate B strain, examine whether aQIV had immunological superiority for the B strain absent from aTIV comparators, and evaluate reactogenicity and safety among adults ≥65â¯years. METHODS: In a multicenter, double-blind, randomized controlled trial, adults ≥65â¯years were randomized 2:1:1 to vaccination with aQIV (nâ¯=â¯889), aTIV-1 (nâ¯=â¯445), or aTIV-2 (nâ¯=â¯444) during the 2017-2018 influenza season. Immunogenicity was assessed by hemagglutination inhibition (HI) assay conducted on serum samples collected before vaccination and 21â¯days after vaccination for homologous influenza strains. RESULTS: aQIV met non-inferiority criteria for geometric mean titer ratios (GMT ratios) and seroconversion rate (SCR) differences against aTIV. The upper bounds of the 2-sided 95% confidence interval (CI) for GMT ratios were <1.5 for all 4 strains (A/H1N1â¯=â¯1.27, A/H3N2â¯=â¯1.09, B-Yamagataâ¯=â¯1.08, B-Victoriaâ¯=â¯1.08). The upper bounds of the 95% CI of the SCR differences were <10% for all 4 strains (A/H1N1â¯=â¯7.76%, A/H3N2â¯=â¯4.96%, B-Yamagataâ¯=â¯3.27%, B-Victoriaâ¯=â¯2.55%). aQIV also met superiority criteria (upper bound of 95% CI for GMT ratios <1 and SCR differences <0) for B strain absent from aTIV comparators (B-Yamagata GMT ratioâ¯=â¯0.70, SCR differenceâ¯=â¯-8.81%; B-Victoria GMT ratioâ¯=â¯0.78, SCR differenceâ¯=â¯-8.11%). aQIV and aTIV vaccines were immunogenic and well-tolerated. The immunological benefit of aQIV was also demonstrated in age subgroups 65-74â¯years, 75-84â¯years, and ≥85â¯years and in those with high comorbidity risk scores. Reactogenicity profiles were generally comparable. CONCLUSION: aQIV induces a similar immune response as the licensed aTIV vaccine against homologous influenza strains and has a comparable reactogenicity and safety profile. Superior immunogenicity against the additional B strain was observed, indicating that aQIV could provide a broader protection than aTIV against influenza in older adults (NCT03314662).