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BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. METHODS AND FINDINGS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. TRIAL REGISTRATION: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).
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Vacuna contra Difteria, Tétanos y Tos Ferina , Esquemas de Inmunización , Inmunoglobulina E , Humanos , Lactante , Método Doble Ciego , Inmunoglobulina E/inmunología , Inmunoglobulina E/sangre , Femenino , Masculino , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Vacuna contra Difteria, Tétanos y Tos Ferina/efectos adversos , Australia , Vacunas Combinadas/inmunología , Vacunas Combinadas/efectos adversos , Vacunas Combinadas/administración & dosificación , Vacuna contra la Tos Ferina/inmunología , Vacuna contra la Tos Ferina/efectos adversos , Vacuna contra la Tos Ferina/administración & dosificación , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/prevención & control , Vacuna Antipolio de Virus Inactivados/inmunología , Vacuna Antipolio de Virus Inactivados/efectos adversos , Vacuna Antipolio de Virus Inactivados/administración & dosificación , Vacunas contra Haemophilus/inmunología , Vacunas contra Haemophilus/efectos adversos , Vacunas contra Haemophilus/administración & dosificación , Tos Ferina/prevención & control , Tos Ferina/inmunología , Inmunogenicidad Vacunal , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunologíaRESUMEN
BACKGROUND: Rotarix (GlaxoSmithKline) oral rotavirus vaccine is licensed as 2 doses in the first 6 months of life. In settings with high child mortality rates, clinical protection conferred by 2 doses of Rotarix is reduced. We assessed vaccine immune response when an additional dose of Rotarix was given to Australian Aboriginal children 6 toâ <12 months old. METHODS: ORVAC is a 2-stage, double-blind, randomized, placebo-controlled trial. Australian Aboriginal children 6 toâ <12 months old who had received 1 or 2 prior doses of Rotarix rotavirus vaccine were randomized 1:1 to receive an additional dose of Rotarix or matched placebo. The primary immunological end point was seroresponse defined as an anti-rotavirus immunoglobulin A levelâ ≥20 AU/mL, 28-56 days after the additional dose of Rotarix or placebo. RESULTS: Between March 2018 and August 2020, a total of 253 infants were enrolled. Of these, 178 infants (70%) had analyzable serological results after follow-up; 89 were randomized to receive Rotarix, and 89 to receive placebo. The proportion with seroresponse was 85% after Rotarix compared with 72% after placebo. There were no occurrences of intussusception or any serious adverse events. CONCLUSIONS: An additional dose of Rotarix administered to Australian Aboriginal infants 6 toâ <12 months old increased the proportion with a vaccine seroresponse. CLINICAL TRIALS REGISTRATION: NCT02941107.
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Infecciones por Rotavirus , Vacunas contra Rotavirus , Lactante , Niño , Humanos , Infecciones por Rotavirus/prevención & control , Australia , Vacunas Atenuadas , Anticuerpos Antivirales , Método Doble Ciego , Inmunogenicidad VacunalRESUMEN
We have previously demonstrated that Mucosal-Associated Invariant T (MAIT) cells secrete multiple cytokines after exposure to Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever in humans. However, whether cytokine secreting MAIT cells can enhance or attenuate the clinical severity of bacterial infections remain debatable. This study characterizes human MAIT cell functions in subjects participating in a wild-type S. Typhi human challenge model. Here, we found that MAIT cells exhibit distinct functional signatures associated with protection against typhoid fever. We also observed that the cytokine patterns of MAIT cell responses, rather than the average number of cytokines expressed, are more predictive of typhoid fever outcomes. These results might enable us to objectively, based on functional parameters, identify cytokine patterns that may serve as predictive biomarkers during natural infection and vaccination.
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Células T Invariantes Asociadas a Mucosa , Fiebre Tifoidea , Citocinas , Humanos , Salmonella typhi/fisiología , Fiebre Tifoidea/microbiología , Fiebre Tifoidea/prevención & control , VacunaciónRESUMEN
Background: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods: Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteremia) or at day 14 postchallenge. Results: The primary study objective was achieved following challenge with 1-5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24-85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia. Conclusions: Challenge with S. Paratyphi A at a dose of 1-5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology. Clinical Trials Registration: NCT02100397.
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Bacteriemia/microbiología , Bacteriemia/patología , Fiebre Paratifoidea/microbiología , Fiebre Paratifoidea/patología , Salmonella paratyphi A/aislamiento & purificación , Adulto , Sangre/microbiología , Heces/microbiología , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Temperatura , Factores de Tiempo , Adulto JovenRESUMEN
Salmonella Typhi (S. Typhi), the causative agent of typhoid fever, causes significant morbidity and mortality worldwide. Currently available vaccines are moderately efficacious, and identification of immunological responses associated with protection or disease will facilitate the development of improved vaccines. We investigated S. Typhi-specific modulation of activation and homing potential of circulating regulatory T cells (Treg) by flow and mass cytometry using specimens obtained from a human challenge study. Peripheral blood mononuclear cells were obtained from volunteers pre- and at multiple time-points post-challenge with wild-type S. Typhi. We identified differing patterns of S. Typhi-specific modulation of the homing potential of circulating Treg between volunteers diagnosed with typhoid (TD) and those who were not (No TD). TD volunteers demonstrated up-regulation of the gut homing molecule integrin α4ß7 pre-challenge, followed by a significant down-regulation post-challenge consistent with Treg homing to the gut. Additionally, S. Typhi-specific Treg from TD volunteers exhibited up-regulation of activation molecules post-challenge (e.g., HLA-DR, LFA-1). We further demonstrate that depletion of Treg results in increased S. Typhi-specific cytokine production by CD8+ TEM in vitro. These results suggest that the tissue distribution of activated Treg, their characteristics and activation status may play a pivotal role in typhoid fever, possibly through suppression of S. Typhi-specific effector T cell responses. These studies provide important novel insights into the regulation of immune responses that are likely to be critical in protection against typhoid and other enteric infectious diseases.
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Linfocitos T CD8-positivos/inmunología , Leucocitos Mononucleares/inmunología , Modelos Biológicos , Salmonella typhi/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Fiebre Tifoidea/inmunología , Adolescente , Adulto , Estudios de Casos y Controles , Citometría de Flujo , Humanos , Espectrometría de Masas , Persona de Mediana Edad , Fiebre Tifoidea/microbiología , Adulto JovenRESUMEN
BACKGROUND: Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. METHODS: Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a). RESULTS: Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (TEM) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S. Typhi-specific TEM. CONCLUSIONS: These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates.
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Linfocitos T CD8-positivos/inmunología , Salmonella typhi/inmunología , Fiebre Tifoidea/inmunología , Fiebre Tifoidea/prevención & control , Adolescente , Adulto , Femenino , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/patología , Humanos , Cinética , Masculino , Persona de Mediana Edad , Especificidad de la Especie , Resultado del Tratamiento , Fiebre Tifoidea/microbiología , Adulto JovenRESUMEN
BACKGROUND: Typhoid fever is a major global health problem, the control of which is hindered by lack of a suitable animal model in which to study Salmonella Typhi infection. Until 1974, a human challenge model advanced understanding of typhoid and was used in vaccine development. We set out to establish a new human challenge model and ascertain the S. Typhi (Quailes strain) inoculum required for an attack rate of 60%-75% in typhoid-naive volunteers when ingested with sodium bicarbonate solution. METHODS: Groups of healthy consenting adults ingested escalating dose levels of S. Typhi and were closely monitored in an outpatient setting for 2 weeks. Antibiotic treatment was initiated if typhoid diagnosis occurred (temperature ≥38°C sustained ≥12 hours or bacteremia) or at day 14 in those remaining untreated. RESULTS: Two dose levels (10(3) or 10(4) colony-forming units) were required to achieve the primary objective, resulting in attack rates of 55% (11/20) or 65% (13/20), respectively. Challenge was well tolerated; 4 of 40 participants fulfilled prespecified criteria for severe infection. Most diagnoses (87.5%) were confirmed by blood culture, and asymptomatic bacteremia and stool shedding of S. Typhi was also observed. Participants who developed typhoid infection demonstrated serological responses to flagellin and lipopolysaccharide antigens by day 14; however, no anti-Vi antibody responses were detected. CONCLUSIONS: Human challenge with a small inoculum of virulent S. Typhi administered in bicarbonate solution can be performed safely using an ambulant-model design to advance understanding of host-pathogen interactions and immunity. This model should expedite development of diagnostics, vaccines, and therapeutics for typhoid control.
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Salmonella typhi/patogenicidad , Fiebre Tifoidea/microbiología , Adolescente , Adulto , Atención Ambulatoria , Anticuerpos Antibacterianos/sangre , Bacteriemia , Derrame de Bacterias , Femenino , Interacciones Huésped-Patógeno , Humanos , Masculino , Persona de Mediana Edad , Modelos Inmunológicos , Bicarbonato de Sodio , Fiebre Tifoidea/inmunología , Fiebre Tifoidea/prevención & control , Vacunas Tifoides-ParatifoidesRESUMEN
PURPOSE OF REVIEW: Strains of Salmonella enterica subsp. enterica are amongst the most commonly identified invasive bacterial pathogens in resource-poor settings, and cause significant mortality, particularly in children. In this study we review recent progress in the development of vaccines against S. Typhi, S. Paratyphi and nontyphoidal Salmonella for children. RECENT FINDINGS: Typhoid remains common and S. Paratyphi A is increasingly recognized as a cause of enteric fever in Asia. In rural Africa, nontyphoidal salmonellae are among the most common invasive bacterial infections, although S. Typhi predominates in some urban centres. Licensed vaccines against typhoid have moderate but useful efficacy but neither of the two available vaccines can be used in infants. Although Ty21a may afford some cross-protection against S. Paratyphi B, there are no vaccines that specifically target paratyphoid or any nontyphoidal Salmonella. Several live attenuated vaccines are under development and may offer some advantages over Ty21a. Vi-conjugate vaccines should offer children excellent protection from typhoid once licensed. SUMMARY: There are few effective vaccines against Salmonella sp. and those that do exist target only one serovar, S. Typhi. Research is urgently needed to combat emerging agents of enteric fever such as S. Paratyphi A as well as nontyphoidal serovars, which commonly cause invasive disease in Africa.
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Infecciones por Salmonella/prevención & control , Vacunas contra la Salmonella/uso terapéutico , Niño , Preescolar , Humanos , Programas de Inmunización/organización & administración , Vacunas Atenuadas/uso terapéutico , Vacunas Conjugadas/uso terapéuticoRESUMEN
A 48-year-old man with poorly controlled HIV presented with severe human monkeypox virus (hMPXV) infection, having completed 2 weeks of tecovirimat at another hospital. He had painful, ulcerating skin lesions on most of his body and oropharyngeal cavity, with subsequent Ludwig's angina requiring repeated surgical interventions. Despite commencing a second, prolonged course of tecovirimat, he did not objectively improve, and new lesions were still noted at day 24. Discussion at the UK National Health Service England High Consequence Infectious Diseases Network recommended the use of 3% topical and then intravenous cidofovir, which was given at 5 mg/kg; the patient made a noticeable improvement after the first intravenous dose. He received further intravenous doses at 7 days and 21 days after the dose and was discharged at day 52. Cidofovir is not licensed for use in treatment of hMPXV infection. Data for cidofovir use in hMPXV are restricted to studies in animals. Four other documented cases of cidofovir use against hMPXV have been reported in the USA in 2022, but we present its first use in the UK. The scarcity of studies into the use of cidofovir in this condition clearly shows the need for robust studies to assess efficacy, optimum dosage, timing, and route of administration.
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Infecciones por VIH , Mpox , Organofosfonatos , Masculino , Humanos , Persona de Mediana Edad , Cidofovir/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Mpox/tratamiento farmacológico , Medicina Estatal , Citosina/uso terapéutico , Antivirales/uso terapéuticoRESUMEN
Objectives: A novel 'subscription-type' funding model was launched in England in July 2022 for ceftazidime/avibactam and cefiderocol. We explored the views of infection consultants on important aspects of the delinked antimicrobial funding model. Methods: An online survey was sent to all infection consultants in NHS acute hospitals in England. Results: The response rate was 31.2% (235/753). Most consultants agreed the model is a welcome development (69.8%, 164/235), will improve treatment of drug-resistant infections (68.5%, 161/235) and will stimulate research and development of new antimicrobials (57.9%, 136/235). Consultants disagreed that the model would lead to reduced carbapenem use and reported increased use of cefiderocol post-implementation. The presence of an antimicrobial pharmacy team, requirement for preauthorization by infection specialists, antimicrobial stewardship ward rounds and education of infection specialists were considered the most effective antimicrobial stewardship interventions. Under the new model, 42.1% (99/235) of consultants would use these antimicrobials empirically, if risk factors for antimicrobial resistance were present (previous infection, colonization, treatment failure with carbapenems, ward outbreak, recent admission to a high-prevalence setting).Significantly higher insurance and diversity values were given to model antimicrobials compared with established treatments for carbapenem-resistant infections, while meropenem recorded the highest enablement value. Use of both 'subscription-type' model drugs for a wide range of infection sites was reported. Respondents prioritized ceftazidime/avibactam for infections by bacteria producing OXA-48 and KPC and cefiderocol for those producing MBLs and infections with Stenotrophomonas maltophilia, Acinetobacter spp. and Burkholderia cepacia. Conclusions: The 'subscription-type' model was viewed favourably by infection consultants in England.
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OBJECTIVES: To develop a disease stratification model for COVID-19 that updates according to changes in a patient's condition while in hospital to facilitate patient management and resource allocation. DESIGN: In this retrospective cohort study, we adopted a landmarking approach to dynamic prediction of all-cause in-hospital mortality over the next 48 hours. We accounted for informative predictor missingness and selected predictors using penalised regression. SETTING: All data used in this study were obtained from a single UK teaching hospital. PARTICIPANTS: We developed the model using 473 consecutive patients with COVID-19 presenting to a UK hospital between 1 March 2020 and 12 September 2020; and temporally validated using data on 1119 patients presenting between 13 September 2020 and 17 March 2021. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is all-cause in-hospital mortality within 48 hours of the prediction time. We accounted for the competing risks of discharge from hospital alive and transfer to a tertiary intensive care unit for extracorporeal membrane oxygenation. RESULTS: Our final model includes age, Clinical Frailty Scale score, heart rate, respiratory rate, oxygen saturation/fractional inspired oxygen ratio, white cell count, presence of acidosis (pH <7.35) and interleukin-6. Internal validation achieved an area under the receiver operating characteristic (AUROC) of 0.90 (95% CI 0.87 to 0.93) and temporal validation gave an AUROC of 0.86 (95% CI 0.83 to 0.88). CONCLUSIONS: Our model incorporates both static risk factors (eg, age) and evolving clinical and laboratory data, to provide a dynamic risk prediction model that adapts to both sudden and gradual changes in an individual patient's clinical condition. On successful external validation, the model has the potential to be a powerful clinical risk assessment tool. TRIAL REGISTRATION: The study is registered as 'researchregistry5464' on the Research Registry (www.researchregistry.com).
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COVID-19 , Humanos , Estudios Retrospectivos , Mortalidad Hospitalaria , Hospitales de Enseñanza , Medición de Riesgo , Reino UnidoRESUMEN
BACKGROUND: Streptococcus pyogenes is a leading cause of infection-related morbidity and mortality. A reinvigorated vaccine development effort calls for new clinically relevant human S pyogenes experimental infection models to support proof of concept evaluation of candidate vaccines. We describe the initial Controlled Human Infection for Vaccination Against S pyogenes (CHIVAS-M75) study, in which we aimed to identify a dose of emm75 S pyogenes that causes acute pharyngitis in at least 60% of volunteers when applied to the pharynx by swab. METHODS: This observational, dose-finding study was done in a clinical trials facility in Melbourne (VIC, Australia). Groups of healthy volunteers aged 18-40 years, at low risk of complicated S pyogenes disease, and without high type-specific anti-emm75 IgG antibodies against the challenge strain were challenged and closely monitored as inpatients for up to 6 days, and then as outpatients for 6 months. Antibiotics were started upon diagnosis (clinical signs and symptoms of pharyngitis and a positive rapid molecular test) or after 5 days in those without pharyngitis. Rapid test results were confirmed by standard bacterial culture. After a sentinel participant, cohorts of five and then ten participants were challenged, with protocol-directed dose-escalation or de-escalation for subsequent cohorts. The primary outcome was the proportion of participants at each dose level with pharyngitis by day 5 after challenge. The study is registered with ClinicalTrials.gov, NCT03361163. FINDINGS: Between July 10, 2018, and Sept 23, 2019, 25 healthy adults were challenged with emm75 S pyogenes and included in analyses. Pharyngitis was diagnosed in 17 (85%; 95% CI 62-97) of 20 participants at the starting dose level (1-3 × 105 colony-forming units [CFU]/mL). This high proportion prompted dose de-escalation. At the lower dose level (1-3 × 104 CFU/mL), pharyngitis was diagnosed in one of five participants. Immunological, biochemical, and microbiological results supported the clinical picture, with acute symptomatic pharyngitis characterised by pharyngeal colonisation by S pyogenes accompanied by significantly elevated C-reactive protein and inflammatory cytokines (eg, interferon-γ and interleukin-6), and modest serological responses to streptolysin O and deoxyribonuclease B. There were no severe (grade 3) or serious adverse events related to challenge. INTERPRETATION: We have established a reliable pharyngitis human infection model with reassuring early safety findings to accelerate development of vaccines and other interventions to control disease due to S pyogenes. FUNDING: Australian National Health and Medical Research Council.
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Faringitis , Escarlatina , Adulto , Australia , Humanos , Faringitis/tratamiento farmacológico , Faringe/microbiología , Streptococcus pyogenesRESUMEN
OBJECTIVE: There are no vaccines for most of the major invasive Salmonella strains causing severe infection in humans. We evaluated the specificity of adaptive T memory cell responses generated after Salmonella Typhi exposure in humans against other major invasive Salmonella strains sharing capacity for dissemination. METHODS: T memory cells from eleven volunteers who underwent controlled oral challenge with wt S. Typhi were characterised by flow cytometry for cross-reactive cellular cytokine/chemokine effector responses or evidence of degranulation upon stimulation with autologous B-lymphoblastoid cells infected with either S. Typhi, Salmonella Paratyphi A (PA), S. Paratyphi B (PB) or an invasive nontyphoidal Salmonella strain of the S. Typhimurium serovar (iNTSTy). RESULTS: Blood T-cell effector memory (TEM) responses after exposure to S. Typhi in humans evolve late, peaking weeks after infection in most volunteers. Induced multifunctional CD4+ Th1 and CD8+ TEM cells elicited after S. Typhi challenge were cross-reactive with PA, PB and iNTSTy. The magnitude of multifunctional CD4+ TEM cell responses to S. Typhi correlated with induction of cross-reactive multifunctional CD8+ TEM cells against PA, PB and iNTSTy. Highly multifunctional subsets and T central memory and T effector memory cells that re-express CD45 (TEMRA) demonstrated less heterologous T-cell cross-reactivity, and multifunctional Th17 elicited after S. Typhi challenge was not cross-reactive against other invasive Salmonella. CONCLUSION: Gaps in cross-reactive immune effector functions in human T-cell memory compartments were highly dependent on invasive Salmonella strain, underscoring the importance of strain-dependent vaccination in the design of T-cell-based vaccines for invasive Salmonella.
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INTRODUCTION: Combination vaccines containing whole-cell pertussis antigens were phased out from the Australian national immunisation programme between 1997 and 1999 and replaced by the less reactogenic acellular pertussis (aP) antigens. In a large case-control study of Australian children born during the transition period, those with allergist diagnosed IgE-mediated food allergy were less likely to have received whole-cell vaccine in early infancy than matched population controls (OR: 0.77 (95% CI, 0.62 to 0.95)). We hypothesise that a single dose of whole-cell vaccine in early infancy is protective against IgE-mediated food allergy. METHODS AND ANALYSIS: This adaptive double-blind randomised controlled trial is investigating whether a mixed whole-cell/aP vaccine schedule prevents allergic disease in the first year of life. The primary outcome is IgE-mediated food allergy by 12 months of age. Secondary outcomes include new onset of atopic dermatitis by 6 or 12 months of age; sensitisation to at least one allergen by 12 months of age; seroconversion in anti-pertussis toxin IgG titres after vaccination with aP booster at 18 months of age; and solicited systemic and local adverse events following immunisation with pertussis-containing vaccines. Analyses will be performed using a Bayesian group sequential design. ETHICS AND DISSEMINATION: This study has been approved by the Child and Adolescent Health Service Human Research Ethics Committee, Perth, Western Australia (RGS 00019). The investigators will ensure that this trial is conducted in accordance with the principles of the Declaration of Helsinki and with the International Conference on Harmonisation Guidelines for Good Clinical Practice. Individual consent will be requested. Parents will be reimbursed reasonable travel and parking costs to attend the study visits. The dissemination of these research findings will follow the National Health and Medical Research Council of Australia Open Access Policy. TRIAL REGISTRATION NUMBER: ACTRN12617000065392p.
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Vacuna contra Difteria, Tétanos y Tos Ferina , Tos Ferina , Anticuerpos Antibacterianos , Australia , Teorema de Bayes , Estudios de Casos y Controles , Humanos , Lactante , Recién Nacido , Vacuna contra la Tos Ferina , Ensayos Clínicos Controlados Aleatorios como Asunto , Australia Occidental , Tos Ferina/prevención & controlRESUMEN
BACKGROUND: Rates of food allergy have increased markedly in Australia and other high- income countries in recent years. On the basis of ecological observations, and the known immunologic characteristics of whole-cell pertussis (wP) compared with acellular pertussis (aP) vaccines, we hypothesized that wP vaccination in infancy protects against the development of food allergy. OBJECTIVE: To determine whether infants who receive wP in infancy were less likely to develop IgE-mediated food allergy than those who received aP. METHODS: Retrospective cohort-nested case-control study of Australian children born in the period 1997 to 1999, the period of transition from using wP-containing to aP-containing vaccines. Children diagnosed with IgE-mediated food allergy were individually matched to 10 controls by date of birth, socioeconomic decile, and jurisdiction of birth. The odds ratio of vaccination with wP versus aP among cases and matched controls was calculated using conditional logistic regression. RESULTS: The odds ratio of receiving the first dose as wP (rather than aP) among cases of food allergy compared with controls was 0.77 (95% CI, 0.62-0.95). The results of secondary analyses (any dose as wP vs aP-only, and wP-only vs aP-only) were broadly similar. CONCLUSIONS: Australian infants who received wP vaccines were less likely to be diagnosed with food allergy in childhood than contemporaneous children who received aP vaccines. If a protective effect is confirmed in a randomized controlled trial, wP or mixed wP and aP vaccination schedules could form part of an effective strategy for combating the rise in food allergies.
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Hipersensibilidad a los Alimentos , Tos Ferina , Australia/epidemiología , Estudios de Casos y Controles , Niño , Hipersensibilidad a los Alimentos/epidemiología , Humanos , Inmunoglobulina E , Lactante , Estudios Retrospectivos , VacunaciónRESUMEN
There is an urgent need for rapid SARS-CoV-2 testing in hospitals to limit nosocomial spread. We report an evaluation of point of care (POC) nucleic acid amplification testing (NAAT) in 149 participants with parallel combined nasal and throat swabbing for POC versus standard lab RT-PCR testing. Median time to result is 2.6 (IQR 2.3-4.8) versus 26.4 h (IQR 21.4-31.4, p < 0.001), with 32 (21.5%) positive and 117 (78.5%) negative. Cohen's κ correlation between tests is 0.96 (95% CI 0.91-1.00). When comparing nearly 1,000 tests pre- and post-implementation, the median time to definitive bed placement from admission is 23.4 (8.6-41.9) versus 17.1 h (9.0-28.8), p = 0.02. Mean length of stay on COVID-19 "holding" wards is 58.5 versus 29.9 h (p < 0.001). POC testing increases isolation room availability, avoids bed closures, allows discharge to care homes, and expedites access to hospital procedures. POC testing could mitigate the impact of COVID-19 on hospital systems.
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Prueba de Ácido Nucleico para COVID-19 , COVID-19/diagnóstico , Control de Infecciones/métodos , Pruebas en el Punto de Atención , SARS-CoV-2/aislamiento & purificación , Adulto , Anciano , Prueba de Ácido Nucleico para COVID-19/normas , Infección Hospitalaria/prevención & control , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Pruebas en el Punto de Atención/normas , SARS-CoV-2/genéticaAsunto(s)
Salmonella typhi/patogenicidad , Fiebre Tifoidea/microbiología , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND AND AIMS: We aimed to understand the risk factors associated with incomplete vaccination, which may help to identify and prioritise opportunities to intervene. METHODS: Consenting parents of children <6â¯years old attending an outpatient clinic completed a questionnaire, which captured demographic information and their level of agreement with belief statements about vaccination using a 7-point Likert scale. Vaccination status was determined from the Australian Childhood Immunisation Register and deemed either "complete" (no doses overdue) or "incomplete" (1 or more doses overdue) at the time of questionnaire completion. RESULTS: Of 589 children of respondents, 116 (20%) had an incomplete vaccination status. Of these, nearly two-thirds (63%) of parents believed that their child was, in fact, fully-vaccinated. Compared to those with a complete vaccine status, children with an incomplete vaccine status were more likely to be born overseas (pâ¯<â¯0.001), have a larger family size (pâ¯=â¯0.02) and to have parents with lower educational attainment (pâ¯=â¯0.001). Parents of children with an incomplete status reported more doubt about the importance of vaccination and greater concern about vaccine safety, compared to parents of children with a complete status. CONCLUSION: Most parents are supportive of vaccination. Sociodemographic factors may contribute more to the risk of incomplete vaccination than attitudes or beliefs. Some parents are unaware of their child's vaccination status, suggesting that simple and modern reminders may assist parents to keep up to date.
RESUMEN
INTRODUCTION: Rotavirus vaccines were introduced into the Australian National Immunisation Program in 2007. Despite this, Northern Territory Indigenous children continue to be hospitalised with rotavirus at a rate more than 20 times higher than non-Indigenous children in other Australian jurisdictions, with evidence of waning protection in the second year of life. We hypothesised that scheduling an additional (third) dose of oral human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to <12 months would improve protection against clinically significant all-cause gastroenteritis. METHODS AND ANALYSIS: This Bayesian adaptive clinical trial will investigate whether routinely scheduling an additional dose of Rotarix for Australian Indigenous children aged 6 to <12 months old confers significantly better protection against clinically important all-cause gastroenteritis than the current two-dose schedule at 2 and 4 months old. There are two coprimary endpoints: (1) seroconversion from baseline serum anti-rotavirus immunoglobulin A (IgA) titre <20 U/mL prior to an additional dose of Rotarix/placebo to serum anti-rotavirus IgA titre >20 U/mL following the administration of the additional dose of Rotarix/placebo and (2) time from randomisation to medical attendance (up to age 36 months old) for which the primary reason is acute gastroenteritis/diarrhoea. Secondary endpoints include the change in anti-rotavirus IgA log titre, time to hospitalisation for all-cause diarrhoea and for rotavirus-confirmed gastroenteritis/diarrhoea, and rotavirus notification. Analysis will be based on Bayesian inference with adaptive sample size. ETHICS, REGISTRATION AND DISSEMINATION: Ethics approval has been granted by Central Australian Human Research Ethics Committee (HREC-16-426) and Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC-2016-2658). Study investigators will ensure the trial is conducted in accordance with the principles of the Declaration of Helsinki and with the ICH Guidelines for Good Clinical Practice. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. The trial is registered with Clinicaltrials.gov (NCT02941107) and important modifications to this protocol will be updated. TRIAL REGISTRATION NUMBER: NCT02941107; Pre-results.