RESUMO
AIM: To describe the clinical profile of acute rheumatic fever (ARF) presentations to paediatric cardiology tertiary services in Western Australia (WA). METHODS: A retrospective clinical audit of individuals with confirmed ARF referred to the only paediatric tertiary cardiac service in WA (1 January 1987 to 31 December 2020). Comparisons between inpatient, outpatient, remote and non-remote groups were assessed. RESULTS: Four hundred seventy-one episodes of ARF in 457 individuals (235 male; median age = 8 years) met clinical criteria. The majority were Aboriginal and Torres Strait Islander children (91.2%), with 62.1% living in remote areas. The number of ARF and rheumatic heart disease (RHD) diagnoses per year increased from 1987 to 2017 with notable peaks in 2013 and 2017. The average annual incidence of tertiary-referred ARF in WA of 4-15-year-olds from 1987 to 2020 was 4.96 per 100 000. ARF features included carditis (59.9%), chorea (31%), polyarthritis (30%) and polyarthralgia (24.2%). RHD was evident in 61.8% of cases and predominantly manifested as mitral regurgitation (55.7%). Thirty-four children (7.4%) with severe RHD underwent valvular surgery. 12% had at least one recurrent ARF episode. Remote individuals had more than double the rate of recurrence compared to non-remote individuals (P = 0.0058). Compared to non-remote episodes, remote presentations had less polyarthritis (P = 0.0022) but greater proportions of raised ESR (P = 0.01), ASOT titres (P = 0.0073), erythema marginatum (P = 0.0218) and severe RHD (P = 0.0133). CONCLUSION: The high proportion of Aboriginal and Torres Strait Islander Australians affected by ARF/RHD in WA reflects the significant burden of disease within this population. Children from remote communities were more likely to present with concurrent severe RHD. Our study reinforces the persisting need to improve primary and secondary ARF initiatives in rural and remote communities.
Assuntos
Febre Reumática , Cardiopatia Reumática , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Incidência , Estudos Retrospectivos , Febre Reumática/epidemiologia , Cardiopatia Reumática/epidemiologia , Austrália Ocidental/epidemiologia , Povos Aborígenes Australianos e Ilhéus do Estreito de TorresRESUMO
Violence is a major public health problem globally, with the highest rates in low- and middle-income countries (LMICs) in the Americas and southern Africa. Parenting programmes in high-income countries can diminish risk for violence, by reducing risk factors such as child aggression and harsh parenting, and increasing protective factors such as child cognitive development and school readiness. However, there is critical need to identify low-cost programmes with replicable benefits that work in real-world LMICs contexts. A three-arm, randomised, single-blind trial evaluated effects of two low-cost, group-based parenting programmes recommended for LMICs (ACT: Raising Safe Kids; DBS: dialogic book-sharing) on child aggression (primary outcome), child development, parenting, maltreatment, and stress. Participants were 369 children with medium-high levels of aggression (mean age 3.1 years at baseline) in poor households. Interventions were implemented in city health and education services in southern Brazil. Maternal reports, filmed observations, child tasks, and hair cortisol were assessed at baseline, 1-month post-intervention, and 8-month follow-up. Intention-to-treat analyses compared each of ACT and DBS with a control group. Three hundred sixty-eight (99.7%) participants completed follow-up assessments 8 months after the interventions. There was no effect of ACT (standardised mean difference, SMD 0.11, 95% CI - 0.05, 0.27) or DBS (SMD 0.05, 95% CI - 0.11, 0.21) on the primary outcome of child aggression. ACT reduced harsh parenting behaviour post-intervention (SMD - 0.23; 95% CI - 0.46, - 0.01), but not at follow-up. DBS improved book-sharing practices at both time points (e.g., maternal sensitivity at follow-up SMD 0.33; 95% CI 0.08, 0.57). There were no benefits of either programme for other parenting, child development, or stress outcomes. Two parenting programmes in Brazil had small effects on parenting practices but did not reduce child aggression or several other important risk/protective factors for violence. Effective early interventions that reduce violence in real-world LMIC settings are highly desirable but may be challenging to achieve.
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Agressão , Poder Familiar , Violência , Humanos , Brasil , Pré-Escolar , Feminino , Masculino , Violência/prevenção & controle , Método Simples-Cego , Criança , Fatores de RiscoRESUMO
BACKGROUND: Adults <55 years of age comprise a quarter of all acute coronary syndromes (ACS) hospitalisations. There is a paucity of data characterising this group, particularly sex differences. This study aimed to compare the clinical and risk profile of patients with ACS aged <55 years with older counterparts, and measure short-term outcomes by age and sex. METHOD: The study population comprised patients with ACS enrolled in the AUS-Global Registry of Acute Coronary Events (GRACE), Cooperative National Registry of Acute Coronary Syndrome Care (CONCORDANCE) and SNAPSHOT ACS registries. We compared clinical features and combinations of major modifiable risk factors (hypertension, smoking, dyslipidaemia, and diabetes) by sex and age group (20-54, 55-74, 75-94 years). All-cause mortality and major adverse events were identified in-hospital and at 6-months. RESULTS: There were 16,658 patients included (22.3% aged 20-54 years). Among them, 20-54 year olds had the highest proportion of ST-elevation myocardial infarction compared with sex-matched older age groups. Half of 20-54 year olds were current smokers, compared with a quarter of 55-74 year olds, and had the highest prevalence of no major modifiable risk factors (14.2% women, 12.7% men) and of single risk factors (27.6% women, 29.0% men), driven by smoking. Conversely, this age group had the highest proportion of all four modifiable risk factors (6.6% women, 4.7% men). Mortality at 6 months in 20-54 year olds was similar between men (2.3%) and women (1.7%), although lower than in older age groups. CONCLUSIONS: Younger adults with ACS are more likely to have either no risk factor, a single risk factor, or all four modifiable risk factors, than older patients. Targeted risk factor prevention and management is warranted in this age group.
Assuntos
Síndrome Coronariana Aguda , Diabetes Mellitus , Adulto , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Síndrome Coronariana Aguda/epidemiologia , Fatores de Risco , Fumar/epidemiologia , Fatores Etários , Sistema de Registros , Mortalidade Hospitalar , Resultado do TratamentoRESUMO
BACKGROUND: Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer-BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). METHODS: Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8-12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. FINDINGS: Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. INTERPRETATION: Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. FUNDING: UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.
Assuntos
Adjuvantes de Vacinas/administração & dosagem , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Imunização Secundária/efeitos adversos , Imunização Secundária/métodos , Imunogenicidade da Vacina , Vacinas de mRNA/administração & dosagem , Vacina de mRNA-1273 contra 2019-nCoV/administração & dosagem , Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Idoso , Vacina BNT162/administração & dosagem , Vacina BNT162/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , ChAdOx1 nCoV-19/administração & dosagem , ChAdOx1 nCoV-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Reino Unido , Vacinação/efeitos adversos , Vacinação/métodos , Vacinas de mRNA/imunologiaRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) remains a leading cause of pediatric morbidity, with no approved vaccine. We assessed the safety and immunogenicity of the Ad26.RSV.preF vaccine candidate in adults and children. METHODS: In this randomized, double-blind, phase 1/2a, placebo-controlled study, 12 adults (18-50 years) and 36 RSV-seropositive children (12-24 months) were randomized 2:1 to Ad26.RSV.preF (1 × 1011 viral particles [vp] for adults, 5 × 1010 vp for children) or placebo, at day 1 and 29, with 6-month immunogenicity and 1-year safety follow-up. Respiratory syncytial virus infection was an exploratory outcome in children. RESULTS: In adults, solicited adverse events (AEs) were generally mild to moderate, with no serious AEs. In children, no vaccination-related serious AEs were reported; fever was reported in 14 (58.3%) Ad26.RSV.preF recipients. Baseline pediatric geometric mean titers for RSV A2 neutralization increased from 121 (95% confidence interval [CI], 76-191) to 1608 (95% CI, 730-3544) at day 29, and 2235 (95% CI, 1586-3150) at day 57, remaining elevated over 7 months. Respiratory syncytial virus infection was confirmed in fewer children receiving Ad26.RSV.preF (1, 4.2%) than placebo (5, 41.7%). CONCLUSIONS: Ad26.RSV.preF demonstrated immunogenicity in healthy adults and toddlers, with no safety concerns raised. Evaluations in RSV-seronegative children are underway.
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Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Humanos , Adulto , Criança , Anticorpos Neutralizantes , Anticorpos Antivirais , Vírus Sincicial Respiratório Humano/genética , Adenoviridae/genética , Imunogenicidade da VacinaRESUMO
BACKGROUND: Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings. METHODS: We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110. FINDINGS: 41 344 children were vaccinated in April-May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI -12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed. INTERPRETATION: Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses. FUNDING: The study was funded by the Bill & Melinda Gates Foundation.
Assuntos
Polissacarídeos Bacterianos/administração & dosagem , Toxoide Tetânico/uso terapêutico , Febre Tifoide/prevenção & controle , Vacinas Tíficas-Paratíficas/administração & dosagem , Vacinação , Vacinas Conjugadas/administração & dosagem , Adolescente , Bangladesh/epidemiologia , Criança , Pré-Escolar , Países em Desenvolvimento , Encefalite Japonesa/epidemiologia , Feminino , Humanos , Lactente , Vacinas contra Encefalite Japonesa/administração & dosagem , Masculino , Salmonella typhi/imunologia , Toxoide Tetânico/imunologia , Febre Tifoide/epidemiologia , Febre Tifoide/imunologiaRESUMO
BACKGROUND: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. METHODS: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. FINDINGS: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12â906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14â080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. INTERPRETATION: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. FUNDING: UK Vaccine Task Force and National Institute for Health Research.
Assuntos
Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunogenicidade da Vacina , Idoso , Anticorpos Antivirais/sangue , Vacina BNT162 , Vacinas contra COVID-19/administração & dosagem , ChAdOx1 nCoV-19 , Estudos de Equivalência como Asunto , Feminino , Humanos , Esquemas de Imunização , Imunoglobulina G/sangue , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5â×â1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2â×â1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24â422 participants were recruited and vaccinated across the four studies, of whom 17â178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12â282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11â962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
Assuntos
Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Esquemas de Imunização , Imunização Secundária , Adolescente , Adulto , Idoso , Formação de Anticorpos , Infecções Assintomáticas , Vacinas contra COVID-19/efeitos adversos , ChAdOx1 nCoV-19 , Humanos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2/imunologia , Adulto JovemRESUMO
BACKGROUND: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant. METHODS: Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 - relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18-55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2-11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6-84·5) for B.1.1.7 and 81·5% (67·9-89·4) for non-B.1.1.7 lineages. INTERPRETATION: ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2. FUNDING: UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
Assuntos
Anticorpos Neutralizantes/sangue , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , SARS-CoV-2/imunologia , Adolescente , Adulto , COVID-19/epidemiologia , Teste de Ácido Nucleico para COVID-19 , Vacinas contra COVID-19/efeitos adversos , ChAdOx1 nCoV-19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Amplificação de Ácido Nucleico , Pandemias/prevenção & controle , Método Simples-Cego , Reino Unido/epidemiologia , Carga Viral , Adulto JovemRESUMO
Although medication adherence is commonly measured in electronic datasets using the proportion of days covered (PDC), no standardized approach is used to calculate and report this measure. We conducted a scoping review to understand the approaches taken to calculate and report the PDC for cardiovascular medicines to develop improved guidance for researchers using this measure. After prespecifying methods in a registered protocol, we searched Ovid Medline, Embase, Scopus, CINAHL Plus and grey literature (1 July 2012 to 14 December 2020) for articles containing the terms "proportion of days covered" and "cardiovascular medicine", or synonyms and subject headings. Of the 523 articles identified, 316 were reviewed in full and 76 were included (93% observational studies; 47% from the USA; 2 grey literature articles). In 45 articles (59%), the PDC was measured from the first dispensing/claim date. Good adherence was defined as 80% PDC in 61 articles, 56% of which contained a rationale for selecting this threshold. The following parameters, important for deriving the PDC, were often not reported/unclear: switching (53%), early refills (45%), in-hospital supplies (45%), presupply (28%) and survival (7%). Of the 46 articles where dosing information was unavailable, 59% reported how doses were imputed. To improve the transparent and systematic reporting of the PDC, we propose the TEN-SPIDERS tool, covering the following PDC parameters: Threshold, Eligibility criteria, Numerator and denominator, Survival, Presupply, In-hospital supplies, Dosing, Early Refills, and Switching. Use of this tool will standardize reporting of the PDC to facilitate reliable comparisons of medication adherence estimates between studies.
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Aranhas , Animais , Adesão à Medicação , Estudos RetrospectivosRESUMO
OBJECTIVE: We evaluated the best time to initiate delivery in late preterm pre-eclampsia in order to optimise long-term infant and maternal outcomes. DESIGN: Parallel-group, non-masked, randomised controlled trial. SETTING: Forty-six maternity units in the UK. POPULATION: Women with pre-eclampsia between 34+0 and 36+6 weeks of gestation, without severe disease, were randomised to planned delivery or expectant management. MAIN OUTCOME MEASURES: Infant neurodevelopmental outcome at 2 years of age, using the Parent Report of Children's Abilities - Revised (PARCA-R) composite score. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were enrolled in the trial, with 450 women allocated to planned delivery and 451 women allocated to expectant management. At the 2-year follow-up, the intention-to-treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) allocated to expectant management. The mean composite standardised PARCA-R scores were 89.5 (SD 18.2) in the planned delivery group and 91.9 (SD 18.4) in the expectant management group, with an adjusted mean difference of -2.4 points (95% CI -5.4 to 0.5 points). CONCLUSIONS: In infants of women with late preterm pre-eclampsia, the average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management was pursued. With the lower than anticipated follow-up rate there was limited power to demonstrate that these scores did not differ, but the small between-group difference in PARCA-R scores is unlikely to be clinically important.
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Pré-Eclâmpsia , Nascimento Prematuro , Cesárea , Criança , Parto Obstétrico , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Pré-Eclâmpsia/terapia , Gravidez , Conduta ExpectanteRESUMO
Background and Purpose: Although a target of 80% medication adherence is commonly cited, it is unclear whether greater adherence improves survival after stroke or transient ischemic attack (TIA). We investigated associations between medication adherence during the first year postdischarge, and mortality up to 3 years, to provide evidence-based targets for medication adherence. Methods: Retrospective cohort study of 1-year survivors of first-ever stroke or TIA, aged ≥18 years, from the Australian Stroke Clinical Registry (July 2010June 2014) linked with nationwide prescription refill and mortality data (until August 2017). Adherence to antihypertensive agents, statins, and nonaspirin antithrombotic medications was based on the proportion of days covered from discharge until 1 year. Cox regression with restricted cubic splines was used to investigate nonlinear relationships between medication adherence and all-cause mortality (to 3 years postdischarge). Models were adjusted for age, sex, socioeconomic position, stroke factors, primary care factors, and concomitant medication use. Results: Among 8363 one-year survivors of first-ever stroke or TIA (44% aged ≥75 years, 44% female, 18% TIA), 75% were supplied antihypertensive agents. In patients without intracerebral hemorrhage (N=7446), 84% were supplied statins, and 65% were supplied nonaspirin antithrombotic medications. Median adherence was ≈90% for each medication group. Between 1% and 100% adherence, greater adherence to statins or antihypertensive agents, but not nonaspirin antithrombotic agents, was associated with improved survival. When restricted to linear regions above 60% adherence, each 10% increase in adherence was associated with a reduction in all-cause mortality of 13% for antihypertensive agents (hazard ratio, 0.87 [95% CI, 0.810.95]), 13% for statins (hazard ratio, 0.87 [95% CI, 0.800.95]), and 15% for nonaspirin antithrombotic agents (hazard ratio, 0.85 [95% CI, 0.790.93]). Conclusions: Greater levels of medication adherence after stroke or TIA are associated with improved survival, even among patients with near-perfect adherence. Interventions to improve medication adherence are needed to maximize survival poststroke.
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AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/mortalidade , Adesão à Medicação/estatística & dados numéricos , Prevenção Secundária/métodos , Idoso , Anti-Hipertensivos/uso terapêutico , Estudos de Coortes , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/mortalidade , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos RetrospectivosRESUMO
BACKGROUND: In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. METHODS: In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: Between Sept 29, 2014, and Dec 10, 2018, 901 women were recruited. 450 women (448 women and 471 infants analysed) were allocated to planned delivery and 451 women (451 women and 475 infants analysed) to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group (289 [65%] women) compared with the expectant management group (338 [75%] women; adjusted relative risk 0·86, 95% CI 0·79-0·94; p=0·0005). The incidence of the co-primary perinatal outcome by intention to treat was significantly higher in the planned delivery group (196 [42%] infants) compared with the expectant management group (159 [34%] infants; 1·26, 1·08-1·47; p=0·0034). The results from the per-protocol analysis were similar. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. INTERPRETATION: There is strong evidence to suggest that planned delivery reduces maternal morbidity and severe hypertension compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater neonatal morbidity. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision making on timing of delivery. FUNDING: National Institute for Health Research Health Technology Assessment Programme.
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Cesárea , Trabalho de Parto Induzido , Pré-Eclâmpsia/terapia , Nascimento Prematuro , Adulto , Pressão Sanguínea , Parto Obstétrico/métodos , Gerenciamento Clínico , Inglaterra , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Tempo de Internação , Morte Materna , Morbidade , Morte Perinatal , Gravidez , País de Gales , Adulto JovemRESUMO
This retrospective study assessed maternal and perinatal outcomes for women with rheumatic heart disease (RHD) admitted to the largest tertiary obstetric hospital in Western Australia from 2009 to 2016. Of 54 women identified, 75.9% were Indigenous, 59.3% lived in rural areas and 40.7% had severe RHD. Heart failure developed in 10% who gave birth. Indigenous women were younger, had higher gravidity (P = 0.0305), were more likely to receive secondary prophylaxis (P = 0.0041) and have sub-optimal antenatal clinic attendance (P = 0.0078). There were no maternal deaths and two perinatal deaths (4.0%), reflecting vigilance in the obstetric management of women with RHD in Western Australia.
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Povos Indígenas/estatística & dados numéricos , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Complicações Cardiovasculares na Gravidez/epidemiologia , Cardiopatia Reumática/epidemiologia , Adulto , Feminino , Maternidades , Humanos , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Centros de Atenção Terciária , Austrália Ocidental/epidemiologiaRESUMO
BACKGROUND: International Classification of Diseases codes for rheumatic heart disease (RHD) (ICD-10 I05-I08) include valvular heart disease of unspecified origin, limiting their usefulness for estimating RHD burden. An expert opinion-based algorithm was developed to increase their accuracy for epidemiological case ascertainment. The algorithm included codes not defaulting to RHD ('probable') plus selected codes pertaining to mitral valve involvement in patients <60 years ('possible'). We aimed to determine the positive predictive value (PPV) for RHD of algorithm-selected hospital admissions. METHODS: Chart reviews of RHD-coded admissions (n=368) to Western Australian tertiary hospitals (2009-2016) authenticated RHD diagnosis. We selected all cases with algorithm-positive codes from populations at high-risk of RHD and an age-stratified random sample from low-risk groups. RHD status was determined from echocardiographic reports or clinical diagnosis in charts. PPVs were compared by population risk status (high-risk/low-risk), age group, gender, principal/secondary diagnosis and probable/possible codes. RESULTS: High-risk patients had higher PPVs than low-risk patients (83.8% vs 54.9%, p<0.0001). PPVs were 91.5% and 51.5% respectively for algorithm-defined 'probable RHD' and 'possible' codes (p<0.0001). The PPVs in low-risk patients were higher for principal diagnoses than secondary diagnoses (84.5% vs 44.8%, weighted p<0.0001) but were similar in high-risk patients (92.5% vs 81.7%, p=0.096). CONCLUSION: The algorithm performs well for RHD coded as a principal diagnosis, 'probable' codes or in populations at high risk of RHD. Refinement is needed for identifying true RHD in low-risk groups.
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Algoritmos , Codificação Clínica/métodos , Hospitalização/tendências , Hospitais/estatística & dados numéricos , Cardiopatia Reumática/diagnóstico , Adulto , Idoso , Austrália/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Cardiopatia Reumática/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVE: To investigate differences in the profile and outcomes between Aboriginal and non-Aboriginal Western Australians (WAs) hospitalized with traumatic brain injury (TBI). SETTING: WA hospitals. PARTICIPANTS: TBI cases aged 15 to 79 years surviving their first admission during 2002-2011. DESIGN: Patients identified from diagnostic codes and followed up for 12 months or more using WA-wide person-based linked hospital and mortality data. MAIN MEASURES: Demographic profile, 5-year comorbidity history, injury mechanism, injury severity, 12-month readmission, and mortality risks. Determinants of 12-month readmission. RESULTS: Of 16 601 TBI survivors, 14% were Aboriginal. Aboriginal patients were more likely to be female, live remotely, and have comorbidities. The mechanism of injury was an assault in 57% of Aboriginal patients (vs 20%) and transport in 33% of non-Aboriginal patients (vs 17%), varying by remoteness. One in 10 Aboriginal TBI patients discharged themselves against medical advice. Crude 12-month readmission but not mortality risk was significantly higher in Aboriginal patients (48% vs 36%). The effect of age, sex, and injury mechanism on 12-month readmission was different for Aboriginal and non-Aboriginal patients. CONCLUSION: These findings suggest an urgent need for multisectoral primary prevention of TBI, as well as culturally secure and logistically appropriate medical and rehabilitation service delivery models to optimize outcomes.
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Lesões Encefálicas Traumáticas/etnologia , Havaiano Nativo ou Outro Ilhéu do Pacífico , Adolescente , Adulto , Idoso , Austrália , Estudos de Coortes , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Abuso Físico/estatística & dados numéricos , População Rural , Distribuição por Sexo , Recusa do Paciente ao Tratamento/estatística & dados numéricos , Adulto JovemAssuntos
Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunização Secundária/métodos , Vacinação em Massa/métodos , Vacina BNT162 , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , ChAdOx1 nCoV-19 , Proteção Cruzada/imunologia , Humanos , Imunidade Heteróloga , Imunização Secundária/efeitos adversos , Imunogenicidade da Vacina , Vacinação em Massa/efeitos adversos , SARS-CoV-2/imunologiaRESUMO
INTRODUCTION: This is the first efficacy study of an oral live attenuated vaccine against Salmonella Paratyphi A using a human challenge model of paratyphoid infection. S. Paratyphi A is responsible for 3.3 million cases of enteric fever every year, with over 19 000 deaths. Although improvements to sanitation and access to clean water are vital to reduce the burden of this condition, vaccination offers a cost-effective, medium-term solution. Efficacy trials of potential S. Paratyphi vaccine candidates in the field are unlikely to be feasible given the large number of participants required. Human challenge models therefore offer a unique, cost-effective solution to test efficacy of such vaccines. METHODS AND ANALYSIS: This is an observer-blind, randomised, placebo-controlled trial phase I/II of the oral live-attenuated vaccine against S. Paratyphi A, CVD 1902. Volunteers will be randomised 1:1 to receive two doses of CVD 1902 or placebo, 14 days apart. One month following second vaccination all volunteers will ingest S. Paratyphi A bacteria with a bicarbonate buffer solution. They will be reviewed daily in the following 14 days and diagnosed with paratyphoid infection if the predefined microbiological or clinical diagnostic criteria are met. All participants will be treated with antibiotics on diagnosis, or at day 14 postchallenge if not diagnosed. The vaccine efficacy will be determined by comparing the relative attack rate, that is, the proportion of those diagnosed with paratyphoid infection, in the vaccine and placebo groups. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the Berkshire Medical Research Ethics Committee (REC ref 21/SC/0330). The results will be disseminated via publication in a peer-reviewed journal and presentation at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN15485902.
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Doenças Cardiovasculares , Salmonella paratyphi A , Humanos , Adulto , Vacinas Atenuadas , Voluntários Saudáveis , Voluntários , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase I como AssuntoRESUMO
BACKGROUND: This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents. METHODS: A phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30 µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. 'Breakthrough infection' analyses were exploratory. FINDINGS: 148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX (adjusted geometric mean ratio [aGMR]) 1.09 95% confidence interval (CI): 0.84, 1.42] and lower for BNT-10 (aGMR 0.78 [95% CI: 0.61, 0.99]). For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 (aGMR 1.0 [95% CI: 0.65, 1.54] and 1.02 [95% CI: 0.71, 1.48], respectively), but higher for NVX (aGMR 1.7 [95% CI: 1.07, 2.69] and 1.43 [95% CI: 0.96, 2.12], respectively). Compared to BNT-30, cellular immune responses were greatest for NVX (aGMR 1.73 [95% CI: 0.94, 3.18]), and lowest for BNT-10 (aGMR 0.65 [95% CI: 0.37, 1.15]) at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported 'breakthrough infection' compared to BNT-30 (adjusted hazard ratio [aHR] 0.11 [95% CI: 0.01, 0.86]) up until day 132 after second dose. BNT-10 recipients were more likely to have a 'breakthrough infection' compared to BNT-30 (aHR 2.14 [95% CI: 1.02, 4.51]) up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules. INTERPRETATION: Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule. FUNDING: National Institute for Health Research and Vaccine Task Force. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number registry: 12348322.
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Vacinas contra COVID-19 , COVID-19 , Humanos , Adolescente , Feminino , Masculino , Vacinas contra COVID-19/efeitos adversos , Vacina BNT162 , Infecções Irruptivas , COVID-19/prevenção & controle , SARS-CoV-2 , Método Simples-Cego , Vacinação , Imunogenicidade da Vacina , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
BACKGROUND: Heterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development. METHODS: Com-COV2 was a single-blinded trial in which adults ≥ 50 years, previously immunised with single dose 'ChAd' (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or 'BNT' (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8-12 weeks later with either the homologous vaccine, or 'Mod' (mRNA-1273, Spikevax, Moderna) or 'NVX' (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration. FINDINGS: In April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N = 540, 45% female) or BNT (N = 532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95% CI (confidence interval): 8.2, 11.5) at D28 to 6.2 (95% CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95% CI:2.5,3.5) to 2.4 (95% CI:1.9, 3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The adjusted GMR (aGMR) for BNT/Mod compared with BNT/BNT increased from 1.36 (95% CI: 1.17, 1.58) at D28 to 1.52 (95% CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95% CI: 0.47, 0.64) at day 28 and 0.62 (95% CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies. INTERPRETATION: Heterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics. ISRCTN: 27841311 EudraCT:2021-001275-16.