Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

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 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 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, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 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 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 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

Recognizing and Moving on from a Failed Paradigm: The Case of Agricultural Landscapes in Anglo-Saxon England c. AD 400–800

A central preoccupation for archaeologists is how and why material culture changes. One of the most intractable examples of this problem can be found between AD 400 and 800 in the enigmatic transformation of sub-Roman into Anglo-Saxon England. That example lies at the heart of this review, explored through the case of the agricultural economy. Although the ideas critically examined below relate specifically to early medieval England, they represent themes of universal interest: the role of migration in the transformation of material culture, politics, and economy in a post-imperial world, the significance of ‘‘core’’ and ‘‘periphery’’ in evolving polities, ethnogenesis as a strategy in kingdom building, property rights as a lens for investigating cultural change, and the relationship between hierarchical political structures and collective forms of governance. The first part of my argument proposes a structured response to paradigmatic stalemate by identifying and testing each underlying assumption, premise, and interpretative framework. The recognition of any fallacies, false premises, and flawed arguments might assist with an overall evaluation of the continuing utility of a discourse—whether it has life in it yet, or should be set aside. In either case, the recognition of its structure should enable arguments to be developed that do not lead into a disciplinary cul-de-sac, prevented by the orthodoxy from exploring new avenues for research. In the second part of the review, I deliberately adopt a starting point outside the limits of the current discourse. Freed from the confines of the conventional consensus, I experiment with an alternative ‘‘bottom-up’’ approach to change in early medieval England that contrasts with conventional ‘‘top-down’’ arguments. I focus in particular on how rights over agricultural property—especially collective rights—and the forms of governance implied by them may assist in illuminating the roles of tradition and transformation in effecting cultural change.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s10814-015-9088-

Antenatal depression and suicidal ideation among rural Bangladeshi women: a community-based study.

Depression during pregnancy is a significant public health problem because of its negative effects on the health of both mother and infant. Data on its prevalence and determinants are lacking in Bangladesh. To estimate the prevalence of depression during pregnancy and to identify potential contributory factors among rural Bangladeshi women, a community-based study was conducted during 2005 in Matlab sub-district, a rural area of eastern Bangladesh. Three hundred and sixty-one pregnant women were identified through an existing health and demographic surveillance system covering a population of 110,000 people. The women were interviewed at home at 34–35 weeks of pregnancy. Information on risk factors was collected through structured questionnaires, with the Bangla version of the Edinburgh Postnatal Depression Scale (EPDS-B) used to measure their psychological status. Both univariate analysis and multivariate logistic regression were applied using the SPSS 15.0 statistical software. The prevalence of depression at 34–35 weeks pregnancy was 33% (95% CI, 27.6–37.5). After adjustment in a multivariate logistic regression model, a history of being beaten by her husband either during or before the current pregnancy had the highest association with depression followed by having an unhelpful or unsupportive mother-in-law or husband, and family preference for a male child. Of the antenatally depressed women, 17 (14%) admitted to thoughts of self-harm during the pregnancy. This paper further explores the reasons why women have considered some form of self-harm during pregnancy. Depression during pregnancy is common among Bangladeshi women, with about a third being affected. The study highlights the need to allocate resources and develop strategies to address depression in pregnancy