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

The effect of saponins from <it>Ampelozizyphus amazonicus</it> Ducke on the renal Na⁺ pumps’ activities and urinary excretion of natriuretic peptides

<p>Abstract</p> <p>Background</p> <p>In a previous study, we showed that a saponin mixture isolated from the roots of <it>Ampelozizyphus amazonicus</it> Ducke (SAP<it>Aa</it>D) reduces urine excretion in rats that were given an oral loading of 0.9 % NaCl (4 ml/100 g body weight). In the present study, we investigated whether atrial natriuretic peptides (ANP) and renal ATPases play a role in the SAP<it>Aa</it>D- induced antidiuresis in rats.</p> <p>Methods</p> <p>To evaluate the effect of SAP<it>Aa</it>D on furosemide-induced diuresis, Wistar rats (250-300 g) were given an oral loading of physiological solution (0.9 % NaCl, 4 ml/100 g body weight) to impose a uniform water and salt state. The solution containing furosemide (Furo, 13 mg/kg) was given 30 min after rats were orally treated with 50 mg/kg SAP<it>Aa</it>D (<it>SAPAaD + Furo</it>) or 0.5 ml of 0.9 % NaCl (<it>NaCl + Furo</it>). In the <it>SAPAaD + NaCl</it> group, rats were pretreated with SAP<it>Aa</it>D and 30 min later they received the oral loading of physiological solution. Animals were individually housed in metabolic cages, and urine volume was measured every 30 min throughout the experiment (3 h). To investigate the role of ANP and renal Na⁺ pumps on antidiuretic effects promoted by SAP<it>Aa</it>D, rats were given the physiological solution (as above) containing SAP<it>Aa</it>D (50 mg/kg). After 90 min, samples of urine and blood from the last 30 min were collected. Kidneys and atria were also removed after previous anesthesia. ANP was measured by radioimmunoassay (RIA) and renal cortical activities of Na⁺- and (Na⁺,K⁺)-ATPases were calculated from the difference between the [³²P] Pi released in the absence and presence of 1 mM furosemide/2 mM ouabain and in the absence and presence of 1 mM ouabain, respectively.</p> <p>Results</p> <p>It was observed that SAP<it>Aa</it>D inhibited furosemide-induced diuresis (at 90 min: from 10.0 ± 1.0 mL, <it>NaCl + Furo</it> group, n = 5, to 5.9 ± 1.0 mL, <it>SAPAaD + Furo</it> group n = 5, p < 0.05), increased both Na⁺-ATPase (from 25.0 ± 5.9 nmol Pi.mg^-1.min^-1, control, to 52.7 ± 8.9 nmol Pi.mg^-1.min^-1, p < 0.05) and (Na⁺,K⁺)-ATPase (from 47.8 ± 13.3 nmol Pi.mg^-1.min^-1, control, to 79.8 ± 6.9 nmol Pi .mg^-1.min^-1, p < 0.05) activities in the renal cortex. SAP<it>Aa</it>D also lowered urine ANP (from 792 ± 132 pg/mL, control, to 299 ± 88 pg/mL, p < 0.01) and had no effect on plasma or atrial ANP.</p> <p>Conclusion</p> <p>We concluded that the SAP<it>Aa</it>D antidiuretic effect may be due to an increase in the renal activities of Na⁺- and (Na⁺,K⁺)-ATPases and/or a decrease in the renal ANP.</p

Nightly patterns of calling activity in anuran assemblages of the Cerrado, Brazil

Anurans living in species-rich assemblages may experience acoustic niche overlap. To deal with potential masking interference during reproductive activity, species can present acoustic partitioning based on differences in calling period. Studies addressing this question in tropical assemblages have mainly focused on the seasonal scale, and little is known about nightly variation in calling. Here, we reported on phenology and abundance of five tropical anuran assemblages at both seasonal and daily scale and tested the effects of temperature and relative humidity on calling activity patterns of 19 species. Based on 420 hourly acoustic surveys, an overall peak of calling activity in between the first and fourth hour after sunset was identified by Rayleigh’s circular test, with a gradual decrease until sunrise. This nightly pattern was followed by most of the species in the assemblages and similarly observed for species presence and abundance of calling males. The acoustic niche overlap was greater than expected by chance within the assemblages, while no pattern of coincidence or segregation was found for the syntopic congeneric species (Dendropsophus, Boana and Leptodactylus). Moreover, the calling activity of the assemblages, measured as richness and diversity of calling species, was negatively influenced by air and water temperature and positively by relative humidity. Thus, climatic variables act as driver factors to determine calling activity and reproduction of anurans at daily scale. The absence of a segregation pattern at the assembly or genus levels in the calling activity over time indicates that the use of the acoustic temporal niche is not a limiting resource for Cerrado anurans.VG would like to thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES) for doctoral fellowship, and RPB thanks the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 308204/2013-1) for research productivity fellowship. VG was supported by CAPES/PROCAD-AM 1701/2018 (Grant No. 88887.374100/2019-00). DL was supported by a Global Marie S. Curie Fellowship (EAVESTROP-661408) granted by the European Commission (Program H2020) and a post-doctoral grant (2016-T2/AMB-1722, Atracción de Talento Investigador, Spain) provided by the Comunidad de Madrid and acknowledges a research project (CGL2017-88764-R, MINECO/AEI/FEDER, Spain) by the Ministerio de Economía, Industria y Competitividad. This paper is developed in the context of National Institutes for Science and Technology (INCT) in Ecology, Evolution and Biodiversity Conservation, supported by MCTIC/CNPq (Proc. 465610/2014-5) and FAPEG (Proc. 201810267000023)