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

Fauna de flebotomíneos (Diptera: Psychodidae) em um foco de leishmaniose tegumentar americana na área periurbana de Manaus, Estado do Amazonas Sandfly fauna (Diptera: Psychodidae) in a focus of American cutaneous leishmaniasis on the urban periphery of Manaus, State of Amazonas

No período de agosto de 2001 a julho de 2002, usando armadilhas CDC e Disney, realizaram-se coletas de flebotomíneos, na base de árvores no peridomicílio e nas matas da Comunidade São João, área periurbana de Manaus, Amazonas. Foram capturados 4.104 espécimes, pertencentes a quatro subtribos, 13 gêneros e 49 espécies da subfamília Phlebotominae. Predominou a subtribo Psychodopygina com 3.403 (83%) espécimes, destacando-se Nyssomyia umbratilis, Nyssomyia anduzei, Trichophoromyia eurypyga, Bichromomyia olmeca nociva e Bichromomyia flaviscutellata. O registro de Nyssomyia umbratilis e Nyssomyia anduzei, incriminadas como vetoras de Leishmania (Viannia) guyanensis, e de Bichromomyia flaviscutellata e Bichromomyia olmeca nociva, de Leishmania (Leishmania) amazonensis, indicam risco de infecção para os moradores da área. A grande maioria (98,5%) dos flebotomíneos foi capturada na área de mata. Nyssomyia anduzei e Bichromomyia olmeca nociva foram coletadas no peridomicílio. A riqueza de espécies vetoras de Leishmania nessa área revela a necessidade de uma vigilância entomológica constante.<br>From August 2001 to July 2002, sand flies were collected from the bases of trees and, using CDC and Disney traps, from areas surrounding homes and forested areas in the São João community, on the urban periphery of Manaus, State of Amazonas. 4,104 specimens belonging to four subtribes, 13 genera and 49 species of the Phlebotominae subfamily were collected. The subtribe Psychodopygina predominated, with 3,403 (83%) specimens, especially of Nyssomyia umbratilis, Nyssomyia anduzei, Trichophoromyia eurypyga, Bichromomyia olmeca nociva and Bichromomyia flaviscutellata. The occurrences of Nyssomyia umbratilis and Nyssomyia anduzei, which have been incriminated as vectors for Leishmania (Viannia) guyanensis, and of Bichromomyia flaviscutellata and Bichromomyia olmeca nociva, for Leishmania (Leishmania) amazonensis, indicate that there is a risk of infection for people living in this area. Most (98.5%) of the sand flies were caught in the forested area. Nyssomyia anduzei and Bichromomyia olmeca nociva were collected from areas surrounding homes. The richness of vector species for Leishmania in this area shows the need for constant entomological surveillance