AZD1222 (ChAdOx1 nCov-19): A Single-Dose biodistribution study in mice.

Biodistribution studies of adenovirus-based vaccines support their clinical development by evaluating their spread and persistence following in vivo administration. AZD1222 (ChAdox1 nCov-19) is a replication-deficient non-human adenovirus-vectored vaccine for coronavirus disease 2019. In this nonclinical study, the biodistribution of AZD1222 was assessed in mice for 29 days following intramuscular injection. Results show that AZD1222 was safe and well tolerated, with a spread that was largely confined to administration sites and the proximal sciatic nerve, with low levels observed in sites that are involved in rapid clearance of particulates by the reticuloendothelial system. Accordingly, levels of AZD1222 decreased from Day 2 to Day 29, indicating clearance. There were no quantifiable levels of AZD1222 in the blood, brain, spinal cord, and reproductive tissue, suggesting a lack of widespread or long-term distribution of AZD1222 vector DNA throughout the body following its administration.

SARS-CoV-2 Spike Protein Expression In Vitro and Hematologic Effects in Mice Vaccinated With AZD1222 (ChAdOx1 nCoV-19).

Severe COVID-19 can be associated with a prothrombotic state, increasing risk of morbidity and mortality. The SARS-CoV-2 spike glycoprotein is purported to directly promote platelet activation via the S1 subunit and is cleaved from host cells during infection. High plasma concentrations of S1 subunit are associated with disease progression and respiratory failure during severe COVID-19. There is limited evidence on whether COVID-19 vaccine-induced spike protein is similarly cleaved and on the immediate effects of vaccination on host immune responses or hematology parameters. We investigated vaccine-induced S1 subunit cleavage and effects on hematology parameters using AZD1222 (ChAdOx1 nCoV-19), a simian, replication-deficient adenovirus-vectored COVID-19 vaccine. We observed S1 subunit cleavage in vitro following AZD1222 transduction of HEK293x cells. S1 subunit cleavage also occurred in vivo and was detectable in sera 12 hours post intramuscular immunization (1x1010 viral particles) in CD-1 mice. Soluble S1 protein levels decreased within 3 days and were no longer detectable 7-14 days post immunization. Intravenous immunization (1x109 viral particles) produced higher soluble S1 protein levels with similar expression kinetics. Spike protein was undetectable by immunohistochemistry 14 days post intramuscular immunization. Intramuscular immunization resulted in transiently lower platelet (12 hours) and white blood cell (12-24 hours) counts relative to vehicle. Similarly, intravenous immunization resulted in lower platelet (24-72 hours) and white blood cell (12-24 hours) counts, and increased neutrophil (2 hours) counts. The responses observed with either route of immunization represent transient hematologic changes and correspond to expected innate immune responses to adenoviral infection.

Developmental and reproductive safety of AZD1222 (ChAdOx1 nCoV-19) in mice.

AZD1222 (ChAdOx1 nCoV-19) is a COVID-19 vaccine that is not yet licensed for use during pregnancy. To support the inclusion of pregnant and breastfeeding people in AZD1222 clinical studies, a non-clinical developmental and reproductive toxicity study was performed to evaluate its effects on fertility and reproductive processes of female CD-1 mice during the embryofetal development phase, and postnatal outcomes during the littering phase. Immunogenicity assessments were also made in dams, fetuses, and pups. There were no vaccine-related unscheduled deaths throughout the study. Furthermore, there were no vaccine-related effects on female reproduction, fetal or pup survival, fetal external, visceral, or skeletal findings, pup physical development, and no abnormal gross pathology findings in pups or dams. Antibody responses raised in dams were maintained throughout gestation and postnatal periods, and seroconversion in fetuses and pups indicate placental and lactational transfer of immunoglobulins. Together with clinical data from non-pregnant people, these results support the inclusion of pregnant and breastfeeding people in AZD1222 clinical studies.

Comparative reprotoxicity of three oximes.

One-generation reproductive toxicity studies have been conducted on the following three oximes: acetaldehyde oxime (AAO), aldecarb oxime (ADO), and methyl isobutyl ketoxime (MIBKO). The studies followed the OECD 415 guideline (One-Generation Reproduction Toxicity Study), with a few modifications. Rats were exposed to the test material for 10 weeks prior to mating and 2 weeks of mating. Males were killed following mating, and females were continuously exposed through gestation and lactation. For MIBKO, the F1 generation was exposed from weaning until approximately 7 weeks of age to include when the vaginal opening occurred in females or when balanopreputial separation occurred in males. With the exception of an increased number of stillbirths in the ADO high-dose-group animals, no adverse effects were observed in any of the reproductive or litter parameters or in the F1 pups. Toxicity to the F0 animals included signs of hemolytic anemia, along with compensatory extramedullary hematopoiesis and hemosiderosis of the spleen. This occurred for all three test materials. For AAO, the no-observed-adverse-effect level (NOAEL) for the F0 generation was considered to be less than 5 mg/kg/day, based on decreased mean corpuscular hemoglobin concentration values and histological changes in the spleen. The NOAEL for the F1 generation and reproductive toxicity was considered to be 50 mg/kg/day, the highest dose tested. For ADO, the NOAEL for parental toxicity was considered to be less than 5 mg/kg/day, based on the histological changes observed in the livers of females in all groups. The NOAEL for reproductive toxicity and the F1 generation was considered to be 25 mg/kg/day, based on the higher number of stillborn pups in the high-dose group. For MIBKO, the NOAEL for parental toxicity was considered to be 30 mg/kg/day, based on the histological effects on the spleen. The NOAEL for the F1 generation and reproductive toxicity was 100 mg/kg/day, the highest dose tested.

Relationship between childhood socioeconomic position and adverse childhood experiences (ACEs): a systematic review.

BACKGROUND: 'Adverse childhood experiences' (ACEs) are associated with increased risk of negative outcomes in later life: ACEs have consequently become a policy priority in many countries. Despite ACEs being highly socially patterned, there has been very little discussion in the political discourse regarding the role of childhood socioeconomic position (SEP) in understanding and addressing them. The aim here was to undertake a systematic review of the literature on the relationship between childhood SEP and ACEs. METHODS: MEDLINE, PsycINFO, ProQuest and Cochrane Library databases were searched. Inclusion criteria were: (1) measurement of SEP in childhood; (2) measurement of multiple ACEs; (3) ACEs were the outcome; and (4) statistical quantification of the relationship between childhood SEP and ACEs. Search terms included ACEs, SEP and synonyms; a second search additionally included 'maltreatment'. Overall study quality/risk of bias was calculated using a modified version of the Hamilton Tool. RESULTS: In the ACEs-based search, only 6 out of 2825 screened papers were eligible for qualitative synthesis. The second search (including maltreatment) increased numbers to: 4562 papers screened and 35 included for synthesis. Eighteen papers were deemed 'high' quality, five 'medium' and the rest 'low'. Meaningful statistical associations were observed between childhood SEP and ACEs/maltreatment in the vast majority of studies, including all except one of those deemed to be high quality. CONCLUSION: Lower childhood SEP is associated with a greater risk of ACEs/maltreatment. With UK child poverty levels predicted to increase markedly, any policy approach that ignores the socioeconomic context to ACEs is therefore flawed. PROSPERO REGISTRATION NUMBER: CRD42017064781.