Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies

The area-based social patterning of injuries among 10 to 19 year olds Changes over time in the Stockholm County

<p>Abstract</p> <p>Background</p> <p>Area-based studies of childhood injuries strongly suggest that neighborhood socio-demographic and economic circumstances impact on various – though not all – types of injuries. The primary aim of this study was to investigate the stability over time of the association between area characteristics and childhood injuries of various causes.</p> <p>Methods</p> <p>Register-based and ecological, the study encompassed Stockholm County's 138 parishes, and considered two time periods (1993–95; 2003–05). Two indices were measured: economic deprivation and social fragmentation, and parishes were allocated to their respective quintile on each index. Data on both unintentional and intentional injuries for children (boys and girls) aged 10–14 and 15–19 respectively were gathered from the County Council's hospital inpatient register. For each period and index, gender, age and cause-specific comparisons were made to assess the rate ratios (with 95% confidence intervals) of being injured using parishes belonging to the best index level as a comparison group. A series of simple and partial Pearson correlations were also calculated to assess the independent contribution of each index.</p> <p>Results</p> <p>Regardless of time period, there were rather few significant rate ratios and, when they occurred, there were both under and excess risks. For instance, in each period, boys from both age groups living in parishes with the highest levels of economic deprivation had lower rate of injury as a motor vehicle rider. Most strikingly, intentional injuries were more frequent during the second time period and in considerable excess among girls aged 15–19 from more economically deprived areas. Also, during that last period, none of the injury causes correlated significantly with the index of social fragmentation after adjustment for economic deprivation (partial correlation).</p> <p>Conclusion</p> <p>Over a ten-year period, differential economic deprivation among parishes has widened more than social fragmentation in Stockholm County. The correlation between those indices is high in both periods of time whilst the association between the levels of each index and injury rates varies depending on group of injuries or time period considered. It is of concern that intentional injuries have increased numerically and are significantly and positively correlated with economic deprivation (net of social fragmentation), in particular among girls.</p

Evaluating the Effectiveness of an Autism-Specific Workplace Tool for Employers: A Randomised Controlled Trial

A randomised controlled trial evaluated the effectiveness of the Integrated Employment Success Tool (IEST™) in improving employers’ self-efficacy in modifying the workplace for individuals on the autism spectrum. Employers (N = 84) were randomised to the IEST™ or support as usual groups. Measurements of self-efficacy, knowledge and attitudes towards disability in the workplace were obtained at baseline and post-test. Results revealed a significant improvement in self-efficacy within the IEST™ group between baseline and post-test (p = 0.016). At post-test, there were no significant differences between groups in relation to self-efficacy in implementing autism-specific workplace modifications and employer attitudes towards disability in the workplace. Given the lack of significant outcomes, further research is needed to determine the effectiveness of the IEST™ for employers

Systematic review of beliefs, behaviours and influencing factors associated with disclosure of a mental health problem in the workplace

Stigma and discrimination present an important barrier to finding and keeping work for individuals with a mental health problem. This paper reviews evidence on: 1) employment-related disclosure beliefs and behaviours of people with a mental health problem; 2) factors associated with the disclosure of a mental health problem in the employment setting; 3) whether employers are less likely to hire applicants who disclose a mental health problem; and 4) factors influencing employers' hiring beliefs and behaviours towards job applicants with a mental health problem

Cytomegaloviral determinants of CD8+ T cell programming and RhCMV/SIV vaccine efficacy

Simian immunodeficiency virus (SIV) insert-expressing, 68–1 Rhesus Cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex (MHC)-E- and -II-restricted, SIV-specific CD8(+) T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) has not been characterized. We show that these unconventional responses resulted from a chance genetic rearrangement in 68–1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions (Rh157.5/Rh157.4 and Rh158–161), revealing three patterns of unconventional response inhibition. Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)-derived sequences (UL128/UL130; UL146/UL147) leads to either of two distinct CD8(+) T cell response types – MHC-Ia-restricted-only, or a mix of MHC-II- and MHC-Ia-restricted CD8(+) T cells. Response magnitude and functional differentiation are similar to RhCMV 68–1, but neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E-restricted CD8(+) T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all genes that inhibit these responses from the HCMV/HIV vector

The diffusion of a new service: Combining service consideration and brand choice

We propose an individual-level model of a two-stage service diffusion process. In the first stage, customers decide whether to "consider" joining the service. This (Consideration) stage is modeled by a hazard model. Customers who decide to consider the service move on to the Choice stage, wherein they choose among the service alternatives and an outside No Choice option. This stage is modeled by a conditional Multinomial Logit model. The service provider does not observe the transition in the first stage of potential customers who have yet to choose a brand. Such potential customers may have started to consider joining the service, yet chose the outside alternative in each period thereafter. One of the main contributions of the model is its ability to distinguish between these two non-adopter types. We estimated the model using data on the adoption process of newly introduced service plans offered by a commercial bank. We employed the hierarchical Bayes Monte Carlo Markov Chain procedure to estimate individual as well as population parameters. The empirical results indicate that the model outperforms competing models in breadth of analysis, model fit, and prediction accuracy

Ecological and genetic analysis of copper and streptomycin resistance in Pseudomonas syringae pv. syringae

Strains of Pseudomonas syringae pv. syringae resistant to copper, streptomycin, or both compounds were recovered from symptomless and diseased tissue of four woody hosts in three nurseries in Oklahoma. In strains resistant to copper and streptomycin (Cu^r Sm^r), resistance to both compounds was cotransferred with a single plasmid which was either 68, 190, or 220 kilobase pairs (kb). All Cu^s Sm^r strains contained a 68-kb conjugative plasmid. Cu^r Sm^s, strains contained one plasmid which varied in size from 60 to 73 kb. All conjugative plasmids which transferred streptomycin resistance contained sequences homologous to the strA and strB Sm^r genes from the broad-host-range plasmid RSF1010. The Sm^r determinant was subsequently cloned from a 68-kb Cu^r Sm^r plasmid designated pPSR1. A restriction map detailing the organization of the homologous Sm^r genes from pPSR1 and RSF1010 and cloned Sm^r genes from P. syringae pv. papulans and Xanthomonas campestris pv. vesicatoria revealed the conservation of all sites studied. The Cu^r genes cloned from P. syringae pv. tomato PT23 and X. campestris pv. vesicatoria XV10 did not hybridize to the Cu^r plasmids identified in the present study, indicating that copper resistance in these P. syringae pv. syringae strains may be conferred by a distinct genetic determinant.Peer reviewedPlant Patholog

Public Preferences for Forest Ecosystem Management in Japan with Emphasis on Species Diversity

We carried out online choice experiments (CE) to investigate what value Japanese individuals assign to rare versus familiar species in forest ecosystem, and to determine how preference heterogeneity arises. CE attributes comprised a forestry charge as the price attribute and rare versus familiar species of animals or plants as the good to be valued. Species numbers in a 5 km-mesh forest area were evaluated without the use of species names to focus purely on responses to numerical changes. Positional effects were also tested to validate results regarding alternatives and attributes other than the price attribute. A random parameter logit model was adopted to capture preferences for species diversity. After confirming that no positional effects existed, we found that (1) rare animals were valued more highly than rare plants, (2) familiar plants were assigned a positive value, but familiar animals were not assigned significant value at the mean parameter estimate, and (3) preference heterogeneities existed for all species. The sources of preference heterogeneity were analyzed with a latent class model having principal components of environmental attitudes. The influence of such attitudes was shown to be significant and suggested that attention should be paid to belief systems rather than solely demographics

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