IgD attenuates the IgM-induced anergy response in transitional and mature B cells

Self-tolerance by clonal anergy of B cells is marked by an increase in IgD and decrease in IgM antigen receptor surface expression, yet the function of IgD on anergic cells is obscure. Here we define the RNA landscape of the in vivo anergy response, comprising 220 induced sequences including a core set of 97. Failure to co-express IgD with IgM decreases overall expression of receptors for self-antigen, but paradoxically increases the core anergy response, exemplified by increased Sdc1 encoding the cell surface marker syndecan-1. IgD expressed on its own is nevertheless competent to induce calcium signalling and the core anergy mRNA response. Syndecan-1 induction correlates with reduction of surface IgM and is exaggerated without surface IgD in many transitional and mature B cells. These results show that IgD attenuates the response to self-antigen in anergic cells and promotes their accumulation. In this way, IgD minimizes tolerance-induced holes in the pre-immune antibody repertoire.This work was supported by NIH grant U19 AI100627 and NHMRC grants 585490, 1016953 and 1081858 to C.C.G., NHMRC CJ Martin Fellowship 595989 to J.H.R., an Endeavour Award from the Australian Government to Z.S. and the National Collaborative Research Infrastructure Scheme Australian Phenomics Facilit

IgD attenuates the IgM-induced anergy response in transitional and mature B cells

Self-tolerance by clonal anergy of B cells is marked by an increase in IgD and decrease in IgM antigen receptor surface expression, yet the function of IgD on anergic cells is obscure. Here we define the RNA landscape of the in vivo anergy response, comprising 220 induced sequences including a core set of 97. Failure to co-express IgD with IgM decreases overall expression of receptors for self-antigen, but paradoxically increases the core anergy response, exemplified by increased Sdc1 encoding the cell surface marker syndecan-1. IgD expressed on its own is nevertheless competent to induce calcium signalling and the core anergy mRNA response. Syndecan-1 induction correlates with reduction of surface IgM and is exaggerated without surface IgD in many transitional and mature B cells. These results show that IgD attenuates the response to self-antigen in anergic cells and promotes their accumulation. In this way, IgD minimizes tolerance-induced holes in the pre-immune antibody repertoire

Injection fears and COVID-19 vaccine hesitancy.

BACKGROUND: When vaccination depends on injection, it is plausible that the blood-injection-injury cluster of fears may contribute to hesitancy. Our primary aim was to estimate in the UK adult population the proportion of COVID-19 vaccine hesitancy explained by blood-injection-injury fears. METHODS: In total, 15 014 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, took part (19 January-5 February 2021) in a non-probability online survey. The Oxford COVID-19 Vaccine Hesitancy Scale assessed intent to be vaccinated. Two scales (Specific Phobia Scale-blood-injection-injury phobia and Medical Fear Survey-injections and blood subscale) assessed blood-injection-injury fears. Four items from these scales were used to create a factor score specifically for injection fears. RESULTS: In total, 3927 (26.2%) screened positive for blood-injection-injury phobia. Individuals screening positive (22.0%) were more likely to report COVID-19 vaccine hesitancy compared to individuals screening negative (11.5%), odds ratio = 2.18, 95% confidence interval (CI) 1.97-2.40, p < 0.001. The population attributable fraction (PAF) indicated that if blood-injection-injury phobia were absent then this may prevent 11.5% of all instances of vaccine hesitancy, AF = 0.11; 95% CI 0.09-0.14, p < 0.001. COVID-19 vaccine hesitancy was associated with higher scores on the Specific Phobia Scale, r = 0.22, p < 0.001, Medical Fear Survey, r = 0.23, p = <0.001 and injection fears, r = 0.25, p < 0.001. Injection fears were higher in youth and in Black and Asian ethnic groups, and explained a small degree of why vaccine hesitancy is higher in these groups. CONCLUSIONS: Across the adult population, blood-injection-injury fears may explain approximately 10% of cases of COVID-19 vaccine hesitancy. Addressing such fears will likely improve the effectiveness of vaccination programmes

Time intervals and routes to diagnosis for lung cancer in 10 jurisdictions: cross-sectional study findings from the International Cancer Benchmarking Partnership (ICBP)

OBJECTIVE: Differences in time intervals to diagnosis and treatment between jurisdictions may contribute to previously reported differences in stage at diagnosis and survival. The International Cancer Benchmarking Partnership Module 4 reports the first international comparison of routes to diagnosis and time intervals from symptom onset until treatment start for patients with lung cancer. DESIGN: Newly diagnosed patients with lung cancer, their primary care physicians (PCPs) and cancer treatment specialists (CTSs) were surveyed in Victoria (Australia), Manitoba and Ontario (Canada), Northern Ireland, England, Scotland and Wales (UK), Denmark, Norway and Sweden. Using Wales as the reference jurisdiction, the 50th, 75th and 90th percentiles for intervals were compared using quantile regression adjusted for age, gender and comorbidity. PARTICIPANTS: Consecutive newly diagnosed patients with lung cancer, aged ≥40 years, diagnosed between October 2012 and March 2015 were identified through cancer registries. Of 10 203 eligible symptomatic patients contacted, 2631 (27.5%) responded and 2143 (21.0%) were included in the analysis. Data were also available from 1211 (56.6%) of their PCPs and 643 (37.0%) of their CTS. PRIMARY AND SECONDARY OUTCOME MEASURES: Interval lengths (days; primary), routes to diagnosis and symptoms (secondary). RESULTS: With the exception of Denmark (-49 days), in all other jurisdictions, the median adjusted total interval from symptom onset to treatment, for respondents diagnosed in 2012-2015, was similar to that of Wales (116 days). Denmark had shorter median adjusted primary care interval (-11 days) than Wales (20 days); Sweden had shorter (-20) and Manitoba longer (+40) median adjusted diagnostic intervals compared with Wales (45 days). Denmark (-13), Manitoba (-11), England (-9) and Northern Ireland (-4) had shorter median adjusted treatment intervals than Wales (43 days). The differences were greater for the 10% of patients who waited the longest. Based on overall trends, jurisdictions could be grouped into those with trends of reduced, longer and similar intervals to Wales. The proportion of patients diagnosed following presentation to the PCP ranged from 35% to 75%. CONCLUSION: There are differences between jurisdictions in interval to treatment, which are magnified in patients with lung cancer who wait the longest. The data could help jurisdictions develop more focused lung cancer policy and targeted clinical initiatives. Future analysis will explore if these differences in intervals impact on stage or survival

COVID-19 Vaccine Hesitancy in the UK: The Oxford Coronavirus Explanations, Attitudes, and Narratives Survey (OCEANS) II

BACKGROUND: Our aim was to estimate provisional willingness to receive a coronavirus 2019 (COVID-19) vaccine, identify predictive socio-demographic factors, and, principally, determine potential causes in order to guide information provision. METHODS: A non-probability online survey was conducted (24th September-17th October 2020) with 5,114 UK adults, quota sampled to match the population for age, gender, ethnicity, income, and region. The Oxford COVID-19 vaccine hesitancy scale assessed intent to take an approved vaccine. Structural equation modelling estimated explanatory factor relationships. RESULTS: 71.7% (n=3,667) were willing to be vaccinated, 16.6% (n=849) were very unsure, and 11.7% (n=598) were strongly hesitant. An excellent model fit (RMSEA=0.05/CFI=0.97/TLI=0.97), explaining 86% of variance in hesitancy, was provided by beliefs about the collective importance, efficacy, side-effects, and speed of development of a COVID-19 vaccine. A second model, with reasonable fit (RMSEA=0.03/CFI=0.93/TLI=0.92), explaining 32% of variance, highlighted two higher-order explanatory factors: 'excessive mistrust' (r=0.51), including conspiracy beliefs, negative views of doctors, and need for chaos, and 'positive healthcare experiences' (r=-0.48), including supportive doctor interactions and good NHS care. Hesitancy was associated with younger age, female gender, lower income, and ethnicity, but socio-demographic information explained little variance (9.8%). Hesitancy was associated with lower adherence to social distancing guidelines. CONCLUSIONS: COVID-19 vaccine hesitancy is relatively evenly spread across the population. Willingness to take a vaccine is closely bound to recognition of the collective importance. Vaccine public information that highlights prosocial benefits may be especially effective. Factors such as conspiracy beliefs that foster mistrust and erode social cohesion will lower vaccine up-take

Effects of different types of written vaccination information on COVID-19 vaccine hesitancy in the UK (OCEANS-III):a single-blind, parallel-group, randomised controlled trial

BACKGROUND: The effectiveness of the COVID-19 vaccination programme depends on mass participation: the greater the number of people vaccinated, the less risk to the population. Concise, persuasive messaging is crucial, particularly given substantial levels of vaccine hesitancy in the UK. Our aim was to test which types of written information about COVID-19 vaccination, in addition to a statement of efficacy and safety, might increase vaccine acceptance. METHODS: For this single-blind, parallel-group, randomised controlled trial, we aimed to recruit 15 000 adults in the UK, who were quota sampled to be representative. Participants were randomly assigned equally across ten information conditions stratified by level of vaccine acceptance (willing, doubtful, or strongly hesitant). The control information condition comprised the safety and effectiveness statement taken from the UK National Health Service website; the remaining conditions addressed collective benefit, personal benefit, seriousness of the pandemic, and safety concerns. After online provision of vaccination information, participants completed the Oxford COVID-19 Vaccine Hesitancy Scale (outcome measure; score range 7-35) and the Oxford Vaccine Confidence and Complacency Scale (mediation measure). The primary outcome was willingness to be vaccinated. Participants were analysed in the groups they were allocated. p values were adjusted for multiple comparisons. The study was registered with ISRCTN, ISRCTN37254291. FINDINGS: From Jan 19 to Feb 5, 2021, 15 014 adults were recruited. Vaccine hesitancy had reduced from 26·9% the previous year to 16·9%, so recruitment was extended to Feb 18 to recruit 3841 additional vaccine-hesitant adults. 12 463 (66·1%) participants were classified as willing, 2932 (15·6%) as doubtful, and 3460 (18·4%) as strongly hesitant (ie, report that they will avoid being vaccinated for as long as possible or will never get vaccinated). Information conditions did not alter COVID-19 vaccine hesitancy in those willing or doubtful (adjusted p values >0·70). In those strongly hesitant, COVID-19 vaccine hesitancy was reduced, in comparison to the control condition, by personal benefit information (mean difference -1·49, 95% CI -2·16 to -0·82; adjusted p=0·0015), directly addressing safety concerns about speed of development (-0·91, -1·58 to -0·23; adjusted p=0·0261), and a combination of all information (-0·86, -1·53 to -0·18; adjusted p=0·0313). In those strongly hesitant, provision of personal benefit information reduced hesitancy to a greater extent than provision of information on the collective benefit of not personally getting ill (-0·97, 95% CI -1·64 to -0·30; adjusted p=0·0165) or the collective benefit of not transmitting the virus (-1·01, -1·68 to -0·35; adjusted p=0·0150). Ethnicity and gender were found to moderate information condition outcomes. INTERPRETATION: In the approximately 10% of the population who are strongly hesitant about COVID-19 vaccines, provision of information on personal benefit reduces hesitancy to a greater extent than information on collective benefits. Where perception of risk from vaccines is most salient, decision making becomes centred on the personal. As such, messaging that stresses the counterbalancing personal benefits is likely to prove most effective. The messaging from this study could be used in public health communications. Going forwards, the study highlights the need for future health campaigns to engage with the public on the terrain that is most salient to them. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and NIHR Oxford Health Biomedical Research Centre

Online Social Endorsement and Covid-19 Vaccine Hesitancy in the United Kingdom

Funder: University of Oxford Covid-19 Research Response Fund; Grant(s): Project Reference: 0009519 We explore the implications of online social endorsement for the Covid-19 vaccination program in the United Kingdom. Vaccine hesitancy is a long-standing problem, but it has assumed great urgency due to the pandemic. By early 2021, the United Kingdom had the world’s highest Covid-19 mortality per million of population. Our survey of a nationally representative sample of UK adults ( N = 5,114) measured socio-demographics, social and political attitudes, media diet for getting news about Covid-19, and intention to use social media and personal messaging apps to encourage or discourage vaccination against Covid-19. Cluster analysis identified six distinct media diet groups: news avoiders, mainstream/official news samplers, super seekers, omnivores, the social media dependent, and the TV dependent. We assessed whether these media diets, together with key attitudes, including Covid-19 vaccine hesitancy, conspiracy mentality, and the news-finds-me attitude (meaning giving less priority to active monitoring of news and relying more on one’s online networks of friends for information), predict the intention to encourage or discourage vaccination. Overall, super-seeker and omnivorous media diets are more likely than other media diets to be associated with the online encouragement of vaccination. Combinations of (a) news avoidance and high levels of the news-finds-me attitude and (b) social media dependence and high levels of conspiracy mentality are most likely to be associated with online discouragement of vaccination. In the direct statistical model, a TV-dependent media diet is more likely to be associated with online discouragement of vaccination, but the moderation model shows that a TV-dependent diet most strongly attenuates the relationship between vaccine hesitancy and discouraging vaccination. Our findings support public health communication based on four main methods. First, direct contact, through the post, workplace, or community structures, and through phone counseling via local health services, could reach the news avoiders. Second, TV public information advertisements should point to authoritative information sources, such as National Health Service (NHS) and other public health websites, which should then feature clear and simple ways for people to share material among their online social networks. Third, informative social media campaigns will provide super seekers with good resources to share, while also encouraging the social media dependent to browse away from social media platforms and visit reliable and authoritative online sources. Fourth, social media companies should expand and intensify their removal of vaccine disinformation and anti-vax accounts, and such efforts should be monitored by well-resourced, independent organizations. </jats:p