Ethnic differences in SARS-CoV-2 vaccine hesitancy in United Kingdom healthcare workers: Results from the UK-REACH prospective nationwide cohort study

BackgroundIn most countries, healthcare workers (HCWs) represent a priority group for vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to their elevated risk of COVID-19 and potential contribution to nosocomial SARS-CoV-2 transmission. Concerns have been raised that HCWs from ethnic minority groups are more likely to be vaccine hesitant (defined by the World Health Organisation as refusing or delaying a vaccination) than those of White ethnicity, but there are limited data on SARS-CoV-2 vaccine hesitancy and its predictors in UK HCWs. MethodsNationwide prospective cohort study and qualitative study in a multi-ethnic cohort of clinical and non-clinical UK HCWs. We analysed ethnic differences in SARS-CoV-2 vaccine hesitancy adjusting for demographics, vaccine trust, and perceived risk of COVID-19. We explored reasons for hesitancy in qualitative data using a framework analysis. Findings11,584 HCWs were included in the cohort analysis. 23% (2704) reported vaccine hesitancy. Compared to White British HCWs (21.3% hesitant), HCWs from Black Caribbean (54.2%), Mixed White and Black Caribbean (38.1%), Black African (34.4%), Chinese (33.1%), Pakistani (30.4%), and White Other (28.7%) ethnic groups were significantly more likely to be hesitant. In adjusted analysis, Black Caribbean (aOR 3.37, 95% CI 2.11 - 5.37), Black African (aOR 2.05, 95% CI 1.49 - 2.82), White Other ethnic groups (aOR 1.48, 95% CI 1.19 - 1.84) were significantly more likely to be hesitant. Other independent predictors of hesitancy were younger age, female sex, higher score on a COVID-19 conspiracy beliefs scale, lower trust in employer, lack of influenza vaccine uptake in the previous season, previous COVID-19, and pregnancy. Qualitative data from 99 participants identified the following contributors to hesitancy: lack of trust in government and employers, safety concerns due to the speed of vaccine development, lack of ethnic diversity in vaccine studies, and confusing and conflicting information. Participants felt uptake in ethnic minority communities might be improved through inclusive communication, involving HCWs in the vaccine rollout, and promoting vaccination through trusted networks. InterpretationDespite increased risk of COVID-19, HCWs from some ethnic minority groups are more likely to be vaccine hesitant than their White British colleagues. Strategies to build trust and dispel myths surrounding the COVID-19 vaccine in these communities are urgently required. Public health communications should be inclusive, non-stigmatising and utilise trusted networks. FundingMRC-UK Research and Innovation (MR/V027549/1), the Department of Health and Social Care through the National Institute for Health Research (NIHR), and NIHR Biomedical Research Centres and NIHR Applied Research Collaboration East Midlands. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched Pubmed using the following search terms ((COVID-19).ti,ab OR (SARS-CoV-2).ti,ab) AND ((vaccine).ti,ab OR (vaccination).ti,ab OR (immunisation).ti,ab)) AND ((healthcare worker).ti,ab OR (health worker).ti,ab OR (doctor).ti,ab OR (nurse).ti,ab OR (healthcare professional).ti,ab)) AND ((hesitancy).ti,ab OR (refusal).ti,ab OR (uptake).ti,ab)). The search returned 60 results, of which 38 were excluded after title and abstract screening, 11 studies were not conducted in a population of healthcare workers, 20 did not present data on vaccine intention or uptake, 5 were related to vaccines other than the SARS-CoV-2 vaccine, 1 was unrelated to vaccination and 1 had been withdrawn. The 22 remaining articles were survey studies focussed on SARS-CoV-2 vaccine intention in healthcare workers. Estimates of SARS-CoV-2 vaccine acceptance varied widely from 27{middle dot}7% - 94{middle dot}5% depending on the country in which the study was performed, and the occupational group studied. Only 2 studies (both conducted in the USA) had a sample size greater than 10,000. Most studies found females, non-medical healthcare staff and those refusing influenza vaccine to be more likely to be hesitant. There was conflicting evidence about the effects of age and previous COVID-19 on hesitancy. Only 3 studies (all from the USA), presented data disaggregated by ethnicity, all finding Black ethnic HCWs were most likely to be hesitant. Common themes amongst studies that investigated reasons for vaccine hesitancy were concerns about safety of vaccines, fear of side effects and short development timeframes. We did not find any studies on SARS-CoV-2 vaccine hesitancy in UK healthcare workers in the published literature. Added value of this studyThis study is amongst the largest SARS-CoV-2 vaccine hesitancy studies in the literature. It is the largest study outside the USA and is the only study in UK HCWs. Our work focusses on the association of ethnicity with vaccine hesitancy, and we are the first study outside the USA to present results by ethnic group. The large number of ethnic minority HCWs in our study allows for examination of the outcome by more granular ethnicity categories than have previously been studied, allowing us to detect important differences in vaccine hesitancy levels within the broad White and Asian ethnic groupings. Our large sample size and the richness of our cohort study dataset allows us to control for many potential confounders in our multivariable analysis, and provide novel data on important potential drivers of hesitancy including discrimination, COVID-19 conspiracy beliefs, religion/religiosity and personality traits. Additionally, we combine quantitative with qualitative data providing a deeper understanding of the drivers of hesitancy and potential strategies to improve vaccine uptake in HCWs from ethnic minority communities. Implications of all the available evidenceAround a quarter of UK healthcare workers reported SARS-CoV-2 vaccine hesitancy. In accordance with previous studies in other countries, we determined that female sex and lack of influenza vaccine in the previous season were important predictors of SARS-CoV-2 vaccine hesitancy in UK HCWs, although in contrast to most studies in the published literature, after adjustment we do not demonstrate differences in hesitancy levels by occupational role. Importantly, previous literature provides conflicting evidence of the effects of age and previous SARS-CoV-2 infection on vaccine hesitancy. In our study, younger HCWs and those with evidence of previous COVID-19 were more likely to be hesitant. This study provides novel data on increased hesitancy levels within Black Caribbean, Mixed White and Black Caribbean, Black African, Chinese, Pakistani and White Other ethnic groups. Mistrust (of vaccines in general, in SARS-CoV-2 vaccines specifically, in healthcare systems and research) and misinformation appear to be important drivers of hesitancy within HCWS in the UK. Our data indicate that despite facing an increased risk of COVID-19 compared to their White colleagues, UK HCWs from some ethnic minority groups continue to exhibit greater levels of SARS-CoV-2 vaccine hesitancy. This study provides policy makers with evidence to inform strategies to improve uptake.

Design of an encodable tyrosine kinase-inducible domain: detection of tyrosine kinase activity by terbium luminescence.

Tyrosine kinases are critical mediators of intracellular signaling and of intracellular responses to extracellular signaling. Changes in tyrosine kinase activity are implicated in numerous human diseases, including cancers, diabetes, and pathogen infectivity. To address questions in tyrosine phosphorylation, we have designed a protein tyrosine kinase-inducible domain, a small, genetically encodable protein motif whose structure is dependent on its tyrosine phosphorylation state. Tyrosine kinase-inducible domain peptides are based on EF-hand loops in which a structurally critical Glu12 residue is replaced by tyrosine at residue 11 or at residue 15 of the protein. Tyrosine kinase-inducible domain peptides bind terbium(III) in a phosphorylation-dependent manner, showing strong terbium luminescence when phosphorylated but weak terbium luminescence when not phosphorylated. Lanthanide binding was confirmed by NMR. A tyrosine kinase-inducible domain peptide, pKID-Abl, was designed to incorporate a recognition sequence of the Abl kinase. Incubation of pKID-Abl with Abl kinase resulted in a large increase in terbium luminescence. This increase in luminescence was abolished when pKID-Abl and Abl kinase were incubated with the Abl kinase inhibitor Gleevec. In addition, incubation of phosphorylated pKID-Abl with the tyrosine phosphatase YOP resulted in a large reduction in terbium luminescence. pKID-Abl was employed as a fluorescent sensor of Abl tyrosine kinase activity in HeLa cell extracts, exhibiting low luminescence with extracts from serum-starved cells and increased luminescence using extracts from EGF-treated cells. These results indicate that tyrosine kinase-inducible domains may be used as sensors of tyrosine kinase and tyrosine phosphatase activity and in the detection of tyrosine kinase inhibitors.

Determinants of specificity of MDM2 for the activation domains of p53 and p65: proline27 disrupts the MDM2-binding motif of p53.

Transcriptional activation and repression via the transcription factors p53 and p65 are mediated by hydrophobic short linear motifs (FXX phi phi) in their activation domains (ADs). To understand the molecular basis for specificity in binding to disparate biological targets, a series of chimeric peptides was synthesized, with sequences derived from the ADs of p53, which binds both the general transcriptional machinery and the repressor protein MDM2, and p65, which is reported to bind the general transcriptional machinery but not MDM2. The FXX phi phi motifs of p53 and p65 differ by only two residues, whereas the flanking sequences have no sequence identity. The affinities of the chimeric peptides to MDM2(25-117) and hTAF(II)31(1-140) were determined. Specificity for binding MDM2 via FXX phi phi motifs derives almost entirely from Trp23 of p53, with a 3.0 kcal mol(-1) loss of binding energy when Trp23 is changed to p65-derived Leu. The identity of the N-terminal flanking sequence did not significantly affect binding to MDM2. In contrast, replacement of the C-terminal sequence of p53 with that of p65 increased the affinity of the chimera for MDM2 by 1.1 kcal mol(-1), contrary to expectations. Replacement of the highly conserved residue Pro27 of p53 with Ser from p65 resulted in a 2.3 kcal mol(-1) improvement in binding to MDM2, generating a ligand (p53-P27S) (Kd = 4.7 nM) that exhibits the highest MDM2 affinity observed for a genetically encodable ligand. The basis for the increased affinity of p53-P27S over p53 was examined by circular dichroism and nuclear magnetic resonance. Pro27 disrupts the recognition alpha-helix of p53, with p53-P27S significantly more alpha-helical than p53.

Differential effect of the GPIIb/IIIa antagonist orbofiban on human platelet aggregate formation in vitro.

Platelet microaggregates have been demonstrated in the systemic circulation of patients with atherosclerotic cardiovascular diseases. Glycoprotein IIb/IIIa antagonists have been reported to play roles in platelet activation, which may be associated with pro-thrombotic events. We report the effect of the orally active GPIIb/IIIa antagonist, orbofiban, on human platelet microaggregate formation in vitro. Laser light scatter (LSS) technology was used to monitor small, medium and large platelet aggregates formed in platelet-rich plasma in response to ADP or thrombin receptor activating peptide (TRAP)-6. ADP at 0.5 microM induced only small platelet aggregates that were prevented by orbofiban in a concentration-dependent manner. Likewise, orbofiban dissolved small aggregates after their formation. In marked contrast, in the presence of strong agonist stimulation (20 microM ADP or 3 microM TRAP-6) which generated primarily large platelet aggregates, orbofiban blocked the large aggregates while significantly augmenting small aggregates by three- to sixfold. The data suggest that GPIIb/IIIa antagonists do not induce platelet microaggregation directly but may augment small platelet microaggregate formation indirectly at conditions of strong stimuli. The percentage of the microaggregate population expressing P-selectin remained the same in the presence of orbofiban, indicating that these small microaggregates remain activated, although the mean intensity of expression was diminished, possibly reflecting the reduced size of the particles or density of P-selectin molecules. In summary, an increase in small platelet microaggregates might have contributed to pro-thrombotic events in orbofiban-treated patients.