Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine.

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.

Immunogenicity of COVID-19 vaccines in patients with follicular lymphoma receiving frontline chemoimmunotherapy.

Immune responses to primary COVID-19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016-004010-10). COVID-19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4+ T cells) or cyclophosphamide-based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS-CoV-2 spike protein using the Abbott Architect and interferon-gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T-cell responses. Within the FL cohort, multivariable analysis identified low pre-treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T-cell responses, and bendamustine and high/intermediate FLIPI-2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID-19 vaccines in FL patients is influenced by multiple disease- and treatment-related factors, among which B-cell depletion showed differential effects on antibody and T-cell responses.

Evaluation of QuantiFERON SARS-CoV-2 interferon-γ release assay following SARS-CoV-2 infection and vaccination.

T cells are important in preventing severe disease from SARS-CoV-2, but scalable and field-adaptable alternatives to expert T-cell assays are needed. The interferon-gamma release assay QuantiFERON platform was developed to detect T-cell responses to SARS-CoV-2 from whole blood with relatively basic equipment and flexibility of processing timelines. Forty-eight participants with different infection and vaccination backgrounds were recruited. Whole blood samples were analysed using the QuantiFERON SARS-CoV-2 assay in parallel with the well-established 'Protective Immunity from T Cells in Healthcare workers' (PITCH) ELISpot, which can evaluate spike-specific T-cell responses. The primary aims of this cross-sectional observational cohort study were to establish if the QuantiFERON SARS-Co-V-2 assay could discern differences between specified groups and to assess the sensitivity of the assay compared with the PITCH ELISpot. The QuantiFERON SARS-CoV-2 distinguished acutely infected individuals (12-21 days post positive PCR) from naïve individuals (P < 0.0001) with 100% sensitivity and specificity for SARS-CoV-2 T cells, whilst the PITCH ELISpot had reduced sensitivity (62.5%) for the acute infection group. Sensitivity with QuantiFERON for previous infection was 12.5% (172-444 days post positive test) and was inferior to the PITCH ELISpot (75%). Although the QuantiFERON assay could discern differences between unvaccinated and vaccinated individuals (55-166 days since second vaccination), the latter also had reduced sensitivity (44.4%) compared to the PITCH ELISpot (66.6%). The QuantiFERON SARS-CoV-2 assay showed potential as a T- cell evaluation tool soon after SARS-CoV-2 infection but has lower sensitivity for use in reliable evaluation of vaccination or more distant infection.

Impaired humoral and cellular response to primary COVID-19 vaccination in patients less than 2 years after allogeneic bone marrow transplant.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.

Comparison of two T-cell assays to evaluate T-cell responses to SARS-CoV-2 following vaccination in naïve and convalescent healthcare workers.

T-cell responses to SARS-CoV-2 following infection and vaccination are less characterized than antibody responses, due to a more complex experimental pathway. We measured T-cell responses in 108 healthcare workers (HCWs) using the commercialized Oxford Immunotec T-SPOT Discovery SARS-CoV-2 assay service (OI T-SPOT) and the PITCH ELISpot protocol established for academic research settings. Both assays detected T-cell responses to SARS-CoV-2 spike, membrane, and nucleocapsid proteins. Responses were significantly lower when reported by OI T-SPOT than by PITCH ELISpot. Four weeks after two doses of either Pfizer/BioNTech BNT162b or ChAdOx1 nCoV-19 AZD1222 vaccine, the responder rate was 63% for OI T-SPOT Panels 1 + 2 (peptides representing SARS-CoV-2 spike protein excluding regions present in seasonal coronaviruses), 69% for OI T-SPOT Panel 14 (peptides representing the entire SARS-CoV-2 spike), and 94% for the PITCH ELISpot total spike. The two OI T-SPOT panels correlated strongly with each other showing that either readout quantifies spike-specific T-cell responses, although the correlation between the OI T-SPOT panels and the PITCH ELISpot total spike was moderate. The standardization, relative scalability, and longer interval between blood acquisition and processing are advantages of the commercial OI T-SPOT assay. However, the OI T-SPOT assay measures T-cell responses at a significantly lower magnitude compared to the PITCH ELISpot assay, detecting T-cell responses in a lower proportion of vaccinees. This has implications for the reporting of low-level T-cell responses that may be observed in patient populations and for the assessment of T-cell durability after vaccination.

Risk factors associated with heel pressure ulcer development in adult population: A systematic literature review.

AIMS: The main aim of this systematic literature review was to identify risk factors for development of heel pressure ulcers and quantify their effect. BACKGROUND: Pressure ulcers remain one of the key patient safety challenges across all health care settings and heels are the second most common site for developing pressure ulcers after the sacrum. DESIGN: Quantitative systematic review. METHODS: Data sources: Electronic databases were searched for studies published between 1809 to March 2020 using keywords, Medical Subject Headings, and other index terms, as well as combinations of these terms and appropriate synonyms. STUDY ELIGIBILITY CRITERIA: Previous systematic literature reviews, cohort, case control and cross-sectional studies investigating risk factors for developing heel pressure ulcers. Only articles published in English were reviewed with no restrictions on date of publication. PARTICIPANTS: patients aged 18 years and above in any care setting. Study selection, data extraction, risk of bias and quality assessment were completed by two independent reviewers. Disagreements were resolved by discussion. RESULTS: Thirteen studies met the eligibility criteria and several potential risk factors were identified. However, eligible studies were mainly moderate to low quality except for three high quality studies. CONCLUSIONS: There is a paucity of high quality evidence to identify risk factors associated with heel pressure ulcer development. Immobility, diabetes, vascular disease, impaired nutrition, perfusion issues, mechanical ventilation, surgery, and Braden subscales were identified as potential risk factors for developing heel pressure ulcers however, further well-designed studies are required to elucidate these factors. Other risk factors may also exist and require further investigation. PROSPERO ID: PROSPERO International prospective register of systematic reviews: CRD42017071459.

UK multisite evaluation of the impact of clinical educators in EDs from a learner's perspective.

BACKGROUND: In England, demand for emergency care is increasing while there is also a staffing shortage. The Royal College of Emergency Medicine (RCEM) suggested that appointment of senior doctors as clinical educators (CEs) would enable support and development of learners in EDs and improve retention and well-being. This study aimed to evaluate the impact of CEs in ED on learners. METHODS: CEs were placed in 54 NHS Acute Trust EDs for a pilot beginning July 2018 and ending October 2020. Learners from multiple disciplines working at 54 NHS Acute Trust EDs where CEs were deployed were invited to complete an online survey designed to identify the impact of CEs in July of 2019, as part of an interim service evaluation. RESULTS: Respondents numbered 493 from 49 of 54 study sites, including 286 (58%) medical (non-consultant) and 72 (14.6%) all other nursing, allied health professionals. 9 out of 10 learners reported having experienced a change to their learning as a result of the deployment of CEs in their department. 49.9% (246/493) reported that CEs had a positive impact on their well-being. 95% (340/358) reported an improved accessibility to undertaking clinical based assessments. 78% (281/358) perceived that access to CEs increased likelihood of passing assessments. Of those responding, 80.9% (399/493) reported they would remain/return to the same ED with a CE, and 92.5% (456/493) responded that they would prefer to go to a Trust with a CE. CONCLUSIONS: According to survey respondents, deployment of CEs across NHS Trusts has resulted in improvement and increased accessibility of learning and assessment opportunities for learners within ED. The impact of CEs on well-being is uncertain with half reporting improvement and the remaining half unsure. Further evaluation within the project will continue to explore the service benefit and workforce impact of the CEED intervention.

Understanding the distribution of A&E attendances and hospital admissions for the case managed population: A single case cross sectional study.

AIM: To describe the characteristics of case-managed patients presenting at accident and emergency (A & E) and to explore the distribution of their attendances and admissions. BACKGROUND: Recently, the UK Government announced extended-hours primary care provision in an effort to reduce the growing utilization of A & E. No evidence is available to understand the use of acute services by this high-risk patient group. METHOD: A cross-sectional design utilising routinely collected anonymsed A & E attendance and hospital admission data from 2010 to 2015. RESULTS: The case-managed population is typically 70years and older and most often arrive at A & E via emergency services and during the night (00:00-08:59). A large proportion are subsequently admitted having a statistically significant A & E conversion rate. No variables were predictive of admission. CONCLUSION: The high level of A&E conversion could indicate case-managed patients are presenting appropriately with acute clinical need. However, inadequate provision in primary-care could drive decisions for admitting vulnerable patients.

Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens.

BACKGROUND: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. METHODS: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. FINDINGS: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. CONCLUSIONS: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease. FUNDING: Department for Health and Social Care, Medical Research Council.