Effectiveness of successive booster vaccine doses against SARS-CoV-2 related mortality in residents of long-term care facilities in the VIVALDI study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused severe disease in unvaccinated long-term care facility (LTCF) residents. Initial booster vaccination following primary vaccination is known to provide strong short-term protection, but data are limited on duration of protection and the protective effect of further booster vaccinations. OBJECTIVE: To evaluate the effectiveness of third, fourth and fifth dose booster vaccination against SARS-CoV-2 related mortality amongst older residents of LTCFs. DESIGN: Prospective cohort study. SETTING: LTCFs for older people in England participating in the VIVALDI study. METHODS: Residents aged >65 years at participating LTCFs were eligible for inclusion if they had at least one polymerase chain reaction or lateral flow device result within the analysis period 1 January 2022 to 31 December 2022. We excluded individuals who had not received at least two vaccine doses before the analysis period. Cox regression was used to estimate relative hazards of SARS-CoV-2 related mortality following 1-3 booster vaccinations compared with primary vaccination, stratified by previous SARS-CoV-2 infection and adjusting for age, sex and LTCF size (total beds). RESULTS: A total of 13,407 residents were included. Our results indicate that third, fourth and fifth dose booster vaccination provide additional short-term protection against SARS-CoV-2 related mortality relative to primary vaccination, with consistent stabilisation beyond 112 days to 45-75% reduction in risk relative to primary vaccination. CONCLUSIONS: Successive booster vaccination doses provide additional short-term protection against SARS-CoV-2 related mortality amongst older LTCF residents. However, we did not find evidence of a longer-term reduction in risk beyond that provided by initial booster vaccination.

Severe Acute Respiratory Syndrome Coronavirus 2 Anti-Spike Antibody Levels Following Second Dose of ChAdOx1 nCov-19 or BNT162b2 Vaccine in Residents of Long-term Care Facilities in England (VIVALDI).

General population studies have shown strong humoral response following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination with subsequent waning of anti-spike antibody levels. Vaccine-induced immune responses are often attenuated in frail and older populations, but published data are scarce. We measured SARS-CoV-2 anti-spike antibody levels in long-term care facility residents and staff following a second vaccination dose with Oxford-AstraZeneca or Pfizer-BioNTech. Vaccination elicited robust antibody responses in older residents, suggesting comparable levels of vaccine-induced immunity to that in the general population. Antibody levels are higher after Pfizer-BioNTech vaccination but fall more rapidly compared to Oxford-AstraZeneca recipients and are enhanced by prior infection in both groups.

Changes in COVID-19 outbreak severity and duration in long-term care facilities following vaccine introduction, England, November 2020 to June 2021.

We describe the impact of changing epidemiology and vaccine introduction on characteristics of COVID-19 outbreaks in 330 long-term care facilities (LTCF) in England between November 2020 and June 2021. As vaccine coverage in LTCF increased and national incidence declined, the total number of outbreaks and outbreak severity decreased across the LTCF. The number of infected cases per outbreak decreased by 80.6%, while the proportion of outbreaks affecting staff only increased. Our study supports findings of vaccine effectiveness in LTCF.

Necrotizing pneumonia (aetiology, clinical features and management).

PURPOSE OF REVIEW: Necrotizing pneumonia is a severe form of community-acquired pneumonia characterized by rapid progression of consolidation to necrosis and cavitation which may lead to pulmonary gangrene. Morbidity and mortality are high and chronic sequelae are frequent. The lack of guidance supports the review of the latest recommendations in the management of these pneumonias. RECENT FINDINGS: Antibiotic therapy alone may not be enough to alter the course of the infection, and regimens, adjunctive therapies like intravenous immunoglobulins, surgery may be required to alter the course of the disease especially with pulmonary gangrene. SUMMARY: The causative agents, clinical features and management of necrotizing pneumonias are discussed.

When the heart rules the head: ischaemic stroke and intracerebral haemorrhage complicating infective endocarditis.

Sir William Osler meticulously described the clinical manifestations of infective endocarditis in 1885, concluding that: 'few diseases present greater difficulties in the way of diagnosis … which in many cases are practically insurmountable'. Even with modern investigation techniques, diagnosing infective endocarditis can be hugely challenging, yet is critically important in patients presenting with stroke (both cerebral infarction and intracranial haemorrhage), its commonest neurological complication. In ischaemic stroke, intravenous thrombolysis carries an unacceptably high risk of intracranial haemorrhage, while in intracerebral haemorrhage, mycotic aneurysms require urgent treatment to avoid rebleeding, and in all cases, prompt treatment with antibiotics and valve surgery may be life-saving. Here, we describe typical presentations of ischaemic stroke and intracerebral haemorrhage caused by infective endocarditis. We review the diagnostic challenges, the importance of rapid diagnosis, treatment options and controversies.

Built Environment and SARS-CoV-2 Transmission in Long-Term Care Facilities: Cross-Sectional Survey and Data Linkage.

OBJECTIVES: To describe the built environment in long-term care facilities (LTCF) and its association with introduction and transmission of SARS-CoV-2 infection. DESIGN: Cross-sectional survey with linkage to routine surveillance data. SETTING AND PARTICIPANTS: LTCFs in England caring for adults ≥65 years old, participating in the VIVALDI study (ISRCTN14447421) were eligible. Data were included from residents and staff. METHODS: Cross-sectional survey of the LTCF built environment with linkage to routinely collected asymptomatic and symptomatic SARS-CoV-2 testing and vaccination data between September 1, 2020, and March 31, 2022. We used individual and LTCF level Poisson and Negative Binomial regression models to identify risk factors for 4 outcomes: incidence rate of resident infections and outbreaks, outbreak size, and duration. We considered interactions with variant transmissibility (pre vs post Omicron dominance). RESULTS: A total of 134 of 151 (88.7%) LTCFs participated in the survey, contributing data for 13,010 residents and 17,766 staff. After adjustment and stratification, outbreak incidence (measuring infection introduction) was only associated with SARS-CoV-2 incidence in the community [incidence rate ratio (IRR) for high vs low incidence, 2.84; 95% CI, 1.85-4.36]. Characteristics of the built environment were associated with transmission outcomes and differed by variant transmissibility. For resident infection incidence, factors included number of storeys (0.64; 0.43-0.97) and bedrooms (1.04; 1.02-1.06), and purpose-built vs converted buildings (1.99; 1.08-3.69). Air quality was associated with outbreak size (dry vs just right 1.46; 1.00-2.13). Funding model (0.99; 0.99-1.00), crowding (0.98; 0.96-0.99), and bedroom temperature (1.15; 1.01-1.32) were associated with outbreak duration. CONCLUSIONS AND IMPLICATIONS: We describe previously undocumented diversity in LTCF built environments. LTCFs have limited opportunities to prevent SARS-CoV-2 introduction, which was only driven by community incidence. However, adjusting the built environment, for example by isolating infected residents or improving airflow, may reduce transmission, although data quality was limited by subjectivity. Identifying LTCF built environment modifications that prevent infection transmission should be a research priority.

Anti-nucleocapsid antibody levels following initial and repeat SARS-CoV-2 infections in a cohort of long-term care facility residents in England (VIVALDI).

Background: We have previously demonstrated that older residents of long-term care facilities (LTCF) in the UK show levels of anti-spike antibodies that are comparable to the general population following primary series and booster vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, data on the humoral response to other SARS-CoV-2 proteins associated with natural infection are scarce in this vulnerable population. Methods: We measured quantitative levels of anti-nucleocapsid antibodies in blood samples taken from LTCF residents and staff after initial and repeat SARS-CoV-2 infections, between December 2020 and March 2023. Data on SARS-CoV-2 infection and vaccination were obtained through linkage to national datasets. Linear mixed effects models were used to investigate anti-nucleocapsid antibody levels, using log10 scale, in relation to time from most recent infection. This included evaluation of associations between repeat infection, staff/resident status, age, sex, Omicron infection and vaccination history and peak antibody level and slope of decline with time. Results: We analysed 405 antibody observations from 220 residents and 396 observations from 215 staff. Repeat infection was associated with 8.5-fold (95%CI 4.9-14.8-fold) higher initial (peak) median anti-nucleocapsid antibody level, with steeper subsequent slope of decline. There were no significant differences in antibody level associated with resident (vs. staff) status or age, but Omicron infection was associated with 3.6-fold (95%CI 2.4-5.4-fold) higher levels. There was stronger evidence of waning of antibody levels over time in a sensitivity analysis in which observations were censored in cases with suspected undetected repeat infection. Conclusions: We found similar levels of anti-nucleocapsid antibody in residents and staff of LTCFs. Repeat infection and infection with an Omicron strain were associated with higher peak values. There was evidence of waning of anti-nucleocapsid antibody levels over time.

COVID-19 had a severe impact on care homes in the UK early in the pandemic. However, deaths and disease caused by the SARS-CoV-2 virus have decreased over time following successful introduction of vaccinations and resistance linked to prior infection. There has been a lot of research carried out on the body's immune response to the viral spike protein, which was used to create vaccines against the virus. Less is known about our immune response to other proteins produced by the virus, such as nucleocapsid, which have not been used in current vaccines. We evaluated antibody levels against the viral nucleocapsid protein in older care home residents following initial and repeat SARS-CoV-2 infection and compared these values to those observed in younger care home staff. This was done through a large established cohort study, in which residents and staff of participating homes could volunteer to provide blood samples for analysis. We found similar levels of antibody levels among staff and older residents of care homes. These findings are in line with previous studies, in which we have shown that care home residents who survive SARS-CoV-2 infection can develop robust immunity. Higher peak antibody levels were observed following repeat infection in both residents and staff.

VIVALDI ASCOT and Ethnography Study: protocol for a mixed-methods longitudinal study to evaluate the impact of COVID-19 and other respiratory infection outbreaks on care home residents' quality of life and psychosocial well-being.

INTRODUCTION: Older adults in care homes experienced some of the highest rates of mortality from SARS-CoV-2 globally and were subjected to strict and lengthy non-pharmaceutical interventions, which severely impacted their daily lives. The VIVALDI ASCOT and Ethnography Study aims to assess the impact of respiratory outbreaks on care home residents' quality of life, psychological well-being, loneliness, functional ability and use of space. This study is linked to the VIVALDI-CT, a randomised controlled trial of staff's asymptomatic testing and sickness payment support in care homes (ISRCTN13296529). METHODS AND ANALYSIS: This is a mixed-methods, longitudinal study of care home residents (65+) in Southeast England. Group 1-exposed includes residents from care homes with a recent COVID-19 or other respiratory infection outbreak. Group 2-non-exposed includes residents from care homes without a recent outbreak. The study has two components: (a) a mixed-methods longitudinal face-to-face interviews with 100 residents (n=50 from group 1 and n=50 from group 2) to assess the impact of outbreaks on residents' quality of life, psychological well-being, loneliness, functional ability and use of space at time 1 (study baseline) and time 2 (at 3-4 weeks after the first visit); (b) ethnographic observations in communal spaces of up to 10 care homes to understand how outbreaks and related restrictions to the use of space and social activities impact residents' well-being. The study will interview only care home residents who have the mental capacity to consent. Data will be compared and integrated to gain a more comprehensive understanding of the impact of outbreaks on residents' quality of life and well-being. ETHICS AND DISSEMINATION: The VIVALDI ASCOT and Ethnography Study obtained ethical approval from the Health Research Authority (HRA) Social Care REC (24/IEC08/0001). Only residents with the capacity to consent will be included in the study. Findings will be published in scientific journals.

Protocol for VIVALDI social care: Pilot study to reduce infections, outbreaks and antimicrobial resistance in care homes for older adults.

Care home residents are vulnerable to severe outcomes from infections such as COVID-19 and influenza. However, measures to control outbreaks, such as care home closures to visitors and new admissions, have a detrimental impact on their quality of life. Many infections and outbreaks could be prevented but the first step is to measure them reliably. This is challenging in care homes due to the lack of data and research infrastructure. During the pandemic, the VIVALDI study measured COVID-19 infections in residents and staff by partnering with care providers and using routinely collected data. This study aims to establish sentinel surveillance and a research database to enable observational and future interventional studies in care homes. The project has been co-produced with care providers, staff, residents, relatives, and researchers. The study (October 2023 to March 2025) will explore the feasibility of establishing a network of 500-1500 care homes for older adults in England that is underpinned by a linked data platform. No data will be collected from staff. The cohort will be created by regularly extracting resident identifiers from Digital Social Care Records (DSCR), followed by pseudonymisation and linkage to routinely collected datasets. Following extensive consultation, we decided not to seek informed consent from residents for data collection, but they can 'opt out' of the study. Our goal is to be inclusive, and it is challenging to give every resident the opportunity to 'opt in' due to cognitive impairment and the requirement for consultees. The project, and all requests to use the data will be overseen by relatives, residents, staff, and care providers. The study has been approved by the Health Research Authority Confidentiality Advisory Group (23/CAG/0134&0135) and the South-West Frenchay Research Ethics Committee (23/SW/0105). It is funded by the UK Health Security Agency.

Infections like flu or COVID-19 are common in care homes and infected residents can become seriously unwell. When infections spread, the measures that are often used to stop outbreaks, like care home closures to visitors and new admissions, can have a detrimental impact on residents. The first step to solving this problem is being able to measure how often infections and outbreaks happen, and how this varies across care homes. This is currently difficult because there are no systems to collect data from care home residents. During the COVID-19 pandemic, care homes worked with researchers and Government to deliver a research study called VIVALDI which measured COVID-19 infections in residents and staff and monitored what happened to them. This pilot study builds on what we learned in the pandemic and aims to reduce the impact of common infections on residents. We will set up a network of 500-1500 care homes for older adults in England that are interested in research. By collecting limited data (NHS numbers) from residents in these homes and linking to other datasets already held in the secure NHS environment, we can measure the extent of infections in residents. We are not collecting data from staff, and any residents in the datasets cannot be identified. We will also create an anonymous database (names, dates of birth, NHS numbers removed), which researchers can use to find new ways to prevent infection in care homes. This will be stored securely by the research team. If the project is successful, and residents and relatives support it, we hope this approach can be used permanently to monitor infections in care homes. The study has been designed in partnership with care providers, experienced care staff, policymakers, academics, and residents and their relatives, who will also oversee the study and all research outputs.

The Development and Evaluation of a Combined Infection-Rheumatology Assessment Service in Response to the Chikungunya Fever Epidemic.

The chikungunya virus is an arthritogenic alphavirus. Acute infection may be followed by persistent arthralgia, often causing significant functional impairment. The 2014-2015 chikungunya fever (CHIKF) epidemic resulted in a marked increase in cases presenting to rheumatology and tropical diseases services. A combined multidisciplinary rheumatology-tropical diseases service for assessment, management, and follow-up of patients with proven CHIKF and persistent (≥ 4 weeks) arthralgia was proposed and rapidly developed at The Hospital for Tropical Diseases in London. Rapid set up of a multidisciplinary clinic in response to the epidemic was achieved. Of a total of 54 patients, 21 (38.9%) patients with CHIKF developed persistent arthralgia and were reviewed by the multidisciplinary service. A combined assessment approach enabled comprehensive multidisciplinary assessment of CHIKF, assessment of joint pathology through ultrasound, and appropriate follow-up. A combined rheumatology-tropical diseases service was successfully used to identify and assess CHIKF-associated morbidity. Future outbreaks may be approached by establishing tailored multidisciplinary clinics.

Clinical Effectiveness of SARS-CoV-2 Booster Vaccine Against Omicron Infection in Residents and Staff of Long-term Care Facilities: A Prospective Cohort Study (VIVALDI).

Background: Successive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have caused severe disease in long-term care facility (LTCF) residents. Primary vaccination provides strong short-term protection, but data are limited on duration of protection following booster vaccines, particularly against the Omicron variant. We investigated the effectiveness of booster vaccination against infections, hospitalizations, and deaths among LTCF residents and staff in England. Methods: We included residents and staff of LTCFs within the VIVALDI study (ISRCTN 14447421) who underwent routine, asymptomatic testing (December 12, 2021-March 31, 2022). Cox regression was used to estimate relative hazards of SARS-CoV-2 infection, and associated hospitalization and death at 0-13, 14-48, 49-83, 84-111, 112-139, and 140+ days after dose 3 of SARS-CoV-2 vaccination compared with 2 doses (after 84+ days), stratified by previous SARS-CoV-2 infection and adjusting for age, sex, LTCF capacity, and local SARS-CoV-2 incidence. Results: A total of 14 175 residents and 19 793 staff were included. In residents without prior SARS-CoV-2 infection, infection risk was reduced 0-111 days after the first booster, but no protection was apparent after 112 days. Additional protection following booster vaccination waned but was still present at 140+ days for COVID-associated hospitalization (adjusted hazard ratio [aHR], 0.20; 95% CI, 0.06-0.63) and death (aHR, 0.50; 95% CI, 0.20-1.27). Most residents (64.4%) had received primary course vaccine of AstraZeneca, but this did not impact pre- or postbooster risk. Staff showed a similar pattern of waning booster effectiveness against infection, with few hospitalizations and no deaths. Conclusions: Our findings suggest that booster vaccination provided sustained protection against severe outcomes following infection with the Omicron variant, but no protection against infection from 4 months onwards. Ongoing surveillance for SARS-CoV-2 in LTCFs is crucial.

VIVALDI Cohort Profile: Using linked, routinely collected data and longitudinal blood sampling to characterise COVID-19 infections, vaccinations, and related outcomes in care home staff and residents in England.

VIVALDI (ISRCTN14447421) is a government-funded longitudinal open observational cohort study of staff and residents in care homes for older people in England. The study aimed to describe epidemiology (including seroprevalence) and immune responses to COVID-19 in a subset of care homes, in the context of extremely high mortality in this setting, in the first 12-18 months of the pandemic. Data linkage to routine health data was undertaken for all staff and residents and a subset of individuals who consented to sequential blood sampling to investigate SARS-CoV-2 immunity. This paper aims to describe the samples stored within the VIVALDI biobank and associated linked data, available for use by researchers. Over 70,000 individuals from 346 care homes were included in the data linkage cohort (1 st March 2020-31 st March 2023). 4971 samples from 2264 individuals (1415 staff, 827 residents) collected between 29 th October 2020 and 10 th March 2023 are stored. Amongst these samples, there was a maximum of seven per participant however, 217 (26.2%) residents and 551 (38.9%) staff participated in one round only. Key study findings include high COVID-19 seroprevalence among surviving residents, exceeding rates in community-dwelling peers. COVID-19 vaccinations generated robust immune responses in staff and residents which waned, supporting the need for booster vaccination, particularly in response to new variants. Prior infection significantly improved vaccine-induced immune responses, however protection from infection declined following Omicron variant emergence. This is a unique cohort of pre- and post-infection samples linked to data on COVID-19 infections, vaccinations, and outcomes. The cohort spans host immune response evolution to infection and vaccination in this rarely sampled population of frail older care home residents who are especially vulnerable to infection and severe outcomes. These samples can be used to investigate biological mechanisms behind disparate infection responses in older people and make a valuable contribution to research into ageing.

Shaping care home COVID-19 testing policy: a protocol for a pragmatic cluster randomised controlled trial of asymptomatic testing compared with standard care in care home staff (VIVALDI-CT).

INTRODUCTION: Care home residents have experienced significant morbidity, mortality and disruption following outbreaks of SARS-CoV-2. Regular SARS-CoV-2 testing of care home staff was introduced to reduce transmission of infection, but it is unclear whether this remains beneficial. This trial aims to investigate whether use of regular asymptomatic staff testing, alongside funding to reimburse sick pay for those who test positive and meet costs of employing agency staff, is a feasible and effective strategy to reduce COVID-19 impact in care homes. METHODS AND ANALYSIS: The VIVALDI-Clinical Trial is a multicentre, open-label, cluster randomised controlled, phase III/IV superiority trial in up to 280 residential and/or nursing homes in England providing care to adults aged >65 years. All regular and agency staff will be enrolled, excepting those who opt out. Homes will be randomised to the intervention arm (twice weekly asymptomatic staff testing for SARS-CoV-2) or the control arm (current national testing guidance). Staff who test positive for SARS-CoV-2 will self-isolate and receive sick pay. Care providers will be reimbursed for costs associated with employing temporary staff to backfill for absence arising directly from the trial.The trial will be delivered by a multidisciplinary research team through a series of five work packages.The primary outcome is the incidence of COVID-19-related hospital admissions in residents. Secondary outcomes include the number and duration of outbreaks and home closures. Health economic and modelling analyses will investigate the cost-effectiveness and cost consequences of the testing intervention. A process evaluation using qualitative interviews will be conducted to understand intervention roll out and identify areas for optimisation to inform future intervention scale-up, should the testing approach prove effective and cost-effective. Stakeholder engagement will be undertaken to enable the sector to plan for results and their implications and to coproduce recommendations on the use of testing for policy-makers. ETHICS AND DISSEMINATION: The study has been approved by the London-Bromley Research Ethics Committee (reference number 22/LO/0846) and the Health Research Authority (22/CAG/0165). The results of the trial will be disseminated regardless of the direction of effect. The publication of the results will comply with a trial-specific publication policy and will include submission to open access journals. A lay summary of the results will also be produced to disseminate the results to participants. TRIAL REGISTRATION NUMBER: ISRCTN13296529.

Strong peak immunogenicity but rapid antibody waning following third vaccine dose in older residents of care homes.

Third-dose coronavirus disease 2019 vaccines are being deployed widely but their efficacy has not been assessed adequately in vulnerable older people who exhibit suboptimal responses after primary vaccination series. This observational study, which was carried out by the VIVALDI study based in England, looked at spike-specific immune responses in 341 staff and residents in long-term care facilities who received an mRNA vaccine following dual primary series vaccination with BNT162b2 or ChAdOx1. Third-dose vaccination strongly increased antibody responses with preferential relative enhancement in older people and was required to elicit neutralization of Omicron. Cellular immune responses were also enhanced with strong cross-reactive recognition of Omicron. However, antibody titers fell 21-78% within 100 d after vaccine and 27% of participants developed a breakthrough Omicron infection. These findings reveal strong immunogenicity of a third vaccine in one of the most vulnerable population groups and endorse an approach for widespread delivery across this population. Ongoing assessment will be required to determine the stability of immune protection.

The diagnostic performance of novel skin-based in-vivo tests for tuberculosis infection compared with purified protein derivative tuberculin skin tests and blood-based in vitro interferon-γ release assays: a systematic review and meta-analysis.

BACKGROUND: Novel skin-based tests for tuberculosis infection might present suitable alternatives to current tests; however, diagnostic performance of new tests compared with the purified protein derivative-tuberculin skin test (TST) or interferon-γ release assays (IGRA) needs systematic assessment. METHODS: In this systematic review and meta-analysis, we searched English (Medline OVID), Chinese (Chinese Biomedical Literature Database and the China National Knowledge Infrastructure), and Russian (e-library) databases from the inception of each database to May 15, 2019, (with updated search of the Russian and English databases on Oct, 20 2020) using terms "ESAT6" OR "CFP10" AND "skin test" AND "Tuberculosis" OR "C-Tb" OR "Diaskintest". We included studies reporting on the performance of index tests alone or compared with a comparator. Inclusion criteria varied according to review objectives and performance outcome, but reporting of test cut-offs for positivity applied to study population was required from all studies. We used a hierarchy of reference standards for tuberculosis infection consistent with the 2020 WHO framework to evaluate diagnostic performance. Two authors independently reviewed the titles and abstracts for English and Chinese (LF and MK) and Russian studies (MK and VN). Study quality was assessed with QUADAS-2. Pooled random-effects estimates are presented when appropriate for total agreement proportion, sensitivity in microbiologically confirmed tuberculosis and specificity in cohorts with low risk of tuberculosis infection. This study is registered with PROSPERO, CRD42019135572. FINDINGS: We identified 1466 original articles, of which 37 (2·5%) studies, including 10 915 individuals (7111 Diaskintest, 2744 C-Tb, 887 EC, 173 DPPD), were included in the qualitative analysis (29 [78%] studies of Diaskintest, five [15%] studies of C-Tb, two [5%] studies of EC-skintest, and one [3%] study of DPPD). 22 (1·5%) studies including 5810 individuals (3143 Diaskintest, 2129 C-Tb, 538 EC-skintest) were included in the quantitative analysis: 15 (68%) of Diaskintest, five (23%) of C-Tb, and two (9%) of EC-skintest. Tested sub-populations included individuals with HIV, children (0-18 years), and individuals exposed to tuberculosis. Studies were heterogeneous with moderate to high risk of bias. Nine head-to-head studies of index test versus TST and IGRA permitted direct comparisons and pooling. In a mixed cohort of people with and without tuberculosis, Diaskintest pooled agreement with IGRA was 87·16% (95% CI 79·47-92·24) and 55·45% (46·08-64·45) with TST-5 mm cut-off (TST5 mm). Diaskintest sensitivity was 91·18% (95% CI 81·72-95·98) compared with 88·24% (78·20-94·01) for TST5 mm, 89·66 (78·83-95·28) for IGRA QuantiFERON, and 90·91% (79·95-96·16) for TSPOT.TB. C-Tb agreement with IGRA in individuals with active tuberculosis was 79·80% (95% CI 76·10-83·07) compared with 78·92% (74·65-82·63) for TST5 mm/15 mm cut-off (TST5 mm/15 mm). TST5/15mm reflects threshold in cohorts that applied stratified cutoffs: 5 mm for HIV-infected, immunocompromised, or BCG-naive individuals, and 15mm for BCG-vaccinated immunocompetent individuals. C-Tb sensitivity was 74·52% (95% CI 70·39-78·25) compared with a sensitivity of 78·18% (67·75-85·94) for TST5 mm/15 mm, and 71·67% (63·44-78·68) for IGRA. Specificity was 97·85% (95% CI 93·96-99·25) for C-Tb versus 93·31% (90·22-95·48) for TST 15 mm cut-off and 99·15% (79·66-99·97) for IGRA. EC-skintest sensitivity was 86·06% (95% CI 82·39-89·07). INTERPRETATION: Novel skin-based tests for tuberculosis infection appear to perform similarly to IGRA or TST; however, study quality varied. Evaluation of test performance, patient-important outcomes, and diagnostic use in current clinical algorithms will inform implementation in key populations. FUNDING: StopTB (New Diagnostics Working Group) and FIND. TRANSLATIONS: For the Chinese and Russian translations of the abstract see Supplementary Materials section.

Prevalence and duration of detectable SARS-CoV-2 nucleocapsid antibodies in staff and residents of long-term care facilities over the first year of the pandemic (VIVALDI study): prospective cohort study in England.

BACKGROUND: Long-term care facilities (LTCFs) have reported high SARS-CoV-2 infection rates and related mortality, but the proportion of infected people among those who have survived, and duration of the antibody response to natural infection, is unknown. We determined the prevalence and stability of nucleocapsid antibodies (the standard assay for detection of previous infection) in staff and residents in LTCFs in England. METHODS: This was a prospective cohort study of residents 65 years or older and of staff 65 years or younger in 201 LTCFs in England between March 1, 2020, and May 7, 2021. Participants were linked to a unique pseudo-identifier based on their UK National Health Service identification number. Serial blood samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid protein using the Abbott ARCHITECT i-system (Abbott, Maidenhead, UK) immunoassay. Primary endpoints were prevalence and cumulative incidence of antibody positivity, which were weighted to the LTCF population. Incidence rate of loss of antibodies (seroreversion) was estimated from Kaplan-Meier curves. FINDINGS: 9488 samples were included, 8636 (91·0%) of which could be individually linked to 1434 residents and 3288 staff members. The cumulative incidence of nucleocapsid seropositivity was 34·6% (29·6-40·0) in residents and 26·1% (23·0-29·5) in staff over 11 months. 239 (38·6%) residents and 503 women (81·3%) were included in the antibody-waning analysis, and median follow-up was 149 days (IQR 107-169). The incidence rate of seroreversion was 2·1 per 1000 person-days at risk, and median time to reversion was 242·5 days. INTERPRETATION: At least a quarter of staff and a third of surviving residents were infected with SAR-CoV-2 during the first two waves of the pandemic in England. Nucleocapsid-specific antibodies often become undetectable within the first year following infection, which is likely to lead to marked underestimation of the true proportion of people with previous infection. Given that natural infection might act to boost vaccine responses, better assays to identify natural infection should be developed. FUNDING: UK Government Department of Health and Social Care.

Duration of vaccine effectiveness against SARS-CoV-2 infection, hospitalisation, and death in residents and staff of long-term care facilities in England (VIVALDI): a prospective cohort study.

Background: Residents and staff in long-term care facilities have been prioritised for vaccination against SARS-CoV-2, but data on potential waning of vaccine effectiveness and the effect of booster doses in this vulnerable population are scarce. We aimed to evaluate effectiveness of one, two, and three vaccine doses against infection and severe clinical outcomes in staff and residents of long-term care facilities in England over the first year following vaccine roll-out. Methods: The VIVALDI study is a prospective cohort study done in 331 long-term care facilities in England. Residents aged 65 years or older and staff aged 18 years or older were eligible for participation. Participants had routine PCR testing throughout the study period between Dec 8, 2020, and Dec 11, 2021. We retrieved all PCR results and cycle threshold values for PCR-positive samples from routine testing in long-term care facilities, and positive PCR results from clinical testing in hospitals through the UK's COVID-19 Datastore. PCR results were linked to participants using pseudo-identifiers based on individuals' unique UK National Health Service (NHS) numbers, which were also used to retrieve vaccination records from the National Immunisation Management Service, hospitalisation records from NHS England, and deaths data from the Office for National Statistics through the COVID-19 Datastore. In a Cox proportional hazards regression, we estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. This study is registered with the ISRCTN Registry, ISRCTN 14447421. Findings: 80 186 residents and staff of long-term care facilities had records available for the study period, of whom 15 518 eligible residents and 19 515 eligible staff were included in the analysis. For residents without evidence of previous SARS-CoV-2 exposure, vaccine effectiveness decreased from 61·7% (95% CI 35·1 to 77·4) to 22·0% (-14·9 to 47·0) against infection; from 89·0% (70·6 to 95·9) to 56·3% (30·1 to 72·6) against hospitalisation; and from 96·4% (84·3 to 99·2) to 64·4% (36·1 to 80·1) against death, when comparing 14-83 days after dose two and 84 days or more after dose two. For staff without evidence of previous exposure, vaccine effectiveness against infection decreased slightly from 57·9% (43·1 to 68·9) at 14-83 days after dose two to 42·1% (29·9 to 52·2) at 84 days or more after dose two. There were no hospitalisations or deaths among unexposed staff at 14-83 days, but seven hospitalisations (vaccine effectiveness 91·0% [95% CI 74·3 to 96·8]) and one death were observed at 84 days or more after dose two. High vaccine effectiveness was restored following a third vaccine dose, with vaccine effectiveness in unexposed residents of 72·7% (55·8 to 83·1) against infection, 90·1% (80·6 to 95·0) against hospitalisation, and 97·5% (88·1 to 99·5) against death; and vaccine effectiveness in unexposed staff of 78·2% (70·0 to 84·1) against infection and 95·8% (49·9 to 99·6) against hospitalisation. There were no COVID-19-related deaths among unexposed staff after the third vaccine dose. Interpretation: Our findings showed substantial waning of SARS-CoV-2 vaccine effectiveness against all outcomes in residents of long-term care facilities from 12 weeks after a primary course of ChAdOx1-S or mRNA vaccines. Boosters restored protection, and maximised immunity across all outcomes. These findings show the importance of boosting and the need for ongoing surveillance in this vulnerable cohort. Funding: UK Government Department of Health and Social Care.

Outcomes of SARS-CoV-2 omicron infection in residents of long-term care facilities in England (VIVALDI): a prospective, cohort study.

Background: The SARS-CoV-2 omicron variant (B.1.1.529) is highly transmissible, but disease severity appears to be reduced compared with previous variants such as alpha and delta. We investigated the risk of severe outcomes following infection in residents of long-term care facilities. Methods: We did a prospective cohort study in residents of long-term care facilities in England who were tested regularly for SARS-CoV-2 between Sept 1, 2021, and Feb 1, 2022, and who were participants of the VIVALDI study. Residents were eligible for inclusion if they had a positive PCR or lateral flow device test during the study period, which could be linked to a National Health Service (NHS) number, enabling linkage to hospital admissions and mortality datasets. PCR or lateral flow device test results were linked to national hospital admission and mortality records using the NHS-number-based pseudo-identifier. We compared the risk of hospital admission (within 14 days following a positive SARS-CoV-2 test) or death (within 28 days) in residents who had tested positive for SARS-CoV-2 in the period shortly before omicron emerged (delta-dominant) and in the omicron-dominant period, adjusting for age, sex, primary vaccine course, past infection, and booster vaccination. Variants were confirmed by sequencing or spike-gene status in a subset of samples. Results: 795 233 tests were done in 333 long-term care facilities, of which 159 084 (20·0%) could not be linked to a pseudo-identifier and 138 012 (17·4%) were done in residents. Eight residents had two episodes of infection (>28 days apart) and in these cases the second episode was excluded from the analysis. 2264 residents in 259 long-term care facilities (median age 84·5 years, IQR 77·9-90·0) were diagnosed with SARS-CoV-2, of whom 253 (11·2%) had a previous infection and 1468 (64·8%) had received a booster vaccination. About a third of participants were male. Risk of hospital admissions was markedly lower in the 1864 residents infected in the omicron-period (4·51%, 95% CI 3·65-5·55) than in the 400 residents infected in the pre-omicron period (10·50%, 7·87-13·94), as was risk of death (5·48% [4·52-6·64] vs 10·75% [8·09-14·22]). Adjusted hazard ratios (aHR) also indicated a reduction in hospital admissions (0·64, 95% CI 0·41-1·00; p=0·051) and mortality (aHR 0·68, 0·44-1·04; p=0·076) in the omicron versus the pre-omicron period. Findings were similar in residents with a confirmed variant. Interpretation: Observed reduced severity of the omicron variant compared with previous variants suggests that the wave of omicron infections is unlikely to lead to a major surge in severe disease in long-term care facility populations with high levels of vaccine coverage or natural immunity. Continued surveillance in this vulnerable population is important to protect residents from infection and monitor the public health effect of emerging variants. Funding: UK Department of Health and Social Care.