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1.
JAMA Pediatr ; 2022 Oct 24.
Article in English | MEDLINE | ID: covidwho-2084959

ABSTRACT

This cohort study investigates the risk of SARS-CoV-2 reinfection among young children with and without spike-specific T-cell responses.

2.
Cell Rep Med ; 3(9): 100739, 2022 09 20.
Article in English | MEDLINE | ID: covidwho-2004612

ABSTRACT

Age is the strongest determinant of COVID-19 mortality, and over 2 billion people have received primary series vaccination with BNT162b2 (mRNA) or ChAdOx1 (adenoviral vector). However, the profile of sustained vaccine immunogenicity in older people is unknown. Here, we determine spike-specific humoral and cellular immunity to 8 months following BNT162b2 or ChAdOx1 in 245 people aged 80-98 years. Vaccines are strongly immunogenic, with antibodies retained in every donor, while titers fall to 23%-26% from peak. Peak immunity develops rapidly with standard interval BNT162b2, although antibody titers are enhanced 3.7-fold with extended interval. Neutralization of ancestral variants is superior following BNT162b2, while neutralization of Omicron is broadly negative. Conversely, cellular responses are stronger following ChAdOx1 and are retained to 33%-60% of peak with all vaccines. BNT162b2 and ChAdOx1 elicit strong, but differential, sustained immunogenicity in older people. These data provide a baseline to assess optimal booster regimen in this vulnerable age group.


Subject(s)
COVID-19 Vaccines , COVID-19 , Aged , BNT162 Vaccine , COVID-19/prevention & control , Humans , Immunogenicity, Vaccine , RNA, Messenger
3.
Lancet Healthy Longev ; 3(7): e470-e480, 2022 07.
Article in English | MEDLINE | ID: covidwho-1915225

ABSTRACT

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.


Subject(s)
COVID-19 , COVID-19 Vaccines , Humans , Long-Term Care , Prospective Studies , SARS-CoV-2 , State Medicine , Vaccine Efficacy
4.
Lancet Healthy Longev ; 3(7): e461-e469, 2022 07.
Article in English | MEDLINE | ID: covidwho-1915222

ABSTRACT

Background: Older age and frailty are risk factors for poor clinical outcomes following SARS-CoV-2 infection. As such, COVID-19 vaccination has been prioritised for individuals with these factors, but there is concern that immune responses might be impaired due to age-related immune dysregulation and comorbidity. We aimed to study humoral and cellular responses to COVID-19 vaccines in residents of long-term care facilities (LTCFs). Methods: In this observational cohort study, we assessed antibody and cellular immune responses following COVID-19 vaccination in members of staff and residents at 74 LTCFs across the UK. Staff and residents were eligible for inclusion if it was possible to link them to a pseudo-identifier in the COVID-19 datastore, if they had received two vaccine doses, and if they had given a blood sample 6 days after vaccination at the earliest. There were no comorbidity exclusion criteria. Participants were stratified by age (<65 years or ≥65 years) and infection status (previous SARS-CoV-2 infection [infection-primed group] or SARS-CoV-2 naive [infection-naive group]). Anticoagulated edetic acid (EDTA) blood samples were assessed and humoral and cellular responses were quantified. Findings: Between Dec 11, 2020, and June 27, 2021, blood samples were taken from 220 people younger than 65 years (median age 51 years [IQR 39-61]; 103 [47%] had previously had a SARS-CoV-2 infection) and 268 people aged 65 years or older of LTCFs (median age 87 years [80-92]; 144 [43%] had a previous SARS-CoV-2 infection). Samples were taken a median of 82 days (IQR 72-100) after the second vaccination. Antibody responses following dual vaccination were strong and equivalent between participants younger then 65 years and those aged 65 years and older in the infection-primed group (median 125 285 Au/mL [1128 BAU/mL] for <65 year olds vs 157 979 Au/mL [1423 BAU/mL] for ≥65 year olds; p=0·47). The antibody response was reduced by 2·4-times (467 BAU/mL; p≤0·0001) in infection-naive people younger than 65 years and 8·1-times (174 BAU/mL; p≤0·0001) in infection-naive residents compared with their infection-primed counterparts. Antibody response was 2·6-times lower in infection-naive residents than in infection-naive people younger than 65 years (p=0·0006). Impaired neutralisation of delta (1.617.2) variant spike binding was also apparent in infection-naive people younger than 65 years and in those aged 65 years and older. Spike-specific T-cell responses were also significantly enhanced in the infection-primed group. Infection-naive people aged 65 years and older (203 SFU per million [IQR 89-374]) had a 52% lower T-cell response compared with infection-naive people younger than 65 years (85 SFU per million [30-206]; p≤0·0001). Post-vaccine spike-specific CD4 T-cell responses displayed single or dual production of IFN-γ and IL-2 were similar across infection status groups, whereas the infection-primed group had an extended functional profile with TNFα and CXCL10 production. Interpretation: These data reveal suboptimal post-vaccine immune responses within infection-naive residents of LTCFs, and they suggest the need for optimisation of immune protection through the use of booster vaccination. Funding: UK Government Department of Health and Social Care.


Subject(s)
COVID-19 , Vaccines , Aged, 80 and over , Antibodies, Viral , COVID-19 Vaccines , Humans , Immunity, Cellular , Long-Term Care , Middle Aged , SARS-CoV-2 , Vaccination
5.
Front Immunol ; 13: 882515, 2022.
Article in English | MEDLINE | ID: covidwho-1903016

ABSTRACT

Children and adolescents generally experience mild COVID-19. However, those with underlying physical health conditions are at a significantly increased risk of severe disease. Here, we present a comprehensive analysis of antibody and cellular responses in adolescents with severe neuro-disabilities who received COVID-19 vaccination with either ChAdOx1 (n=6) or an mRNA vaccine (mRNA-1273, n=8, BNT162b2, n=1). Strong immune responses were observed after vaccination and antibody levels and neutralisation titres were both higher after two doses. Both measures were also higher after mRNA vaccination and were further enhanced by prior natural infection where one vaccine dose was sufficient to generate peak antibody response. Robust T-cell responses were generated after dual vaccination and were also higher following mRNA vaccination. Early T-cells were characterised by a dominant effector-memory CD4+ T-cell population with a type-1 cytokine signature with additional production of IL-10. Antibody levels were well-maintained for at least 3 months after vaccination and 3 of 4 donors showed measurable neutralisation titres against the Omicron variant. T-cell responses also remained robust, with generation of a central/stem cell memory pool and showed strong reactivity against Omicron spike. These data demonstrate that COVID-19 vaccines display strong immunogenicity in adolescents and that dual vaccination, or single vaccination following prior infection, generate higher immune responses than seen after natural infection and develop activity against Omicron. Initial evidence suggests that mRNA vaccination elicits stronger immune responses than adenoviral delivery, although the latter is also higher than seen in adult populations. COVID-19 vaccines are therefore highly immunogenic in high-risk adolescents and dual vaccination might be able to provide relative protection against the Omicron variant that is currently globally dominant.


Subject(s)
COVID-19 Vaccines , COVID-19 , 2019-nCoV Vaccine mRNA-1273 , Adolescent , Adult , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Child , Humans , RNA, Messenger , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , mRNA Vaccines
6.
Sci Rep ; 12(1): 10484, 2022 06 21.
Article in English | MEDLINE | ID: covidwho-1900654

ABSTRACT

Neutrophilia and an elevated neutrophil:lymphocyte ratio are both characteristic features of severe COVID-19 infection. However, functional neutrophil responses have been poorly investigated in this setting. We utilised a novel PMA-based stimulation assay to determine neutrophil-derived reactive oxygen species (ROS) generation in patients with severe COVID-19 infection, non-COVID related sepsis and healthy study participants. ROS production was markedly elevated in COVID-19 patients with median values ninefold higher than in healthy controls and was particularly high in patients on mechanical ventilation. ROS generation correlated strongly with neutrophil count and elevated levels were also seen in patients with non-COVID related sepsis. Relative values, adjusted for neutrophil count, were high in both groups but extreme low or high values were seen in two patients who died shortly after testing, potentially indicating a predictive value for neutrophil function. Our results show that the high levels of neutrophils observed in patients with COVID-19 and sepsis exhibit functional capacity for ROS generation. This may contribute to the clinical features of acute disease and represents a potential novel target for therapeutic intervention.


Subject(s)
COVID-19 , Sepsis , Humans , Leukocyte Count , Neutrophils , Reactive Oxygen Species
8.
J Infect Dis ; 2022 Apr 16.
Article in English | MEDLINE | ID: covidwho-1883018

ABSTRACT

General population studies have shown strong humoral response following 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 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.

9.
Vaccine ; 40(32): 4348-4360, 2022 07 30.
Article in English | MEDLINE | ID: covidwho-1867878

ABSTRACT

Several population groups display an increased risk of severe disease and mortality following SARS-CoV-2 infection. These include those who are immunocompromised (IC), have a cancer diagnosis, human immunodeficiency virus (HIV) infection or chronic inflammatory disease including autoimmune disease, primary immunodeficiencies, and those with kidney or liver disease. As such, improved understanding of the course of COVID-19 disease, as well as the efficacy, safety, and benefit-risk profiles of COVID-19 vaccines in these vulnerable groups is paramount in order to inform health policy makers and identify evidence-based vaccination strategies. In this review, we seek to summarize current data, including recommendations by national health authorities, on the impact and benefit-risk profiles of COVID-19 vaccination in these populations. Moving forward, although significant efforts have been made to elucidate and characterize COVID-19 disease course and vaccine responses in these groups, further larger-scale and longer-term evaluation will be instrumental to help further guide management and vaccination strategies, particularly given concerns about waning of vaccine-induced immunity and the recent surge of transmission with SARS-CoV-2 variants of concern.


Subject(s)
COVID-19 Vaccines , COVID-19 , Vulnerable Populations , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Population Groups , SARS-CoV-2 , Vaccination/adverse effects , Vaccines
10.
iScience ; 25(7): 104480, 2022 Jul 15.
Article in English | MEDLINE | ID: covidwho-1867295

ABSTRACT

Clinical outcomes for patients with COVID-19 are heterogeneous and there is interest in defining subgroups for prognostic modeling and development of treatment algorithms. We obtained 28 demographic and laboratory variables in patients admitted to hospital with COVID-19. These comprised a training cohort (n = 6099) and two validation cohorts during the first and second waves of the pandemic (n = 996; n = 1011). Uniform manifold approximation and projection (UMAP) dimension reduction and Gaussian mixture model (GMM) analysis was used to define patient clusters. 29 clusters were defined in the training cohort and associated with markedly different mortality rates, which were predictive within confirmation datasets. Deconvolution of clinical features within clusters identified unexpected relationships between variables. Integration of large datasets using UMAP-assisted clustering can therefore identify patient subgroups with prognostic information and uncovers unexpected interactions between clinical variables. This application of machine learning represents a powerful approach for delineating disease pathogenesis and potential therapeutic interventions.

11.
Lancet Healthy Longev ; 3(5): e347-e355, 2022 05.
Article in English | MEDLINE | ID: covidwho-1821559

ABSTRACT

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.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged, 80 and over , Cohort Studies , Female , Humans , Long-Term Care , Male , Prospective Studies , State Medicine
12.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-334389

ABSTRACT

Third dose COVID-19 vaccines are being deployed widely but their efficacy has not been assessed adequately in vulnerable elderly people who exhibit suboptimal responses after primary series vaccination. We studied spike-specific immune responses in 341 staff and residents in long-term care facilities (LTCF) who received an mRNA vaccine following dual primary series vaccination with BNT162b2 or ChAdOx1. Third dose vaccination strongly increased antibody responses with preferential enhancement in older people and was required to elicit neutralisation of Omicron. Cellular immune responses were also enhanced with strong cross-reactive recognition of Omicron. However, antibody titres fell 21-78% within 100 days post vaccine and 27% of participants developed a breakthrough Omicron infection. These findings reveal strong immunogenicity of a 3rd 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.

13.
Proc Natl Acad Sci U S A ; 119(15): e2119893119, 2022 04 12.
Article in English | MEDLINE | ID: covidwho-1778688

ABSTRACT

The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.


Subject(s)
COVID-19 , Pandemics , COVID-19/drug therapy , COVID-19 Vaccines , Drug Development , Humans , Pandemics/prevention & control , SARS-CoV-2
14.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332392

ABSTRACT

CD4 + T-cells are essential for protection against viruses including SARS-CoV-2. Mutations in SARS-CoV-2 variants of concern (VOC) can enhance infectivity and reduce antibody recognition. CD4 + T-cell sensitivity to mutations is less well understood because few epitopes have been mapped. Characterising > 100 SARS-CoV-2-specific CD4 + T-cell clones from convalescent healthcare workers, we mapped and HLAII restricted 21 epitopes across three viral proteins. Responses to the same spike epitopes were also present after vaccination of uninfected individuals. Lack of CD4 + T-cell cross-reactivity with endemic beta-coronaviruses suggests these responses arose from naïve T-cells rather than pre-existing cross-reactive coronavirus-specific T-cell responses. 10/17 spike epitopes were mutated in VOCs and CD4 + T-cell recognition of 7 was impaired, including 3 of 4 epitopes mutated in Omicron. Broad CD4 + T-cell targeting of epitopes likely limits evasion by current VOCs. However, continued genomic surveillance is vital to identify new emerging mutations able to evade CD4 + T-cell immunity.

15.
Immun Ageing ; 18(1): 34, 2021 Aug 20.
Article in English | MEDLINE | ID: covidwho-1759763

ABSTRACT

BACKGROUND: Several SARS-CoV-2 vaccines have shown clinical efficacy against Covid-19 infection but there remains uncertainty about the immune responses elicited by different regimens. This is a particularly important question for older people who are at increased clinical risk following infection and in whom immune senescence may limit vaccine responses. The BNT162b2 mRNA and ChAdOx1 adenovirus vaccines were the first two vaccines deployed in the UK programme using an 8-12 week 'extended interval'. OBJECTIVES: We undertook analysis of the spike-specific antibody and cellular immune response in 131 participants aged 80+ years after the second dose of 'extended interval' dual vaccination with either BNT162b2 mRNA (n = 54) or ChAdOx1 (n = 77) adenovirus vaccine. Blood samples were taken 2-3 weeks after second vaccine and were paired with samples taken at 5-weeks after first vaccine which have been reported previously. Antibody responses were measured using the Elecsys® electrochemiluminescence immunoassay assay and cellular responses were assessed by IFN-γ ELISpot. RESULTS: Antibody responses against spike protein became detectable in all donors following dual vaccination with either vaccine. 4 donors had evidence of previous natural infection which is known to boost vaccine responses. Within the 53 infection-naïve donors the median antibody titre was 4030 U/ml (IQR 1892-8530) following BNT162b2 dual vaccination and 1405 (IQR 469.5-2543) in the 74 patients after the ChAdOx1 vaccine (p = < 0.0001). Spike-specific T cell responses were observed in 30% and 49% of mRNA and ChAdOx1 recipients respectively and median responses were 1.4-times higher in ChAdOx1 vaccinees at 14 vs 20 spots/million respectively (p = 0.022). CONCLUSION: Dual vaccination with BNT162b2 or ChAdOx1 induces strong humoral immunity in older people following an extended interval protocol. Antibody responses are 2.9-times higher following the mRNA regimen whilst cellular responses are 1.4-times higher with the adenovirus-based vaccine. Differential patterns of immunogenicity are therefore elicited from the two vaccine platforms. It will be of interest to assess the relative stability of immune responses after these homologous vaccine regimens in order to assess the potential need for vaccine boosting. Furthermore, these findings indicate that heterologous vaccine platforms may offer the opportunity to further optimize vaccine responses.

16.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330319

ABSTRACT

Background Long-term care facilities (LTCF) have been prioritised for vaccination, but data on potential waning of vaccine effectiveness (VE) and the impact of booster doses in this vulnerable population remains scarce. Methods We included residents and staff from 331 LTCFs enrolled in VIVALDI ( ISRCTN 14447421 ), who underwent routine PCR testing between Dec 8, 2020 - Dec 11, 2021 in a Cox proportional hazards regression, estimating VE against SARS-CoV2 infection, COVID-19-related hospitalisation, and COVID-19-related death after 1-3 vaccine doses, stratifying by previous SARS-CoV2 exposure. Results For 15,518 older residents, VE declined from 50·7% (15·5, 71·3) to 17·2% (∼23·9, 44·6) against infection;from 85·4% (60·7, 94·.6) to 54·3% (26·2, 71·7) against hospitalisation;and from 94·4% (76·4, 98·7) to 62·8% (32·9, 79·4) against death, when comparing 2-12 weeks and ≥12 weeks after two doses. For 19,515 staff, VE against infection declined slightly from 50·3% (32·7, 63·3) to 42·1% 29·5, 52·4). High VE was restored following a third dose, with VE of 71·6% (53·5, 82·7) and 78·3% (70·1, 84·3) against infection and 89·9% (80·0, 94·6) and 95·8% (50·4, 99·6) against hospitalisation, for residents and staff respectively;and 97·5% (88·1, 99·5) against death for residents. Interpretation Substantial waning of VE is observed against all outcomes in residents from 12 weeks after a primary course of AstraZeneca or mRNA vaccines. Boosters restore protection, and maximise immunity across all outcomes. These findings demonstrate the importance of boosting and the need for ongoing surveillance of VE in this vulnerable cohort. Funding UK Government Department of Health and Social Care. Research in Context Evidence before this study We searched MEDLINE and medRxiv for studies reporting vaccine effectiveness (VE) over time after two or three doses against SARS-CoV2 infection, COVID-19-related hospitalisation, or COVID-19-related death amongst staff or residents of long-term care facilities (LTCFs), that were published between Jan 1, 2020, and December 21, 2021. We used variations of the search terms “COVID-19” OR “SARS-CoV-2” AND “vaccine effectiveness” OR “vaccine efficacy” AND “care homes” OR “long term care facilities”. We identified 8 articles reporting two-dose data from LTCFs, including 1 peer-reviewed paper from Israel, 1 preprint from Denmark, 1 preprint from Norway, 1 peer-reviewed paper from France, two peer-reviewed papers from Spain, 1 peer-reviewed paper from the USA, and 1 preprint from England;however none of these studies examined waning of protection over time after two doses. Five studies (mRNA vaccines 3-4 weeks interval) reported short-term two-dose VE of 49-71% in residents, and 82-90% in staff. Two-dose VE was reported to be 75-88% against hospitalisation, 87-97% against death, and 86% against either outcome. An English study of residents (Pfizer or AstraZeneca, 8-12 week interval) reported 73% VE against infection and noted VE waning from 7 weeks after the first dose, but did not examine waning after the second dose. All of these studies were set prior to emergence of the Delta variant and did not examine waning of immunity due to short lengths of follow-up after Dose 2. Only one study (USA) compared Pfizer/Moderna two-dose VE against infection in LTCF residents before (67·5% [60·1-73·5%]) and during (53·1% [49·1-56·7%]) Delta variant predominance;however, authors could not access vaccination dates therefore did not account for any waning of immunity over time;they also did not examine any severe clinical outcomes. We identified only one correspondence piece from Israel (Pfizer 3-4 week interval) describing the benefit of a third ‘booster’ dose in LTCFs;it reported relative rate reductions of 71% for infection and 80%, for hospitalisation in the period after booster roll-out. However, individual-level VE estimates by time since vaccination were not reported, and adju tment for prior infection was not undertaken. Overall, there was a paucity of data on non-mRNA vaccines, waning of immunity over time after two doses, and VE following a third (booster) dose in LTCF populations, which we address in this study. Added value of this study We report findings from a prospective cohort study that includes 15,518 residents and 19,515 staff from 331 LTCFs across England, who underwent routine PCR testing 2-3 times per month, looking at SARS-CoV2 vaccine effectiveness over 12 months (Dec 8, 2020-Dec 11, 2021), which is the longest duration of follow-up of any study within this vulnerable cohort. We evaluated the effectiveness of first, second, and booster vaccine doses of AstraZeneca, Pfizer, and Moderna against infection, hospitalisation, and death over the 12 months when the Alpha and Delta variants were dominant. Our findings affirm that complete vaccination with two doses of AstraZeneca or mRNA vaccines offers moderate protection against infection, and high protection against severe clinical outcomes, however this protection declines over time, particularly for residents. A third booster dose of an mRNA vaccine restores, and indeed maximises, VE to 71·6% (53·5, 82·7) and 78·3% (70·1, 84·3) against infection, and 89·9% (80·0, 94·6) and 95·8% (50·4, 99·6) against hospitalisation, for residents and staff respectively, and to 97·5% (88·1, 99·5) against death for residents, with similar protection offered after the third dose irrespective of primary course type. This is the first study to examine and describe waning of immunity over a one-year period, as well as vaccine effectiveness of a booster dose, in a large cohort of LTCF staff and residents. Implications of all the available evidence Taken together, our findings indicate high short-term immunity against SARS-CoV2 infection and very high immunity against severe clinical outcomes of COVID-19 for LTCF residents and staff following vaccination. However substantial waning in vaccine-derived immunity is seen beyond 3 months, irrespective of vaccine type, suggesting the need for regular boosting to maintain protection in this vulnerable cohort. Although this analysis took place in the pre-Omicron period, these trends of waning immunity over time are likely to be generalisable across variants, carrying important implications for long-term vaccination policy in LTCFs. Ongoing surveillance in this vulnerable cohort remains crucial, in order to describe further changes in vaccine-induced immunity, particularly in the context of new variants.

18.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-323027

ABSTRACT

Background: Residents of long-term care facilities (LTCF) have experienced high mortality rates from SARS-CoV-2 infection and as such have been prioritized for Covid-19 vaccination. Several countries have implemented an extended interval of up to 12 weeks between first and second vaccine doses to increase population coverage after single administration. Methods: Spike-specific immune responses that were induced following single administration of BNT162b2 or ChAdOx1 were studied in 89 staff and 35 residents within LTCFs. Quantitative antibody and cellular responses were determined as well as antibody inhibition of spike protein-ACE2 binding from viral variants. Results: 20% of staff and 34% of residents were found to have serological evidence of prior SARS-CoV-2 infection and all of these donors demonstrated strong antibody responses that were independent of age. Antibody responses were detectable within 99% and 79% of ‘infection-naive’ staff and residents respectively but were 8.2-fold lower within residents. This effect resulted from slower kinetics of antibody generation within residents which reached levels comparable to staff after only 42 days. In contrast spike-specific cellular responses were equivalent between both groups. Antibody inhibition activity against the B.1.351 and P.1 viral variants of concern was low using serum from ‘infection-naive’ older donors. Prior history of natural infection thus has a marked impact on the magnitude and quality of antibody response after a single Covid-19 vaccine in care home residents. Interpretation: Residents who are infection-naive have delayed antibody responses to the first dose of vaccine and might be considered for an early second vaccine where possible. Funding: UK Government Department of Health and Social CareDeclaration of Interests: LS reports grants from the Department of Health and Social Care during the conduct of the study and is a member of the Social Care Working Group, which reports to the Scientific Advisory Group for Emergencies. AH is a member of the New and Emerging Respiratory Virus Threats Advisory Group at the Department of Health.Ethics Approval Statement: Ethical approval for this study was obtained from the South Central - Hampshire B Research Ethics Committee, REC Ref: 20/SC/023.

19.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-322165

ABSTRACT

Following the UK’s approach to extend the COVID vaccination interval from 3-4 weeks to 12 weeks, there was considerable international debate about the optimal approach for vaccine deployment in countries experiencing surges in cases and pressures on health service utilisation.We found that adults aged ≥70 years mount robust antibody responses after a single dose of the Pfizer BioNtech vaccine, with significantly higher antibody concentrations in previously-infected vaccinees. Two doses of Pfizer BioNtech vaccine produced very high S-antibody levels across all age-groups, with significantly higher antibodies in those with prior SARS-CoV-2 infection. Antibody levels were significantly higher after two doses of vaccine in those aged 70 years and above when compared with convalescent sera from clinically mild to moderate PCR confirmed cases. Our findings provide additional support for the UK approach of prioritising the first dose of vaccine.

20.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-321099

ABSTRACT

Background: Whilst an effective vaccine may present the safest way to achieve adequate population immunity from the COVID-19 pandemic, a key challenge towards successful uptake is vaccine hesitancy. We examine and provide novel insights on the key drivers and barriers towards COVID-19 vaccine uptake.Methods: This study involved an anonymous cross-sectional online survey circulated across the UK. Multi-nominal logistic models examined demographic factors that may impact vaccine uptake. We used principle component analysis and text mining to explore perception related to vaccine uptake.Findings: The survey had 4884 respondents of which 9·44% were BAME (Black Asian Minority Ethnic). Overall 3873 (79·3%) respondents were interested in taking approved vaccines while 677 (13·9%) respondents were unsure, and 334 (6·8%) respondents would not take a vaccine. Participants aged over 70 years (Odds Ratio (OR) = 4·63) and the BAME community (OR = 5·48) were more likely to accept approved vaccines. Smokers (OR=0·45) and respondents with no known illness (OR = 0·70) were less likely to accept approved vaccines. The study identified 16 key reasons for not accepting approved vaccines - the most common (60%) being the possibility of the COVID-19 vaccine having side effects.Interpretation: This study provides an insight into potential governmental policy recommendations essential in designing strategies to reduce vaccine hesitancy. These strategies could increase engagement and encourage participation from BAME groups, smokers and those with no diagnosed health conditions, ensuring adequate immunity. This proves crucial in managing the COVID-19 pandemic.Funding: This study was independently funded and there was no funding source associated with this study.Declaration of Interests: This research has been supported by NIHR CRN West Midlands. MJB has received grants and travel expenses from Vifor International and Tillots Pharma, outside of the submitted work. All other authors report no competing interests.Ethics Approval Statement: The interview questions were collated, reviewed and refined internally by a group of researchers. This was followed by an external review and further refinement by a group of volunteers made up of patients, public and user groups, the CRN West Midlands Equality, Diversity and Inclusion Research Champions Group. Feedback from this group was used to modify questions prior to the survey going live. The study was approved by local approval processes and by theClinical Research Network, West Midlands. From ethics discussions, no ethical-related issues were identified. Consent was obtained from participants prior to completion of the form. Participants were provided with information about the study, and how the data was going to be disseminated in the initial page of the survey.

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