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1.
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
2.
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
4.
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.

5.
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
6.
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.

7.
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.

8.
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.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-318753

ABSTRACT

Background: Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials.Methods: We determined the serological and cellular response to spike protein in 100 people aged 80-96 years at 2 weeks after second vaccination with the Pfizer BNT162b2 mRNA vaccine.Findings: Antibody responses were seen in every donor with high titres in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated with humoral response. Previous SARS-CoV-2 infection substantially increased antibody responses after one vaccine and antibody and cellular responses remained 28-fold and 3-fold higher respectively after dual vaccination. Post-vaccine sera mediated strong neutralisation of live Victoria (Wuhan-like prototype) infection and although neutralisation titres were reduced 14-fold against the P.1 variant first discovered in Brazil they remained largely effective.Interpretation: These data demonstrate that the mRNA vaccine platform delivers strong humoral immunity in people up to 96 years of age and retains broad efficacy against the P.1 Variant of Concern.Funding: This work was supported by the UK Coronavirus Immunology Consortium (UK-CIC) funded by DHSC/UKRI and the National Core Studies Immunity programme. Declaration of Interest: None to declare. Ethical Approval: The work was performed under the CIA UPH IRAS approval (REC 20W\0240) and conducted according to the Declaration of Helsinki and good clinical practice.

10.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-318751

ABSTRACT

Background: Extended-interval Covid vaccination regimens are now used widely in order to accelerate population coverage but the relative immunogenicity of different vaccines in older people remains uncertain.Methods: We recruited 165 participants aged 80+ years who had received a single dose of either BNT162b2 mRNA or ChAdOx1 adenovirus vaccine and studied adaptive immune responses after 5 weeks.Findings: Antibody responses against spike protein were detectable in 93% and 87% of mRNA or ChAdOx1 recipients respectively with median antibody titres of 19.3 and 19.6 U/ml (p=0.41). Spike-specific T cell responses were observed in 12% and 31% of mRNA and ChAdOx1 recipients respectively and median responses were 3-fold higher in ChAdOx1 vaccinees at 2 vs 6 spots/million respectively (p=<0.0001). Humoral and cellular immune responses against spike were correlated in both cohorts. Evidence of previous natural infection was seen in 8 donors and associated with 691-fold and 4-fold increase in humoral and cellular immune responses across the whole cohort.Interpretation: Single doses of either the BNT162b2 or ChAdOx1vaccine in older people thus induce humoral immunity in most donors and are markedly enhanced by previous infection. Cellular responses are weaker but show relative enhancement after the ChAdOx1 platform.Funding Statement: This work was partially supported by the UK Coronavirus Immunology Consortium (UK-CIC) funded by DHSC/UKRI and the National Core Studies Immunity programme.Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: The work was performed under the CIA UPH IRAS approval (REC 20W\0240) and conducted according to the Declaration of Helsinki and good clinical practice.

11.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327186

ABSTRACT

Background 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 such as Long-Term Care Facility (LTCF) residents but published data are scarce. Methods VIVALDI is a prospective cohort study in England which links serial blood sampling in LTCF staff and residents to routine healthcare records. We measured quantitative titres of SARS-CoV-2 anti-spike antibodies in residents and staff following second vaccination dose with ChAdOx1 nCov-19 (Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech). We investigated differences in peak antibody levels and rates of decline using linear mixed effects models. Results We report on 1317 samples from 402 residents (median age 86 years, IQR 78-91) and 632 staff (50 years, 37-58), ≤280 days from second vaccination dose. Peak antibody titres were 7.9-fold higher after Pfizer-BioNTech vaccine compared to Oxford-AstraZeneca (95%CI 3.6-17.0;P <0.01) but rate of decline was increased, and titres were similar at 6 months. Prior infection was associated with higher peak antibody levels in both Pfizer-BioNTech (2.8-fold, 1.9-4.1;P <0.01) and Oxford-AstraZeneca (4.8-fold, 3.2-7.1;P <0.01) recipients and slower rates of antibody decline. Increasing age was associated with a modest reduction in peak antibody levels for Oxford-AstraZeneca recipients. Conclusions Double-dose vaccination elicits robust and stable antibody responses in older LTCF 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.

12.
Lancet Healthy Longev ; 3(1): e13-e21, 2022 01.
Article in English | MEDLINE | ID: covidwho-1665611

ABSTRACT

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.


Subject(s)
COVID-19 , Pandemics , Antibodies, Viral , Female , Humans , Long-Term Care , Nucleocapsid , Prevalence , Prospective Studies , SARS-CoV-2 , State Medicine
13.
Lancet Infect Dis ; 21(11): 1529-1538, 2021 11.
Article in English | MEDLINE | ID: covidwho-1637724

ABSTRACT

BACKGROUND: The effectiveness of SARS-CoV-2 vaccines in older adults living in long-term care facilities is uncertain. We investigated the protective effect of the first dose of the Oxford-AstraZeneca non-replicating viral-vectored vaccine (ChAdOx1 nCoV-19; AZD1222) and the Pfizer-BioNTech mRNA-based vaccine (BNT162b2) in residents of long-term care facilities in terms of PCR-confirmed SARS-CoV-2 infection over time since vaccination. METHODS: The VIVALDI study is a prospective cohort study that commenced recruitment on June 11, 2020, to investigate SARS-CoV-2 transmission, infection outcomes, and immunity in residents and staff in long-term care facilities in England that provide residential or nursing care for adults aged 65 years and older. In this cohort study, we included long-term care facility residents undergoing routine asymptomatic SARS-CoV-2 testing between Dec 8, 2020 (the date the vaccine was first deployed in a long-term care facility), and March 15, 2021, using national testing data linked within the COVID-19 Datastore. Using Cox proportional hazards regression, we estimated the relative hazard of PCR-positive infection at 0-6 days, 7-13 days, 14-20 days, 21-27 days, 28-34 days, 35-48 days, and 49 days and beyond after vaccination, comparing unvaccinated and vaccinated person-time from the same cohort of residents, adjusting for age, sex, previous infection, local SARS-CoV-2 incidence, long-term care facility bed capacity, and clustering by long-term care facility. We also compared mean PCR cycle threshold (Ct) values for positive swabs obtained before and after vaccination. The study is registered with ISRCTN, number 14447421. FINDINGS: 10 412 care home residents aged 65 years and older from 310 LTCFs were included in this analysis. The median participant age was 86 years (IQR 80-91), 7247 (69·6%) of 10 412 residents were female, and 1155 residents (11·1%) had evidence of previous SARS-CoV-2 infection. 9160 (88·0%) residents received at least one vaccine dose, of whom 6138 (67·0%) received ChAdOx1 and 3022 (33·0%) received BNT162b2. Between Dec 8, 2020, and March 15, 2021, there were 36 352 PCR results in 670 628 person-days, and 1335 PCR-positive infections (713 in unvaccinated residents and 612 in vaccinated residents) were included. Adjusted hazard ratios (HRs) for PCR-positive infection relative to unvaccinated residents declined from 28 days after the first vaccine dose to 0·44 (95% CI 0·24-0·81) at 28-34 days and 0·38 (0·19-0·77) at 35-48 days. Similar effect sizes were seen for ChAdOx1 (adjusted HR 0·32, 95% CI 0·15-0·66) and BNT162b2 (0·35, 0·17-0·71) vaccines at 35-48 days. Mean PCR Ct values were higher for infections that occurred at least 28 days after vaccination than for those occurring before vaccination (31·3 [SD 8·7] in 107 PCR-positive tests vs 26·6 [6·6] in 552 PCR-positive tests; p<0·0001). INTERPRETATION: Single-dose vaccination with BNT162b2 and ChAdOx1 vaccines provides substantial protection against infection in older adults from 4-7 weeks after vaccination and might reduce SARS-CoV-2 transmission. However, the risk of infection is not eliminated, highlighting the ongoing need for non-pharmaceutical interventions to prevent transmission in long-term care facilities. FUNDING: UK Government Department of Health and Social Care.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Nursing Homes/statistics & numerical data , Age Factors , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , COVID-19 Nucleic Acid Testing/statistics & numerical data , COVID-19 Vaccines/administration & dosage , England/epidemiology , Female , Humans , Immunization Schedule , Incidence , Male , Mass Vaccination/methods , Mass Vaccination/statistics & numerical data , Prospective Studies , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Treatment Outcome
14.
Nat Immunol ; 23(1): 40-49, 2022 01.
Article in English | MEDLINE | ID: covidwho-1585824

ABSTRACT

SARS-CoV-2 infection is generally mild or asymptomatic in children but a biological basis for this outcome is unclear. Here we compare antibody and cellular immunity in children (aged 3-11 years) and adults. Antibody responses against spike protein were high in children and seroconversion boosted responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Neutralization of viral variants was comparable between children and adults. Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal coronaviruses. Importantly, children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months. Therefore, children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein. These findings provide insight into the relative clinical protection that occurs in most children and might help to guide the design of pediatric vaccination regimens.


Subject(s)
Antibodies, Viral/immunology , Coronavirus 229E, Human/immunology , Coronavirus OC43, Human/immunology , Cross Protection/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adaptive Immunity/immunology , Adult , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Child , Child, Preschool , Cross Reactions/immunology , Humans
15.
SSRN; 2021.
Preprint in English | SSRN | ID: ppcovidwho-297180

ABSTRACT

Background: Age and frailty are risk factors for poor clinical outcomes following SARS-CoV-2 infection. As such, COVID-19 vaccination has been prioritised for this group but there is concern that immune responses may be impaired due to immune senescence and co-morbidity. Methods: We studied antibody and cellular immune responses following COVID-19 vaccination in 202 staff and 286 residents of long-term care facilities (LTCF). Due to the high prevalence of previous infection within this environment 50% and 51% of these two groups respectively had serological evidence of prior natural SARS-CoV-2 infection. Results: In both staff and residents with previous infection the antibody responses following dual vaccination were strong and equivalent across the age course. In contrast, within infection-naïve donors these responses were reduced by 2.4-fold and 8.1-fold respectively such that values within the resident population were 2.6-fold lower than in staff. Impaired neutralisation of delta variant spike binding was also apparent within donors without prior infection. Spike-specific T cell responses were also markedly enhanced by prior infection and within infection-naive donors were 52% lower within residents compared to staff. Post-vaccine spike-specific CD4+ T cell responses displayed single or dual production of IFN-γ+ and IL-2+ whilst previous infection primed for an extended functional profile with TNF-ɑ+ and CXCL10 production. Interpretation: These data reveal suboptimal post-vaccine immune responses within infection-naïve elderly residents of LTCF and indicate the need for further optimization of immune protection through the use of booster vaccination.

16.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-294620

ABSTRACT

SARS-CoV-2 infection is generally mild or asymptomatic in children but the biological basis for this is unclear. We studied the profile of antibody and cellular immunity in children aged 3-11 years in comparison with adults. Antibody responses against spike and receptor binding domain (RBD) were high in children and seroconversion boosted antibody responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Seroneutralisation assays against alpha, beta and delta SARS-CoV-2 variants demonstrated comparable neutralising activity between children and adults. T cell responses against spike were >2-fold higher in children compared to adults and displayed a T H 1 cytokine profile. SARS-CoV-2 spike-specific T cells were also detected in many seronegative children, revealing pre-existing responses that were cross-reactive with seasonal Alpha and Beta-coronaviruses. Importantly, all children retained high antibody titres and cellular responses at 6 months after infection whilst relative antibody waning was seen in adults. Spike-specific responses in children also remained broadly stable beyond 12 months. Children thus distinctly generate robust, cross-reactive and sustained immune responses after SARS-CoV-2 infection with focussed specificity against spike protein. These observations demonstrate novel features of SARS-CoV-2-specific immune responses in children and may provide insight into their relative clinical protection. Furthermore, this information will help to guide the introduction of vaccination regimens in the paediatric population.

17.
Euro Surveill ; 26(46)2021 11.
Article in English | MEDLINE | ID: covidwho-1526748

ABSTRACT

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.


Subject(s)
COVID-19 , Vaccines , Disease Outbreaks/prevention & control , Humans , Long-Term Care , SARS-CoV-2
18.
Elife ; 102021 09 29.
Article in English | MEDLINE | ID: covidwho-1468709

ABSTRACT

Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However, vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials. We determined the serological and cellular response to spike protein in 100 people aged 80-96 years at 2 weeks after the second vaccination with the Pfizer BNT162b2 mRNA vaccine. Antibody responses were seen in every donor with high titers in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated with humoral response. Previous SARS-CoV-2 infection substantially increased antibody responses after one vaccine and antibody and cellular responses remained 28-fold and 3-fold higher, respectively, after dual vaccination. Post-vaccine sera mediated strong neutralization of live Victoria infection and although neutralization titers were reduced 14-fold against the P.1 variant first discovered in Brazil they remained largely effective. These data demonstrate that the mRNA vaccine platform delivers strong humoral immunity in people up to 96 years of age and retains broad efficacy against the P.1 variant of concern.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , RNA, Messenger/immunology , SARS-CoV-2/immunology , Age Factors , Aged, 80 and over , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Female , Humans , Immunity, Cellular , Immunity, Humoral/immunology , Male , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods
19.
Lancet Healthy Longev ; 2(9): e554-e560, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1433992

ABSTRACT

BACKGROUND: In several countries, extended interval COVID-19 vaccination regimens are now used to accelerate population coverage, but the relative immunogenicity of different vaccines in older people remains uncertain. In this study we aimed to assess the antibody and cellular responses of older people after a single dose of either the BNT162b2 vaccine (tozinameran; Pfizer-BioNTech) or ChAdOx1 nCoV-19 vaccine (Oxford University-AstraZeneca). METHODS: Participants aged 80 years or older, who did not live in a residential or care home or require assisted living, and had received a single dose of either the BNT162b2 vaccine or ChAdOx1 nCoV-19 vaccine were eligible to participate. Participants were recruited through local primary care networks in the West Midlands, UK. Blood samples and dried blood spots were taken 5-6 weeks after vaccination to assess adaptive immune responses using Elecsys electrochemiluminescence immunoassay and cellular responses by ELISpot. Primary endpoints were percentage response and quantification of adaptive immunity. FINDINGS: Between Dec 29, 2020, and Feb 28, 2021, 165 participants were recruited and included in the analysis. 76 participants had received BNT162b2 (median age 84 years, IQR 82-89; range 80-98) and 89 had received ChAdOx1 nCoV-19 (median age 84 years, 81-87; 80-99). Antibody responses against the spike protein were detectable in 69 (93%) of 74 BNT162b2 vaccine recipients and 77 (87%) of 89 ChAdOx1 nCoV-19 vaccine recipients. Median antibody titres were of 19·3 U/mL (7·4-79·4) in the BNT162b2 vaccine recipients and 19·6 U/mL (6·1-60·0) in the ChAdOx1 nCoV-19 vaccine recipients (p=0·41). Spike protein-specific T-cell responses were observed in nine (12%) of 73 BNT162b2 vaccine recipients and 27 (31%) of 88 ChAdOx1 nCoV-19 vaccine recipients, and median responses were three-times higher in ChAdOx1 nCoV-19 vaccine recipients (24 spots per 1 × 106 peripheral blood mononuclear cells) than BNT162b2 vaccine recipients (eight spots per 1 × 106 peripheral blood mononuclear cells; p<0·0001). Humoral and cellular immune responses against spike protein were correlated in both cohorts. Evidence of previous SARS-CoV-2 infection was seen in eight participants (n=5 BNT162b2 recipients and n=3 ChAdOx1 nCoV-19 recipients), and was associated with 691-times and four-times increase in humoral and cellular immune responses across the whole cohort. INTERPRETATION: Single doses of either BNT162b2 or ChAdOx1 nCoV-19 in older people induces humoral immunity in most participants, and is markedly enhanced by previous infection. Cellular responses were weaker, but showed enhancement after the ChAdOx1 nCoV-19 vaccine at the 5-6 week timepoint. FUNDING: Medical Research Council, National Institute for Health Research, and National Core Studies.

20.
Lancet Healthy Longev ; 2(9): e544-e553, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1433991

ABSTRACT

BACKGROUND: Residents of long-term care facilities (LTCFs) have been prioritised for COVID-19 vaccination because of the high COVID-19 mortality in this population. Several countries have implemented an extended interval of up to 12 weeks between the first and second vaccine doses to increase population coverage of single-dose vaccination. We aimed to assess the magnitude and quality of adaptive immune responses following a single dose of COVID-19 vaccine in LTCF residents and staff. METHODS: From the LTCFs participating in the ongoing VIVALDI study (ISRCTN14447421), staff and residents who had received a first dose of COVID-19 vaccine (BNT162b2 [tozinameran] or ChAdOx1 nCoV-19), had pre-vaccination and post-vaccination blood samples (collected between Dec 11, 2020, and Feb 16, 2021), and could be linked to a pseudoidentifier in the COVID-19 Data Store were included in our cohort. Past infection with SARS-CoV-2 was defined on the basis of nucleocapsid-specific IgG antibodies being detected through a semiquantitative immunoassay, and participants who tested positive on this assay after but not before vaccination were excluded from the study. Processed blood samples were assessed for spike-specific immune responses, including spike-specific IgG antibody titres, T-cell responses to spike protein peptide mixes, and inhibition of ACE2 binding by spike protein from four variants of SARS-CoV-2 (the original strain as well as the B.1.1.7, B.1.351, and P.1 variants). Responses before and after vaccination were compared on the basis of age, previous infection status, role (staff or resident), and time since vaccination. FINDINGS: Our cohort comprised 124 participants from 14 LTCFs: 89 (72%) staff (median age 48 years [IQR 35·5-56]) and 35 (28%) residents (87 years [77-90]). Blood samples were collected a median 40 days (IQR 25-47; range 6-52) after vaccination. 30 (24%) participants (18 [20%] staff and 12 [34%] residents) had serological evidence of previous SARS-CoV-2 infection. All participants with previous infection had high antibody titres following vaccination that were independent of age (r s=0·076, p=0·70). In participants without evidence of previous infection, titres were negatively correlated with age (r s=-0·434, p<0·0001) and were 8·2-times lower in residents than in staff. This effect appeared to result from a kinetic delay antibody generation in older infection-naive participants, with the negative age correlation disappearing only in samples taken more than 42 days post-vaccination (r s=-0·207, p=0·20; n=40), in contrast to samples taken after 0-21 days (r s=-0·774, p=0·0043; n=12) or 22-42 days (r s=-0·437, p=0·0034; n=43). Spike-specific cellular responses were similar between older and younger participants. In infection-naive participants, antibody inhibition of ACE2 binding by spike protein from the original SARS-CoV-2 strain was negatively correlated with age (r s=-0·439, p<0·0001), and was significantly lower against spike protein from the B.1.351 variant (median inhibition 31% [14-100], p=0·010) and the P.1 variant (23% [14-97], p<0·0001) than against the original strain (58% [27-100]). By contrast, a single dose of vaccine resulted in around 100% inhibition of the spike-ACE2 interaction against all variants in people with a history of infection. INTERPRETATION: History of SARS-CoV-2 infection impacts the magnitude and quality of antibody response after a single dose of COVID-19 vaccine in LTCF residents. Residents who are infection-naive have delayed antibody responses to the first dose of vaccine and should be considered for an early second dose where possible. FUNDING: UK Government Department of Health and Social Care.

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