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BackgroundSuccessive 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 effectiveness of booster vaccination against infections, hospitalisations and deaths among LTCF residents and staff in England. MethodsWe 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 hospitalisation and death at 0-13, 14-48, 49-83 and 84 days after dose 3 of SARS-CoV-2 vaccination compared to 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. Results14175 residents and 19973 staff were included. In residents without prior SARS-CoV-2 infection, infection risk was reduced 0-83 days after first booster, but no protection was apparent after 84 days. Additional protection following booster vaccination waned, but was still present at 84+ days for COVID-associated hospitalisation (aHR: 0.47, 0.24-0.89) and death (aHR: 0.37, 0.21-0.62). Most residents (64.4%) had received primary course of AstraZeneca, but this did not impact on pre- or post-booster risks. Staff showed a similar pattern of waning booster effectiveness against infection, with few hospitalisations and no deaths. ConclusionsBooster vaccination provides sustained protection against severe outcomes following infection with the Omicron variant, but no protection against infection from 3 months onwards. Ongoing surveillance for SARS-CoV-2 in LTCFs is crucial. SummaryThe COVID-19 pandemic has severely impacted residents in long-term care facilities (LTCFs). Booster vaccination provides sustained moderate protection against severe outcomes, but no protection against infection was apparent from around 3 months onwards. Ongoing surveillance in LTCFs is crucial.
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The Omicron variant of SARS-CoV-2 is now globally dominant but despite high prevalence little is known regarding the immune response in children. We determined the antibody and cellular immune response following Omicron infection in children aged 6-14 years and related this to prior SARS-CoV-2 infection and vaccination status. Primary Omicron infection elicited a weak antibody response and only 53% of children developed detectable neutralising antibodies. In contrast, children with secondary Omicron infection following prior infection with a pre-Omicron variant developed 24-fold higher antibody titres and neutralisation of Omicron. Vaccination elicited the highest levels of antibody response and was also strongly immunogenic following prior natural infection with Omicron. Cellular responses against Omicron were robust and broadly equivalent in all study groups. These data reveal that primary Omicron infection elicits a weak humoral immune response in children and may presage a clinical profile of recurrent infection as seen with antecedent seasonal coronaviruses. Vaccination may represent the most effective approach to control infection whilst cellular immunity should offer strong clinical protection.
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BackgroundLong-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. MethodsWe 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. ResultsFor 15,518 older residents, VE declined from 50{middle dot}7% (15{middle dot}5, 71{middle dot}3) to 17{middle dot}2% ([~]23{middle dot}9, 44{middle dot}6) against infection; from 85{middle dot}4% (60{middle dot}7, 94{middle dot}.6) to 54{middle dot}3% (26{middle dot}2, 71{middle dot}7) against hospitalisation; and from 94{middle dot}4% (76{middle dot}4, 98{middle dot}7) to 62{middle dot}8% (32{middle dot}9, 79{middle dot}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{middle dot}3% (32{middle dot}7, 63{middle dot}3) to 42{middle dot}1% 29{middle dot}5, 52{middle dot}4). High VE was restored following a third dose, with VE of 71{middle dot}6% (53{middle dot}5, 82{middle dot}7) and 78{middle dot}3% (70{middle dot}1, 84{middle dot}3) against infection and 89{middle dot}9% (80{middle dot}0, 94{middle dot}6) and 95{middle dot}8% (50{middle dot}4, 99{middle dot}6) against hospitalisation, for residents and staff respectively; and 97{middle dot}5% (88{middle dot}1, 99{middle dot}5) against death for residents. InterpretationSubstantial 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. FundingUK Government Department of Health and Social Care. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe 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{middle dot}5% [60{middle dot}1-73{middle dot}5%]) and during (53{middle dot}1% [49{middle dot}1-56{middle dot}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 adjustment 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 studyWe 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{middle dot}6% (53{middle dot}5, 82{middle dot}7) and 78{middle dot}3% (70{middle dot}1, 84{middle dot}3) against infection, and 89{middle dot}9% (80{middle dot}0, 94{middle dot}6) and 95{middle dot}8% (50{middle dot}4, 99{middle dot}6) against hospitalisation, for residents and staff respectively, and to 97{middle dot}5% (88{middle dot}1, 99{middle dot}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 evidenceTaken 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.
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In contrast to the increasing levels of high avidity S antibody measured by the Roche assay in the first 6 months following natural infection, marked waning is seen post 2 or 3 doses of vaccine. Although the kinetics differ between those with vaccine-induced immunity compared to those infected prior to vaccination (hybrid immunity), waning rates appear to be similar following 2 or 3 doses of vaccine. These data should allow countries to optimise the timing of future doses of vaccine.
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BackgroundGeneral 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. MethodsVIVALDI 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. ResultsWe 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. ConclusionsDouble-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.
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BackgroundRecently there has been a rapid, global increase in SARS-CoV-2 infections associated with the Omicron variant (B.1.1.529). Although severity of Omicron cases may be reduced, the scale of infection suggests hospital admissions and deaths may be substantial. Definitive conclusions about disease severity require evidence from populations with the greatest risk of severe outcomes, such as residents of Long-Term Care Facilities (LTCFs). MethodsWe used a cohort study to compare the risk of hospital admission or death in LTCF residents in England who had tested positive for SARS-CoV-2 in the period shortly before Omicron emerged (Delta dominant) and the Omicron-dominant period, adjusting for age, sex, vaccine type, and booster vaccination. Variants were confirmed by sequencing or spike-gene status in a subset. ResultsRisk of hospital admission was markedly lower in 1241 residents infected in the Omicron-period (4.01% hospitalised, 95% CI: 2.87-5.59) compared to 398 residents infected in the pre-Omicron period (10.8% hospitalised, 95% CI: 8.13-14.29, adjusted Hazard Ratio 0.50, 95% CI: 0.29-0.87, p=0.014); findings were similar in residents with confirmed variant. No residents with previous infection were hospitalised in either period. Mortality was lower in the Omicron versus the pre-Omicron period, (p<0.0001). ConclusionsRisk of severe outcomes in LTCF residents with the SARS-CoV-2 Omicron variant was substantially lower than that seen for previous variants. This suggests the current wave of Omicron infections is unlikely to lead to a major surge in severe disease in LTCF populations with high levels of vaccine coverage and/or natural immunity. Trial Registration NumberISRCTN 14447421
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IntroductionThere are limited data on immune responses after COVID-19 vaccine boosters in individuals receiving primary immunisation with BNT162b2 (Pfizer-BioNTech) or AZD1222 (AstraZeneca). MethodsA prospective, cohort study to assess SARS-CoV-2 antibody responses before and after booster vaccination with BNT162b2 in adults receiving either (i) two BNT162b2 doses <30 days apart (BNT162b2-control), (ii) two BNT162b2 doses [≥]30 days apart (BNT162b2-extended) or (iii) two AZD1222 doses [≥]30 days apart (AZD1222-extended) in London, England. SARS-CoV-2 spike protein antibody geometric mean titres (GMTs) before and 2-4 weeks after booster were compared. ResultsOf 750 participants, 626 provided serum samples for up to 38 weeks after their second vaccine dose. Antibody GMTs peaked at 2-4 weeks after the second dose, before declining by 68% at 36-38 weeks after dose 2 for BNT162b2-control participants, 85% at 24-29 weeks for BNT162b2-extended participants and 78% at 24-29 weeks for AZD1222-extended participants. Antibody GMTs was highest in BNT162b2-extended participants (942 [95%CI, 797-1113]) than AZD1222-extended (183 [124-268]) participants at 24-29 weeks or BNT162b2-control participants at 36-38 weeks (208; 95%CI, 150-289). At 2-4 weeks after booster, GMTs were significantly higher than after primary vaccination in all three groups: 18,104 (95%CI, 13,911-23,560; n=47) in BNT162b2-control (76.3-fold), 13,980 (11,902-16,421; n=118) in BNT162b2-extended (15.9-fold) and 10,799 (8,510-13,704; n=43) in AZD1222-extended (57.2-fold) participants. BNT162b2-control participants (median:262 days) had a longer interval between primary and booster doses than BNT162b2-extended or AZD1222-extended (both median:186 days) participants. ConclusionsWe observed rapid serological responses to boosting with BNT162b2, irrespective of vaccine type or schedule used for primary immunisation, with higher post-booster responses with longer interval between primary immunisation and boosting. Boosters will not only provide additional protection for those at highest risk of severe COVID-19 but also prevent infection and, therefore, interrupt transmission, thereby reducing infections rates in the population. Ongoing surveillance will be important for monitoring the duration of protection after the booster.
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BackgroundLong Term Care Facilities (LTCF) have reported high SARS-CoV-2 infection rates and related mortality, but the proportion infected amongst survivors 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 prior infection - in staff and residents from 201 LTCFs. MethodsProspective cohort study of residents aged >65 years and staff of LTCFs in England (11 June 2020-7 May 2021). Serial blood samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid protein. Prevalence and cumulative incidence of antibody-positivity were weighted to the LTCF population. Cumulative incidence of sero-reversion was estimated from Kaplan-Meier curves. Results9488 samples were included, 8636 (91%) of which could be individually-linked to 1434 residents or 3288 staff members. The cumulative incidence of nucleocapsid seropositivity was 35% (95% CI: 30-40%) in residents and 26% (95% CI: 23-30%) in staff over 11 months. The incidence rate of loss of antibodies (sero-reversion) was 2{middle dot}1 per 1000 person-days at risk, and median time to reversion was around 8 months. InterpretationAt least one-quarter of staff and one-third of surviving residents were infected during the first two pandemic waves. 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 those with prior infection. Since natural infection may act to boost vaccine responses, better assays to identify natural infection should be developed. FundingUK Government Department of Health and Social Care. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSA search was conducted of Ovid MEDLINE and MedRxiv on 21 July 2021 to identify studies conducted in long term care facilities (LTCF) that described seroprevalence using the terms "COVID-19" or "SARS-CoV-2" and "nursing home" or "care home" or "residential" or "long term care facility" and "antibody" or "serology" without date or language restrictions. One meta-analysis was identified, published before the introduction of vaccination, that included 2 studies with a sample size of 291 which estimated seroprevalence as 59% in LTCF residents. There were 28 seroprevalence surveys of naturally-acquired SARS-CoV-2 antibodies in LTCFs; 16 were conducted in response to outbreaks and 12 conducted in care homes without known outbreaks. 16 studies included more than 1 LTCF and all were conducted in Autumn 2020 after the first wave of infection but prior to subsequent peaks. Seroprevalence studies conducted following a LTCF outbreak were biased towards positivity as the included population was known to have been previously infected. In the 12 studies that were conducted outside of known outbreaks, seroprevalence varied significantly according to local prevalence of infection. The largest of these was a cross-sectional study conducted in 9,000 residents and 10,000 staff from 362 LTCFs in Madrid, which estimated seroprevalence in staff as 31{middle dot}5% and 55{middle dot}4% in residents. However, as this study was performed in one city, it may not be generalisable to the whole of Spain and sequential sampling was not performed. Of the 28 studies, 9 undertook longitudinal sampling for a maximum of four months although three of these reported from the same cohort of LTCFs in London. None of the studies reported on antibody waning amongst the whole resident population. Added value of this studyWe estimated the proportion of care home staff and residents with evidence of SARS-CoV-2 natural infection using data from over 3,000 staff and 1,500 residents in 201 geographically dispersed LTCFs in England. Population selection was independent of outbreak history and the sample is therefore more reflective of the population who reside and work in LTCFs. Our estimates of the proportion of residents with prior natural infection are substantially higher than estimates based on population-wide PCR testing, due to limited testing coverage at the start of the pandemic. 1361 individuals had at least one positive antibody test and participants were followed for up to 11 months, which allowed modelling of the time to loss of antibody in over 600 individuals in whom the date of primary infection could be reliably estimated. This is the longest reported serological follow up in a population of LTCF residents, a group who are known to be most at risk of severe outcomes following infection with SARS-CoV-2 and provides important evidence on the duration that nucleocapsid antibodies remained detectable over the first and second waves of the pandemic. Implications of all available researchA substantial proportion of the LTCF population will have some level of natural immunity to infection as a result of past infection. Immunological studies have highlighted greater antibody responses to vaccination in seropositive individuals, so vaccine efficacy in this population may be affected by this large pool of individuals who have survived past infection. In addition, although the presence of nucleocapsid-specific antibodies is generally considered as the standard marker for prior infection, we find that antibody waning is such that up to 50% of people will lose detectable antibody responses within eight months. Individual prior natural infection history is critical to assess the impact of factors such as vaccine response or protection against re-infection. These findings may have implications for duration of immunity following natural infection and indicate that alternative assays for prior infection should be developed.
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Long term care facilities (LTCF) provide residential and/or nursing care support for frail and elderly people and many have suffered from a high prevalence of SARS-CoV-2 infection. Although mortality rates have been high in LTCF residents there is little information regarding the features of SARS-CoV-2-specific immunity after infection in this setting or how this may influence immunity to other infections. We studied humoral and cellular immunity against SARS-CoV-2 in 152 LTCF staff and 124 residents over a prospective 4-month period shortly after the first wave of infection and related viral serostatus to heterologous immunity to other respiratory viruses and systemic inflammatory markers. LTCF residents developed high levels of antibodies against spike protein and RBD domain which were stable over 4 months of follow up. Nucleocapsid-specific responses were also elevated in elderly donors but showed waning across all populations. Antibodies showed stable and equivalent levels of functional inhibition against spike-ACE2 binding in all age groups with comparable activity against viral variants of concern. SARS-CoV-2 seropositive donors showed high levels of antibodies to other beta-coronaviruses but serostatus did not impact humoral immunity to influenza or RSV. SARS-CoV-2-specific cellular responses were equivalent across the life course but virus-specific populations showed elevated levels of activation in older donors. LTCF residents who are survivors of SARS-CoV-2 infection thus show robust and stable immunity which does not impact responses to other seasonal viruses. These findings augur well for relative protection of LTCF residents to re-infection. Furthermore, they underlie the potent influence of previous infection on the immune response to Covid-19 vaccine which may prove to be an important determinant of future vaccine strategy. One sentence summeryCare home residents show waning of nucleocapsid specific antibodies and enhanced expression of activation markers on SARS-CoV-2 specific cells
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IntroductionIn January 2021, the UK decided to prioritise the delivery of the first dose of BNT162b2 (Pfizer/BioNTech) and AZD1222 (AstraZeneca) vaccines by extending the interval until the second dose up to 12 weeks. MethodsSerological responses were compared after BNT162b2 and AZD1222 vaccination with varying intervals in uninfected and previously-infected adults aged 50-89 years. These findings are evaluated against real-world national vaccine effectiveness (VE) estimates against COVID-19 in England. ResultsWe recruited 750 participants aged 50-89 years, including 126 (16.8%) with evidence of previous infection; 421 received BNT162b2 and 329 and AZD1222. For both vaccines, over 95% had seroconverted 35-55 days after dose one, and 100% seroconverted 7+ days after dose 2. Following a 65-84 day interval between two doses, geometric mean titres (GMTs) at 14-34 days were 6-fold higher for BNT162b2 (6703; 95%CI, 5887-7633) than AZD1222 (1093; 806-1483), which in turn were higher than those receiving BNT162b2 19-29 days apart (694; 540 - 893). For both vaccines, VE was higher across all age-groups from 14 days after dose two compared to one dose, but the magnitude varied with interval between doses. Higher two-dose VE was observed with >6 week intervals between BNT162b2 doses compared to the authorised 3-week schedule, including [≥]80 year-olds. ConclusionOur findings support the UK approach of prioritising the first dose of COVID-19 vaccines, with evidence of higher protection following extended schedules. Given global vaccine constraints, these results are relevant to policymakers, especially with highly transmissible variants and rising incidence in many countries. FundingPublic Health England
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ObjectivesTo assess the relative immunogenicity of standard or extended interval BNT162b2 vaccination. DesignPopulation based cohort study comparing immune responses 2 weeks after the second vaccine, with appropriate time-matched samples in participants who received standard or extended interval double vaccination. SettingPrimary care networks, Birmingham, UK. December 2020 to April 2021. Participants172 people aged over 80 years of age. All donors received the BNT162b2 Pfizer/BioNTech vaccination and were vaccinated with either a standard 3 week interval between doses or an extended interval schedule. Main outcome measuresPeak quantitative spike-specific antibody and cellular immune responses. ResultsIn donors without evidence of previous infection the peak antibody response was 3.5-fold higher in donors who had undergone delayed interval vaccination. Cellular immune responses were 3.6-fold lower. ConclusionPeak antibody responses after the second BNT162b2 vaccine are markedly enhanced in older people when this is delayed to 12 weeks although cellular responses are lower. Extended interval vaccination may therefore offer the potential to enhance and extend humoral immunity. Further follow up is now required to assess long term immunity and clinical protection. What is already known on this topicThe BNT162b2 vaccine is highly effective against Covid-19 infection and was delivered with a 3-week time interval in registration studies. However, this interval has been extended in many countries in order to extend population coverage with a single vaccine. It is not known how immune responses after the second dose are influenced by delaying the second vaccine. What this study addsWe provide the first assessment of immune responses in the first 14 weeks after standard or extended interval BNT162b2 vaccination and show that delaying the second dose acts to strongly boost the peak antibody response in older people. The extended interval vaccination may offer a longer period of clinical protection. This information will be of value in optimizing vaccine regimens and help guide guide vaccination policies.
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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 TH1 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.
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BackgroundThe effectiveness of SARS-CoV-2 vaccines in frail older adults living in Long-Term Care Facilities (LTCFs) is uncertain. We estimated protective effects of the first dose of ChAdOx1 and BNT162b2 vaccines against infection in this population. MethodsCohort study comparing vaccinated and unvaccinated LTCF residents in England, undergoing routine asymptomatic testing (8 December 2020 - 15 March 2021). We estimated the relative hazard of PCR-positive infection using Cox proportional hazards regression, adjusting for age, sex, prior infection, local SARS-CoV-2 incidence, LTCF bed capacity, and clustering by LTCF. ResultsOf 10,412 residents (median age 86 years) from 310 LTCFs, 9,160 were vaccinated with either ChAdOx1 (6,138; 67%) or BNT162b2 (3,022; 33%) vaccines. A total of 670,628 person days and 1,335 PCR-positive infections were included. Adjusted hazard ratios (aHRs) for PCR-positive infection relative to unvaccinated residents declined from 28 days following the first vaccine dose to 0{middle dot}44 (0{middle dot}24, 0{middle dot}81) at 28-34 days and 0{middle dot}38 (0{middle dot}19, 0{middle dot}77) at 35-48 days. Similar effect sizes were seen for ChAdOx1 (aHR 0{middle dot}32 [0{middle dot}15-0{middle dot}66] and BNT162b2 (aHR 0{middle dot}35 [0{middle dot}17, 0{middle dot}71]) vaccines at 35-48 days. Mean PCR cycle threshold values were higher, implying lower infectivity, for infections [≥]28 days post-vaccination compared with those prior to vaccination (31{middle dot}3 vs 26{middle dot}6, p<0{middle dot}001). InterpretationThe first dose of BNT162b2 and ChAdOx1 vaccines was associated with substantially reduced SARS-CoV-2 infection risk in LTCF residents from 4 weeks to at least 7 weeks. FundingUK Government Department of Health and Social Care. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe conducted a systematic search for studies which evaluated SARS-CoV-2 vaccine effectiveness in residents of long-term care facilities (LTCFs) published between 01/01/2020 and 11/03/2021. We used variations of search terms for "COVID-19" AND "vaccine effectiveness" OR "vaccine efficacy" AND "care homes" OR "long term care facilities" OR "older people" on Ovid MEDLINE and MedRxiv. We identified one pre-print article regarding LTCFs in Denmark, which reported that a single dose of BNT162b was ineffective against SARS-CoV-2 infection in residents, however, participants received the second vaccine dose 24 days following the first dose on average, which is likely to be too soon to capture the protective effects of a single vaccine dose. Additionally, we identified two pre-print reports of studies evaluating vaccine effectiveness against symptomatic infection and hospitalisation amongst older adults in the community. The first of these found 81% vaccine effectiveness against COVID-19-related hospitalisation at 28-34 days following a single dose of BNT162b or ChAdOx1 in [≥]80-year-olds. The second of these found vaccine effectiveness against symptomatic infection of 60% at 28-34 days and 73% at 35+ days following a single dose of ChAdOx1 in [≥]70-year-olds. No studies were identified that focused on the effectiveness of a single vaccine dose against infection amongst LTCF residents at more than 4 weeks post-vaccination, a particularly important question in the context of the UK policy decision to extend the dose interval beyond 3 weeks. Added value of this studyWe conducted a prospective cohort study of 10,412 residents aged [≥]65 years, from 310 LTCFs across England, to investigate the protective effect of the first dose of the ChAdOx1 and BNT162b vaccines against SARS-CoV-2 infection in frail older adults. We retrieved results from routine monthly PCR testing, as well as outbreak and clinical testing for SARS-CoV-2, thereby capturing data on asymptomatic as well as symptomatic infections, which we linked to vaccination records. We estimated vaccine effectiveness to be 56% (19-76%) at 28-34 days, and 62% (23-81%) at 35-48 days following a single dose of ChAdOx1 or BNT162. Our findings suggest that the risk of SARS-CoV-2 infection is substantially reduced from 28 days following the first dose of either vaccine and that this effect is maintained for at least 7 weeks, with similar protection offered by both vaccine types. We also found that PCR cycle threshold (Ct) values, which are negatively associated with the ability to isolate virus, were significantly higher in infections occurring at [≥] 28days post vaccination compared to those occurring in the unvaccinated period, suggesting that vaccination may reduce onward transmission of SARS-CoV-2 in breakthrough infections. To the best of our knowledge, our findings constitute the first real-world evidence on vaccine effectiveness against infection for ChAdOx1, in any age group. We can also infer that both vaccines are effective against the B.1.1.7 variant, because our analysis period coincided with the rapid emergence of B.1.1.7 in England during the second wave of the pandemic. Implications of all the available evidenceOur findings add to the growing body of evidence on the protective effect of the BNT162b vaccines in residents of LTCFs and demonstrate the effectiveness of ChAdOx1 in this vulnerable population. Evaluating single-dose vaccine efficacy has become increasingly important in light of extended dosing intervals that have been implemented in order to maximise vaccine coverage across high-risk groups. Further work is required to evaluate the effectiveness of the first vaccine dose after 8-12 weeks, as well as following the second dose, and to evaluate the long-term impact of vaccination on SARS-CoV-2 infection, transmission and mortality in LTCFs. This will inform policy decisions regarding the ongoing need for disease control measures in LTCF such as visitor restrictions, which continue to have a detrimental impact on the wellbeing of residents, their relatives, and staff. Supplementary material attached.
ABSTRACT
BackgroundSARS-CoV-2 infection represents a major challenge for Long Term Care Facilities (LTCFs) and many residents and staff are now sero-positive following persistent outbreaks. We investigated the relationship between the presence of SARS-CoV-2 specific antibodies and subsequent infection in this population. MethodsProspective cohort study of infection in staff and residents in 100 LTCFs in England between October 2020 and February 2021. Blood samples were collected at baseline (June 2020), 2 and 4 months and tested for IgG antibodies to nucleocapsid and spike protein. PCR testing for SARS-CoV-2 was undertaken weekly in staff and monthly in residents. The primary analysis estimated the relative hazard of a PCR-positive test by baseline antibody status, from Cox regression adjusted for age and gender, and stratified by LTCF. FindingsStudy inclusion criteria were met by 682 residents and 1429 staff. Baseline IgG antibodies to nucleocapsid were detected in 226 residents (33%) and 408 staff (29%). A total of 93 antibody-negative residents had a PCR-positive test (0.054 per month at risk) compared to 4 antibody-positive residents (0.007 per month at risk). There were 111 PCR-positive tests in antibody-negative staff (0.042 per month at risk) compared to 10 in antibody-positive staff (0.009 per month at risk). The adjusted hazard ratios for reinfection in staff and residents with a baseline positive versus negative antibody test were 0.13 (95% CI 0.05-0.40) and 0.39 ((95% CI: 0.19-0.77) respectively. Of 12 reinfected participants with data on symptoms, 11 were symptomatic. Antibody titres to spike and nucleocapsid were comparable in PCR-positive and PCR-negative cases. InterpretationThe presence of IgG antibodies to nucleocapsid was associated with substantially reduced risk of reinfection in staff and residents for up to 10 months after primary infection. FundingUK Government Department of Health and Social Care Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe performed a systematic search of MEDLINE (Ovid) and MedRxiv on 18 January 2021 for studies in LTCFs that described the risk of infection in individuals who were seropositive for SARS-CoV-2 compared to individuals who were seronegative. Search terms were deliberately broad to improve capture of relevant literature and included "SARS-CoV-2"OR "COVID-19" OR "coronavirus" AND "care home" OR "nursing home" OR "long term care facility" with no date or language restrictions. We did not identify any publications that focussed on risk of reinfection in seropositive individuals, but subsequent to our search one study has been published using data from two LTCFs in London, UK. This study reported a 96% reduction in the odds of reinfection in individuals who were seropositive compared to those who were seronegative based on 4-month follow-up in 161 participants. We found 10 studies that performed seroprevalence surveys in either staff or staff and residents in LTCFs in 8 cohorts. Five of these were carried out in response to SARS-CoV-2 outbreaks within the care homes, either as part of the subsequent investigation or as post-infection surveillance. The largest of these, which enrolled both staff and residents, was performed in 6 LTCFs and performed longitudinal antibody testing. Added value of this studyWe undertook a cohort study in staff and residents from 100 LTCFs in England to investigate whether individuals with evidence of prior SARS-CoV-2 infection could be infected twice. Staff and residents were offered up to three rounds of antibody testing and antibody results were linked to PCR test results which were obtained weekly from staff and monthly from residents through the national SARS-CoV-2 testing programme. This study, which was conducted in >2000 staff and residents, suggests that antibodies provide high levels of protection against reinfection for up to 10 months. Almost all cases of reinfection were symptomatic, but no cases required hospital treatment. Amongst those with detectable baseline antibodies, quantitative antibody titres against spike protein and nucleocapsid were comparable between cases of reinfection and those who did not become reinfected. Implications of all available evidenceDespite high background rates of infection in LTCFs, the overall risk of reinfection was low in this population. This is broadly consistent with findings from large cohort studies of hospital staff, but, importantly, extends the evidence of substantial protection to frail elderly, who are vulnerable to severe outcomes of SARS-CoV-2 due to age-related changes in immunity (immune-senescence) and high levels of comorbidity. The low risk of reinfection in our study suggests identification of immune correlates of protection in this population will require pooling of data across multiple cohorts. As vaccination coverage in residents approaches 100% in England, it will be important to understand whether vaccination and natural infection provide comparable levels of protection against infection. Such insights will inform future policy decisions regarding re-vaccination schedules in LTCF, and the longer-term need for non-pharmaceutical interventions to prevent SARS-CoV-2 transmission, such as asymptomatic testing and visitor restrictions.
ABSTRACT
The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT and/or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a setpoint for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.