Effectiveness of successive booster vaccine doses against SARS-CoV-2 related mortality in residents of Long-Term Care Facilities in the VIVALDI study (preprint)

We evaluated the effectiveness of 1-3 booster vaccinations against SARS-CoV-2 related mortality among a cohort of 13407 older residents of long-term care facilities (LTCFs) participating in the VIVALDI study in England in 2022. Cox regression was used to estimate relative hazards of SARS-CoV-2 related death following booster vaccination relative to 2 doses (after 84+ days), stratified by previous SARS-CoV-2 infection and adjusting for age, sex and LTCF capacity. Each booster provided additional short-term protection relative to primary vaccination, with consistent pattern of waning to 45-75% reduction in risk beyond 112 days.

Clinical effectiveness of SARS-CoV-2 booster vaccine against Omicron infection in residents and staff of Long-Term Care Facilities: a prospective cohort study (VIVALDI) (preprint)

Background Successive 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. Methods We included residents and staff of LTCFs within the VIVALDI study ( ISRCTN 14447421 ) who underwent routine, asymptomatic testing (December 12 2021-March 31 2022). Cox regression was used to estimate relative hazards of SARS-CoV-2 infection, and associated 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. Results 14175 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. Conclusions Booster 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. Summary The 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.

Strong peak immunogenicity but rapid antibody waning following third vaccine dose in elderly residents of care homes (preprint)

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.

Duration of vaccine effectiveness against SARS-CoV2 infection, hospitalisation, and death in residents and staff of Long-Term Care Facilities (VIVALDI): a prospective cohort study, England, Dec 2020-Dec 2021 (preprint)

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.

SARS-CoV-2 anti-spike antibody levels following second dose of ChAdOx1 nCov-19 or BNT162b2 in residents of long-term care facilities in England (VIVALDI) (preprint)

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.

Severe outcomes in residents of Long Term Care Facilities following infection with SARS-CoV-2 Omicron variant (VIVALDI study) (preprint)

Background Recently 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). Methods We 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. Results Risk of hospital admission was markedly lower in 398 residents infected in the pre-Omicron period (10.8% hospitalised, 95% CI: 8.13-14.29) compared to 1241 residents infected in the Omicron-period (4.01% hospitalised, 95% CI: 2.87-5.59, 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). Conclusions Risk 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 Number: ISRCTN 14447421

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

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.

Robust SARS-CoV-2-specific and heterologous immune responses after natural infection in elderly residents of Long-Term Care Facilities (preprint)

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

Profile of Humoral and Cellular Immune Responses to Single BNT162b2 or ChAdOx1 Vaccine in Residents and Staff Within Residential Care Homes (VIVALDI Study) (preprint)

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.

Children develop strong and sustained cross-reactive immune responses against spike protein following SARS-CoV-2 infection (preprint)

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 profiles in children were strong with high titres against spike protein and receptor binding domain (RBD). SARS-CoV-2 seroconversion in children strongly boosted antibody responses against seasonal beta-coronaviruses, partly through cross-recognition of the S2 domain, indicating a broad humoral response that was not seen in adults. T cell responses against spike were also >2-fold higher in children compared to adults and displayed a strong Th1 cytokine profile. SARS-CoV-2 spike-reactive cellular responses were present in more than half the seronegative children, indicating pre-existing cross-reactive responses or sensitization against SARS-CoV-2. Importantly, all children retained high antibody titres and cellular responses for more than 6 months after infection whilst relative antibody waning was seen in adults. 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 several novel features of SARS-CoV-2-specific immune responses in children and may provide insights into relative clinical protection in this group. Such information on the profile of natural infection will help to guide the introduction of vaccination regimens into the paediatric population.

BNT162b2 Vaccination in People Over 80 Years of Age Induces Strong Humoral Immune Responses with Cross Neutralisation of P.1 Brazilian Variant (preprint)

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 20\NW\0240) and conducted according to the Declaration of Helsinki and good clinical practice.

Vaccine effectiveness of the first dose of ChAdOx1 nCoV-19 and BNT162b2 against SARS-CoV-2 infection in residents of Long-Term Care Facilities (VIVALDI study) (preprint)

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.

Incidence of SARS-CoV-2 infection according to baseline antibody status in staff and residents of 100 Long Term Care Facilities (VIVALDI study) (preprint)

Background SARS-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. Methods Prospective 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. Findings Study 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. Interpretation The 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. Funding UK Government Department of Health and Social Care Research in context Evidence before this study We 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 study We 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 evidence Despite 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.