Association between serologically confirmed COVID-19 infection and cognitive functioning in community dwelling older adults.

Introduction: COVID-19 infection can impact the central nervous system, and is often associated with cognitive decline. However, there are no studies linking serologically confirmed COVID-19 infection with objectively assessed cognitive functioning. We explored whether presence of SARS-CoV-2 antibodies account for variability in participants' scores on a neuropsychological assessment. Methods: In this cross-sectional study participants were 657 (mean age = 72.97; SD = 6.07 years; women = 47.7%) individuals randomly selected from the general population of the canton of Zurich and included in the Corona Immunitas study. We conducted serological tests between October 2020 and May 2021 to detect and quantify SARS-CoV-2 antibodies in peripheral venous blood samples. We assessed cognitive function, vaccination status (vaccinated; not vaccinated), number of health conditions, and demographic variables between January and August 2021. We studied the association between seropositivity and global cognitive function and five cognitive domains (language expression, language comprehension, temporal orientation, spatial orientation, and memory) with linear regression models. Based on SARS-CoV-2 antibodies and vaccination status, we stratified participants into three groups: No SARS-CoV-2 antibodies (N = 402); SARS-CoV-2 antibodies due to vaccination (N = 218); history of SARS-CoV-2 infection and no vaccination (N = 37). Results: In the regression model adjusted for age, sex, educational level, and number of health conditions, compared to those without SARS-CoV-2 antibodies, those with SARS-CoV-2 antibodies due to vaccination had better global cognitive functioning (Standardized beta = 0.10; 95% CI = 0.02; 0.17), and those with SARS-CoV-2 antibodies due to infection had poorer cognitive functioning (Standardized beta = -0.10; 95% CI = -0.18; -0.03). Regarding cognitive domains, compared to those without SARS-CoV-2 antibodies, those with SARS-CoV-2 antibodies due to infection scored more poorly on language comprehension and temporal orientation, and those with SARS-CoV-2 antibodies due to vaccination scored better on memory. Discussion: By linking serologically confirmed presence of SARS-CoV-2 antibodies to poorer global cognitive functioning in community dwelling older adults we strengthen existing evidence in support of cognitive decline related to COVID-19. Given the large number of infected older adults, and the endurance of the pandemic, our results highlight the need to address COVID-19 related cognitive decline in the clinical and public health areas of prevention, diagnosis, and treatment.

Development of hybrid immunity during a period of high incidence of infections with Omicron subvariants: A prospective population based multi-region cohort study

BackgroundSeroprevalence and the proportion of people with neutralizing activity against SARS-CoV-2 variants was high in early 2022. Since it is unclear how immunity in the general population evolves, the aim of this study was to assess the development of functional and hybrid immunity in the general population during a period of high incidence of infections with Omicron variants. MethodsThis prospective population based multi-region cohort study is part of the Corona Immunitas research programme in Switzerland. In March 2022, we randomly selected individuals from the general population in southern (canton of Ticino) and north-eastern (canton of Zurich) Switzerland, who were assessed again in June/July 2022. We supplemented the June/July 2022 sample with a random sample from western Switzerland (canton of Vaud). We assessed SARS-CoV-2 specific IgG antibodies against spike and nucleocapsid proteins and the presence of SARS-CoV-2 neutralising antibodies against three variants (wildtype, Delta, Omicron). FindingsIn June/July 2022, seroprevalence was >98% in 2553 individuals from the general Swiss population. The proportion of individuals with neutralising antibodies against wildtype, Delta, and Omicron was 94.2%, 90.8%, and 84.9%, and at least 51% of the participants developed hybrid immunity. Individuals with hybrid immunity had, compared to those with only vaccine- or infection-induced immunity, highest levels of both, anti-spike IgG antibodies titres (4518 vs. 4304 vs. 269 WHO U/ml) and neutralisation capacity against wildtype (99.8% vs. 98% vs. 47.5%), Delta (99% vs. 92.2% vs. 38.7%), and Omicron (96.4% vs. 79.5% vs. 47.5%). InterpretationThis first study on functional and hybrid immunity in the general population after Omicron waves showed that SARS-CoV-2 has become endemic. The high levels of antibodies and neutralization in the general populations support the emerging recommendations of some countries where booster vaccinations are still strongly recommended for vulnerable persons but less strongly recommended for individuals in the general population. FundingThe Corona Immunitas research network is coordinated by the Swiss School of Public Health (SSPH+) and funded by fundraising of SSPH+ including funds of the Swiss Federal Office of Public Health and private funders (ethical guidelines for funding stated by SSPH+ were respected), by funds of the cantons of Switzerland (Vaud, Zurich, and Basel), and by institutional funds of the Universities. Study registrationISRCTN18181860 Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched Pubmed, Medline, Scopus and Web of Knowledge, for primary population-based studies prospectively assessing infection-, vaccine-induced, and hybrid immunity and the respective neutralising activity of antibodies against SARS-CoV-2 and its variants of concern. We included articles published between 1 January and 28 September 2022, without language restrictions, and retrieved 540 publications after deduplication. None of the screened studies measured the prevalence of immune response and neutralisation capacity prospectively in population-based, representative samples accounting for type of acquired immunity. Evidence from five studies, all conducted in non-representative, convenience and relatively small samples (N<254), and/or in sub-populations (e.g., healthcare workers and children), shows that hybrid immunity confers higher immune protection and exhibits better neutralising capacity compared to vaccine- and infection-induced immunity. Furthermore, one of the screened studies highlights that antibodies developed by individuals with hybrid immunity show the slowest decline over a period of 10 months. Added value of this studyWe took advantage of an ongoing cohort study on anti-SARS-CoV-2 seroprevalence conducted in a representative sample of the general Swiss population (N=2553) using standard, previously validated methods, to measure changes over time in seroprevalence, neutralisation capacity against wildtype and variants of concerns of the virus (i.e., ACE2r-block), waning of antibodies, and new infections. This is the first study, conducted in the general population and during the pandemic phase characterized by very high incidence of Omicron infections, to assess the extent of hybrid immunity (51%) and neutralising antibodies against the wildtype (94.2%), Delta (90.8%), and Omicron variants (84.9%). Our findings show that individuals with hybrid immunity, compared to those with only vaccine- or infection-induced immunity, had the highest levels of both anti-spike IgG antibodies titres and neutralisation capacity against wildtype, Delta, and Omicron variants. We also found that, from March to June/July 2022, anti-spike IgG antibodies remained stable in the general population (>96%), while anti-nucleocapsid IgG antibodies fluctuated due to their fast waning (7.3% of participants anti-nucleocapsid IgG antibodies became undetectable) and the parallel spread of Omicron infections (18.6% of participants acquired anti-nucleocapsid IgG antibodies). Implications of all the available evidenceBy mid-2022, SARS-CoV-2 has become endemic, and a majority of individuals developed hybrid immunity with high levels of neutralisation against the wildtype, Delta, and Omicron variants of SARS-CoV-2. Combined with existing evidence, our results indicate that hybrid immunity confers higher levels of neutralising activity compared to both vaccine-induced and infection-induced immunity. This study extends findings on the immunological protection conferred by hybrid immunity from sub-populations to the general population. The high levels of antibodies and neutralization in the general populations support the emerging recommendations of some countries where booster vaccinations are still strongly recommended for vulnerable persons but less strongly recommended for individuals in the general population. Monitoring the prevalence, waning, and neutralising activity of antibodies against potential new variants of concern in populations remains crucial.

Comparative adverse effects, perceptions and attitudes related to BNT162b2, mRNA1273, or JNJ-78436735 SARS-CoV-2 vaccines: A population-based longitudinal cohort

ImportanceLong-term control of SARS-CoV-2 requires effective vaccination strategies. This has been challenged by public mistrust and spread of misinformation regarding vaccine safety. Hence, better understanding and communication on the longer-term and comparative experiences of general population individuals following SARS-CoV-2 vaccination are required. ObjectiveTo evaluate and compare self-reported adverse effects following SARS-CoV-2 vaccination, participants perceptions regarding vaccinations and their compliance with recommended public health measures. Design, Setting and ParticipantsPopulation-based longitudinal cohort of 575 adults, randomly selected from all individuals presenting to the reference vaccination center of the Canton of Zurich, Switzerland, for receipt of BNT162b2, mRNA1273, or JNJ-78436735. ExposuresBNT162b2, mRNA1273, or JNJ-78436735 vaccines. Main Outcomes and MeasuresPrimary outcomes included period prevalence, onset, duration, and severity of self-reported adverse effects over 12 weeks following vaccination with a specific focus on the proportion of participants reporting allergic reactions, menstrual irregularities, or cardiac adverse effects, or requiring hospitalization. Secondary outcomes included risk factors associated with reporting adverse effects, perception of vaccine importance, trust in public health authorities and pharmaceutical companies, and compliance with recommended public health measures. Results454 (79.0%) participants reported at least one adverse effect during 12 weeks after vaccination. Prevalence was highest among mRNA-1273 recipients (88.7% vs. 77.3% after BNT162b2, 69.1% after JNJ-78436735). Most adverse effects were systemic (72%), occurred within 24 hours (67.9%), and resolved in less than three days (76.3%). 85.2% were reported as mild or moderate. Allergic reactions were reported by 0.4% of participants, hospitalizations by 0.7%, cardiac adverse effects by 1.4%. Menstrual irregularities were reported by 9% of female participants younger than 50 years. Female sex, younger age, higher education, and receipt of mRNA-1273 were associated with reporting adverse effects. Compared to JNJ-78436735 recipients, a higher proportion of mRNA vaccine recipients agreed that vaccination is important (87.5% vs. 28.5%), and trusted public health authorities (80.2% vs. 30.3%) and pharmaceutical companies (71.7% vs. 23.6%). Conclusions and RelevanceOur population-based cohort provided real-world data on self-reported adverse effects following SARS-CoV-2 vaccination and highlights the importance of transparent communication regarding adverse effects and building trust in public health authorities to ensure successful future vaccination campaigns. Main PointsOur representative population-based cohort study demonstrated the safety of three SARS-CoV-2 vaccines and provides real-world estimates on adverse effect incidence.Transparent communication of expected adverse effects to vaccine-seeking individuals is pivotal to build trust in current or future vaccination campaigns.

Post COVID-19 condition after Wildtype, Delta, and Omicron variant SARS-CoV-2 infection and vaccination: pooled analysis of two population-based cohorts

BackgroundPost COVID-19 condition (PCC) is an important complication of SARS-CoV-2 infection, affecting millions worldwide. Further evidence is needed on the risk of PCC after vaccination and infection with newer variants. This study aimed to evaluate the prevalence and severity of PCC across different variants and vaccination histories. MethodsWe used pooled data from 1350 SARS-CoV-2-infected individuals from two representative population-based cohorts in Switzerland, diagnosed between Aug 5, 2020, and Feb 25, 2022. We descriptively analysed the prevalence and severity of PCC, defined as the presence and frequency of PCC-related symptoms six months after infection, among vaccinated and non-vaccinated individuals infected with Wildtype, Delta, and Omicron SARS-CoV-2. We used multivariable logistic regression models to assess the association and estimate the risk reduction of PCC after infection with newer variants and prior vaccination. We further assessed associations with the severity of PCC using multinomial logistic regression. To identify groups of individuals with similar symptom patterns and evaluate differences in the presentation of PCC across variants, we performed exploratory hierarchical cluster analyses. FindingsWe found strong evidence that vaccinated individuals infected with Omicron had a reduced risk of developing PCC compared to non-vaccinated Wildtype-infected individuals (odds ratio 0.42, 95% confidence interval 0.24-0.68). The risk among non-vaccinated individuals was similar after infection with Delta or Omicron compared to Wildtype SARS-CoV-2. We found no differences in PCC prevalence with respect to the number of received vaccine doses or timing of last vaccination. The prevalence of PCC-related symptoms among vaccinated, Omicron-infected individuals was lower across severity levels. In cluster analyses, we identified four clusters of diverse systemic, neurocognitive, cardiorespiratory, and musculoskeletal symptoms, with similar patterns across variants. InterpretationThe risk of PCC appears to be lowered with infection by the Omicron variant and after prior vaccination. This evidence is crucial to guide future public health measures and vaccination strategies. FundingSwiss School of Public Health (SSPH+), University of Zurich Foundation, Cantonal Department of Health Zurich, Swiss Federal Office of Public Health Study registrationsISRCTN14990068, ISRCTN18181860 Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE, EMBASE, and medRxiv for primary studies assessing the prevalence and symptoms associated with post COVID-19 condition (PCC) after infection with different SARS-CoV-2 variants and among infected individuals with and without prior vaccination. We used a specific search strategy limited to the timeframe between Jan 01, 2020, and Aug 29, 2022, without language restriction (reported in Supplementary Table S1). We further searched identified systematic reviews for additional references. We screened 221 unique records and identified four studies investigating the association of Delta or Omicron variant infections and 11 studies investigating the association of prior vaccination with PCC. Current evidence is uncertain whether infection with emerging variants may be associated with a reduction of the risk of developing PCC. Two studies found a decreased risk of PCC with Omicron compared to Delta infection, or to individuals infected during any prior wave. One study found a lower risk of PCC with Alpha compared to Wildtype SARS-CoV-2, but an increased risk among those infected with the Delta or Omicron variant. One study primarily examined symptom clusters across different waves. All identified studies defined PCC as symptoms occurring at [≥]4 weeks or [≥]12 weeks after infection, and were conducted among hospitalised patients, healthcare workers, or users of the United Kingdom ZOE symptom app. Evidence regarding the preventive effects of vaccination on PCC was of higher certainty, with eight out of 11 studies reporting a substantially reduced PCC incidence with mRNA- and adenovirus vector-based vaccines. The magnitude of the effect in these studies varied, with estimated adjusted odds ratios ranging from 0.22 to 0.85. Nonetheless, three studies found no difference between vaccinated and non-vaccinated infected individuals, including two of three studies evaluating PCC at six months after infection. The third study with a six-month horizon found a higher odds ratio than any other study reporting a reduction at [≥]4 weeks or [≥]12 weeks. Study populations and designs varied strongly, and only one study evaluated the independent effects of SARS-CoV-2 variants and vaccination. Added value of this studyThis study investigates the association of PCC with infection with Delta and Omicron variants and prior vaccination compared to Wildtype SARS-CoV-2 infection among unvaccinated individuals. We found that infection with the Omicron variant and prior vaccination were associated with a lower risk of developing PCC six months after infection. Compared to previous work, this study is the first to evaluate PCC with a longer-term follow-up, while simultaneously evaluating the risk reduction by Delta and Omicron variants and prior vaccination on PCC. By relying on prospectively collected data from two representative population-based cohorts, we were able to provide an in-depth analysis of the longer-term risk reduction through prior vaccination and novel variants, the severity of PCC-related symptoms, and symptom clusters across pandemic waves between 2020 and early 2022. Implications of all the available evidenceIn conjunction with existing evidence, our study suggests that infection with the Omicron variant and prior vaccination are likely to substantially reduce the risk of developing PCC compared to infection with Wildtype SARS-CoV-2 without prior vaccination. We demonstrate that this risk reduction persists up to six months after infection, and that PCC-related symptoms are reduced to a similar extent across different levels of severity. However, the risk of having mild to even potentially severe PCC six months after infection is not eliminated. Hence, vaccinations will likely continue to be an important mainstay in the management of the further course of the pandemic. The prevention of further infection and PCC may still provide important benefits for public health, even if SARS-CoV-2 further evolves to cause milder infections and becomes endemic. Therefore, information from this study will be crucial to guide vaccination strategies and decisions on timing and enforcement of public health measures worldwide.

Natural course of post COVID-19 condition and implications for trial design and outcome selection: A population-based longitudinal cohort study

BackgroundEvidence from population-based studies on the longer-term natural course of post COVID-19 condition is limited, but crucial for informing patients and healthcare providers and for effectively designing clinical trials. ObjectivesTo evaluate longer-term symptoms and health outcomes within a cohort of SARS-CoV-2 infected individuals. DesignPopulation-based, longitudinal cohort. SettingGeneral population, Canton of Zurich, Switzerland. Patients1543 adults with confirmed SARS-CoV-2 infection and 628 adults without infection. MeasurementsChanges in self-reported health status over time, factors associated with persistence of non-recovery, and prevalence and excess risk of symptoms at 6 and 12 months post-infection compared to non-infected individuals. Results25% of SARS-CoV-2 infected individuals did not recover by 6 months. Of those, 67% and 58% also did not recover at 12 and 18 months after infection, respectively. Hospitalization for acute COVID-19, pre-existing fatigue and pain or discomfort, and presence of specific systemic, cardiovascular, or musculoskeletal symptoms at 6 months were associated with persistent non-recovery. Symptom prevalence was higher among infected individuals compared to non-infected individuals at 6 months (adjusted risk difference (aRD)=17%) and 12 months (aRD=20%). aRDs for individual symptoms ranged from 2% to 12%, with the highest excess risks observed for altered taste or smell, post-exertional malaise, fatigue, and reduced concentration and memory. LimitationsWe relied on self-reported assessments and did not assess the effects of vaccination or infection with emerging variants of concern. ConclusionThese findings emphasize the need for effective interventions to reduce the burden of post COVID-19 condition. They further demonstrate the importance of using multiple outcome measures and of considering the expected rates of natural recovery and heterogenous patient trajectories in the design and interpretation of clinical trials.

Variation in SARS-CoV-2 seroprevalence in school-children across districts, schools and classes

Importance: Understanding transmission and impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in school children is critical to implement appropriate mitigation measures. Objective: To determine the variation in SARS-CoV-2 seroprevalence in school children across districts, schools, grades, and classes, and the relationship of SARS-CoV-2 seroprevalence with self-reported symptoms. Design: Cross-sectional analysis of baseline measurements of a longitudinal cohort study (Ciao Corona) from June-July 2020. Setting: 55 randomly selected schools and classes stratified by district in the canton of Zurich, Switzerland (1.5 million inhabitants). Participants: Children, aged 6-16 years old, attending grades 1-2, 4-5 and 7-8. Exposure: Exposure to circulating SARS-CoV-2 between February and June 2020 including public lock-down and school closure (March 16-May 10, 2020). Main Outcomes and Measures: Variation in seroprevalence of SARS-CoV-2 in children across 12 cantonal districts, schools, and grades using a Luminex-based antibody test with four targets for each of IgG, IgA and IgM. Clustering of cases within classes. Analysis of associations of seropositivity and symptoms. Comparison of seroprevalence with a randomly selected adult population, based on Luminex-based IgG and IgA antibody test of Corona Immunitas. Results: In total, 55 schools and 2585 children were recruited (1337 girls, median age 11, age range 6-16 years). Overall seroprevalence was 2.8 % (95% CI 1.6-4.1%), ranging from 1.0% to 4.5% across districts. Seroprevalence was 3.8% (1.9-6.1%) in grades 1-2, 2.5% (1.1-4.2%) in grades 4-5, and 1.5% (0.5-3.0%) in grades 7-8. At least one case was present in 36/55 tested schools and in 43/128 classes with [≥]50% participation rate and [≥]5 children tested. 73% of children reported COVID-19 compatible symptoms since January 2020, but none were reported more frequently in seropositive compared to seronegative children. Seroprevalence of children was very similar to seroprevalence of randomly selected adults in the same region in June-July 2020, measured with the same Corona Immunitas test, combining IgG and IgA (3.1%, 95% CI 1.4-5.4%, versus 3.3%, 95% CI 1.4-5.5%). Conclusions and Relevance: Seroprevalence was inversely related to age and revealed a dark figure of around 90 when compared to 0.03% confirmed PCR+ cases in children in the same area by end of June. We did not find clustering of SARS-CoV-2 seropositive cases in schools so far, but the follow-up of this school-based study will shed more light on transmission within and outside schools. Trial registration: ClinicalTrials.gov Identifier: NCT04448717, registered June 26, 2020. https://clinicaltrials.gov/ct2/show/NCT04448717

Are COVID-19 proximity tracing apps working under real-world conditions? Indicator development and assessment of drivers for app (non-)use

Digital proximity tracing (DPT) apps have been released to mitigate SARS-CoV-2 transmission, but it remains unclear how their effectiveness should be monitored. The aim of this study was to formalize indicators for measuring the fulfillment of assumptions for appropriate proximity tracing app functioning. Six indicators were developed to monitor the SwissCovid app functioning and effectiveness in the Swiss population. Using official statistics and survey data, we calculated indicator values and examined socio-demographic factors associated with the SwissCovid app utilization. Indicators show that 1 in 3 adults in Switzerland have downloaded the app. However, only 15% of new cases also triggered DPT-app notifications, and indicators also reveal ignored app notifications. In the full survey sample (n=2098), higher monthly household income or being a non-smoker were associated with higher SwissCovid app uptake; older age or having a non-Swiss nationality with a lower uptake. In a subsample including more detailed information (n=701), high trust in health authorities was associated with higher SwissCovid app uptake. The indicators help to monitor key drivers of DPT-apps effectiveness and hint to non-compliance issues. Streamlining procedures, removing technical hurdles, and communicating the usefulness of DPT-apps are crucial to promote uptake, compliance, and ultimately effectiveness of DPT-apps for pandemic mitigation.