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.

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.

Heterogenous Cellular and Humoral Immune Trajectories after SARS-CoV-2 Infection: Compensatory Responses in a Population-Based Cohort

To better understand the development of immunity against SARS-CoV-2 over time, we evaluated humoral and cellular responses a population-based cohort of SARS-CoV-2-infected individuals covering the full spectrum of COVID-19 up to 217 days after diagnosis. We characterized anti-Spike (S)-IgA and -IgG antibody responses in 431 individuals and found that about 85% develop and maintain anti-S-IgG responses over time. In a subsample of 64 participants selected for a detailed characterization of immune responses, we additionally evaluated anti-Nucleocapsid (N)-IgG antibodies and T cell responses specific to viral Membrane (M), N, and S proteins. Most participants had detectable T cell responses to at least one of the four peptide pools analyzed, which were more frequent than antibody seropositivity. We found a moderate correlation between antibody and T cell responses, which declined over time and suggests important variability in response patterns between individuals. The heterogeneity of immune trajectories was further analyzed using cluster analyses taking into account joint antibody and T cell responses over time. We identified five distinct immune trajectory patterns, which were characterized by specific antibody, T cell and T cell subset patterns along with disease severity and demographic factors. Higher age, male sex, higher disease severity and being a non-smoker was significantly associated with stronger immune responses. Overall, the results highlight that there is a consistent and maintained antibody response among most SARS-CoV-2-infected individuals, while T cell responses appear to be more heterogenous but potentially compensatory among those with low antibody responses. One Sentence SummaryPresence of heterogenous immune response trajectories after SARS-CoV-2 infection with potential compensatory role of T cells among individuals with low antibody responses.

Estimating the burden of post-COVID-19 syndrome in a population-based cohort study of SARS-CoV-2 infected individuals: Implications for healthcare service planning

BackgroundLonger-term consequences after SARS-CoV-2 infection are becoming an important burden to societies and healthcare systems. Data on post-COVID-19 syndrome in the general population are required for the timely planning of healthcare services and resources. The objective of this study was to assess the prevalence of impaired health status and physical and mental health symptoms among individuals at least six months after SARS-CoV-2 infection, and to characterize their healthcare utilization. MethodsThis population-based prospective cohort study (Zurich SARS-CoV-2 Cohort) enrolled 431 adults from the general population with polymerase chain reaction-confirmed SARS-CoV-2 infection reported to health authorities between 27 February 2020 and 05 August 2020 in the Canton of Zurich, Switzerland. We evaluated the proportion of individuals reporting not to have fully recovered since SARS-CoV-2 infection, and the proportion reporting fatigue (Fatigue Assessment Scale), dyspnea (mMRC dyspnea scale) or depression (DASS-21) at six to eight months after diagnosis. Furthermore, the proportion of individuals with at least one healthcare contact after their acute illness was evaluated. Multivariable logistic regression models were used to assess factors associated with these main outcomes. ResultsSymptoms were present in 385 (89%) participants at diagnosis and 81 (19%) were initially hospitalized. At six to eight months, 111 (26%) reported not having fully recovered. 233 (55%) participants reported symptoms of fatigue, 96 (25%) had at least grade 1 dyspnea, and 111 (26%) had DASS-21 scores indicating symptoms of depression. 170 (40%) participants reported at least one general practitioner visit related to COVID-19 after acute illness, and 10% (8/81) of initially hospitalized individuals were rehospitalized. Individuals that have not fully recovered or suffer from fatigue, dyspnea or depression were more likely to have further healthcare contacts. However, a third of individuals (37/111) that have not fully recovered did not seek further care. ConclusionsIn this population-based study, a relevant proportion of participants suffered from longer-term consequences after SARS-CoV-2 infection. With millions infected across the world, our findings emphasize the need for the timely planning of resources and patient-centered services for post-COVID-19 care. RegistrationISRCTN14990068

Digital proximity tracing app notifications lead to faster quarantine in non-household contacts: results from the Zurich SARS-CoV-2 Cohort Study

BackgroundDigital proximity tracing (DPT) apps may warn exposed individuals faster than manual contact tracing (MCT), leading to earlier interruption of transmission chains through quarantine. However, it is yet unclear whether these apps lead to a reduction in transmissions under real-world conditions. This study aimed at evaluating whether the SwissCovid DPT app is effective in warning close contacts of SARS-CoV-2 infected cases and prompting them to quarantine earlier. MethodsA population-based sample of adult index cases and close contacts identified through MCT and enrolled in the Zurich SARS-CoV-2 Cohort study were surveyed regarding use of the SwissCovid app and SARS-CoV-2 exposure setting. We analyzed ooutcomes related to app effectiveness and adherence (i.e., receipt and uploading of notification codes by index cases; receipt of app warnings and steps taken by close contacts). Furthermore, we performed adjusted time-to-event analyses stratified by exposure setting to estimate the effect of the app on time between relevant exposure and entering quarantine among close contacts. FindingsWe included 393 index cases and 261 close contacts in the analysis. Among index cases using SwissCovid, 88% reported receiving and uploading a notification code in the app to trigger a warning among proximity contacts. Among close contacts using the app, 38% reported receiving an app warning due to the risk exposure. We found that non-household contacts who were notified by the app started quarantine at a median of 2 days after exposure, while those not notified started quarantine at a median of 3 days. In stratified multivariable analyses, app notified contacts had a greater probability of going into quarantine earlier than those without app notification (HR 1{middle dot}53, 95% CI 1{middle dot}15-2{middle dot}03). InterpretationOur study showed that non-household contacts notified by the app started quarantine one day earlier than those not notified by the app. These findings constitute the first evidence that DPT may reach exposed contacts faster than MCT, leading to earlier quarantine and potential interruption of SARS-CoV-2 transmission chains. FundingCantonal Health Directorate Zurich, University of Zurich Foundation and the Swiss Federal Office of Public Health.