BACKGROUND:Long-term prospective data on antibody and T-cell responses beyond the third COVID-19 mRNA vaccine dose, particularly in relation to prior SARS-CoV-2 infections and breakthrough infections, remain limited. METHODS:Health care workers (HCWs) vaccinated with BNT162b2 were enrolled in January 2021. Blood samples were collected before and one month after each of four vaccine doses through December 2022. IgG antibodies against the spike receptor-binding domain (RBD) and the nucleocapsid (N) proteins were analysed, and T-cell responses (IFN-γ, IL-2, TNF-α) were measured after spike peptide stimulation. Neutralising antibodies (NAbs) against Omicron BA.1 were assessed in a subset (n = 61). RBD-IgG and cytokine levels were compared between infected and infection-naïve individuals, adjusted for age and sex. RESULTS:Among 108 HCWs, 32% were infected before vaccination. Breakthrough infections were rare before dose 3 but increased with the emergence of Omicron, affecting 77% of the participants until study end. RBD-IgG levels were consistently significantly higher in individuals with hybrid immunity than in infection-naïve participants, except one month after dose 3. When breakthrough infections were excluded, this difference only persisted through dose 3. IFN-γ responses largely mirrored RBD-IgG, while IL-2 responses were less affected by repeat doses and TNF-α responses were highly variable. CONCLUSIONS:Individuals with hybrid immunity had significantly higher RBD-IgG levels than infection-naïve subjects up to 23 months post-vaccination when including breakthrough infections, while elevated antibody responses were limited to the first year in those infected pre-vaccination. Differences were more pronounced for antibody than T-cell responses when comparing individuals with and without breakthrough infections.

BACKGROUND AND OBJECTIVE:Post-infectious sequelae can increase burden on healthcare systems. We aimed to assess the long-term effect of COVID-19 on healthcare utilization across all levels of care. METHODS:In this register-based cohort study, we included all adult (≥18 years) residents in Sweden's two largest counties with a registered COVID-19 index date between 31 January 2020 and 9 February 2022. Each exposed individual was matched 1:1 to a control without registered COVID-19 on index date based on gender, birth year, vaccination status and the change in number of healthcare contacts between 2018 and 2019. We counted the number of healthcare contacts across all levels of care during the pre-index (13-1 months) and post-index (4-15 months) full-year periods. A difference-in-difference (DID) analysis was used to assess changes in the number of healthcare contacts and specific diagnoses, between each individual's pre- and post-periods, as well as comparing individuals with and without COVID-19. RESULTS:The study included 753,905 matched pairs, comprising 1,415,432 unique individuals. Trends in healthcare contacts were parallel between the matched groups prior to the index date. The DID analysis revealed a mean increase of 0.33 (95%CI 0.30-0.36) healthcare contacts following COVID-19, mainly observed from a smaller proportion of the population (5%) and by contacts with primary healthcare. The largest diagnosis-specific difference was observed for reactions to severe stress (0.02, 0.01-0.03). The estimate varied across gender, acute COVID-19 severity, virus variant period and vaccination status. CONCLUSION:This study demonstrates increased healthcare utilization after COVID-19 in a smaller proportion of the population.

INTRODUCTION:Patients with non-small cell lung cancer (NSCLC) faced an elevated risk for severe COVID-19 outcomes and were prioritized for early vaccination. However, immune responses to SARS-CoV-2 vaccines remain poorly characterized in this group, especially in patients receiving immune checkpoint inhibitor PD-1/PDL-1 (ICI) therapy. MATERIALS AND METHODS:In this prospective observational study, we evaluated humoral and cellular immune responses to COVID-19 vaccination in 20 NSCLC patients receiving ICI therapy and compared to responses in 38 controls. Patients received two doses of either BNT162b2 (Pfizer-BioNTech) or ChAdOx1-S (AstraZeneca) vaccines followed by a third dose of BNT162b2 while controls received three doses of BNT162b2. Serum IgG to the receptor-binding domain (RBD) of the spike protein and T-cell cytokine responses (IFN-γ, IL-2 and TNF) induced by spike peptide stimulation of whole blood were assessed at multiple time points. RESULTS AND DISCUSSION:After two doses, patients exhibited lower and more variable IgG responses than controls, but a third dose raised antibody levels to match those observed in controls. The largest fold-increase in antibody concentrations after the third dose occurred in patients receiving BNT162b2 after two doses of ChAdOx1-S. T-cell responses were significantly lower in patients after two doses but improved following the third dose. Antibody and IFN-γ responses were significantly correlated both after the second and third doses in patients, suggesting coordinated humoral and cellular immunity. No associations were found between immune responses and patient age. These findings highlight the immunogenicity of COVID-19 vaccines in NSCLC patients on ICI therapy and support that booster vaccinations are needed to enhance immunity in this vulnerable group.

Increased COVID-19-related morbidity and mortality have been reported in solid organ transplant recipients (SOTRs). Most studies are underpowered for rigorous matching. We report infections, hospitalization, ICU care, mortality from COVID-19, and pertinent vaccination data in Swedish SOTRs 2020–2021. We conducted a nationwide cohort study, encompassing all Swedish residents. SOTRs were identified with ICD-10 codes and immunosuppressant prescriptions. Comparison cohorts were weighted based on a propensity score built from potential confounders (age, sex, comorbidities, socioeconomic factors, and geography), which achieved a good balance between SOTRs and non-SOTR groups. We included 10,372,033 individuals, including 9073 SOTRs. Of the SARS-CoV-2 infected, 47.3% of SOTRs and 19% of weighted comparator individuals were hospitalized. ICU care was given to 8% of infected SOTRs and 2% of weighted comparators. The case fatality rate was 7.7% in SOTRs, 6.2% in the weighted comparison cohort, and 1.3% in the unweighted comparison cohort. SOTRs had an increased risk of contracting COVID-19 (HR = 1.15 p < 0.001), being hospitalized (HR = 2.89 p < 0.001), receiving ICU care (HR = 4.59 p < 0.001), and dying (HR = 1.42 p < 0.001). SOTRs had much higher morbidity and mortality than the general population during 2020–2021. Also compared with weighted comparators, SOTRs had an increased risk of contracting COVID-19, being hospitalized, receiving ICU care, and dying. In Sweden, SOTRs were vaccinated earlier than weighted comparators. Lung transplant recipients had the worst outcomes. Excess mortality among SOTRs was concentrated in the second half of 2021.

Objectives: The objective of this study was to provide a comprehensive characterization of patients diagnosed with post-COVID-19 condition (PCC) during the first 16 months of use of the International Classification of Diseases revision 10 (ICD-10) diagnosis code U09.9 in Sweden. Methods: We used data from national registers and primary health care databases for all adult inhabitants of the two largest regions in Sweden, comprising 4.1 million inhabitants (approximately 40% of the Swedish population). We present the cumulative incidence and incidence rate of PCC overall and among subgroups and describe patients with COVID-19 with or without PCC regarding sociodemographic characteristics, comorbidities, subsequent diseases, COVID-19 severity, and virus variants. Results: Of all registered COVID-19 cases available for PCC diagnosis (n = 506,107), 2.0% (n = 10,196) had been diagnosed with PCC using ICD-10 code U09.9 as of February 15, 2022 in the two largest regions in Sweden. The cumulative incidence was higher among women than men (2.3% vs 1.6%, P <0.001). The majority of PCC cases (n = 7162, 70.2%) had not been hospitalized for COVID-19. This group was more commonly female (69.9% vs 52.9%, P <0.001), had a tertiary education (51.0% vs 44.1%, P <0.001), and was older (median age difference 5.7 years, P <0.001) than non-hospitalized patients with COVID-19 without PCC. Conclusion: This characterization furthers the understanding of patients diagnosed with PCC and could support policy makers with appropriate societal and health care resource allocation.

OBJECTIVES:To evaluate the risks of any menstrual disturbance and bleeding following SARS-CoV-2 vaccination in women who are premenopausal or postmenopausal.DESIGN:A nationwide, register based cohort study.SETTING:All inpatient and specialised outpatient care in Sweden from 27 December 2020 to 28 February 2022. A subset covering primary care for 40% of the Swedish female population was also included.PARTICIPANTS:2 946 448 Swedish women aged 12-74 years were included. Pregnant women, women living in nursing homes, and women with history of any menstruation or bleeding disorders, breast cancer, cancer of female genital organs, or who underwent a hysterectomy between 1 January 2015 and 26 December 2020 were excluded.INTERVENTIONS:SARS-CoV-2 vaccination, by vaccine product (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 (AZD1222)) and dose (unvaccinated and first, second, and third dose) over two time windows (one to seven days, considered the control period, and 8-90 days).MAIN OUTCOME MEASURES:Healthcare contact (admission to hospital or visit) for menstrual disturbance or bleeding before or after menopause (diagnosed with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes N91, N92, N93, N95).RESULTS:2 580 007 (87.6%) of 2 946 448 women received at least one SARS-CoV-2 vaccination and 1 652 472 (64.0%) 2 580 007 of vaccinated women received three doses before the end of follow-up. The highest risks for bleeding in women who were postmenopausal were observed after the third dose, in the one to seven days risk window (hazard ratio 1.28 (95% confidence interval 1.01 to 1.62)) and in the 8-90 days risk window (1.25 (1.04 to 1.50)). The impact of adjustment for covariates was modest. Risk of postmenopausal bleeding suggested a 23-33% increased risk after 8-90 days with BNT162b2 and mRNA-1273 after the third dose, but the association with ChAdOx1 nCoV-19 was less clear. For menstrual disturbance or bleeding in women who were premenopausal, adjustment for covariates almost completely removed the weak associations noted in the crude analyses.CONCLUSIONS:Weak and inconsistent associations were observed between SARS-CoV-2 vaccination and healthcare contacts for bleeding in women who are postmenopausal, and even less evidence was recorded of an association for menstrual disturbance or bleeding in women who were premenopausal. These findings do not provide substantial support for a causal association between SARS-CoV-2 vaccination and healthcare contacts related to menstrual or bleeding disorders.

Abstract Objective To investigate the effectiveness of primary covid-19 vaccination (first two doses and first booster dose within the recommended schedule) against post-covid-19 condition (PCC). Design Population based cohort study. Setting Swedish Covid-19 Investigation for Future Insights—a Population Epidemiology Approach using Register Linkage (SCIFI-PEARL) project, a register based cohort study in Sweden. Participants All adults (≥18 years) with covid-19 first registered between 27 December 2020 and 9 February 2022 (n=589 722) in the two largest regions of Sweden. Individuals were followed from a first infection until death, emigration, vaccination, reinfection, a PCC diagnosis (ICD-10 diagnosis code U09.9), or end of follow-up (30 November 2022), whichever came first. Individuals who had received at least one dose of a covid-19 vaccine before infection were considered vaccinated. Main outcome measure The primary outcome was a clinical diagnosis of PCC. Vaccine effectiveness against PCC was estimated using Cox regressions adjusted for age, sex, comorbidities (diabetes and cardiovascular, respiratory, and psychiatric disease), number of healthcare contacts during 2019, socioeconomic factors, and dominant virus variant at time of infection. Results Of 299 692 vaccinated individuals with covid-19, 1201 (0.4%) had a diagnosis of PCC during follow-up, compared with 4118 (1.4%) of 290 030 unvaccinated individuals. Covid-19 vaccination with any number of doses before infection was associated with a reduced risk of PCC (adjusted hazard ratio 0.42, 95% confidence interval 0.38 to 0.46), with a vaccine effectiveness of 58%. Of the vaccinated individuals, 21 111 received one dose only, 205 650 received two doses, and 72 931 received three or more doses. Vaccine effectiveness against PCC for one dose, two doses, and three or more doses was 21%, 59%, and 73%, respectively. Conclusions The results of this study suggest a strong association between covid-19 vaccination before infection and reduced risk of receiving a diagnosis of PCC. The findings highlight the importance of primary vaccination against covid-19 to reduce the population burden of PCC.

Antigen-specific class-switched antibodies are detected at the same time or even before IgM in serum of non-vaccinated individuals infected with SARS-CoV-2. These derive from the first wave of plasmablasts formed. Hence, the phenotype and specificity of plasmablasts can reveal information about early B-cell activation. Here we have analyzed B cells and plasmablasts circulating in blood of COVID-19 patients not previously exposed to SARS-CoV-2 during and after disease. We find that during infection with the original Wuhan strain, plasmablasts in blood produce IgA1, IgG1, and IgM, and that most express CCR10 and integrin β1, only some integrin β7, while the majority lack CCR9. Plasmablast-secreted antibodies are reactive to the spike (S) and nucleocapsid (N) proteins of the Wuhan strain as well as later variants of concern, but also bind S proteins from endemic and non-circulating betacoronaviruses. In contrast, after recovery, antibodies produced from memory B cells target variants of SARS-CoV-2 and SARS-CoV-1 but compared to previously non-infected individuals do not show increased binding to endemic coronaviruses. This suggests that the early antibody response to a large extent stems from pre-existing cross-reactive class-switched memory B cells, and that although newly formed memory cells target the novel SARS-CoV-2 virus the numbers of broadly cross-reactive memory B cells do not increase extensively. The observations give insight into the role of pre-existing memory B cells in early antibody responses to novel pathogens and may explain why class-switched antibodies are detected early in the serum of COVID-19 patients.

Background: A broad vaccination coverage is crucial for preventing the spread of Covid-19 and reduce serious illness or death. The aim of this study was to examine social inequalities in Covid-19 vaccination uptake as of 17th May 2021 among Swedish adults aged >= 60 years. Methods: The study population comprised a general population cohort aged 60 years or older (n = 350,805), representative of the Swedish population. Data were collected through the nationwide linked multi-register observational study SCIFI-PEARL, and associations between sociodemographic determinants and Covid-19 vaccination uptake were analysed using logistic regression. Intersectional analyses of sociodemographic heterogeneity were performed by taking several overlapping social dimensions into account. Data availability extended to 17 May 2021. Findings: The overall vaccination coverage was 87.2% by 17th May 2021. Younger age, male sex, lower income, living alone, and being born outside Sweden, were all associated with a lower uptake of vaccination. The lowest Covid-19 vaccination uptake was seen in individuals born in low-or middle-income countries, of which only 60% had received vaccination, with an odds ratio (OR) of not being vaccinated of 6.05 (95% CI: 5.85-6.26) compared to individuals born in Sweden. These associations persisted after adjustments for possible confounding factors. The intersectional analyses showed even larger variations in vaccination in cross-classified sociodemographic subgroups (ranging from 44% to 97%) with marked differences in uptake of vaccination within sociodemographic groups. Interpretation: The uptake of Covid-19 vaccine during the spring of 2021 in Sweden varied substantially both between and within sociodemographic groups. The use of an intersectional approach, taking several overlapping social dimensions into account at the same time rather than only using one-dimensional measures, contributes to a better understanding of the complexity in the uptake of vaccination. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

Background: Studies on sociodemographic disparities in Covid-19 vaccination uptake in the general population are still limited and mostly focused on older adults. This study examined sociodemographic differences in Covid-19 vaccination uptake in the total Swedish population aged 18-64 years. Methods: National Swedish register data within the SCIFI-PEARL project were used to cross-sectionally investigate sociodemographic differences in Covid-19 vaccination among Swedish adults aged 18- 64 years (n = 5,987,189) by 12 October 2021. Using logistic regression models, analyses were adjusted for sociodemographic factors, region of residence, history of Covid-19, and comorbidities. An intersectional analysis approach including several cross-classified subgroups was used to further address the complexity of sociodemographic disparities in vaccination uptake. Findings: By 12 October 2021, 76.0% of the Swedish population 18-64 years old had received at least two doses of Covid-19 vaccine, an additional 5.5% had received only one dose, and 18.5% were nonvaccinated. Non-vaccinated individuals were, compared to vaccinated, more often younger, male, had a lower income, were not gainfully employed, and/or were born outside Sweden. The social patterning for vaccine dose two was similar, but weaker, than for dose one. After multivariable adjustments, findings remained but were attenuated indicating the need to consider different sociodemographic factors simultaneously. The intersectional analysis showed a large variation in vaccine uptake ranging from 32% to 96% in cross-classified subgroups, reflecting considerable sociodemographic heterogeneity in vaccination coverage. Interpretation: Our study, addressing the entire Swedish population aged 18-64 years, showed broad sociodemographic disparities in Covid-19 vaccine uptake but also wide heterogeneities in coverage. The intersectional analysis approach indicates that focusing on specific sociodemographic factors in isolation and group average risks without considering the heterogeneity within such groups will risk missing the full variability of vaccine coverage. (C) 2022 The Author(s). Published by Elsevier Ltd.

Understanding persistence and evolution of B cell clones after COVID-19 infection and vaccination is crucial for predicting responses against emerging viral variants and optimizing vaccines. Here, we collected longitudinal samples from patients with severe COVID-19 every third to seventh day during hospitalization and every third month after recovery. We profiled their antigen-specific immune cell dynamics by combining single-cell RNA-Seq, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq), and B cell receptor–Seq (BCR-Seq) with oligo-tagged antigen baits. While the proportion of Spike receptor binding domain–specific memory B cells (MBC) increased from 3 months after infection, the other Spike- and Nucleocapsid-specific B cells remained constant. All patients showed ongoing class switching and sustained affinity maturation of antigen-specific cells, and affinity maturation was not significantly increased early after vaccine. B cell analysis revealed a polyclonal response with limited clonal expansion; nevertheless, some clones detected during hospitalization, as plasmablasts, persisted for up to 1 year, as MBC. Monoclonal antibodies derived from persistent B cell families increased their binding and neutralization breadth and started recognizing viral variants by 3 months after infection. Overall, our findings provide important insights into the clonal evolution and dynamics of antigen-specific B cell responses in longitudinally sampled patients infected with COVID-19.

Background: We estimated real-world vaccine effectiveness (VE) against COVID-19 infection, hospitalization, ICU admission, and death up to 13 months after vaccination. VE before and after the emergence of Omicron was investigated. Methods: We used registered data from the entire Swedish population above age 12 (n = 9,153,456). Cox regression with time-varying exposure was used to estimate weekly/monthly VE against COVID-19 outcomes from 27 December 2020 to 31 January 2022. The analyses were stratified by age, sex, and vaccine type (BNT162b2, mRNA-1273, and AZD1222). Results: Two vaccine doses offered good long-lasting protection against infection before Omicron (VE were above 85% for all time intervals) but limited protection against Omicron infection (dropped to 43% by week four and no protection by week 14). For severe COVID-19 outcomes, higher VE was observed during the entire follow-up period. Among individuals above age 65, the mRNA vaccines showed better VE against infection than AZD1222 but similar high VE against hospitalization. Conclusions: Our findings provide strong evidence for long-term maintained protection against severe COVID-19 by the basic two-dose schedule, supporting more efforts to encourage unvaccinated persons to get the basic two doses, and encourage vaccinated persons to get a booster to ensure better population-level protection.

Vaccines against enteric diseases could improve global health. Despite this, only a few oral vaccines are currently available for human use. One way to facilitate such vaccine development could be to identify a practical and relatively low cost biomarker assay to assess oral vaccine induced primary and memory IgA immune responses in humans. Such an IgA biomarker assay could complement antigen-specific immune response measurements, enabling more oral vaccine candidates to be tested, whilst also reducing the work and costs associated with early oral vaccine development. With this in mind, we take a holistic systems biology approach to compare the transcriptional signatures of peripheral blood mononuclear cells isolated from volunteers, who following two oral priming doses with the oral cholera vaccine Dukoral®, had either strong or no vaccine specific IgA responses. Using this bioinformatical method, we identify TNFRSF17, a gene encoding the B cell maturation antigen (BCMA), as a candidate biomarker of oral vaccine induced IgA immune responses. We then assess the ability of BCMA to reflect oral vaccine induced primary and memory IgA responses using an ELISA BCMA assay on a larger number of samples collected in clinical trials with Dukoral® and the oral enterotoxigenic Escherichia coli vaccine candidate ETVAX. We find significant correlations between levels of BCMA and vaccine antigen-specific IgA in antibodies in lymphocyte secretion (ALS) specimens, as well as with proportions of circulating plasmablasts detected by flow cytometry. Importantly, our results suggest that levels of BCMA detected early after primary mucosal vaccination may be a biomarker for induction of long-lived vaccine specific memory B cell responses, which are otherwise difficult to measure in clinical vaccine trials. In addition, we find that ALS-BCMA responses in individuals vaccinated with ETVAX plus the adjuvant double mutant heat-labile toxin (dmLT) are significantly higher than in subjects given ETVAX only. We therefore propose that as ALS-BCMA responses may reflect the total vaccine induced IgA responses to oral vaccination, this BCMA ELISA assay could also be used to estimate the total adjuvant effect on vaccine induced-antibody responses, independently of antigen specificity, further supporting the usefulness of the assay.

Background: It has been hypothesised that the measles-mumps-rubella (MMR) vaccine may afford cross-protection against SARS-CoV-2 which may contribute to the wide variability in disease severity of Covid-19. Methods: We employed a test negative case-control study, utilising a recent measles outbreak during which many healthcare workers received the MMR vaccine, to investigate the potential protective effect of MMR against SARS-CoV-2 in 5905 subjects (n = 805 males, n = 5100 females). Results: The odds ratio for testing positive for SARS-CoV-2, in recently MMR-vaccinated compared to not recently MMR-vaccinated individuals was 0.91 (95% CI 0.76, 1.09). An interaction analysis showed a significant interaction for sex. After sex-stratification, the odds ratio for testing positive for males was 0.43 (95% CI 0.24, 0.79, P = 0.006), and 1.01 (95% CI 0.83, 1.22, P = 0.92) for females. Conclusion: Our results indicate that there may be a protective effect of the MMR vaccine against SARSCoV-2 in males but not females. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of mortality and morbidity in children in low-income countries. We have tested an oral ETEC vaccine, ETVAX, consisting of inactivated E coli overexpressing the most prevalent colonization factors and a toxoid, LCTBA, administered together with a mucosal adjuvant, double-mutant heat-labile toxin (dmLT), for capacity to induce mucosal immune responses and immunological memory against the primary vaccine antigens, ie, colonization factors, heat-labile toxin B-subunit and O antigen. The studies show that ETVAX could induce strong intestine-derived and/or fecal immune responses in a majority of vaccinated Swedish adults and in different age groups, including infants, in Bangladesh.