Mass cytometry reveals cellular correlates of immune response heterogeneity to SARS-CoV-2 vaccination in the elderly (preprint)

Heterogeneity in vaccine response, particularly in vulnerable populations like the elderly, represents a significant public health challenge. We conducted an in-depth examination of immune cell profiles before and after SARS-CoV-2 vaccination utilizing mass cytometry in a cohort of healthy Norwegian seniors (65–80 years). We have demonstrated that higher pre-vaccination frequencies of CD27+IgD− class-switched memory B cells and subsets of CD27−CD24+CD38+ transitional B cells were associated with a robust vaccine response. Post-vaccination, high responders exhibited increased frequencies of IFN-γ+CD4+ T cells with antigen recall and a concurrent decrease in TH17 cell subset frequencies compared to low responders. The presence of a γδ T cell subset displaying polyfunctional cytokine responses was also associated with better vaccine response in the elderly. This comprehensive analysis sheds light on inherent differences in immune cell frequencies and functions that should offer insights for targeted vaccination strategies in older populations.

Genome-wide Association Study of Long COVID (preprint)

Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.

Elevated symptoms of depression and anxiety among family members and friends of critically ill COVID-19 patients - An observational study of five cohorts across four countries (preprint)

Background. Little is known regarding the mental health impact of having a significant person (family member and/or close friend) with COVID-19 of different severity. Methods. The study included five prospective cohorts from four countries (Iceland, Norway, Sweden, and the UK) with self-reported data on COVID-19 and symptoms of depression and anxiety during March 2020-March 2022. We calculated the prevalence ratio (PR) of depression and anxiety in relation to having a significant person with COVID-19 and performed a longitudinal analysis in the Swedish cohort to describe the temporal patterns of the results. Results. 162,237 and 168,783 individuals were included in the analysis of depression and anxiety, respectively, of whom 24,718 and 27,003 reported a significant person with COVID- 19. Overall, the PR was 1.07 (95% CI: 1.05-1.10) for depression and 1.08 (95% CI: 1.03-1.13) for anxiety among significant others of COVID-19 patients. The respective PRs for depression and anxiety were 1.04 (95% CI: 1.01-1.07) and 1.03 (95% CI: 0.98-1.07) if the significant person was never hospitalized, 1.15 (95% CI: 1.08-1.23) and 1.24 (95% CI: 1.14-1.34) if the patient was hospitalized, 1.42 (95% CI: 1.27-1.57) and 1.45 (95% CI: 1.31-1.60) if admitted to the ICU, and 1.34 (95% CI: 1.22-1.46) and 1.36 (95% CI: 1.22-1.51) if the significant person died. Individuals of hospitalized, ICU admitted, or deceased patients showed higher prevalence of depression and anxiety during the entire 12 months after the COVID-19 diagnosis of the significant person. Conclusions. Close friends and family members of critically ill COVID-19 patients show elevated prevalence of depression and anxiety throughout the first year after the diagnosis.

Mental distress among Norwegian adults during the Covid-19 pandemic: predictors of initial response and subsequent trajectories (preprint)

Background: Understanding factors associated with mental distress during a pandemic is imperative for planning interventions to reduce the negative mental health impact of future crises. Our aim was to identify factors associated with change in levels of mental distress in the Norwegian adult population at the onset of the Covid-19 pandemic, relative to pre-pandemic levels, and with longitudinal changes in mental distress until vaccination against Covid-19 became widespread in Norway (the first 1.5 years of the pandemic). Methods: The Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective longitudinal study with baseline recruitment from 1999-2009. Baseline characteristics and eight waves of data collection during the pandemic (between March 2020 and September 2021) were used for this analysis. Mental distress was measured with the 5-item version of Hopkins Symptoms Checklist (HSCL-5). A piecewise latent growth model was fitted to identify initial change in mental distress (March-early April 2020, adjusting for pre-pandemic mental distress measured during prior years of data collection) and longitudinal changes across the pandemic in three distinct periods. Findings: Our sample consisted of 105 972 adult participants (59.6% females). Mental distress levels peaked at the beginning of the pandemic. Several factors were associated with initial increases in distress: chronic medical conditions, living alone, history of psychiatric disorders, relatively lower educational background, female sex, younger age, and obesity. Several of these factors were also associated with long-term change. Being quarantined or having to isolate was associated with the likelihood of increasing distress during the pandemic. We observed a reduction in distress associated with Covid-19 vaccination status, while being infected with SARS-CoV-2 was associated with increasing distress late in the pandemic. Interpretation: Pre-pandemic vulnerability factors -- like having a chronic disease -- as well as Covid-19-related factors -- like being quarantined or infected by SARS-CoV-2 -- were associated with increased mental distress during the pandemic. This knowledge is important for planning of interventions to support vulnerable individuals during pandemics and other health crises.

Titers of antibodies the receptor-binding domain (RBD) of ancestral SARS-CoV-2 are predictive for levels of neutralizing antibodies to multiple variants (preprint)

Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 sera. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

Multiplexed measurement of binding- and neutralizing antibodies to SARS-CoV-2 variants in 12.000 post-vaccine sera (preprint)

Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 sera. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

Immunity in Omicron SARS-CoV-2 breakthrough COVID-19 in vaccinated adults (preprint)

The new SARS-CoV-2 variant of concern (VOC) Omicron has more than 30 mutations in the receptor binding domain (RBD) of the Spike protein enabling viral escape from antibodies in vaccinated individuals and increased transmissibility. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a superspreader event had robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. We compared cases from a Christmas party where 81 of 110 (74%) developed Omicron breakthrough COVID-19, with Delta breakthrough cases and vaccinated non-infected controls. Omicron cases had significantly increased activated SARS-CoV-2 wild type Spike-specific (vaccine) cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, activated anti-Spike plasmablasts and anti-RBD memory B cells compared to controls. Omicron cases had significantly increased de novo memory T cell responses to non-Spike viral antigens compared to Delta breakthrough cases demonstrating development of broad immunity. The rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity.

Excess risk and clusters of symptoms after COVID-19 in a large Norwegian cohort (preprint)

Physical, psychological and cognitive symptoms have been reported as post-acute sequelae for COVID-19 patients but are also common in the general, uninfected population. We aimed to calculate the excess risk and identify patterns of 22 symptoms up to 12 months after COVID-19 infection. We followed more than 70,000 participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa) during the COVID-19 pandemic. Infected and non-infected cohort participants registered presence of 22 different symptoms in March 2021. One year after the initial infection, 13 of 22 symptoms were associated with SARS-CoV-2 infection, based on relative risks between infected and uninfected subjects. For instance, 17.4% of SARS-CoV-2 infected cohort participants reported fatigue that persist 12 months after infection, compared to new occurrence of fatigue that had lasted less than 12 months in 3.8% of non-infected subjects (excess risk 13.6%). The adjusted relative risk for fatigue was 4.8 (95 % CI 3.5 to 6.7). Two main underlying factors explained 50% of the variance in the 13 symptoms. Brain fog, poor memory, dizziness, heart palpitations, and fatigue had high loadings on the first factor, while shortness-of breath and cough had high loadings on the second factor. Lack of taste and smell showed low to moderate correlation to other symptoms. Anxiety, depression and mood swings were not strongly related to COVID-19. Our results suggest that there are clusters of symptoms after COVID-19 due to different mechanisms and question whether it is meaningful to describe long COVID as one syndrome.

Association between ChAdOx1 nCoV-19 vaccination and bleeding episodes: large population-based cohort study (preprint)

Objective To compare prevalence of skin, nose and gingival bleedings after receipt of adeno-vectored or mRNA-vaccines against covid-19. The hypothesis is that milder symptoms indicating altered thrombocyte function may affect a larger proportion of vaccinated individuals than the recently reported severe cases with thrombosis and thrombocytopenia.Design Large, population-based cohort study.Setting Norway, nationwide.ParticipantsMore than 80 000 cohort participants responding to electronic questionnaires about covid-19 vaccination and potential side effects during weeks 11-13, 2021. Response rate 58% (81267/138924), 83% were female, 85% health care workers and 80% were aged 40-55 years. Main outcome measuresSelf-reported episodes of skin, nose and gingival bleedings. Variation in rates by registered vaccine type, age, sex, occupation, previous covid-19 infection and chronic disease. ResultsFour of the 3416 subjects (0.2%) who were vaccinated with a single dose of mRNA vaccine reported skin bleeding as a side effect, as opposed to 163 of 5132 subjects (3.2%) vaccinated with a single dose of the adenovirus-vectored vaccine, OR (odds ratio)=16.0 (95% confidence interval (CI) 7.5-34.1). Corresponding ORs for nose and gingival bleeding were 8.0 (4.0-15.8) and 9.3 (4.3-20.0), respectively.ConclusionsThese findings could potentially indicate that the adenovirus-vectored vaccine may lead to mild bleeding episodes in a larger proportion of vaccinated individuals, and not only in rare cases with documented thrombosis and thrombocytopenia. Studies are needed to understand the possible mechanisms behind these observations, and to establish or refute whether they share similarities with the severe thromboembolic bleeding complications.  

Public adherence to governmental recommendations regarding quarantine and testing for COVID-19 in two Norwegian cohorts (preprint)

BackgroundCombatting the COVID-19 pandemic relies at present on non-pharmacological interventions. Governments are using various approaches from general advice to full lockdown. There is a need to describe and understand adherence to public health actions. MethodsParticipants from two ongoing cohorts, the Norwegian Mother, Father and Child Cohort Study (MoBa) and The Norwegian Influenza Pregnancy Cohort (NorFlu), answered questionnaires every 14 days since March 2020. From the summer of 2020, testing for presence of SARS-CoV-2 became easily available. Recommendations were that respiratory symptoms should lead to testing, and that confirmed or suspected COVID-19 should be followed by quarantine. We estimated the adherence to these guidelines in responses from cohort participants in the period August to October 2020. ResultsLess than 40% of men who were ill and less than 45% of women who were ill, tested themselves for SARS-CoV-2 during the same 14-day periods. Among subjects tested for COVID-19, about 53% of men and 59% of women reported quarantine. For subjects with a confirmed or suspected COVID-19 diagnosis, the proportions quarantined were 65% for men and 72% for women. ConclusionsPublic adherence to governmental recommendations regarding testing and quarantine were lower than expected in a country with high trust in government. This leaves considerable room for improvement in adherence, possibly reducing the need for more restrictive interventions.

The association between work situation and life satisfaction during the COVID-19 pandemic: prospective cohort study in Norway (preprint)

ABSTRACT Objectives To analyse the population effects on life quality of being laid off from work, having to work from home, or having been diagnosed with COVID-19. Design Nationwide population-based cohort study. Setting Norway. Participants We followed more than 80,000 participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa) during the COVID-19 pandemic. We analysed current life satisfaction in April and again in September/October 2020 for subjects whose work situation and infection status had changed. Main outcome measures Self-reported satisfaction with life, using a scale from 0 (worst) to 10 (best). Results Temporary and permanent layoffs, working from a home-based office, and getting a COVID-19 diagnosis were associated with modestly, but significantly lower concurrent life satisfaction, both on a population level and for subjects who changed status. The associations with change in work situation were stronger for men. For men with permanent job loss, the adjusted odds ratio for low life satisfaction (<6) was 3.2 (95% CI 2.4 to 4.2) in April and 4.9 (95% CI 3.5 to 6.9) in autumn. A suspected or confirmed COVID-19 diagnosis was associated with an adjusted odds ratio for low life satisfaction of 1.9 (95% CI 1.6 to 2.3) in spring. The strength of associations between work situation and life satisfaction did not vary much across socio-economic strata, but layoffs were more common among those with low education. Conclusion Layoffs, home office and infection status had clear impact on the quality of life as measured with a global life satisfaction scale. These findings suggest that social differentials in quality of life, are increasing during the pandemic. Funding This work was funded by the Norwegian Research Council’s Centres of Excellence Funding Scheme (no. 262700) and by the Norwegian Institute of Public Health (NIPH). SUMMARY BOXES What is already known on this topic − Being laid off from work or having to work from a home-based office is usually associated with reduced life quality. − The population effect has not been estimated during the present surge in cases of COVID-19 in Europe. What this study adds − This population-based study shows that life satisfaction in Norway has been stable from the first to the second wave of the pandemic, but that both layoffs and working from home is associated with reduced life satisfaction, especially among men. − The reduced life satisfaction in people working from a home-based office implies that large proportions of the population are affected.