COVID-19 vaccination was a rare potential etiology for cause of death after medicolegal autopsy. A Finnish nationwide study. (preprint)

COVID-19 vaccinations began globally at the end of 2020. By the end of 2021, 9.8 million doses were given in Finland. Regarding safety, most vaccine-related adverse reactions have been mild, but serious and lethal ones have also occurred. Autopsies in post vaccination deaths may give insight to the extent of fatal health conditions with potential COVID-19 vaccine etiology and provide new hypotheses of possible causalities between vaccination and severe health conditions. We searched the complete documentation on all medicolegal autopsies in Finland between December 2020 and December 2021 to assess how often the basis for autopsy was a suspected fatal adverse reaction to COVID-19 vaccination, and whether vaccination remained a potential etiology for any health condition determined as a cause of death after the autopsy. We linked register-based data on individual COVID-19 vaccination course and pre-existing health conditions. We found 428 autopsy cases with a mention of COVID-19 vaccination, and prior to autopsy, vaccination was suspected to play a part in 76 deaths. Post autopsy, a forensic pathologist considered vaccination as a potential etiology in five underlying and seven contributory causes of death. These included seven thromboembolisms, two diabetic ketoacidoses, one myocarditis, one acute pancreatitis, and one eosinophilic granulomatosis with polyangiitis. In relation to the number of vaccinations within Finland, a suspicion of vaccine-related serious adverse reaction was rarely an indication for medicolegal autopsy. Even less frequently was vaccination considered to play a part in the process leading to death, although considerable doubt remains in the accuracy of individual considerations, and autopsy cannot definitively confirm causality between vaccination and death. Regarding vaccination safety, continuing evaluation of suspected vaccine-related deaths is essential, and an autopsy should be part of the investigation when such a suspicion arises.

Hybrid immunity improves the immune response after fourth Covid-19 vaccine dose in individuals with medical conditions predisposing to severe Covid-19 (preprint)

BackgroundData on Covid-19 booster vaccinations and subsequent infections on immune responses in the immunocompromised is limited. We studied antibody responses after the fourth dose and subsequent breakthrough infection to define patient groups benefiting most from boosters. MethodsIn Finland, fourth vaccine (booster) doses were first recommended for severely immunocompromised individuals, whom we invited to participate in 2022. We assessed spike protein specific IgG antibody levels and neutralizing antibodies (NAb) against the ancestral and Omicron BA.1 strains one month after the fourth dose from 488 adult participants and compared to the levels of 35 healthy controls after 3 doses. We used Bayesian generalized linear modelling to assess factors explaining antibody concentrations after the fourth dose. We assessed vaccine-induced and hybrid immunity six months after the last vaccine dose. ResultsChronic kidney disease (CKD) and immunosuppressive therapy (IT) were identified as factors explaining sub-optimal antibody responses. The proportion of participants with a normal antibody response and NAbs were significantly lower in CKD patients as compared to controls. By the 6-month sampling one third of the participants became infected, which enhanced antibody levels notably in most immunocompromised participants. ConclusionsImpaired antibody responses, especially NAbs against the Omicron lineage, predict limited protection in individuals with CKD, and highlight the need for alternative pharmaceutical preventive strategies. Vaccination strategies should take into account development of robust hybrid immunity responses also among the immunocompromised.

Bivalent booster effectiveness against severe COVID-19 outcomes in Finland, September 2022 - January 2023 (preprint)

Bivalent COVID-19 vaccines were introduced in 2022 but knowledge of how their effectiveness against severe COVID-19 outcomes is sustained over time is currently limited. In Finnish register-based cohort analyses, we compared the risk of severe COVID-19 outcomes among those who received bivalent vaccination (exposed) between 1 September 2022 and 31 January 2023 to those who did not (unexposed). Among elderly aged 65-120 years, bivalent vaccination reduced the risk of hospitalisation and death due to COVID-19. Among the elderly the hazard ratios comparing exposed and unexposed ranged from 0.36 to 0.43 during the first 14-30 days since bivalent vaccination but signs of waning were observed as soon as two months after vaccination. Among the chronically ill aged 18-64 years bivalent vaccination did not reduce the risk of severe COVID-19 outcomes. These results are crucial for further developing COVID-19 vaccination programme worldwide.

Changes in SARS-CoV-2 seroprevalence and population immunity in Finland, 2020-2022 (preprint)

Studying the prevalence of SARS-CoV-2 specific antibodies (seroprevalence) allows assessing the impact of epidemic containment measures and vaccinations, as well as estimation of the number of infections regardless of viral testing. We assessed antibody-mediated immunity to SARS-CoV-2 induced by infections and vaccinations from April 2020 to December 2022 in Finland by measuring serum IgG to SARS-CoV-2 nucleoprotein (N-IgG) and spike glycoprotein from randomly selected 18-85-year-old subjects (n=9794). N-IgG seroprevalence remained at <7% until the last quartile (Q) of 2021. After the emergence of the omicron variant, N-IgG seroprevalence increased rapidly and was 31% in Q1/2022 and 54% in Q4/2022. Seroprevalence was highest in youngest age groups from Q2/2022 onwards. We estimated that 51% of the Finnish 18-85-year-old population had antibody-mediated hybrid immunity induced by a combination of vaccinations and infections by the end of 2022. In conclusion, major shifts in the COVID-19 pandemic and resulting population immunity could be observed by serological testing.

Health, socioeconomic and genetic predictors of COVID-19 vaccination uptake: a nationwide machine-learning study (preprint)

Reduced participation in COVID-19 vaccination programs is a key societal concern. Understanding factors associated with vaccination uptake can help in planning effective immunization programs. We considered 2,890 health, socioeconomic, familial, and demographic factors measured on the entire Finnish population aged 30 to 80 (N=3,192,505) and genome-wide information for a subset of 273,765 individuals. Risk factors were further classified into 12 thematic categories and a machine learning model was trained for each category. The main outcome was uptaking the first COVID-19 vaccination dose by 31.10.2021, which has occurred for 90.3% of the individuals. The strongest predictor category was labor income in 2019 (AUC evaluated in a separate test set = 0.710, 95% CI: 0.708-0.712), while drug purchase history, including 376 drug classes, achieved a similar prediction performance (AUC = 0.706, 95% CI: 0.704-0.708). Higher relative risks of being unvaccinated were observed for some mental health diagnoses (e.g. dissocial personality disorder, OR=1.26, 95% CI : 1.24-1.27 ) and when considering vaccination status of first-degree relatives (OR=1.31, 95% CI:1.31-1.32 for unvaccinated mothers) We derived a prediction model for vaccination uptake by combining all the predictors and achieved good discrimination (AUC = 0.801, 95% CI: 0.799-0.803). The 1% of individuals with the highest risk of not vaccinating according to the model predictions had an average observed vaccination rate of only 18.8%. We identified 8 genetic loci associated with vaccination uptake and derived a polygenic score, which was a weak predictor of vaccination status in an independent subset (AUC=0.612, 95% CI: 0.601-0.623). Genetic effects were replicated in an additional 145,615 individuals from Estonia (genetic correlation=0.80, 95% CI: 0.66-0.95) and, similarly to data from Finland, correlated with mental health and propensity to participate in scientific studies. Individuals at higher genetic risk for severe COVID-19 were less likely to get vaccinated (OR=1.03, 95% CI: 1.02-1.05). Our results, while highlighting the importance of harmonized nationwide information, not limited to health, suggest that individuals at higher risk of suffering the worst consequences of COVID-19 are also those less likely to uptake COVID-19 vaccination. The results can support evidence-informed actions for COVID-19 and other areas of national immunization programs.

Sudden hearing loss following vaccination against COVID-19 (preprint)

Importance Spontaneous adverse reaction reports of sudden hearing loss have been observed and a population-based cohort study conducted in Israel showed an increase in the incidence of sudden sensorineural hearing loss (SSNHL) following vaccination with messenger RNA COVID-19 vaccine BNT162b2 (Pfizer-BioNTech). However, in this setting, possibility of confounding remained. Objective To assess a potential association between COVID-19 vaccinations and SSNHL. Design A register-based country-wide observational study with study period from January 1, 2019, until Apr 12, 2022. Setting Residents in Finland: 5.8 million. Participants All individuals identified from population information system alive or born during the study period except individuals having SSNHL during 2015 to 2018 according to specialized care derived diagnosis codes for SSNHL (ICD10-code H91.2) as a primary or secondary diagnosis. Exposures The a priori primary risk period was 0 to 54 days following each COVID-19 vaccine dose. The secondary risk time was 55 or more days after the vaccination. A later vaccine exposure overruled a previous one. A secondary analysis included a risk time of 0 to 54 days following a positive polymerase chain reaction (PCR) test for SARS-CoV-2. Main Outcome We compared incidences of SSNHL following COVID-19 vaccination to incidences before the COVID-19 epidemic in Finland. In our Poisson regression analysis, we adjusted for calendar time, age, sex, diabetes, cardiovascular disease, other chronic diseases, number of visits in primary health care. Results Comparison time constituted of 6.5 million person years, primary risk time of 1.7 million person years, and secondary risk time of 2.1 million person years. Before the epidemic yearly 18.7 / 100,000 people were diagnosed with SSNHL. Our data suggested no increased risk for SSNHL following any COVID-19 vaccination. In particular, adjusted incidence rate ratios, with 95 percent confidence intervals (95% CI) for the BNT162b2 vaccine's three doses were 0.8 (95% CI 0.6 to 1.0), 0.9 (95% CI 0.6 to 1.2), and 1.3 (95% CI 0.9 to 2.0). SARS-CoV-2 infection was not associated with an increased incidence of SSNHL either. Conclusions and relevance Our results show no evidence of increased SSNHL with the COVID-19 vaccinations. We accounted for previous disease and other potential confounding factors. Our results base on diagnosis codes in specialized care but still need to be verified with settings, that are capable to evaluate the degree of hearing loss.

Strong neutralizing antibody responses to SARS-CoV-2 variants following a single vaccine dose in subjects with previous SARS-CoV-2 infection (preprint)

Background Previous SARS-CoV-2 infection primes the immune system and thus individuals who recovered from infection have enhanced immune responses to subsequent vaccination (hybrid immunity). However, it remains unclear how well hybrid immunity induced by severe or mild infection can cross-neutralize emerging variants. We aimed to compare the strength and breadth of antibody responses in vaccinated recovered and uninfected subjects. Methods We measured spike-specific IgG and neutralizing antibodies (NAbs) from vaccinated subjects including 320 with hybrid immunity and 20 without previous infection. From 29 subjects with a previous severe or mild infection, we also measured NAb responses against Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529/BA.1) variants following vaccination. Results A single vaccine dose induced 2-fold higher anti-spike IgG concentrations and 3-fold higher neutralizing potency of antibodies in previously infected compared to uninfected fully vaccinated subjects. We found similar IgG concentrations in previously infected subjects after one or two vaccine doses. NAb titers were higher in subjects with severe compared to those with mild infection. This difference remained after vaccination with sequentially decreasing titers against Alpha, Beta, Delta, and Omicron variants. Conclusions Hybrid immunity induced strong IgG responses, particularly after severe infection. However, the NAb titers were low against heterologous variants, especially against Omicron.

Incidence of SARS-CoV-2 infection and factors associated with complete COVID-19 vaccine uptake among migrant origin persons in Finland. (preprint)

Background: We examined incidence of SARS-CoV-2 infection, COVID-19 vaccine uptake and factors associated with complete COVID-19 vaccine uptake among persons of migrant origin in Finland. Methods: Data on laboratory-confirmed SARS-CoV-2 infection and COVID-19 vaccine doses between March 2020 and November 2021 were linked to FinMonik register sample (n=13,223) and MigCOVID (n=3,668) survey data using unique personal identifier. FinMonik and MigCOVID surveys were conducted among adults born outside Finland. Logistic regression was applied to examine the association of age, sex, age at migration, length of stay, level of education, economic activity, Finnish/Swedish language skills, psychological distress, experiences of discrimination, and self-rated health with vaccine uptake.Results: Among the total sample, complete COVID-19 vaccine uptake was lower among persons of Russia/former Soviet Union (OR 0.68, 95% CI 0.61-0.76), Estonia (OR 0.40, 95% CI 0.36-0.46), and rest of Africa (OR 0.63, 95% CI 0.54-0.72) and higher among persons of Southeast Asia (OR 3.34, 95% CI 2.77-4.02),  rest of Asia (OR 1.90, 95% CI 1.65-2.19) and the Middle East/North Africa (OR 1.41, 95% CI 1.25-1.60) than among persons originating from Europe/North America/Oceania. Male sex, younger age, migration age (<18 years) and shorter length of residence were associated with lower vaccine uptake among total sample, whereas younger age, being economically inactive, poorer language skills, experiences of discrimination and psychological distress were associated with lower vaccine uptake among MigCOVID sub-sample. Conclusion: Our Findings point to a further need of tailored and targeted communication and community outreach strategies to increase vaccine uptake among persons of migrant origin.

High vaccine effectiveness against severe Covid-19 in the elderly in Finland before and after the emergence of Omicron (preprint)

Background. The elderly are highly vulnerable to severe Covid-19. Waning immunity and emergence of Omicron have caused concerns about reduced effectiveness of Covid-19 vaccines. The objective was to estimate vaccine effectiveness (VE) against severe Covid-19 among the elderly.Methods. This nationwide, register-based cohort study included all residents aged 70 years and over in Finland. The follow-up started on December 27, 2020, and ended on February 19, 2022. The study outcomes were Covid-19-related hospitalization and intensive care unit (ICU) admission timely associated with SARS-CoV-2 infection. VE was estimated as one minus the hazard ratio comparing the vaccinated and unvaccinated and taking into account time since vaccination. Omicron-specific VE was evaluated as the effectiveness observed since January 1, 2022.Results. The cohort included 897932 individuals. Comirnaty (BioNTech/Pfizer) VE against Covid-19-related hospitalization was 93% (95% CI90%–95%) and 87% (95% CI 84%–89%) 14–90 and 91–180 days after the second dose; VE increased to 96% (95% CI 95%–97%) 14–60 days after the third dose. VE of other homologous and heterologous three dose series was similar. Protection against severe Covid-19 requiring ICU treatment was even better. Since January 1, 2022, Comirnaty VE was 91% (95% CI 79%–96%) and 76% (95% CI 56%–86%) 14–90 and 91–180 days after the second and 95% (95% CI 94%–97%) 14–60 days after the third dose.Conclusions.VE against severe Covid-19 is high among the elderly. It waned slightly after two doses, but a third restored the protection. VE against severe Covid-19 remained high even after the emergence of Omicron.

High vaccine effectiveness against severe Covid-19 in the elderly in Finland before and after the emergence of Omicron (preprint)

Background. The elderly are highly vulnerable to severe Covid-19. Waning immunity and emergence of Omicron have caused concerns about reduced effectiveness of Covid-19 vaccines. The objective was to estimate vaccine effectiveness (VE) against severe Covid-19 among the elderly. Methods. This nationwide, register-based cohort study included all residents aged 70 years and over in Finland. The follow-up started on December 27, 2020, and ended on February 19, 2022. The study outcomes were Covid-19-related hospitalization and intensive care unit (ICU) admission timely associated with SARS-CoV-2 infection. VE was estimated as 1 minus the hazard ratio comparing the vaccinated and unvaccinated and taking into account time since vaccination. Omicron-specific VE was evaluated as the effectiveness observed since January 01, 2022. Results. The cohort included 897932 individuals. Comirnaty (BioNTech/Pfizer) VE against Covid-19-related hospitalization was 93% (95% confidence interval [CI], 90%-95%) and 87% (84%-89%) 14-90 and 91-180 days after the second dose; VE increased to 96% (95%-97%) 14-60 days after the third dose. VE of other homologous and heterologous 3-dose series was similar. Protection against severe Covid-19 requiring ICU treatment was even better. Since January 01, 2022, Comirnaty VE was 91% (95% CI, 79%-96%) and 76% (56%-86%) 14-90 and 91-180 days after the second and 95% (94%-97%) 14-60 days after the third dose. Conclusions. VE against severe Covid-19 is high among the elderly. It waned slightly after 2 doses, but a third restored the protection. VE against severe Covid-19 remained high even after the emergence of Omicron.

Neutralizing antibodies to SARS-CoV-2 Omicron variant after 3rd mRNA vaccination in health care workers and elderly subjects and response to a single dose in previously infected adults (preprint)

The emergence of SARS-CoV-2 Omicron variant (B.1.1.529) with major spike protein mutations has raised concern over potential neutralization escape and breakthrough infections among vaccinated and previously SARS-CoV-2 infected subjects. We measured cross-protective antibodies against variants in health care workers (HCW, n=20) and nursing home residents (n=9) from samples collected 1-2 months following the booster (3rd) dose. We also assessed the antibody responses in prior to Omicron era infected subjects (n=38) with subsequent administration of a single mRNA vaccine dose. Following booster vaccination HCWs had high IgG antibody concentrations to the spike protein and neutralizing antibodies (NAb) were detectable against all variants. IgG concentrations among the elderly remained lower, and some lacked NAbs against the Beta and Omicron variants. NAb titers were significantly reduced against Delta, Beta and Omicron compared to wild-type virus regardless of age. Vaccination induced high IgG concentrations and variable titers of cross-reactive NAbs in previously infected subjects, whereas NAb titers against Omicron were barely detectable 1-month post-infection. High IgG concentrations with cross-protective neutralizing activity were detected after three COVID-19 vaccine doses in HCWs. However, lower NAb titers seen in the frail elderly suggest inadequate protection against Omicron breakthrough infections, yet protection against severe COVID-19 is expected. Clinical trial registration EudraCT 2021-004788-29

Cohort study of Covid-19 vaccine effectiveness among healthcare workers in Finland, December 2020 - October 2021 (preprint)

Recently, Covid-19 vaccine effectiveness has decreased especially against mild disease due to emergence of the Delta variant and waning protection. In this register-based study among healthcare workers in Finland, the vaccine effectiveness of two-dose mRNA vaccine series against SARS-CoV-2 infection decreased from 82% (95% CI 79-85%) 14-90 days after vaccination to 53% (43-62%) after 6 months. Similar trend was observed for other series. Waning was not observed against Covid-19 hospitalization. These results facilitate decision-making of booster doses for healthcare workers.

High secondary attack rate and persistence of SARS-CoV-2 antibodies in household transmission study participants, Finland 2020 (preprint)

Background Household transmission studies offer the opportunity to assess both secondary attack rate and persistence of SARS-CoV-2 antibodies over time. Methods We invited confirmed COVID-19 cases and their household members to attend up to four household visits with collection of nasopharyngeal and serum samples over 28 days after index case onset. We calculated secondary attack rates (SAR) based on the presence of SARS-CoV-2 nucleoprotein IgG antibodies (IgG Ab) and/or neutralizing antibodies (NAb) overall and per households. Three and six months later, we assessed the persistence of SARS-CoV-2 antibodies. Findings We recruited 39 index cases and 90 household members. Among 87 household members evaluated, SAR was 48% (n=42), including 37 symptomatic secondary cases. In total, 80/129 (62%) participants developed both IgG Ab and NAb, while three participants only developed IgG Ab. Among participants who had both IgG Ab and NAb during the initial follow-up, 68/69 (99%) and 63/70 (90%) had IgG Ab and NAb at 3 months, while at 6 months, 59/75 (79%) and 63/75 (84%) had IgG Ab and NAb, respectively. Participants who required hospital care had initially 5-fold IgG Ab concentrations compared to cases with mild symptoms and 8-fold compared to asymptomatic cases. Interpretation Following detection of a COVID-19 case in a household, other members had a high risk of becoming infected. Follow-up of participants showed strong persistence of antibodies in most cases. Funding This study was supported by THL coordinated funding for COVID-19 research (Finnish Government's supplementary budget) and by the Academy of Finland (Decision number 336431).

High Secondary Attack Rate and Persistence of SARS-CoV-2 Antibodies in Household Transmission Study Participants, Finland 2020 (preprint)

Background: Household transmission studies offer the opportunity to assess both secondary attack rate and persistence of SARS-CoV-2 antibodies over time.Methods: We invited confirmed COVID-19 cases and their household members to attend up to four household visits with collection of nasopharyngeal and serum samples over 28 days after index case onset. We calculated secondary attack rates (SAR) based on the presence of SARS-CoV-2 nucleoprotein IgG antibodies (IgG Ab) and/or neutralizing antibodies (NAb) overall and per households. Three and six months later, we assessed the persistence of SARS-CoV-2 antibodies.Findings: We recruited 39 index cases and 90 household members. Among 87 household members evaluated, SAR was 48% (n=42), including 37 symptomatic secondary cases. In total, 80/129 (62%) participants developed both IgG Ab and NAb, while three participants only developed IgG Ab. Among participants who had both IgG Ab and NAb during the initial follow-up, 68/69 (99%) and 63/70 (90%) had IgG Ab and NAb at 3 months, while at 6 months, 59/75 (79%) and 63/75 (84%) had IgG Ab and NAb, respectively. Participants who required hospital care had initially 5-fold IgG Ab concentrations compared to cases with mild symptoms and 8-fold compared to asymptomatic cases.Interpretation: Following detection of a COVID-19 case in a household, other members had a high risk of becoming infected. Follow-up of participants showed strong persistence of antibodies in most cases.Funding Information: This study was supported by THL coordinated funding for COVID-19 research (Finnish Government’s supplementary budget) and by the Academy of Finland (Decision number 336431).Declaration of Interests: THL has received research funding for studies not related to COVID-19 from GlaxoSmithKline Vaccines (NE, CV, AAP and MM as investigators), Pfizer (AAP) and Sanofi Pasteur (AAP). Other authors have no competing interests.Ethics Approval Statement: The Finnish communicable diseases law and the law on the duties of the Finnish Institute for Health and Welfare allowed the implementation of the initial household transmission study and 3 months convalescent sample collection without seeking further institutional ethical review11,12. The protocol for the follow-up visits at 6 months was reviewed and approved by the HUS ethical committee and registered under the Development of seroprevalence in Finland during the new coronavirus (SARS-CoV-2) epidemic – serological population study protocol HUS/1137/2020. Informed consent was obtained from all cases and contacts or their parents or legal guardian before any procedure was performed.

Persistence of neutralizing antibodies a year after SARS-CoV-2 infection (preprint)

Understanding for how long antibodies persist following Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection provides important insight into estimating the duration of immunity induced by infection. We assessed the persistence of serum antibodies following wild-type SARS-CoV-2 infection six and twelve months after diagnosis in 367 individuals of whom 13% had severe disease requiring hospitalization. We determined the SARS-CoV-2 spike (S-IgG) and nucleoprotein IgG concentrations and the proportion of subjects with neutralizing antibodies (NAb). We also measured the NAb titers among a smaller subset of participants (n=78) against a wild-type virus (B.1) and three variants of concern (VOCs): Alpha (B.1.1.7), Beta (B.1.351) and Delta (B.1.617.2). We found that NAb against the wild-type virus and S-IgG persisted in 89% and 97% of subjects for at least twelve months after infection, respectively. IgG and NAb levels were higher after severe infection. NAb titers were significantly lower against variants compared to the wild-type virus.

Detection of SARS-CoV-2 infection in gargle, spit and sputum specimens (preprint)

The gold standard for SARS-CoV-2 infection diagnosis is RT-PCR from nasopharyngeal specimen (NPS). Its collection involves a close contact between patients and healthcare workers requiring a significant amount of workforce and putting them at risk of infection. We evaluated self-collection of alternative specimens and compared their sensitivity and Ct values to NPS. We visited acute COVID-19 outpatients to collect concomitant nasopharyngeal and gargle specimens and had patients self-collect a gargle and either sputum or spit specimens on the next morning. We included 40 patients and collected 40 concomitant nasopharyngeal and gargle specimens, as well as 40 gargle, 22 spit and 16 sputum specimens on the next day, as 2 patients could not produce sputum. All specimens were as sensitive as NPS. Gargle specimens had a sensitivity of 0.97 (CI 95% 0.92-1,00), whether collected concomitantly to NPS or on the next morning. Next morning spit and sputum specimens showed a sensitivity of 1.00 CI (95% 1.00-1.00) and 0.94 (CI 95% 0.87-1.00), respectively. The gargle specimens had a significantly higher mean cycle threshold (Ct) values, 29.89 (SD 4.63) (p-value <0.001) and 29.25 (SD 3.99) (p-value <0.001) when collected concomitantly and on the next morning compared to NPS (22.07, SD 4.63). Ct value obtained with spit (23.51, SD 4.57, p-value 0.11) and sputum (25.82, SD 9.21, p-value 0.28) specimens were close to NPS. All alternative specimen collection methods were as sensitive as NPS, but spit collection appeared more promising, with a low Ct value and ease of collection. Our findings warrant further investigation.

Analytical and clinical evaluation of antibody tests for SARS-CoV-2 serosurveillance studies used in Finland in 2020 (preprint)

Background: Sensitive and highly specific antibody tests are critical for detection of SARS-CoV-2 antibodies especially in populations where seroprevalence is low. Aim: To set up, optimize and evaluate the analytical and clinical performance of a new in-house microsphere immunoassay for measurement of IgG antibodies to SARS-CoV-2 nucleoprotein for assessment of population seroprevalence in Finland. Methods: We set up a new in-house microsphere immunoassay (FMIA) with SARS-CoV-2 nucleoprotein and optimized its analytical performance. For evaluation of clinical performance, we tested sera collected in a well-characterized cohort of PCR positive-confirmed SARS-CoV-2 patients (n=89) with mostly mild symptoms, and before the COVID-19 pandemic (n=402), for nucleoprotein specific IgG concentrations by FMIA and a commercial chemiluminescent immunoassay and for neutralizing antibodies by the microneutralization test. Results: The analytical performance of FMIA was established in terms of sensitivity, linearity and precision. FMIA discriminated between COVID-19 patient and control samples with high specificity (100%) and sensitivity (100%). We generated FMIA seropositivity cut-offs, 0.46 and 1.71 U/ml, for low- and high-seroprevalence settings, respectively. In addition, we obtained high level of agreement between FMIA results and results by the microneutralization test. Conclusion: The fluorescent microsphere immunoassay showed excellent analytical and clinical performance and is well suited for serosurveillance studies of SARS-CoV-2. However, to optimize analytical sensitivity and clinical specificity of the assay, different seropositivity thresholds depending on the intended use of the assay and the target population, may be needed.

Transmission of SARS-CoV-2 following exposure in school settings: experience from two Helsinki area exposure incidents. (preprint)

Background: The role of children in SARS-CoV-2 transmission is unclear. We investigated two COVID-19 school exposure incidents in the Helsinki area. Methods: We conducted two retrospective cohort studies after schools exposures, with a household transmission extension. We defined a case as an exposed person with either a positive RT-PCR, or positive microneutralisation testing (MNT) as confirmation of SARS-CoV-2 nucleoprotein IgG antibodies detection via fluorescent microsphere immunoassay (FMIA). We recruited close school contacts and families of school cases, calculated attack rates (AR) on school level and families, and identified transmission chains. Findings: In incident A, the index was a pupil. Participation rate was 74% (89/121), and no cases were identified. In incident B, the index was a member of school personnel. Participation rate was 81% (51/63). AR was 16% (8/51): 6 pupils and 1 member of school personnel were MNT and FMIA positive; 1 pupil had a positive RT-PCR, but negative serology samples. We visited all school cases' families (n=8). The AR among close household contacts was 42% (9/20 in 3/8 families) but other plausible sources were always reported. At three months post-exposure, 6/8 school cases were re-sampled and still MNT positive. Interpretation: When the index was a child, no school transmission was identified, while the occurrence of an adult case led to a 16% AR. Further cases were evidenced in 3 families, but other transmission chains were plausible. It is likely that transmission from children to adults is limited. Funding: The Finnish Institute for Health and Welfare funded this study.

Comparison of the clinical characteristics and outcomes of hospitalized adult COVID-19 and influenza patients: a prospective observational study (preprint)

ObjectiveWe compared the clinical characteristics, findings and outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) or influenza to detect relevant differences. MethodsFrom December 2019 to April 2020, we recruited all eligible hospitalized adults with respiratory infection to a prospective observational study at the HUS Jorvi Hospital, Finland. Influenza and SARS-CoV-2 infections were confirmed by RT-PCR. Follow-up lasted for at least 30 days from admission. ResultsWe included 61 patients, of whom 28 were COVID-19 and 33 influenza patients with median ages of 53 and 56 years. Majority of both COVID-19 and influenza patients were men (61% vs 67%) and had at least one comorbidity (68% vs 85%). Pulmonary diseases and current smoking were less common among COVID-19 than influenza patients (5 [18%] vs 15 [45%], P=0.03 and 1 [4%] vs 10 [30%], P=0.008). In chest x-ray at admission, ground-glass opacities and consolidations were more frequent among COVID-19 than influenza patients (19 [68%] and 7 [21%], P < 0.001). Severe disease and intensive care unit (ICU) admission occurred more often among COVID-19 than influenza patients (26 [93%] vs 19 [58%], P=0.003 and 8 [29%] vs 2 [6%], P=0.034). COVID-19 patients were hospitalized longer than influenza patients (6 days [IQR 4-21] vs 3 [2-4], P<0.001). ConclusionBilateral ground-glass opacities and consolidations in chest X-ray may help to differentiate COVID-19 from influenza. Hospitalized COVID-19 patients had more severe disease, required longer hospitalization and were admitted to ICU more often than influenza patients, which has important implications for public health policies.