Immune Responses to SARS-CoV-2 Infection and Vaccine in a Big Italian COVID-19 Hospital: An 18-Month Follow-Up.

OBJECTIVES: This is a longitudinal prospective study which was designed to assess the trend of anti-SARS-CoV-2 antibodies targeting the Spike (anti-S) and Nucleocapside protein (anti-N) viral antigens over a 9-month period after the administration of an anti-SARS-CoV-2 vaccine in a big COVID-19 hospital located in Northern Italy. PARTICIPANTS: 7411 vaccinated workers were included in a linear mixed-effect model analysis performed to model the anti-S decay over the 9 months following the vaccination, during serological screening performed approximately 2, 4, and 9 months following the first jab administration. Serological tests performed in the 9 months preceding vaccine administration were retrospectively analysed to identify the burden of infections occurring before vaccination. RESULTS: The serological assays were used for monitoring the antibody titres during the observational period. Vaccination significantly reduced the rate of infection and elicited a specific humoral response, which lasted during the whole observational period (9 months). A decay was observed in all considered subgroups. At 35 weeks, workers with no history of pre-vaccine infection showed a significantly lower anti-S titre (-2522 U/mL on average (-2589.7 to -2445.7)); younger workers showed significantly higher anti-S titres (140.2 U/mL on average (82.4 to 201.3)). Only seven immunocompromised workers did not show significant levels of anti-S antibodies; three of them, all females, showed a specific T-cell response. CONCLUSIONS: Comparing the 9-month periods before and after the first vaccine dose, a significant reduction in infection rate was observed (1708 cases vs. 156). Pre-vaccine infection, especially if contracted during the first pandemic wave, greatly enhanced the response to vaccination, which was significantly affected also by age both in extent and duration (inversely related). A gender effect on the T-cell immune response was observed in a small group of workers who did not produce antibodies after vaccine administration.

Temporal trends of COVID-19 antibodies in vaccinated healthcare workers undergoing repeated serological sampling: An individual-level analysis within 13 months in the ORCHESTRA cohort.

Short summary: We investigated changes in serologic measurements after COVID-19 vaccination in 19,422 subjects. An individual-level analysis was performed on standardized measurements. Age, infection, vaccine doses, time between doses and serologies, and vaccine type were associated with changes in serologic levels within 13 months. Background: Persistence of vaccine immunization is key for COVID-19 prevention. Methods: We investigated the difference between two serologic measurements of anti-COVID-19 S1 antibodies in an individual-level analysis on 19,422 vaccinated healthcare workers (HCW) from Italy, Spain, Romania, and Slovakia, tested within 13 months from first dose. Differences in serologic levels were divided by the standard error of the cohort-specific distribution, obtaining standardized measurements. We fitted multivariate linear regression models to identify predictors of difference between two measurements. Results: We observed a progressively decreasing difference in serologic levels from <30 days to 210-240 days. Age was associated with an increased difference in serologic levels. There was a greater difference between the two serologic measurements in infected HCW than in HCW who had never been infected; before the first measurement, infected HCW had a relative risk (RR) of 0.81 for one standard deviation in the difference [95% confidence interval (CI) 0.78-0.85]. The RRs for a 30-day increase in time between first dose and first serology, and between the two serologies, were 1.08 (95% CI 1.07-1.10) and 1.04 (95% CI 1.03-1.05), respectively. The first measurement was a strong predictor of subsequent antibody decrease (RR 1.60; 95% CI 1.56-1.64). Compared with Comirnaty, Spikevax (RR 0.83, 95% CI 0.75-0.92) and mixed vaccines (RR 0.61, 95% CI 0.51-0.74) were smaller decrease in serological level (RR 0.46; 95% CI 0.40-0.54). Conclusions: Age, COVID-19 infection, number of doses, time between first dose and first serology, time between serologies, and type of vaccine were associated with differences between the two serologic measurements within a 13-month period.

Determinants of Anti-S Immune Response at 9 Months after COVID-19 Vaccination in a Multicentric European Cohort of Healthcare Workers-ORCHESTRA Project.

Background: The persistence of antibody levels after COVID-19 vaccination has public health relevance. We analyzed the determinants of quantitative serology at 9 months after vaccination in a multicenter cohort. Methods: We analyzed data on anti-SARS-CoV-2 spike antibody levels at 9 months from the first dose of vaccinated HCW from eight centers in Italy, Germany, Spain, Romania and Slovakia. Serological levels were log-transformed to account for the skewness of the distribution and normalized by dividing them by center-specific standard errors. We fitted center-specific multivariate regression models to estimate the cohort-specific relative risks (RR) of an increase of one standard deviation of log antibody level and the corresponding 95% confidence interval (CI), and combined them in random-effects meta-analyses. Finally, we conducted a trend analysis of 1 to 7 months' serology within one cohort. Results: We included 20,216 HCW with up to two vaccine doses and showed that high antibody levels were associated with female sex (p = 0.01), age (RR = 0.87, 95% CI = 0.86-0.88 per 10-year increase), 10-day increase in time since last vaccine (RR = 0.97, 95% CI 0.97-0.98), previous infection (3.03, 95% CI = 2.92-3.13), two vaccine doses (RR = 1.22, 95% CI = 1.09-1.36), use of Spikevax (OR = 1.51, 95% CI = 1.39-1.64), Vaxzevria (OR = 0.57, 95% CI = 0.44-0.73) or heterologous vaccination (OR = 1.33, 95% CI = 1.12-1.57), compared to Comirnaty. The trend in the Bologna cohort, based on 3979 measurements, showed a decrease in mean standardized antibody level from 8.17 to 7.06 (1-7 months, p for trend 0.005). Conclusions: Our findings corroborate current knowledge on the determinants of COVID-19 vaccine-induced immunity and declining trend with time.

SARS-CoV-2 Breakthrough Infections: Incidence and Risk Factors in a Large European Multicentric Cohort of Health Workers.

BACKGROUND: The research aimed to investigate the incidence of SARS-CoV-2 breakthrough infections and their determinants in a large European cohort of more than 60,000 health workers. METHODS: A multicentric retrospective cohort study, involving 12 European centers, was carried out within the ORCHESTRA project, collecting data up to 18 November 2021 on fully vaccinated health workers. The cumulative incidence of SARS-CoV-2 breakthrough infections was investigated with its association with occupational and social-demographic characteristics (age, sex, job title, previous SARS-CoV-2 infection, antibody titer levels, and time from the vaccination course completion). RESULTS: Among 64,172 health workers from 12 European health centers, 797 breakthrough infections were observed (cumulative incidence of 1.2%). The primary analysis using individual data on 8 out of 12 centers showed that age and previous infection significantly modified breakthrough infection rates. In the meta-analysis of aggregated data from all centers, previous SARS-CoV-2 infection and the standardized antibody titer were inversely related to the risk of breakthrough infection (p = 0.008 and p = 0.007, respectively). CONCLUSION: The inverse correlation of antibody titer with the risk of breakthrough infection supports the evidence that vaccination plays a primary role in infection prevention, especially in health workers. Cellular immunity, previous clinical conditions, and vaccination timing should be further investigated.

Effectiveness of a digital data gathering system to manage the first pandemic wave among healthcare workers in a main European coronavirus disease 2019 (COVID-19) tertiary-care hospital.

Objective: To evaluate the information collected from workers infected with severe acute respiratory coronavirus virus 2 (SARS-CoV-2) or close contacts using a digital data gathering system (DDGS) developed at the onset of the coronavirus disease 2019 (COVID-19) pandemic to better manage the spread of infection at our hospital. Design: Observational retrospective study. Setting: Tertiary University Hospital "Spedali Civili" Hospital, Brescia, Italy. Participants: Workers (most of whom are healthcare workers) employed at the hospital. Methods: The information collected by the DDGS was transferred to the IBM SPSS statistical software package and then statistically analyzed. Results: Overall, ∼16% of the hospital workforce was infected by SARS-CoV-2 in the first pandemic wave. Nurses were the professional category with the highest infection rate (∼15%). The asymptomatic rate of infection was between 31% and 62%. Positive molecular swabs were significantly more frequent in workers undergoing the test after sending a signaling form to our DDGS. Among workers sending the signaling forms, the information about symptoms was more predictive in terms of risk, compared to the close-contact information. The concordance between molecular swabs and subsequent serological testing was significantly higher in workers signaling their at-risk condition through the DDGS. Conclusions: Overall, our data demonstrate the advantages of a digital system to gather information from workers, which is useful for managing emergencies such as the COVID-19 pandemic. This holds particularly true for large organizations such as hospitals.

Serological response after SARS-CoV2 vaccination in healthcare workers: a multicenter study.

INTRODUCTION: Characterizing immunological response following COVID-19 vaccination is an important public health issue. The objectives of the present analysis were to investigate the proportion, level and the determinants of humoral response from 21 days to three months after the first dose in vaccinated healthcare workers (HCWs). METHODS: We abstracted data on level of anti-SARS-CoV-2 Spike antibodies (IgG) and sociodemographic characteristics of 17,257 HCWs from public hospitals and public health authorities from three centers in Northern Italy who underwent COVID-19 vaccination (average 70.6 days after first dose). We fitted center-specific multivariate regression models and combined them using random-effects meta-analyses. RESULTS: A humoral response was elicited in 99.3% of vaccinated HCW. Female sex, young age, and previous COVID-19 infection were predictors of post-vaccination antibody level, and a positive association was also detected with pre-vaccination serology level and with time between pre- and post-vaccination testing, while a decline of antibody level was suggested with time since vaccination. CONCLUSIONS: These results stress the importance of analyzing retrospective data collected via occupational health surveillance of HCWs during the COVID-19 epidemic and following vaccination. They need to be confirmed in larger series based on prospectively collected data.

Neurologic and cognitive sequelae after SARS-CoV2 infection: Different impairment for ICU patients.

The exact incidence of neurological and cognitive sequelae of COVID-19 in the long term is yet unknown. The aim of this research is to investigate the type of neurological and cognitive impairment in COVID-19 cases of different severity. Two hundred fifteen patients, who had developed COVID-19, were examined 4 months after the diagnosis by means of neurological exam and extensive cognitive evaluation, investigating general cognition, memory, verbal fluency, visuospatial abilities and executive functions. Fifty-two of them were treated in intensive care unit (ICU patients), whereas 163 were not hospitalized (non-ICU patients). Neurological deficits were found in 2/163 (1.2%) of non-ICU and in 7/52 (13.5%) of the ICU cases, all involving the peripheral nervous system. ICU patients performed significantly worse in all the neuropsychological tests and showed a worse age- and education-corrected cognitive impairment: Cognitive Impairment Index (CII) was higher in ICU than in non-ICU patients (median ICU 3 vs 2, p = .001). CII significantly correlated with age in both groups, was unrelated to length of follow- up, diabetes and hypertension and - only for ICU patients- to PaO2/FiO2 at ICU admission. Obtained results support the greater susceptibility of COVID-19 patients, treated in ICU, to develop neurological deficits and cognitive impairment at a four-month follow up, as compared to cases with mild/moderate symptoms.

Importance of mitigation measures for hospital transmission of SARS-CoV-2 at the onset of the epidemic: the experience of Brescia, Northern Italy.

PURPOSE: Since the first Italian case of SARS-CoV-2 was detected in Lombardy (Northern Italy)  Italy quickly became one of the worst-affected European countries, with a severe impact on health-care workers (HCWs). In the first epidemic, HCWs accounted for 12% of all national COVID-19 cases. We evaluated the burden of COVID-19 among HCWs and other non-health-care workers (nHCWs) in a large Italian hospital. METHODS: From March 1st to May 31st 2020, we performed a retrospective study at ASST Civil Hospital, in the Province of Brescia, Lombardy. The study population included all hospital personnel (n = 9265), categorized by professional status. RESULTS: A SARS-CoV-2 test was performed in 3572 workers (38.5%), with a positive result in 552 (5.9% of all hospital personnel). The temporal trend of SARS-CoV-2 cases in hospital staff broadly reflected that in the community, with a great majority of infections occurred during March 2020 (87.7%). From April onward, a steep decrease of positive cases was observed among hospital personnel, while in the community the decrease was much slower. Medical doctors (8.9%) and nurses (8.5%) were the most affected professional categories with a significantly higher risk of SARS-CoV-2 infection (OR 1.436 and OR 1.410, respectively p < 0.0001). HCWs in COVID-19 units presented a significantly higher risk of infection compared to HCWs in non-COVID units (p < 0.001). CONCLUSION: HCWs were severely affected by the COVID-19 epidemic, probably associated with an overwhelming burden of work and lack of preparedness in prevention of nosocomial transmission of the infection. The rapid decrease of COVID-19 spread in the hospital, registered before the one in the community, suggests that the adopted preventive measures were effective.

Effectiveness of BNT162b2 vaccine against SARS-CoV-2 among healthcare workers.

BACKGROUND:  The present study was aimed at evaluating the effectiveness of BNT162b2 among HCWs of a university hospital while a recrudescence of pandemics was hitting the province, with a high rate of the B.1.1.7 variant. Methods: The study was performed in the context of health surveillance at the workplaces. We monitored the SARS-CoV-2 infection and COVID-19 symptoms among HCWs classified by having received the entire vaccine schedule or not; the latter further classified in not vaccinated workers and workers who had received the first shot more than 14 days earlier. The SARS-CoV-2 infection was diagnosed by conventional RT-PCR on rhino-pharyngeal swabs, followed by gene sequencing in positive vaccinated HCWs. The cumulative incidence of infections in the period was normalised to 100,000 people. Results: At the end of the observation period, HCWs that had completed the full schedule were at lower infection risk than both unvaccinated HCWs and the workforce who had not yet gained the complete theoretical protection from the vaccine (by 2.4-folds). Overall, ninety-two SARS-CoV-2 infections were observed among HCWs, mostly among not protected workers (52 cases) but none of them showed symptoms requiring hospitalisation. Conclusions: The vaccination campaign effectively reduced the appearance of symptoms and the incidence of infections among vaccinated HCWs. Among vaccinated HCWs, gene sequencing was possible in five cases only, 4 B.1.1.7 and 1 B1.525 variants. The high rate of unsuccessful gene sequencing observed among infected vaccinated workers could be explained by a low viral burden. Vaccination for COVID-19 should be mandatory in occupational settings with a high infective risk.

Prospective Observational COVID-19 Screening and Monitoring of Asymptomatic Cancer Center Health-Care Workers with a Rapid Serological Test.

Health-care workers (HCW) are at high risk for SARS-CoV-2 infection and, if asymptomatic, for transmitting the virus to fragile cancer patients. We monitored all asymptomatic HCWs of a cancer institute (94% of all employees agreed to enter the study) with the rapid serological test, VivaDiagTM, identifying SARS-CoV-2 associated-IgM/IgG. The tests were performed at time 0 (n = 606) and after 14 days (n = 393). Overall, the VivaDiagTM results of nine HCWs (1.5%) were positive, with one confirmed to be SARS-CoV-2-positive after oropharyngeal swab testing by RT-PCR. At time 0, all nine cases showed IgM expression while IgG was detected in only one. After 14 days, IgM persisted in all the cases, while IgG became evident in four. A chemiluminescence immunoassay (CLIA) confirmed IgM positivity in 5/13 VivaDiagTM positive cases and IgG positivity in 4/5 VivaDiagTM positive cases. Our study suggests that the VivaDiagTM test can be of help in identifying SARS-CoV-2 infected people in cohorts of subjects with a high prevalence.

COVID19 outbreak in Lombardy, Italy: An analysis on the short-term relationship between air pollution, climatic factors and the susceptibility to SARS-CoV-2 infection.

Short-term exposure to air pollution, as well as to climate variables have been linked to a higher incidence of respiratory viral diseases. The study aims to assess the short-term influence of air pollution and climate on COVID19 incidence in Lombardy (Italy), during the early stage of the outbreak, before the implementation of the lockdown measures. The daily number of COVID19 cases in Lombardy from February 25th to March 10th, 2020, and the daily average concentrations up to 15 days before the study period of particulate matter (PM10, PM2.5), O3, SO2, and NO2 together with climate variables (temperature, relative humidity - RH%, wind speed, precipitation), were analyzed. A univariable mixed model with a logarithm transformation as link function was applied for each day, from 15 days (lag15) to one day (lag1) before the day of detected cases, to evaluate the effect of each variable. Additionally, change points (Break Points-BP) in the relationship between incident cases and air pollution or climatic factors were estimated. The results did not show a univocal relationship between air quality or climate factors and COVID19 incidence. PM10, PM2.5 and O3 concentrations in the last lags seem to be related to an increased COVID19 incidence, probably due to an increased susceptibility of the host. In addition, low temperature and low wind speed in some lags resulted associated with increased daily COVID19 incidence. The findings observed suggest that these factors, in particular conditions and lags, may increase individual susceptibility to the development of viral infections such as SARS-CoV-2.

Neurological and cognitive sequelae of Covid-19: a four month follow-up.

Central and peripheral nervous system involvement during acute COVID-19 is well known. Although many patients report some subjective symptoms months after the infection, the exact incidence of neurological and cognitive sequelae of COVID-19 remains to be determined. The aim of this study is to investigate if objective neurological or cognitive impairment is detectable four months after SARS-CoV-2 infection, in a group of patients who had mild-moderate COVID-19. A cohort of 120 health care workers previously affected by COVID-19 was examined 4 months after the diagnosis by means of neurological and extensive cognitive evaluation and compared to a group of 30 health care workers who did not have COVID-19 and were similar for age and co morbidities. At 4 month follow-up, 118/120 COVID-19 cases had normal neurological examination, two patients had neurological deficits. COVID-19 patients did not show general cognitive impairment at MMSE. In COVID-19 cases the number of impaired neuropsychological tests was not significantly different from non COVID-19 cases (mean 1.69 and 1 respectively, Mann-Whitney p = n.s.), as well as all the mean tests' scores. Anxiety, stress and depression scores resulted to be significantly higher in COVID-19 than in non COVID-19 cases. The results do not support the presence of neurological deficits or cognitive impairment in this selected population of mild-moderate COVID-19 patients four months after the diagnosis. Severe emotional disorders in patients who had COVID-19 in the past are confirmed.

Determinants of SARS-CoV-2 infection in Italian healthcare workers: a multicenter study.

Healthcare workers (HCWs) are at increased risk of being infected with SARS-CoV-2, yet limited information is available on risk factors of infection. We pooled data on occupational surveillance of 10,654 HCW who were tested for SARS-CoV-2 infection in six Italian centers. Information was available on demographics, job title, department of employment, source of exposure, use of personal protective equipment (PPEs), and COVID-19-related symptoms. We fitted multivariable logistic regression models to calculate odds ratios and 95% confidence intervals of infection. The prevalence of infection ranged from 3.0 to 22.0%, and was correlated with that of the respective areas. Women were at lower risk of infection compared to men. Fever, cough, dyspnea and malaise were the symptoms most strongly associated with infection, together with anosmia and ageusia. No differences in the risk of infection were detected according to job title, or working in a COVID-19 designated department. Reported contact with a patient inside or outside the workplace was a risk factor. Use of a mask was strongly protective against risk of infection as was use of gloves. The use of a mask by the source of exposure (patient or colleague) had an independent effect in reducing infection risk.

Serological Response to SARS-CoV-2 in Health Care Workers Employed in a Large Tertiary Hospital in Lombardy, Northern Italy.

BACKGROUND: COVID-19 pandemic is requesting unprecedented efforts by health-care workers (HCWs) in all countries, and especially in Italy during the first semester of 2020. METHODS: This is a retrospective, observational study conducted at the Spedali Civili General Hospital, in Brescia, Northern Italy during the SARS CoV-2 pandemic in the first semester of 2020. Serum samples from HCWs were tested for SARS-CoV-2 spike protein-specific antibodies. An online survey was used to collect demographic, clinical, and epidemiological data. RESULTS: Of the 1893 HCWs included, 433 (22.9%) were found seropositive for SARS-CoV-2 IgG. The cumulative prevalence of SARS-CoV-2 infection (antibodies production or past positive RT-PCR on nasal/throat swab) was 25.1% (475/1893). Fifty-six out of 433 (13%) seropositive participants declared to have been asymptomatic during the study period. The development of COVID-19 signs or symptoms is the main determinant of seropositivity (OR: 11.3, p < 0.0001) along with their duration and severity. 40/290 (14.5%) HCWs with documented positive RT-PCR during the study period did not show any detectable antibody response. IgG levels positively correlate with age, COVID-19-compatible signs and symptoms experienced and their duration. CONCLUSIONS: In this study, carried out in one of the most affected areas in Europe, we demonstrate that most HCWs with COVID-19 related symptoms develop a spike protein-specific antibodies with potential neutralizing effect.

Rapid Serological Assays and SARS-CoV-2 Real-Time Polymerase Chain Reaction Assays for the Detection of SARS-CoV-2: Comparative Study.

BACKGROUND: Real-time polymerase chain reaction (RT-PCR) testing for the identification of viral nucleic acid is the current standard for the diagnosis of SARS-CoV-2 infection, but technical issues limit its utilization for large-scale screening. Serological immunoglobulin M (IgM)/IgG testing has been proposed as a useful tool for detecting SARS-CoV-2 exposure. OBJECTIVE: The objective of our study was to compare the results of the rapid serological VivaDiag test for SARS-CoV-2-related IgM/IgG detection with those of the standard RT-PCR laboratory test for identifying SARS-CoV-2 nucleic acid. METHODS: We simultaneously performed both serological and molecular tests with a consecutive series of 191 symptomatic patients. The results provided by a new rapid serological colorimetric test for analyzing IgM/IgG expression were compared with those of RT-PCR testing for SARS-CoV-2 detection. RESULTS: Of the 191 subjects, 70 (36.6%) tested positive for SARS-CoV-2 based on RT-PCR results, while 34 (17.3%) tested positive based on serological IgM/IgG expression. Additionally, 13 (6.8%) subjects tested positive based on serological test results, but also tested negative based on RT-PCR results. The rapid serological test had a sensitivity of 30% and a specificity of 89% compared to the standard RT-PCR assay. Interestingly, the performance of both assays improved 8 days after symptom appearance. After 10 days had passed since symptom appearance, the predictive value of the rapid serological test was higher than that of the standard molecular assay (proportion of positive results: 40% vs 20%). Multivariate analysis showed that age >58 years (P<.01) and period of >15 days after symptom onset (P<.02) were significant and independent factors associated with serological test positivity. CONCLUSIONS: The rapid serological test analyzed in this study seems limited in terms of usefulness when diagnosing SARS-CoV-2 infection. However, it may be useful for providing relevant information on people's immunoreaction to COVID-19 exposure.