Vaccine effectiveness against SARS-CoV-2 reinfection during periods of Alpha (B.1.1.7), Delta (B.1.617.2) or Omicron (B.1.1.529) dominance: A Danish nationwide study (preprint)

Introduction Individuals with a prior severe acute respiratory corona virus 2 (SARS-CoV-2) infection have a moderate to high degree of protection against reinfection, though seemingly less so when the Omicron variant of SARS-CoV-2 started to circulate. The aim of this study was to evaluate the vaccine effectiveness (VE) against SARS-CoV-2 reinfection, that is, in individuals with prior SARS-CoV-2 infection, during periods with different dominant SARS-CoV-2 variants. Methods A nationwide cohort study design including all individuals with a confirmed SARS-CoV-2 infection, who were alive and residing in Denmark between 1 January 2020 and 31 January 2022 were used. Using Danish nationwide registries, we obtained information on SARS-CoV-2 infections, Coronavirus Disease 2019 (COVID-19) vaccination, age, sex, comorbidity, staying at hospital and region of affiliation. The study population included were individuals with prior SARS-CoV-2 infection. Crude and adjusted estimates of VE against SARS-CoV-2 reinfection with 95% confidence intervals (CIs) were calculated using Poisson and Cox regression models, respectively. The VE estimates were calculated separately for three periods with different dominant SARS-CoV-2 variants (Alpha (B.1.1.7), Delta (B.1.617.2), or Omicron (B.1.1.529)) and by time since vaccination using unvaccinated as the reference. Findings The study population comprised of 209,814 individuals infected before or during the Alpha period, 292,978 before or during the Delta period and 245,530 before or during the Omicron period. Of these, 40,281 individuals had completed their primary vaccination series during the Alpha period (19.2%), 190,026 during the Delta period (64.9%) and 158,563 during the Omicron period (64.6%). VE against reinfection following any COVID-19 vaccine type administered in Denmark, peaked at 85% (95% CI: 37% to 97%) at 104 days or more after vaccination during the Alpha period, 88% (95% CI: 81% to 92%) 14-43 days after vaccination during the Delta period and 60% (95% CI: 58% to 62%) 14-43 days after vaccination during the Omicron period. Waning immunity was observed, and was most pronounced during the Omicron period. Interpretation This study shows that, in previously infected individuals, completing a primary vaccination series was associated with a significant protection against SARS-CoV-2 reinfection compared with no vaccination for all three variant periods. Even though vaccination seems to protect to a lesser degree against reinfection with the Omicron variant, these findings are of public health relevance as they show that previously infected individuals still benefit from COVID-19 vaccination in all three variant periods.

Vaccine effectiveness when combining the ChAdOx1 vaccine as the first dose with an mRNA COVID-19 vaccine as the second dose (preprint)

Background The recommendations in several countries to stop using the ChAdOx1 vaccine has led to vaccine programs combining different vaccine types, which necessitates new knowledge on vaccine effectiveness (VE). In this study, we aimed to estimate the VE when combining the ChAdOx1 vaccine as the first dose and an mRNA vaccine as the second dose. Methods This nationwide population-based cohort study estimated VE against SARS-CoV-2 infection, all-cause and COVID-19 related hospitalization and death after receiving the ChAdOx1 vaccine as the first dose followed by an mRNA vaccine as the second dose. VE estimates were obtained using a Cox regression with calendar time as underlying time and adjusted for sex, age, comorbidity, heritage and hospital admission. Information on all individuals was extracted and linked from high-quality national registries. Results A total of 5,542,079 individuals were included in the analyses (97.6% of the total Danish population). A total of 144,360 were vaccinated with the ChAdOx1 vaccine as the first dose and of these 136,551 individuals received an mRNA vaccine as the second dose. A total of 1,691,464 person-years and 83,034 cases of SARS-CoV-2 infection were included. The VE against SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine was 88% (95% confidence interval (CI): 83; 92) 14 days after the second dose and onwards. There were no COVID-19 related hospitalizations and deaths among the individuals vaccinated with the combination of the ChAdOx1 and an mRNA vaccine during the study period. Conclusion In conclusion, this study found a reduction in the risk of SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine, compared with unvaccinated individuals. This is similar to the VE of two doses of an mRNA vaccine. Longer follow-up time is needed to confirm vaccine induced protection against severe events, such as COVID-19 related hospitalization and death.

Vaccine effectiveness of the BNT162b2 mRNA COVID-19 vaccine against RT-PCR confirmed SARS-CoV-2 infections, hospitalisations and mortality in prioritised risk groups (preprint)

Objective: To estimate in a real life setting, the vaccine effectiveness of the BNT162b2 mRNA vaccine against confirmed SARS-CoV-2 infection, hospital admission, and death among five priority groups for vaccination Design: Cohort study Setting: Roll-out of the BNT162b2 mRNA vaccine in Denmark Participants: 864,096 individuals who were first inline to receive the BNT162b2 mRNA vaccine: 46,101 long-term care facility (LTCF) residents, 61,805 individuals 65 years and older living at home but requiring practical help and personal care (65PHC), 98,533 individuals [≥]85 years of age (+85), 425,799 health-care workers (HCWs), and 231,858 individuals with comorbidities that predispose for severe COVID-19 disease (SCD). Intervention: vaccination with BNT162b2 mRNA vaccine Main outcome measures: RT-PCR confirmed SARS-CoV-2 infections, COVID-19 related admissions within 14 days after a confirmed SARS-CoV-2 infection, all-cause admission, COVID-19 related death within 30 days after confirmed SARS-CoV-2 infection, and all-cause death. Results: Beyond 7 days after the second dose, the VE against SARS-CoV-2 infection in all groups ranged from 53-86%. In 65PHC, HCW and SCD, we observed a substantial reduction in risk of infection 0-7 days after the second dose ranging from 46-71%. The VE against COVID-19 related admissions ranged from 75-87% in all groups except +85 and HCWs where no events occurred. For COVID-19 related deaths, a significant VE was observed in LTCF residents (VE of 89%) and 65PHC (VE of 97%), whereas no events were observed in the three remaining groups. VE against all-cause death ranged from 26-73% in all groups except HCW where an insignificant VE was estimated. For all-cause admission, the VE ranged from 37-50% in all groups except in SCD where a negative VE was observed. Conclusion: In a real-life setting and more than 7 days after the second dose of BNT162b2 mRNA was administered to the most vulnerable individuals, the vaccine was associated with a reduction of SARS-CoV-2 infection (53-86%) and COVID-19 related admissions ([≥]75%) or deaths ([≥]89%).

Sex-differences in COVID-19 associated excess mortality is not exceptional for the COVID-19 pandemic. A population based study from 27 European countries (preprint)

Background Europe experienced increased mortality from February through June, 2020 due to the COVID-19 pandemic, with more COVID-19-associated deaths in males compared to females. However, a sex-difference in excess mortality may be a more general phenomenon, and should be investigated in none-COVID-19 situations as well.Methods Based on death counts from Eurostat, separate excess mortalities were estimated for each of the sexes using the EuroMOMO algorithm. Sex-differences were expressed as differences in excess mortality incidence rates. A general relation between sex-differences and overall excess mortality both during the COVID-19 pandemic and in preceding seasons were investigated.Results Data from 27 European countries were included, covering the seasons 2016/17 to 2019/20. In periods with increased excess mortality, excess was consistently highest among males. From February through May 2020 male excess mortality was 52.7 (95% PI: 56.29; 49.05) deaths per 100,000 person years higher than for females. Increased male excess mortality compared to female was also observed in the seasons 2016/17 to 2018/19. We found a linear relation between sex-differences in excess mortality and overall excess mortality, i.e., 40 additional deaths among males per 100 excess deaths per 100,000 population. This corresponds to an overall female/male mortality incidence ratio of 0.7.Conclusion In situations with overall excess mortality, excess mortality increases more for males than females. We suggest that the sex-differences observed during the COVID-19 pandemic reflects a general sex-disparity in excess mortality.

Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 Vaccine in long-term care facility residents and healthcare workers - a Danish cohort study (preprint)

Abstract Background At the end of 2020, Denmark launched an immunization program against SARS-CoV-2. The Danish health authorities prioritized persons currently living in long-term care facilities (LTCF residents) and frontline healthcare workers (HCW) as the first receivers of vaccination. Here we present preliminary population based vaccine effectiveness (VE) estimates in these two target groups. Methods The study was designed as a retrospective registry- and population-based observational cohort study including all LTCF residents and all HWC. The outcome was a polymerase chain reaction confirmed SARS-CoV-2, and VE was estimated for different periods following first and second dose. We used Poisson and Cox regressions to estimate respectively crude and calendar time-adjusted VE for the BNT162b2 mRNA Covid-19 Vaccine from Pfizer/BioNTech with 95% confidence intervals (CI) for vaccinated versus unvaccinated. Results A total of 39,040 LTCF residents (median age at first dose; 84 years, Interquartile range (IQR): 77-90) and 331,039 HCW (median age at first dose; 47 years, IQR: 36-57) were included. Among LTCF residents, 95.2% and 86.0% received first and second dose from 27 December 2020 until 18 February 2021, for HWC the proportion was 27.8% and 24.4%. During a median follow-up of 53 days , there were 488 and 5,663 confirmed SARS-CoV-2 cases in the unvaccinated groups, whereas there were 57 and 52 in LTCF residents and HCW within the first 7 days after the second dose and 27 and 10 cases beyond seven days of second dose. No protective effect was observed for LTCF residents after first dose. In HCW, VE was 17% (95% CI; 4-28) in the > 14 days after first dose (before second dose). Furthermore, the VE in LTCF residents at day 0-7 of second dose was 52% (95% CI; 27-69) and 46% (95% CI; 28-59) in HCW. Beyond seven days of second dose, VE increased to 64% (95% CI; 14-84) and 90% (95% CI; 82-95) in the two groups, respectively. Conclusion The results were promising regarding the VE both within and beyond seven days of second vaccination with the BNT162b2 mRNA Covid-19 Vaccine currently used in many countries to help mitigate the global SARS-CoV-2 pandemic. Impact of the research: So far, observational studies of the real-word effectiveness of the mRNA Vaccine BNT162b2 has been limited to the period after the administration of the first dose. This is the first report to date to present vaccine effectiveness (VE) estimates after the second BNT162b2 mRNA Covid-19 Vaccine. We estimated a VE of 52% and 46% in LTCF residents and HCW within seven days, which increased to 64% and 90% in the two groups respectively beyond seven days of immunization. These findings supports maintaining a two-dose schedule of the BNT162b2 mRNA Covid-19 Vaccine.

Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19 (preprint)

BACKGROUND The characteristics of COVID-19 outbreak and high fatality rate of COVID-19 infection have attracted the attention of scientists due to the strong interactions between components of metabolic syndrome, metabolic abnormalities, and viral pathobiology of COVID-19. Combined metabolic cofactors supplementation (CMCS) consisting of L-serine, N-acetyl-L-cysteine (NAC), nicotinamide riboside (NR), and L-carnitine tartrate is being studied for the treatment of patients with COVID-19. METHODS We conducted a placebo-controlled, phase-2 clinical trial involving ambulatory COVID-19 patients. A total of 100 patients were randomly assigned on a 3:1 basis to hydroxychloroquine plus CMCS or hydroxychloroquine plus placebo. The total treatment period for the hydroxychloroquine was 5 days, and for the CMCS/placebo was 14 days. Clinical status was evaluated daily by phone, using a binomial scale for subject reported presence or absence for multiple COVID-19 related symptoms. Plasma samples for clinical chemistry analyses were collected on day 0 and day 14. RESULTS A total of 93 patients completed the trial. The combination of CMCS and hydroxychloroquine significantly reduced the average complete recovery time compared with hydroxychloroquine and placebo (6.6 days vs 9.3 days, respectively). Moreover, there was a significant reduction in ALT, AST and LDH levels on day 14 compared to day 0 in the hydroxychloroquine plus CMCS group. The adverse effects were uncommon and self-limiting. CONCLUSIONS In patients with mild-to-moderate COVID-19, CMCS resulted in a significant reduction in recovery time and liver enzymes associated with hepatic function compared to placebo. We observed that CMSC is associated with a low incidence of adverse events.