A standardised protocol for assessment of relative SARS-CoV-2 variant severity, with application to severity risk for COVID-19 cases infected with Omicron BA.1 compared to Delta variants in six European countries (preprint)

Several SARS-CoV-2 variants that evolved during the COVID-19 pandemic have appeared to differ in severity, based on analyses of single-country datasets. With decreased SARS-CoV-2 testing and sequencing, international collaborative studies will become increasingly important for timely assessment of the severity of newly emerged variants. The Joint WHO Regional Office for Europe and ECDC Infection Severity Working Group was formed to produce and pilot a standardised study protocol to estimate relative variant case-severity in settings with individual-level SARS-CoV-2 testing and COVID-19 outcome data during periods when two variants were co-circulating. To assess feasibility, the study protocol and its associated statistical analysis code was applied by local investigators in Denmark, England, Luxembourg, Norway, Portugal and Scotland to assess the case-severity of Omicron BA.1 relative to Delta cases. After pooling estimates using meta-analysis methods (random effects estimates), the risk of hospital admission (adjusted hazard ratio [aHR]=0.41, 95% CI 0.31-0.54), ICU admission (aHR=0.12, 95% CI 0.05-0.27), and death (aHR=0.31, 95% CI 0.28-0.35) was lower for Omicron BA.1 compared to Delta cases. The aHRs varied by age group and vaccination status. In conclusion, this study has demonstrated the feasibility of conducting variant severity analyses in a multinational collaborative framework. The results add further evidence for the reduced severity of the Omicron BA.1 variant.

Comparative effectiveness of the bivalent BA.4-5 and BA.1 mRNA-booster vaccines in the Nordic countries (preprint)

Background: Data on the comparative vaccine effectiveness (CVE) of the bivalent mRNA-booster vaccines containing the original SARS-CoV-2 and omicron BA.4-5 and BA.1 subvariants are limited. Methods: In a period of BA.4-5 subvariants predominance, we estimated the CVE of the bivalent Comirnaty (Pfizer-BioNTech) and Spikevax (Moderna) BA.4-5 and BA.1 mRNA-booster vaccines given as a fourth dose in Denmark, Finland, Norway, and Sweden. From 1 July 2022 to 12 December 2022, we conducted nationwide cohort analyses using target trial emulation to compare risks of Covid-19 hospitalization and death in four-dose (second booster) with three-dose (first booster) vaccinated and between four-dose vaccinated individuals. Results: Compared with having received three vaccine doses, receipt of a bivalent BA.4-5 booster as a fourth dose was associated with a country-combined CVE against Covid-19 hospitalization of 80.5% (95% confidence interval, 69.5% to 91.5%). The corresponding CVE for bivalent BA.1 boosters was 74.0% (68.6% to 79.4%). CVE against Covid-19 death was 77.8% (48.3% to 100%) and 80.1% (72.0% to 88.2%) for bivalent BA.4-5 and BA.1 boosters as a fourth dose, respectively. The CVE of bivalent BA.4-5 vs. BA.1 boosters were 32.3% (10.6% to 53.9%) for Covid-19 hospitalization and 12.3% (-36.1% to 60.7%) for death (the latter estimable in Denmark only). Conclusions: Vaccination with bivalent BA.4-5 or BA.1 mRNA-booster vaccines as a fourth dose was associated with increased protection against Covid-19 hospitalization and death during a period of BA.4-5 predominance. Bivalent BA.4-5 boosters conferred moderately greater vaccine effectiveness against Covid-19 hospitalization compared with bivalent BA.1 boosters.

Comparative effectiveness of heterologous booster schedules with AZD1222, BNT162b2, or mRNA-1273 vaccines against COVID-19 during omicron predominance in the Nordic countries (preprint)

Objective: To investigate the effectiveness of heterologous booster schedules with AZD1222 (Oxford-AstraZeneca, referred to as AZD), BNT162b2 (Pfizer-BioNTech, BNT), and mRNA-1273 (Moderna, MOD) vaccines compared with primary schedules and with homologous mRNA-vaccine booster schedules during a period of omicron predominance. Design: Population-based cohort analyses. Setting: Denmark, Finland, Norway, and Sweden, 27 December 2020 to 28 February 2022. Participants: Adults that had received at least a primary vaccination schedule (ie, two doses) of the AZD, BNT, and/or MOD vaccines during the study period. Main outcome measures: Using the Kaplan-Meier estimator, we compared country-specific risks of SARS-CoV-2 infection and severe COVID-19 outcomes in heterologous booster vaccinated with primary schedule vaccinated (matched analyses) and homologous booster vaccinated (weighted analyses) since emergence of omicron. Results: Heterologous booster schedules improved protection against all outcomes compared with primary schedules, with the largest and most robust effects observed for severe COVID-19. Risk differences for documented infection ranged from -22.4% to -3.1% (comparative vaccine effectiveness [CVE] 9.7% to 60.9%; >63.2% for COVID-19 hospitalisation) across countries for AZD1BNT2BNT3 (AZD as primary dose followed by two doses of BNT) vs AZD1BNT2 and -22.2% to -3.2% (CVE 37.4% to 67.8%; >34.6% for hospitalisation) for BNT1BNT2MOD3 vs BNT1BNT2, the two most common heterologous booster schedules. Heterologous- and homologous booster schedules had comparable effectiveness. Risk differences of documented infection ranged from -0.4% to 4.4% (CVE -20.0% to 2.4%) for AZD1BNT2BNT3 vs BNT1BNT2BNT3 and -19.8% to 1.7% (CVE -14.6% to 53.8%) for BNT1BNT2MOD3 vs BNT1BNT2BNT3; for most comparisons, risk differences for severe COVID-19 outcomes were smaller than 1 per 1000 vaccinated. Previous infection followed by a booster dose conferred the greatest protection. Conclusion: Heterologous booster vaccine schedules are associated with an increased protection against omicron-related COVID-19 outcomes that is comparable to that afforded by homologous booster schedules.

Age and product dependent vaccine effectiveness against SARS-CoV-2 infection and hospitalisation among adults in Norway: a national cohort study, July - November 2021. (preprint)

Background: COVID-19 vaccines have been crucial in the pandemic response and understanding changes in vaccines effectiveness is essential to guide vaccine policies. Though the Delta variant is no longer dominant, understanding vaccines effectiveness properties will provide essential knowledge to comprehend the development of the pandemic and estimate potential changes over time. Methods: In this population-based cohort study, we estimated vaccine effectiveness against SARS-CoV-2 infections, hospitalisations, intensive care admissions, and death using Cox proportional hazard models, across different vaccine product regimens and age groups, between 15 July and 31 November 2021 (Delta variant period). Vaccine status is included as a time-varying covariate and all models were adjusted for age, sex, comorbidities, county of residence, country of birth, and living conditions. Data from the entire adult Norwegian population were collated from the National Preparedness Register for COVID-19 (Beredt C19). Results: The overall adjusted vaccine effectiveness against infection decreased from 81.3% (confidence interval (CI): 80.7 to 81.9) in the first two to nine weeks after receiving a second dose to 8.6% (CI:4.0 to 13.1) after more than 33 weeks, compared to 98.6% (CI: 97.5 to 99.2) and 66.6% (CI: 57.9 to 73.6) against hospitalisation respectively. After the third dose (booster), the effectiveness was 75.9% (CI: 73.4 to 78.1) against infection and 95.0% (CI: 92.6 to 96.6) against hospitalisation. Spikevax or a combination of mRNA products provided the highest protection, but the vaccine effectiveness decreased with time since vaccination for all vaccine regimens. Conclusions: Even though the vaccine effectiveness against infection wanes over time, all vaccine regimens remained effective against hospitalisation after the second vaccine dose. For all vaccine regimens, a booster facilitated recovery of effectiveness. The results from this support the use of heterologous schedules, increasing flexibility in vaccination policy.

Vaccine effectiveness with BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine against reported SARS-CoV-2 Delta and Omicron infection among adolescents, Norway, August 2021 to January 2022 (preprint)

Background: COVID-19 vaccination was recommended for adolescents in Norway since August 2021. In this population-based cohort study, we estimated the BNT162b2 vaccine effectiveness against any PCR-confirmed (symptomatic or not) SARS-CoV-2 infections caused by the Delta and Omicron variant among adolescents (12-17-years-old) in Norway from August 2021 to January 2022. Methods: Using Cox proportional hazard models, we estimated the BNT162b2 vaccine effectiveness against any Delta and Omicron infections. Vaccine status was included as a time-varying covariate and models were adjusted for age, sex, comorbidities, county of residence, country of birth, and living conditions. Data were obtained from the National Preparedness registry for COVID-19, which contains individual-level data from national health and administrative registries. Findings: Vaccine effectiveness against Delta infection peaked at 68% (95%CI: 64-71%) and 62% (95%CI: 57-66%) in days 21-48 after the first dose among 12-15-year-olds and 16-17-year-olds respectively. Among 16-17-year-olds that received two doses, vaccine effectiveness peaked at 93% (95%CI: 90-95%) in days 35-62 and declined to 84% (95%CI: 76-89%) in 63 days or more after the second dose. For both age-groups, we found no protection against Omicron infection after receiving one dose. Among 16-17-year-olds, vaccine effectiveness against Omicron infection peaked at 53% (95%CI: 43-62%) in 7-34 days after the second dose and decreased to 23% (95%CI: 3-40%) in 63 days or more after vaccination. Vaccine effectiveness decreased with time since vaccination for both variants, but waning was observed to occur faster for Omicron. Interpretation: Our results suggest reduced protection from BNT162b2 vaccination against any SARS-CoV-2 infection caused by the Omicron variant compared to the Delta. In addition, waning immunity was observed to occur faster for Omicron. The impact of vaccination among adolescents on reducing infection and thus transmission is limited during omicron dominance. Funding: No funding was received.

Age and product dependent vaccine effectiveness against SARS-CoV-2 infection and hospitalisation among adults in Norway: a national cohort study, January to September 2021. (preprint)

Background: SARS-CoV-2 vaccines show high effectiveness against infection and (severe) disease. However, few studies estimate population level vaccine effectiveness against multiple COVID-19 outcomes, by age and including homologous and heterologous vaccine regimens. Methods: Using Cox proportional hazard models on data from 4 293 544 individuals (99% of Norwegian adults), we estimated overall, age-, and product-specific vaccine effectiveness against SARS-CoV-2 infection, hospitalisation, ICU admission and death in Norway, using data from national registries. Vaccine status was included as time-dependent variable and we adjusted for sex, pre-existing medical conditions, country of birth, county of residence, and crowded living conditions. Results: Adjusted vaccine effectiveness among fully vaccinated is 72.1% (71.2-73.0) against SARS-CoV-2 infection, 92.9% (91.2-94.2) against hospitalisation, 95.5% (92.6-97.2) against ICU admission, and 88.0% (82.5-91.8) against death. Among partially vaccinated, the effectiveness is 24.3% (22.3-26-2) against infection and 82.7% (77.7-86.6) against hospitalisation. Vaccine effectiveness against infection is 84.7% (83.1-86.1) for heterologous mRNA vaccine regimens, 78.3% (76.8-79.7) for Spikevax (Moderna; mRNA-1273), 69.7% (68.6-70.8) for Comirnaty (Pfizer/BioNTech; BNT162b2), and 60.7% (57.5-63.6) for Vaxzevria (AstraZeneca; ChAdOx nCoV-19; AZD1222) with a mRNA dose among fully vaccinated. Conclusion: We demonstrate good protection against SARS-CoV-2 infection and severe disease in fully vaccinated, including heterologous vaccine regimens, which could facilitate rapid immunization. Partially vaccinated were less likely to get severe disease than unvaccinated, though protection against infection was not as high, which could be essential in making vaccine prioritisation policies especially when availability is limited.

No difference in risk of hospitalisation between reported cases of the SARS-CoV-2 Delta variant and Alpha variant in Norway (preprint)

ObjectivesTo estimate the risk of hospitalisation among reported cases of the Delta-variant of SARS-CoV-2 compared to the Alpha variant in Norway. We also estimated the risk of hospitalisation by vaccination status. MethodsWe conducted a cohort study on laboratory-confirmed cases of SARS-CoV-2 in Norway, diagnosed between 3 May and 15 August 2021. We calculated adjusted risk ratios (aRR) with 95% confidence intervals (CIs) using multivariable binomial regression, accounting for variant, vaccination status, demographic characteristics, week of sampling and underlying comorbidities. ResultsWe included 7,977 cases of Delta and 12,078 cases of Alpha. Overall, 347 (1.7%) cases were hospitalised. The aRR of hospitalisation for Delta compared to Alpha was 0.97 (95%CI 0.76-1.23). Partially vaccinated cases had a 72% reduced risk of hospitalisation (95%CI 59%-82%), and fully vaccinated cases had a 76% reduced risk (95%CI 61%-85%), compared to unvaccinated cases. ConclusionsWe found no difference in the risk of hospitalisation for Delta cases compared to Alpha cases in Norway. Further research from a wide variety of settings is needed to better understand the association between the Delta variant and severe disease. Our results support the notion that partially and fully vaccinated persons are highly protected against hospitalisation with COVID-19. HighlightsO_LIThe SARS-CoV-2 Delta variant has dominated in Norway since July 2021 C_LIO_LIThere was no difference in the risk of hospitalisation for Delta cases compared to Alpha C_LIO_LIPartially and fully vaccinated cases had >70% decreased risk of hospitalisation C_LI

High vaccine effectiveness against COVID-19 infection and severe disease among residents and staff of long-term care facilities in Norway, November - June 2021 (preprint)

COVID-19 has caused high morbidity and mortality in long-term care facilities (LTCFs) worldwide. We estimated vaccine effectiveness (VE) among residents and health care workers (HCWs) in LTCFs using Cox regressions. The VE against SARS-CoV-2 infection was 81.5 (95%CI: 75.3 - 86.1 82.7%) and 81.4% (95%CI: 74.5-86.4%) [≥] 7 days after 2nd vaccine dose among residents and staff respectively. The VE against COVID-19 associated death was 93.1% among residents, no hospitalisations occurred among HCW [≥]7 days after 2nd dose.