Estimated number of lives directly saved by COVID-19 vaccination programs in the WHO European Region, December 2020 to March 2023 (preprint)

BackgroundBy March 2023, 54 countries, areas and territories (thereafter "CAT") reported over 2.2 million coronavirus disease 2019 (COVID-19) deaths to the World Health Organization (WHO) Regional Office for Europe (1). Here, we estimate how many lives were directly saved by vaccinating adults in the Region, from December 2020 through March 2023. MethodsWe estimated the number of lives directly saved by age-group, vaccine dose and circulating Variant of Concern (VOC) period, both regionally and nationally, using weekly data on COVID-19 mortality and COVID-19 vaccine uptake reported by 34 CAT, and vaccine effectiveness (VE) data from the literature. We calculated the percentage reduction in the number of expected and reported deaths. FindingsWe found that vaccines reduced deaths by 57% overall (CAT range: 15% to 75%), representing [~]1.4 million lives saved in those aged [≥]25 years (range: 0.7 million to 2.6 million): 96% of lives saved were aged [≥]60 years and 52% were aged [≥]80 years; first boosters saved 51%, and 67% were saved during the Omicron period. InterpretationOver nearly 2.5 years, most lives saved by COVID-19 vaccinationwere in older adults by first booster dose and during the Omicron period, reinforcing the importance of up-to-date vaccination among these most at-risk individuals. Further modelling work should evaluate indirect effects of vaccination and public health and social measures. FundingThis work was supported by a US Centers for Disease Control cooperative agreement (Grant number 6 NU511P000936-02-020), who had no role in data analysis or interpretation. DisclaimerThe authors affiliated with the World Health Organization (WHO) are alone responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of the WHO. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSince first identified in late 2019, COVID-19 has caused disproportionately high mortality rates in older adults. With the rapid development and licensing of novel COVID-19 vaccines, immunization campaigns across the WHO European Region started in late 2020 and early 2021, initially targeting the most vulnerable and exposed populations, including older adults, people with comorbidities and healthcare professionals. Several studies have estimated the number of lives saved by COVID-19 vaccination, both at national and multi-country level in the earlier stages of the pandemic. However, only one multi-country study has assessed the number of lives saved beyond the first year of the pandemic, particularly when the Omicron variant of concern (VOC) circulated, a period when vaccination coverage was high in many countries, areas and territories (CAT), but COVID-19 transmission was at its highest. Added value of this studyHere we quantified the impact of COVID-19 vaccination in adults by age-group, vaccine dose and period of circulation of VOC, across diverse settings, using real world data reported by 34 CAT in the WHO European Region for the period December 2020 to April 2023. We estimated that COVID-19 vaccination programs were associated with a 57% reduction (CAT range: 15% to 75%) in the number of deaths among the [≥]25 years old, representing over 1.5 million lives saved (range: 0.7 million to 2.6 million) in 34 European CAT during the first 2.5 years following vaccine introduction. The first booster savedthe most lives (721,122 / 1,408,967, (57%) of all lives saved). The [≥]60 years old age group accounted for 96% of the total lives saved (1,349,617 / 1,408,967) whereas the [≥]80 years old age group represented 52% of the total lives saved (728,858 / 1,408,967 lives saved) and 67% of all lives were saved during the Omicron period (942,571 / 1,408,967). Implications of all the available evidenceOur results reinforce the importance of up-to-date COVID-19 vaccination, particularly among older age-groups. Communication campaigns supporting COVID-19 vaccination should stress the value of COVID-19 vaccination in saving lives to ensure vulnerable groups are up-to-date with vaccination ahead of periods of potential increased transmission.

Bivalent mRNA vaccine effectiveness against COVID-19 infections, hospitalisations and deaths in Portugal: a cohort study based on electronic health records, September 2022 to May 2023 (preprint)

Background In Portugal, a bivalent COVID-19 vaccine booster was recommended for those with complete primary COVID-19 vaccination, starting on September 6 2022. This study aims to estimate the mRNA bivalent vaccine effectiveness (VE) against COVID-19 infection, hospitalisation and death in the Portuguese population aged 65 and more years with a follow-up of more than six months. Methods We used a cohort approach to analyse six electronic health registries using deterministic linkage. The follow-up period comprehend September 2022 to May 2023. The outcomes included SARS-CoV-2 infection, COVID-19-related hospitalisation and death. Individuals were considered vaccinated 14 days following a bivalent mRNA COVID-19 vaccine uptake. For each outcome, COVID-19 bivalent VE was estimated as one minus the confounder adjusted hazard ratio of bivalent vaccine vs no bivalent vaccine, estimated by Cox regression with time-dependent vaccine exposure. Results In the [≥]80 year-olds, bivalent VE was 23.2 (95%CI: 20.1 to 26.2), 41.3 (95%CI: 34.5 to 47.5) and 50.3 (44.6 to 55.3), against infection, COVID-19-related hospitalisation and death, respectively. In the 65-79 year-old, bivalent VE against infection was 37.7 (35.5 to 39.8), 58.5 (95%CI: 51.9 to 64.2) against hospitalisation and 65.1 (95%CI: 59 to 70.4) against death. Vaccine effectiveness decay was observed for both age groups and in all outcomes, up to 6 months of vaccine uptake. Conclusions In a population with a high risk of SARS-CoV-2 complications, we observed moderate bivalent VE estimates against severe COVID-19 and low protection against infection. The lower VE estimates observed in the [≥]80 year-olds should be interpreted in light of the reference group used for the estimation, i.e., individuals with high vaccine coverage (both primary series and multiple boosters). Significant VE decay was observed up to six months of vaccine uptake, which should be considered when preparing future vaccination campaigns.

Understanding spatiotemporal patterns of COVID-19 incidence in Portugal: a functional data analysis from August 2020 to March 2022 (preprint)

Since the emergence of SARS-CoV-2 and the pandemic, massive amounts of daily data on incidence are being collected by governments and public health authorities, providing relevant information about the dissemination of pandemic in terms of its virological evolution and spatiotemporal distribution of cases, hospitalization, and deaths. We propose a novel approach combining functional data analysis and unsupervised learning algorithms to extract meaningful information about the main spatiotemporal patterns underlying SARS-CoV-2 incidence. We modelled the daily COVID-19 confirmed cases by municipality as a function of time using functional principal component analysis to describe their temporal evolution in order to outline the main temporal patterns of variability. Municipalities were classified according to their spatiotemporal similarities through hierarchical clustering adapted to spatially correlated functional data. The proposed approach is applied to mainland Portugal with data collected between August 2020 and March 2022 by municipality. The results obtained discriminate northern and coastal regions from southern and hinterland, and the effects in 2020-21 from the effects in 2021-22 autumn-winter seasons. Spatiotemporal patterns and classification of municipalities agree with results reported by other works and provides proof-of-concept that the proposed approach can be used to detect the main spatiotemporal patterns of disease incidence. The novel approach extends and refines existing exploratory tools for spatiotemporal analysis of public health data.

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.

Rapid waning of protection induced by prior BA.1/BA.2 infection against BA.5 infection (preprint)

SARS-CoV-2 omicron subvariants BA.1 and BA.2 became dominant in many countries in early 2022. These subvariants are now being displaced by BA.4 and BA.5. While natural infection with BA.1/BA.2 provides some protection against BA.4/BA.5 infection, the duration of this protection remains unknown. We used the national Portuguese COVID-19 registry to investigate the waning of protective immunity conferred by prior BA.1/BA.2 infection towards BA.5. We divided the individuals infected during the period of BA.1/BA.2 dominance (>90% of sample isolates) in successive 15-day intervals and determined the risk of subsequent infection with BA.5 over a fixed period. Compared with uninfected people, one previous infection conferred substantial protection against BA.5 re-infection at 3 months (RR=0.12; 95% CI: 0.11-0.12). However, although still significant, the protection was reduced by two-fold at 5 months post-infection (RR=0.24; 0.23-0.24). These results should be interpreted in the context of vaccine breakthrough infections, as the vaccination coverage in the individuals included in the analyses is >98% since the end of 2021. This waning of protection following BA.1/BA.2 infection highlights the need to assess the stability and durability of immune protection induced with the adapted vaccines (based on BA.1) over time.

Risk of BA.5 infection in individuals exposed to prior SARS-CoV-2 variants (preprint)

The SARS-CoV-2 omicron BA.5 subvariant is progressively displacing earlier subvariants, BA.1 and BA.2, in many countries. One possible explanation is the ability of BA.5 to evade immune responses elicited by prior BA.1 and BA.2 infections. The impact of BA.1 infection on the risk of reinfection with BA.5 is a critical issue because adapted vaccines under current clinical development are based on BA.1. We used the national Portuguese COVID-19 registry to analyze the risk of BA.5 infection in individuals without a documented infection or previously infected during periods of distinct variants' predominance (Wuhan-Hu-1, alpha, delta, BA.1/BA.2). National predominance periods were established according to the national SARS-CoV-2 genetic surveillance data (when one variant represented >90% of the sample isolates). We found that prior SARS-CoV-2 infection reduced the risk for BA.5 infection. The protection effectiveness, related to the uninfected group, for a first infection with Wuhan-Hu-1 was 52.9% (95% CI, 51.9 - 53.9%), for Alpha 54.9% (51.2 - 58.3%), for Delta 62.3% (61.4 - 63.3%), and for BA.1/BA.2 80.0% (79.7 - 80.2%). The results ought to be interpreted in the context of breakthrough infections within a population with a very high vaccine coverage (>98% of the study population completed the primary vaccination series). In conclusion, infection with BA.1/BA.2 reduces the risk for breakthrough infections with BA.5 in a highly vaccinated population. This finding is critical to appraise the current epidemiological situation and the development of adapted vaccines.

SARS-CoV-2 BA.5 vaccine breakthrough risk and severity compared with BA.2: a case-case and cohort study using Electronic Health Records in Portugal (preprint)

Background In a context of multiple Omicron lineages circulation, it is relevant to clarify the effect of vaccination and previous infections on the risk of infection and severe post-infection outcomes. Methods Using electronic health records and SARS-CoV-2 laboratory surveillance data, we conducted a case-case and a cohort study covering the period of Omicron BA.2/BA.5 lineage replacement in Portugal, to compare vaccine effectiveness of complete primary and booster dose against infection, COVID-19 hospitalization, and mortality. Variant classification was performed through whole-genome sequencing (WGS) or Spike Gene Target Failure (SGTF). Findings Between April 25 and June 10, 2022, within a total of 27702 collected samples, 55.5% were classified as BA.2 and the remaining as BA.5. We observed no evidence of reduced vaccine effectiveness for the primary complete vaccination (OR=1.07, CI95%:0.93-1.23) or booster dose vaccination (OR=0.96, CI95%:0.84-1.09) against BA.5 infection compared with BA.2. The protection against reinfection was inferior in BA.5 cases when compared with BA.2 (OR=1.44; CI95%:1.30-1.60). Among those infected with BA.5, booster vaccination was associated with 77% and 88% of reduction in risk of COVID-19 hospitalization and death, respectively, while higher risk reduction was found for BA.2 cases, with 93% and 94%, respectively. Interpretation This study shows that the SARS-CoV-2 Omicron BA.5 lineage is associated with higher odds of reinfection compared with Omicron BA.2, regardless of the vaccination status. Although less effective compared with BA.2, COVID-19 booster vaccination still offers substantial protection against severe outcomes following BA.5 infection.

Comparative complete scheme and booster effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infections with SARS-CoV-2 Omicron (BA.1) and Delta (B.1.617.2) variants (preprint)

IntroductionInformation on vaccine effectiveness and viral loads in a context of novel variants of concern (VOC) emergence is of key importance to inform public health policies. This study aimed to estimate a measure of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.617.2 and sub-lineages) VOC according to vaccination exposure (primary or booster) and time since primary vaccination and to compare cycle threshold (Ct) values between Omicron and Delta VOC infections according to the vaccination status as an indirect measure of viral load. MethodsWe developed a case-case study using data on RT-PCR SARS-CoV-2 positive cases notified in Portugal during weeks 49-51 2021. The odds of vaccination in Omicron cases were compared to Delta using logistic regression adjusted for age group, sex, region and week of diagnosis and laboratory of origin. RT-PCR Ct values were compared by vaccination status and variant using linear regression model. ResultsHigher odds of vaccination were observed in cases infected by Omicron (BA.1) VOC compared to Delta (B.1.617.2) VOC cases for both complete primary vaccination (OR=2.1; CI 95% :1.8 to 2.4) and booster dose (OR= 5.2; CI 95%: 3.1 to 8.8), indicating vaccine effectiveness reduction against Omicron. No differences in distribution of Ct-values between these two VOC were observed for any vaccination exposure categories. ConclusionConsistent lower VE was observed against Omicron infection. Complete primary vaccination may not be protective against SARS-CoV-2 infection in regions where Omicron variant is dominant, but a massive rollout of booster vaccination campaign can contribute to reduce SARS-CoV-2 incidence in the population.

B.1.617.2 SARS-CoV-2 (Delta) variant is associated with increased risk of hospitalization and death compared with B.1.1.7 SARS-CoV-2 (Alpha) variant (preprint)

Introduction The B.1.617.2 variant (Delta) was associated with increased transmissibility and lower vaccine effectiveness than the B.1.1.7 variant (Alpha). However, the effect of the B.1.617.2 variant on disease severity remains unclear. This study aims to assess whether infection with the B.1.617.2 variant was associated with a higher risk of serious illness, compared with other co-circulating variants, measured through hospitalization and death by COVID-19 in Portugal. Methods We conducted a matched cohort study in adult individuals diagnosed with SARS-CoV-2/COVID-19 infection between March 29 and August 1, 2021. Cases were individuals with a positive PCR test notified to the surveillance system. SARS-CoV-2 variants were classified first by genomic sequencing (WGS) and, if this information was unavailable, by detecting the S gene target failure. Delta (B.1.617.2) and Alpha (B.1.1.7) cases were matched on the week of diagnosis at a 1 to k ratio (k being the maximum number of unexposed available in that week) to maximize the inclusion of unexposed, using the nearest-neighbor algorithm. The hazard risk and 95% confidence intervals of hospitalization and death among those infected with the Delta (B.1.617.2) variant vs. Alpha (B.1.1.7) was estimated using a Cox proportional hazards model, adjusting for confounding for sex, age, and vaccination status. Results A total of 2,778 cases were included in the study. Of the total, 1 742 (68%) were identified as B.1.617.2 variant cases and 3 629 (32%) as B.1.1.7 variant. Within the B.1.1.7 variant cases 106 (2.9%) were hospitalized, and 110 (6.3%) within the B.1.617.2 variant cases. A total of 29 deaths were reported, 8 (0.2%) in patients infected with B.1.1.7 variant and 21 (1.2%) in patients with the B.1.617.2 variant. The confounding adjusted risk of hospitalization, in persons infected with the B.1.617.2 variant was 2.44 (95%CI 1.85; 3.20) times higher than the risk of hospitalization among B.1.1.7 variant cases, and the confounding-adjusted risk of death for B.1.617.2 variant cases was 5.20 (95%CI 2.20; 12.29) times higher than the risk of death in patients infected by B.1.1.7 variant. Conclusion The B.1.617.2 variant is associated with an increased risk of hospitalization and death compared with the B.1.1.7 variant.

Omicron (BA.1) SARS-CoV-2 variant is associated with reduced risk of hospitalization and length of stay compared with Delta (B.1.617.2) (preprint)

Introduction Early reports showed that Omicron (BA.1) SARS-CoV-2 could be less severe. However, the magnitude of risk reduction of hospitalization and mortality of Omicron (BA.1) infections compared with Delta (B.1.617.2) is not yet clear. This study compares the risk of severe disease among patients infected with the Omicron (BA.1) variant with patients infected with Delta (B.1.617.2) variant in Portugal. Methods We conducted a cohort study in individuals diagnosed with SARS-CoV-2 infection between 1st and 29th December 2021. Cases were individuals with a positive PCR test notified to the national surveillance system. SARS-CoV-2 variants were classified first by whole genomic sequencing (WGS) and, if this information was unavailable, by detecting the S gene target failure. We considered a hospitalization for all the patients admitted within the 14 days after the SARS-CoV-2 infection; after that period, they were censored. The comparison of the risk of hospitalization between Omicron and Delta VOC was estimated using a Cox proportional hazards model. The mean length of stay was compared using linear regression, and the risk of death between Omicron and Delta patients was estimated with a penalized logistic regression. All models were adjusted for sex, age, previous infection, and vaccination status. Results We included 15 978 participants aged 16 or more years old, 9 397 infected by Delta (B.1.617.2) and 6 581 infected with Omicron (BA.1). Within the Delta (B.1.617.2) group, 148 (1.6%) were hospitalized, and 16 (0.2%) were with the Omicron (BA.1). A total of 26 deaths were reported, all in participants with Delta (B.1.617.2) infection. Adjusted HR for hospitalization for the Omicron (BA.1) variant compared with Delta (B.1.617.2) was 0.25 (95%CI 0.15 to 0.43). The length of stay in hospital for Omicron (BA.1) patients was significantly shorter than for Delta (confounding-adjusted difference -4.0 days (95%CI -7.2 to -0.8). The odds of death were 0.14 (95% CI 0.0011 to 1.12), representing a reduction in the risk of death of 86% when infected with Omicron (BA.1) compared with Delta (B.1.617.2). Conclusion Omicron was associated with a 75% risk reduction of hospitalization compared with Delta (B.1.617.2) and reduced length of hospital stay.

COVID-19 vaccine effectiveness among healthcare workers in Portugal: results from a hospital-based cohort study, December 2020 to November 2021 (preprint)

Introduction: Healthcare workers (HCW) were amongst the first prioritized for COVID-19 vaccination but data on COVID-19 vaccine effectiveness among HCW is still limited. This study aims to estimate the COVID-19 vaccine effectiveness (VE) against SARS-CoV-2 symptomatic infection among HCW from Portuguese hospitals. Methods: In this prospective cohort study, we analysed data from HCW (all professional categories) from two central hospitals in the Lisbon and Tagus Valley and Centre regions of mainland Portugal between December 2020 and November 2021. VE against symptomatic SARS-CoV-2 infection was estimated as one minus the confounder adjusted hazard ratios by Cox models considering age group, sex, presence of chronic disease and occupational exposure to patients diagnosed with COVID-19 as adjustment variables. Results: During the 11 months of follow up, the 2213 HCW contributed a total of 1950 person-years at risk and 171 SARS-CoV-2 events occurred. The COVID-19 incidence rate for unvaccinated HCW was 348.7 per 1000 person-years while for fully vaccinated HCW was 43.0 per 1000 person-years. We observed a VE against symptomatic SARS-CoV-2 infection of 73.9% (95% CI: 26.2-90.8%) for complete vaccination status. Conclusion: This cohort study found a high COVID-19 VE against symptomatic SARS-CoV-2 infection in Portuguese HCW, which is in concordance with previous studies from other countries. Monitoring of VE in this HCW cohort continues during the winter 2021/2022 to evaluate potential VE decay and booster vaccine effect. Keywords: Vaccine effectiveness, SARS-CoV-2 , COVID-19, symptomatic infection, healthcare workers.

COVID-19 vaccine effectiveness against laboratory confirmed symptomatic SARS-CoV-2 infection, COVID-19 related hospitalizations and deaths, among individuals aged 65 years or more in Portugal: a cohort study based on data-linkage of national registries February-September 2021 (preprint)

Background: Using data from electronic health registries, this study intended to estimate the COVID-19 vaccine effectiveness in the population aged 65 years and more, against symptomatic infection, COVID-19 related hospitalizations and deaths, overall and by time since complete vaccination. Methods: We stablished a cohort of individuals aged 65 and more years old, resident in Portugal mainland, using the National Health Service unique identifier User number to link eight electronic health registries. Outcomes included were symptomatic SARS-CoV-2 infections, COVID-19 related hospitalizations or deaths. The exposures of interest were the mRNA vaccines (Cominarty or Spikevax) and the viral vector Vaxzevria vaccine. Complete scheme vaccine effectiveness (VE) was estimated as one minus the confounder adjusted hazard ratio, for each outcome, estimated by time-dependent Cox regression with time dependent vaccine exposure. Results: For the cohort of individuals aged 65-79 years, complete scheme VE against symptomatic infection varied between 43% (Vaxzevria) and 65% (mRNA vaccines). This estimate was slightly lower in the [≥]80 year cohort (53% for mRNA vaccines. VE against COVID-19 hospitalization varied between 89% (95%CI: 52-94) for Vaxzevria and 95% (95%CI: 93-97) for mRNA vaccines for the cohort aged 65-79 years and was 76% (95%CI: 67-83) for mRNA vaccines in the [≥]80 year cohort. High VE against COVID-19 related deaths were estimated, for both vaccine types, 95% and 81% for the 65-79 years and the [≥]80 year cohort, respectively. We observed a significant waning of VE against symptomatic infection, with VE estimates reaching approximately 34% for both vaccine types and cohorts. Significant waning was observed for the COVID-19 hospitalizations in the [≥]80 year cohort (decay from 83% 14-41 days to 63% 124 days after mRNA second dose). No significant waning effect was observed for COVID-19 related deaths in the period of follow-up of either cohorts. Conclusions: In a population with a high risk of SARS-CoV-2 complications, we observed higher overall VE estimates against more severe outcomes for both age cohorts when compared to symptomatic infections. Considering the analysis of VE according to time since complete vaccination, the results showed a waning effect for both age cohorts in symptomatic infection and COVID-19 hospitalization for the 80 and more yo cohort.

mRNA vaccines effectiveness against COVID-19 hospitalizations and deaths in older adults: a cohort study based on data-linkage of national health registries in Portugal (preprint)

BackgroundWe used electronic health registries to estimate the mRNA vaccine effectiveness (VE) against COVID-19 hospitalizations and deaths in older adults. MethodsWe established a cohort of individuals aged 65 and more years, resident in Portugal mainland through data linkage of eight national health registries. For each outcome, VE was computed as one minus the confounder-adjusted hazard ratio, estimated by time-dependent Cox regression. ResultsVE against COVID-19 hospitalization [≥]14 days after the second dose was 94% (95%CI 88 to 97) for age-group 65-79 years old (yo) and 82% (95%CI 72 to 89) for [≥]80 yo. VE against COVID-19 related deaths [≥] 14 days after second dose was 96% (95%CI 92 to 98) for age-group 65-79 yo and 81% (95%CI 74 to 87), for [≥]80 yo individuals. No evidence of VE waning was observed after 98 days of second dose uptake. ConclusionsmRNA vaccine effectiveness was high for the prevention of hospitalizations and deaths in age-group 65-79 yo and [≥]80 yo with a complete vaccination scheme, even after 98 days of second dose uptake.