Discussion
The prospective production of VE estimates using population-based EHR with short time lag between data consolidation and data analysis is an added value to provide necessary evidence to adapt vaccine policies in the different target groups in a timely way In this study, timely, rapid and robust estimates have been calculated using a common protocol applied to population registries for complete primary vaccination, first, second and third booster doses. The harmonization of the outcome and exposure definitions, and the application of common analytical methods enhanced comparability and allowed for joint estimates. These methodological approaches are of high added value especially when the incidence of COVID-19 decreases and fewer events are reported. Results are based on a multi-country collaboration and estimates reflect on the performance of the vaccines in the population across several countries. In addition, the overall study period covered the predominance of the Delta SARS-COV-2 variant, the emergence of the Omicron and its subvariants, as well as the successive administration of first, second and third vaccine boosters which is another key strength of this analysis. Nonetheless, the production of real time VE estimates depends on access approvals to different EHR by the public health instititutes. While such access have been relatively easily granted in exceptional circumstances during pandemic time, the sustainability of such process may be difficult moving forward.
Our results showed a decrease in complete primary vaccination VE against hospitalisation in both agre groups (65–79 and 80-years) from 87–67% in October–November 2021 to 32–36% in October–November 2022. While the first booster initially restored immunity to similar levels to the ones observed at the beginning of the vaccination programme (≥95% by the end of 2021), its VE also decreased to approximately 50–68% by May 2022, around 6-7 months after first booster vaccination campaign and after the emergence of Omicron and its subvariants. VE estimates against COVID-19-related deaths of the first booster available since March–April 2022 showed a similar trend, although less pronounced among ≥80-years, compared to 65–79-years.
The significant decline in VE following the emergence of SARS-CoV-2 Omicron in December 2021 is in line with neutralisation studies indicating vaccine escape by Omicron . It is also highly consistent with reports from the USA, Canada, South Africa and Europe on lower VE against severe disease during the Omicron subvariants predominance, in particular BA.2 and BA.4/BA.5. Rapid waning of first booster VE against hospitalisation during Omicron predominant period has also been reported in the literature (VE of 29–58% 3–6 months after uptake) . This decline in VE motivated the recommendation for an additional booster dose in vulnerable population subgroups, but also the development of adapted vaccines to closely match circulating variants.
Other factors could also contribute to the observed decrease in VE. The Omicron BA.1 wave in early 2022 resulted in the highest SARS-CoV-2 incidence observed throughout the pandemic in Europe, with estimated 48% of the European population infected . This could have enhanced the immunity at a different rate for vaccinated and unvaccinated population, leading to an underestimation of VE .
The administration of a second booster for the ≥80-years and other vulnerable population groups in the Spring of 2022 (only in Portugal and Belgium among the participating study sites) raised VE to around 80% for both hospitalisation and death, and it remained stable between June–July and October–November 2022. However, relative VE did decrease with time since the Spring vaccination campaign and only increased again in October-November 2022, likely reflecting the second booster vaccination rollout in the remaining participating study sites (Supplementary material, appendix 4). Specifically, second booster was recommended in Summer 2022 (Norway, Belgium) and in Autumn 2022 (Navarre, Spain), and Portugal and Belgium introduced the third booster for the ≥80-years in Autumn 2022, resulting in second and third boosters administered simultaneously in different study sites. The observed similar VE estimates for the second and third boosters in our study suggest that the time since the last dose might be more relevant than the total number of doses received.
In addition, adapted bivalent vaccines were introduced and used as booster (first, second, third) from September 2022 onwards , with countries rapidly discontinuing the use of monovalent vaccines. This affects the comparability of the most recent VE estimates with the ones obtained before September 2022, and may have led to the underestimation of the relative benefit of the most recent booster dose. Studies have suggested different effectiveness of monovalent and bivalent vaccines and that bivalent vaccines with BA.4/5 component could provide more protection than those with BA.1 .
There are several limitations to be flagged. Even though all the sites followed a common protocol, there were some differences in the information available at each site and the outcomes definitions allow a small degree of flexibility. Also, because variables for adjustment collected by study sites were limited by the information available within the respective EHR, there might be some residual confounding in the estimates. The VE monitoring system was implemented in highly vaccinated populations, and by October 2021 the primary series vaccination coverage was already >90% in all participating study sites and continued to increase , resulting in a small group of unvaccinated individuals that made VE estimation at the study site level challenging. In particular, at the end of the observation period, this extreme distribution of vaccination led to considerable statistical uncertainty. Henceforth, we envisage that monitoring relative VE, that quantify the additional benefit of each booster dose, will provide more robust results and will be more informative. Up to March–April 2022, we excluded individuals with previous infections. Systematic testing for SARS-CoV-2 was discontinued in most countries during the Omicron wave at the beginning of 2022, self-tests were readily available in the community and the results were not reported in EHR. In this context, the risk of misclassification of previous infection is high, and after April 2022 this exclusion criterion was no longer applied. While most of the vaccines administered as first, second and third boosters were mRNA vaccines in the EU/EEA, it would be of importance to get brand specific estimates. Unfortunatly, there was not sufficient information in some registries to provide vaccine brand specific estimates. Last but not least, the project aims to expand to additional countries in order to have a better geographical representativeness across the EU/EEA.
In conclusion, according to our results, successive COVID-19 vaccine booster doses have been key to maintaining protection against severe disease over time. Despite the reduction in VE, booster vaccination continues to substantially reduce the risk of hospitalisation and death due to COVID-19 in older individuals. Overall, this study demonstrated the feasibility of real-world prospective monitoring of COVID-19 VE in real time using EHR with application of a common protocol across six EU/EEA countries. Although it comes with some methodological challenges, the use of population-based EHR across several sites provide robust estimate at EU level and should be maintained to continue with near-real-time VE estimates in a changing landscape of COVID-19 vaccine recommendations.