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.