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Vaccine
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a r t i c l e i n f o a b s t r a c t
Article history: Introduction: Real-world vaccine effectiveness (VE) estimates are essential to identify potential groups at
Received 1 December 2021 higher risk of break-through infections and to guide policy. We assessed the VE of COVID-19 vaccination
Received in revised form 11 May 2022 against COVID-19 hospitalization, while adjusting and stratifying for patient characteristics.
Accepted 2 June 2022
Methods: We performed a test-negative case-control study in six Dutch hospitals. The study population
Available online 8 June 2022
consisted of adults eligible for COVID-19 vaccination hospitalized between May 1 and June 28, 2021 with
respiratory symptoms. Cases were defined as patients who tested positive for SARS-CoV-2 by PCR during
the first 48 h of admission or within 14 days prior to hospital admission. Controls were patients tested
negative at admission and did not have a positive test during the 2 weeks prior to hospitalization. VE
was calculated using multivariable logistic regression, adjusting for calendar week, sex, age, comorbidity
and nursing home residency. Subgroup analysis was performed for age, sex and different comorbidities.
Secondary endpoints were ICU-admission and mortality.
Results: 379 cases and 255 controls were included of whom 157 (18%) were vaccinated prior to admis-
sion. Five cases (1%) and 40 controls (16%) were fully vaccinated (VE: 93%; 95% CI: 81 – 98), and 40 cases
(11%) and 70 controls (27%) were partially vaccinated (VE: 70%; 95% CI: 50–82). A strongly protective
effect of vaccination was found in all comorbidity subgroups. No ICU-admission or mortality were
reported among fully vaccinated cases. Of unvaccinated cases, mortality was 10% and 19% was admitted
at the ICU.
Conclusion: COVID-19 vaccination provides a strong protective effect against COVID-19 related hospital
admission, in patients with and without comorbidity.
Ó 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.vaccine.2022.06.011
0264-410X/Ó 2022 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
F.A. Niessen, M.J. Knol, S.J.M. Hahné et al. Vaccine 40 (2022) 5044–5049
including patients seeking care for a specified set of symptoms. Yet, dose<14 days prior to symptom onset (or < 28 days for vaccination
comorbidities can be important confounders, and many observa- with a single-dose vaccine) were considered unvaccinated. No data
tional studies on VE of COVID-19 vaccination lack details on was available on prior SARS-CoV-2 infection.
patient comorbidity status as such data cannot be comprehen- Data on comorbidities were collected through chart review. We
sively collected without detailed chart review. Furthermore, strat- classified comorbidities based on underlying conditions as
ified estimates for different risk-groups are essential for further recorded in medical records combined with data on chronic med-
decision making regarding additional COVID-19 vaccination. The ication. Obesity was defined as a Body Mass Index >= 30. Patients
aim of this study was to determine the VE of COVID-19 vaccination were considered immunocompromised when using immunosup-
against COVID-19 hospitalization stratified for comorbidity and pressant medication (systemic corticosteroids or disease modify-
with adjustment for relevant patient characteristics. ing antirheumatic drugs), having end stage renal failure or
having an immune deficiency disorder. Patients with recorded
chronic pulmonary disease, asthma or using chronic inhalation
2. Methods corticosteroids were considered as chronic respiratory patients.
was lower in cases than controls (66 vs 71; p < 0.05). Since the dis- symptom onset and age group was 66% (95% CI: 46–79) for partial
tribution over the three age groups was comparable to the age- vaccination and 93% (95% CI: 82–98) for full vaccination. With
distribution in hospitalized COVID-19 patients in the Netherlands, additional adjustment for sex, comorbidity and nursing home res-
weighing was considered not to be of additional value [10]. Most idency, VE was 70% (95% CI: 50–82) for partial vaccination and 93%
patients (82%) had at least one comorbidity. Obesity was more fre- (95% CI: 80–98) for full vaccination (Table 2). Sensitivity analyses
quent among cases than controls (38% vs 23%), whereas other showed higher VE-estimates when using a more infection-
underlying conditions like chronic pulmonary disease, immune specific case definition and lower VE-estimates when shortening
deficiency, chronic cardiac disease and malignancy were more fre- the interval between disease onset and vaccination (Table 1 in
quent among controls (p < 0.05). Fever at or preceding hospital supplement).
admission was reported by 239 cases (63%) and 109 controls Of all vaccinated patients the majority (67%) was vaccinated
(43%). Median CRP was 100 Ug/l among cases and 61 Ug/l among with Comirnaty, 18% with Vaxzevria, 12% with Spikevax and 1%
controls. Median leukocyte counts were 6.6 *10^9/L and 12.0 (n = 2) with COVID-19 vaccine Janssen. In seven patients the
*10^9/L among cases and controls, respectively. Controls were vaccine-product was unknown. For Comirnaty the product specific
more frequently also tested for other respiratory pathogens (86%, VE was 69% and 94% for partial and full vaccination, respectively
n = 218) than cases (30%, n = 113). Based upon these tests, seven (Table 2). VE was high for all vaccines and for all age groups with
controls had evidence of infection caused by other respiratory no statistical interaction between age groups and vaccination sta-
pathogens: Streptococcus pneumoniae (n = 4), influenza (n = 1), res- tus, although numbers were low especially in the 18–60 year age
piratory syncytial virus (n = 1), and rhinovirus (n = 1). One case also group. Eighty percent of fully vaccinated cases were female and
tested positive for rhinovirus. Vaccination status for influenza and VE for both partial and full vaccination tended to be higher in
Streptococcus pneumoniae was only documented for 1% of the cases males than in females though this difference was not statistically
and 3% of the controls. significant. Subgroup analyses for different comorbidities showed
a protective effect of both full and partial vaccination among all
3.2. Vaccine effectiveness comorbidities (Fig. 1). VE-estimates for full vaccination were above
90% for all comorbidities except among immunocompromised (VE
In total 110 patients (17%) were partially vaccinated (40 cases 75%; 95% CI: 177–98).
(11%) and 70 controls (27%)) and 45 were fully vaccinated (5 cases
(1%) and 40 controls (16%)) (Table 2). VE was adjusted for week of 3.3. Vaccinated vs unvaccinated cases
Table 2
Overall VE and VE by vaccine product adjusted for age, week of symptom onset, nursing home residency and comorbidity.
*Adjusted for time (week of symptom onset), age, sex, nursing home residency, diabetes, chronic cardiac disease, chronic pulmonary disease, immune deficiency, malignancy
and obesity as underlying disease.
Fig. 1. Effectiveness of partial and full vaccination, stratified by age-group, sex and comorbidity, adjusted for week of symptom onset, age, sex, nursing home residency and
comorbidity.
cases, indicating additional protection of vaccination against ICU- the population, yielded comparable VE estimates as in the current
admission compared to protection against hospitalization. How- study. VE was 79% (95% CI: 77–80%) for partial vaccination and 94%
ever, this difference was not statistically significant due to the (95% CI: 93–95%) for full vaccination during the period that the
overall low number of patients needing ICU-admission. alpha variant was dominant [10]. However, these estimates were
VE estimates based on nationwide registration data in the not adjusted for sex and comorbidity. In addition, no distinction
Netherlands, where vaccination status among hospitalized between hospitalization with or due to COVID-19 could be made
COVID-19 cases is compared with vaccination coverage data from based on the registration data, though the majority (an estimated
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F.A. Niessen, M.J. Knol, S.J.M. Hahné et al. Vaccine 40 (2022) 5044–5049
Ethics approval
90%) was admitted due to COVID. Our findings are comparable to
VE estimates against hospitalization during periods that the alpha
This study was performed in accordance with the ethical stan-
variant was dominant reported from other countries, showing VE-
dards as laid down in the 1964 Declaration of Helsinki and its later
estimates ranging from 33 to 74% for partial vaccination and 87–
amendments or comparable ethical standards. This study was
98% for full vaccination [11–15], and confirm the results of other
assessed by the medical research ethics committee Utrecht and
studies also reporting no of large effects of adjustment for comor-
considered not to be subject to the Medical Research Involving
bidity on VE-estimates [11].
Humans Subjects Act (WMO).
In one study performed in the United States, during the period
of alpha-variant dominance, VE against hospitalization in immuno-
compromised patients was 63% (95% CI: 44–76%) as compared to Funding
90% (95% CI: 87–92%) among subjects without immunocompro-
mising conditions [15]. Other studies have also reported lower This project was funded by the Ministry of Health Welfare and
immune response after vaccination among immunocompromised Sport (VWS), the Netherlands.
individuals [16–18]. Among transplant patients the immune
response was enhanced after a third vaccine dose [19,20]. Specific Declaration of Competing Interest
risk groups might, therefore, benefit from an additional vaccine
dose. In the Netherlands, since the beginning of October a third The authors declare that they have no known competing finan-
vaccination is being offered to immunocompromised patients. cial interests or personal relationships that could have appeared
Our study does not indicate other subgroups that might benefit to influence the work reported in this paper.
from an additional vaccine dose in order to provide protection
against COVID-19 requiring hospitalization, however, our study Acknowledgements
did not have enough power to detect small differences in VE for
subgroups. The authors would like to acknowledge the hospitals that con-
Whether will occur in the future or whether VE is affected by tributed to this study: Catharina Ziekenhuis, Medisch Spectrum
new variants such as the delta variant cannot be assessed by our Twente, Onze Lieve Vrouwe Gasthuis, Martini Ziekenhuis, St. Anto-
study since the follow up time was too short. Therefore, follow nius Ziekenhuis and the Canisius Wilhelmina Ziekenhuis. In partic-
up studies are necessary to guide policy making regarding booster ular their research personnel that collected the data. Furthermore,
vaccination. the authors would like to acknowledge Corine de Haas, Ellen
Our findings are subject to a few limitations. First, we were not Vlieger-van Leijden for their help with the logistics and Jan van
able to take into account immune status before hospitalization de Kassteele for his input on the statistical procedures.
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F.A. Niessen, M.J. Knol, S.J.M. Hahné et al. Vaccine 40 (2022) 5044–5049
VECTOR study group [8] Clift AK, Coupland CAC, Keogh RH, Diaz-Ordaz K, Williamson E, Harrison EM,
et al. Living risk prediction algorithm (QCOVID) for risk of hospital admission
and mortality from coronavirus 19 in adults: national derivation and
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C.E. Delsing: Medisch Spectrum Twente, The Netherlands
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H. Kramer: Martini Ziekenhuis, The Netherlands Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against
D. Rusch: Martini Ziekenhuis, The Netherlands symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in
E.A. bij de Vaate: St. Antonius Ziekenhuis, The Netherlands Ontario, Canada: test negative design study. BMJ. 2021;374:n1943.
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