Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease among 948,263 individuals ≥65 years of age: A Danish cohort study

doi:10.21203/rs.3.rs-1715668/v1

This study aimed to estimate the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPV23) against invasive pneumococcal disease (IPD) among individuals ≥ 65 years of age. We used Danish nationwide databases to obtain information on PPV23 vaccination, covariates and IPD, and linked data on an individual-level using a unique personal identifier. A total of 948,263 individuals were included and followed between June 15, 2020 and September 18, 2021 (58.6% were vaccinated during follow-up). The adjusted vaccine effectiveness was 42% (95% confidence interval (CI): 9%-63%) for all-serotype IPD and 58% (95% CI: 21%-78%) for PPV23-serotype IPD, using no vaccination as the reference.

Pneumococcal Polysaccharide Vaccine

Vaccine effectiveness

Invasive pneumococcal disease

Epidemiology

Infection with Streptococcus pneumoniae can cause invasive pneumococcal disease (IPD), which is a severe and life-threatening condition.[1] On April 22, 2020, the Danish government initiated a free-of charge pneumococcal vaccination programme with a 23-valent pneumococcal polysaccharide vaccine (PPV23). The programme initially targeted individuals at particularly high risk of IPD, and on June 15, 2020, the vaccination programme was expanded to include all individuals ≥ 65 years.

The aim of this study was to estimate the effectiveness of PPV23 against all-serotype IPD and PPV23-serotype[2] IPD in individuals ≥ 65 years after the introduction of the Danish national PPV23 programme.

In Denmark, all residents are assigned a unique 10-digit civil personal registration number (CPR number) enabling linkage of different Danish registries on an individual level.[3] For this study, we used information from four Danish nationwide registries. The Danish Vaccination Register (DVR) holds data on vaccinations administered to individuals, including both privately purchased and free-of-charge vaccinations. Since November 15, 2015, all vaccinators have been obliged to register vaccines in this registry. From DVR, information on vaccination with PPV23, the 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively), and influenza vaccines was obtained by use of Anatomical Therapeutic Chemical (ATC) classification codes (Supplementary Table 1). Information on IPD, defined as the detection of Streptococcus pneumoniae from the blood, cerebrospinal fluid, or other normally sterile sites, was obtained from the Danish Microbiology Database (MiBa).[4] This national database contains real-time information on all microbiological laboratory test results from the departments of clinical microbiology.[4] The Danish National Patient Registry (DNPR) has collected information on all admissions to non-psychiatric hospitals since 1977, and on contacts to outpatient clinics and emergency departments since 1995.[3] One primary and one or more optional secondary diagnoses are provided for each hospital-contact the patient has, and coded according to the International Classification of Diseases, 10th revision (ICD-10).[3] From DNPR, we obtained information on comorbid conditions[5] in the five years prior to date of study entry, and computed a comorbidity score for each individual by use of the Charlson Comorbidity Index: 0 (low), 1–2 (moderate), and ≥ 3 (high). The Danish Civil Registration System (CPR) holds information on date of birth, sex, migration, and date of death for all Danish residents.[3]

All individuals ≥ 65 years who were residing in Denmark between June 15, 2020 and September 18, 2021, were identified from the CPR. Since those who have had PPV23 administered within 6 years are expected to be at lower risk of developing IPD, individuals vaccinated with PPV23 within 6 years prior to the date of study entry were excluded. Furthermore, individuals with IPD before study entry were excluded due to an increased risk of subsequent IPD. The study population comprised of the remaining ≥ 65 year olds residing in Denmark. Figure 1 shows the derivation of the analysis sample.

The study population was characterised according to sex, age, prior receipt of PCV7, PCV13, and influenza vaccine, comorbidity score, and selected individual comorbidities (myocardial infarction, chronic pulmonary disease, diabetes, renal disease, cancer, and congestive heart failure). All individuals were followed from June 15, 2020 or the date of immigration (index date), and until the date of IPD, emigration, death, or September 18, 2021, whichever came first. We considered exposure to PPV23 as a time-varying variable, meaning that the included individuals contributed with risk time to the relevant group, i.e. the unvaccinated or vaccinated group. Individuals could move from the unvaccinated group to the vaccinated group, but not in the opposite direction. Since the effectiveness of PPV23 is expected to occur no earlier than 14 days after the date of the PPV23 vaccination, we used a lag period of 14 days, meaning that any outcomes occurring between 0 and 14 days following PPV23 vaccination was included in the unvaccinated group. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) with calendar time as the underlying timescale and adjusted for sex and age as categorical variables, along with 95% confidence intervals (CIs), comparing PPV23 vaccination with no vaccination. The vaccine effectiveness (VE) was calculated as (1-HR)*100% for all-serotype IPD and PPV23-serotype IPD. The statistical analyses were conducted using SAS software version 9.4 (Cary, NC, USA).

A total of 1,171,631 individuals ≥ 65 years were residing in Denmark between June 15, 2020 and September 18, 2021, and after exclusion, 948,263 individuals were included in the study population (Fig. 1). Among these, 555,300 (58.6%) were vaccinated with PPV23 during follow-up. All covariates were distributed equally among unvaccinated and vaccinated individuals except for influenza vaccination, where people vaccinated with PPV23 were more likely to have received an influenza vaccine within two years prior to study entry (Table 1). Median follow-up time for all serotype IPD was 210 days (IQR: 90–336). The VE estimate with calendar time as underlying time scale and adjusted for sex and age was 42% (95% CI: 9%-63%) for all-serotype IPD and 58% (95% CI: 21%-78%) for PPV23-serotype IPD (Table 2). A sensitivity analysis was performed including the 221,248 individuals vaccinated with PPV23 within 6 years prior to study entry, this did not alter the results (data not shown).

Table 1

Patient characteristics according to vaccination status
	Study population at entry	Vaccinated with PPV23 during the study period
Total	948,263 (100)	555,300 (100)
Female sex	511,869 (54.0)	301,892 (54.4)
Age, years
Median [IQR]	74 [69–79]	74 [69–79]
<75	545,298 (57.5)	320,551 (57.7)
75–84	313,782 (33.1)	190,882 (34.4)
≥85	89,183 (9.4)	43,867 (7.9)
Receipt of PCV7 prior to study entry	< 5	< 5
Receipt of PCV13 prior to study entry	16,763 (1.8)	12,227 (2.2)
Receipt of influenza vaccine within two years prior to study entry	468,748 (49.4)	360,803 (65.0)
Charlson Comorbidity Index score*
0	706,171 (74.5)	411,921 (74.2)
1–2	201,731 (21.3)	120,454 (21.7)
≥3	40,361 (4.3)	22,925 (4.1)
Individual comorbidities within 5 years prior to study entry
Myocardial infarction	13,931 (1.5)	8,087 (1.5)
Chronic pulmonary disease	23,327 (2.5)	13,889 (2.5)
Diabetes mellitus	21,465 (2.3)	12,031 (2.2)
Cancer	96,205 (10.2)	59,415 (10.7)
Congestive heart failure	16,098 (1.7)	8,844 (1.6)
Data shown are frequencies (percentages) unless otherwise specified. Persons vaccinated with PPV23 during follow-up contributed to the analysis for both unvaccinated and vaccinated. *Within 5 years prior to study entry. Score of 0 = low comorbidity, score of 1–2 = moderate comorbidity, score of ≥ 3 = high comorbidity.
Abbreviations: IQR, interquartile range; PCV7, pneumococcal conjugate vaccine 7; PCV13, pneumococcal conjugate vaccine 13; PPV23, 23-valent polysaccharide pneumococcal vaccine

Table 2

Hazard ratios and vaccine effectiveness against all-serotype IPD and PPV23-serotype IPD, comparing vaccination with PPV23 with no vaccination, June 15 2020 to September 18 2021
			Hazard ratio (95% CI)		VE, % (95% CI)
Outcomes	Vaccination status	Events, n	Unadjusted	Adjusted*	Unadjusted	Adjusted*
All-serotype IPD	Unvaccinated	66	1 (reference)	1 (reference)	1 (reference)	1 (reference)
	Vaccinated	33	0.57 (0.36 to 0.89)	0.58 (0.37 to 0.91)	43 (11 to 64)	42 (9 to 63)
PPV23-serotype IPD	Unvaccinated	43	1 (reference)	1 (reference)	1 (reference)	1 (reference)
	Vaccinated	14	0.40 (0.21 to 0.77)	0.42 (0.22 to 0.79)	60 (23 to 79)	58 (21 to 78)
**Adjusted for age and sex as categorical variables. Abbreviations: CI, confidence interval; IPD, invasive pneumococcal disease; PPV23, 23-valent polysaccharide pneumococcal vaccine

In this Danish nationwide cohort study comprising individuals ≥ 65 years, vaccination with PPV23 was associated with a significantly lower risk of all-serotype IPD and PPV23-serotype IPD relative to no vaccination. To our knowledge, this is the first study to examine the effectiveness of vaccination with PPV23 against IPD after the initiation of a Danish national vaccination programme with PPV23 for individuals ≥ 65 years in June 2020. Previous reviews reported pooled VE estimates against all-serotype IPD in ≥ 60 year olds ranging from 45% (95% CI: 15%-65%) to 59% (95% CI: 35%-74%) in the included observational studies,[6], [7] and our results fall within this range. More recently in those ≥ 60 years of age, one systematic review covering six observational studies reports VE estimates against PPV23-serotype IPD ranging from 27% (95% CI: 17%-35%) to 42% (95% CI: -2%-67%),[8] whereas another review with 12 included observational studies, reported VE estimates ranging from 25% (95% CI: 11%-37%) to 72.8% (95% CI: 59.1%-81.8%).[9] In accordance, we also found a statistically significant lower risk within this range, of PPV23-serotype IPD following vaccination with PPV23 compared with no vaccination.

Many factors may influence the different VE estimates between the referenced studies and our study, such as the health and age of the study populations, differences in dominant serotypes in the countries where the studies were conducted, waning protection, and length of follow-up. E.g., our study population of 948,263 individuals is larger than in the referenced studies and our design used a lag of 14 days after vaccination to avoid deflation of the VE, which was not applied in the referenced studies. However, our follow-up time was relatively short.

A major strength of our study is the nationwide, cohort design covering all individuals ≥ 65 years residing in Denmark between June 15, 2020 and September 18, 2021 and with complete information on follow-up. Due to the mandatory registration of vaccinations in the DVR from November 2015 onwards, misclassification of information on PPV23 is believed to be unlikely, and if any, it is not expected to be related to later outcomes. The study period covers a time when the COVID-19 pandemic was ever-present with non-pharmacological interventions curbing the transmission of SARS-CoV-2, leading to a decline in IPD cases across the world, including in Denmark.[10] Accordingly, we observed a low number of IPD cases during the study period despite the large size of the study population, resulting in wide CIs and without the ability to include further covariates into the Cox regression model or to conduct subgroup analyses.

We chose to exclude all who have had PPV23 within 6 years of study entry to assess VE in a presumably more homogenous group, i.e. those who received PPV23 as part of the vaccination programme for all individuals 65 years or older. This might exclude the most vulnerable individuals who were offered PPV23 prior to June 15, 2020, but a sensitivity analysis shows that this does not impact the final VE estimates. Further, it cannot be ruled out that health seeking behaviour differed between the unvaccinated and vaccinated group, but the very similar profiles of the groups seems to contradict this. Lastly, due to the observational design of the present study, any causal relationship cannot be assessed.

In conclusion, our study shows that vaccination with PPV23 is associated with a moderate protection against all-serotype IPD and PPV23-serotype IPD in individuals ≥ 65 years old, although the estimates of association had limited statistical precision. These findings provide evidence supporting a continuation of the Danish national PPV23 programme.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Availability of data and material

The data included in this research is part of the Danish national vaccination surveillance system at Statens Serum Institut. The data is available for research upon reasonable request and with permission from the Danish Data Protection Agency and Danish Health and Medicines Authority.

Code availability

Not applicable.

Ethics approval

We used only administrative register data for the study. According to Danish law, ethics approval is exempt for such research, and the Danish Data Protection Agency, which is a dedicated ethics and legal oversight body, thus waives ethical approval for our study of administrative register data, when no individual contact of participants is neccessary and only aggregate results are included as findings. The study is therefore fully compliant with all legal and ethical requirements and there are no further processes available regarding such studies

Authors’ contributions

KFN, LBN, FKL and PVB designed the study with input from HCS, TD, KF and CSJ. KFN and LBN conducted the statistical and data analyses. KFN drafted the article. All authors commented, revised and approved the final manuscript. KFN attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

G. Buchholz, U. Koedel, H.-W. Pfister, S. Kastenbauer, og M. Klein, “Dramatic reduction of mortality in pneumococcal meningitis”, Crit Care, bd. 20, s. 312, okt. 2016, doi: 10.1186/s13054-016-1498-8.
Danish Medicines Agency, “Pneumovax. Summary of Product Characteristics.”, 21. februar 2022.
M. Schmidt m.fl., “The Danish health care system and epidemiological research: from health care contacts to database records”, Clin Epidemiol, bd. 11, s. 563–591, 2019, doi: 10.2147/CLEP.S179083.
K. Schønning m.fl., “Electronic reporting of diagnostic laboratory test results from all healthcare sectors is a cornerstone of national preparedness and control of COVID-19 in Denmark”, APMIS, bd. 129, nr. 7, s. 438–451, 2021, doi: 10.1111/apm.13140.
S. K. Thygesen, C. F. Christiansen, S. Christensen, T. L. Lash, og H. T. Sørensen, “The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients”, BMC Med Res Methodol, bd. 11, s. 83, maj 2011, doi: 10.1186/1471-2288-11-83.
G. Falkenhorst, C. Remschmidt, T. Harder, E. Hummers-Pradier, O. Wichmann, og C. Bogdan, “Effectiveness of the 23-Valent Pneumococcal Polysaccharide Vaccine (PPV23) against Pneumococcal Disease in the Elderly: Systematic Review and Meta-Analysis”, PLoS One, bd. 12, nr. 1, s. e0169368, 2017, doi: 10.1371/journal.pone.0169368.
H. Kraicer-Melamed, S. O’Donnell, og C. Quach, “The effectiveness of pneumococcal polysaccharide vaccine 23 (PPV23) in the general population of 50 years of age and older: A systematic review and meta-analysis”, Vaccine, bd. 34, nr. 13, s. 1540–1550, mar. 2016, doi: 10.1016/j.vaccine.2016.02.024.
J. D. Berild m.fl., “A Systematic Review of Studies Published between 2016 and 2019 on the Effectiveness and Efficacy of Pneumococcal Vaccination on Pneumonia and Invasive Pneumococcal Disease in an Elderly Population”, Pathogens, bd. 9, nr. 4, s. 259, apr. 2020, doi: 10.3390/pathogens9040259.
M. S. Niederman, T. Folaranmi, U. K. Buchwald, L. Musey, A. W. Cripps, og K. D. Johnson, “Efficacy and effectiveness of a 23-valent polysaccharide vaccine against invasive and noninvasive pneumococcal disease and related outcomes: a review of available evidence”, Expert Review of Vaccines, bd. 20, nr. 3, s. 243–256, mar. 2021, doi: 10.1080/14760584.2021.1880328.
A. B. Brueggemann m.fl., “Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data”, The Lancet Digital Health, bd. 3, nr. 6, s. e360–e370, jun. 2021, doi: 10.1016/S2589-7500(21)00077-7.

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease among 948,263 individuals ≥65 years of age: A Danish cohort study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Declarations

Funding

Competing interests

Availability of data and material

Code availability

Ethics approval

Authors’ contributions

Consent to participate

Consent for publication

References

Status:

Version 1