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Protective Effects of the 23-Valent Pneumococcal Polysaccharide Vaccine in the Elderly Population: The EVAN-65 Study

  1. Angel Vila-Córcoles1,
  2. Olga Ochoa-Gondar1,
  3. Imma Hospital1,
  4. Xabier Ansa1,
  5. Angels Vilanova2,
  6. Teresa Rodríguez3,
  7. Carl Llor1, and
  8. and the EVAN Study Groupa
  1. 1Primary Care Service of Tarragona-Valls, Catalonian Health Institute, Tarragona
  2. 2Department of Laboratory and Microbiology, Joan XXIII Hospital, Tarragona
  3. 3Department of Statistic and Research of IDIAP Jordi Gol i Gurina, Barcelona, Spain
  1. Reprints or correspondence: Dr. A. Vila-Corcoles, Institut Catala de la Salut, Prat de la Riba 39, Tarragona 43001, Spain (avila.tarte.ics{at}gencat.net).

  • ↵a Members of the study group are listed at the end of the text.

 
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Abstract

Background. The 23-valent polysaccharide pneumococcal vaccine (PPV) is currently recommended for elderly persons and persons who are at high risk of infection. However, the effectiveness of the 23-valent PPV remains controversial. We assessed the effectiveness of this vaccine in older adults.

Methods. A prospective cohort study was conducted from January 2002 through April 2005; it included all community-dwelling individuals aged ⩾65 years who were assigned to 1 of 8 primary health care centers in Tarragona, Spain (11,241 subjects). The primary outcomes were invasive pneumococcal disease, pneumococcal pneumonia, overall pneumonia rate, and death due to pneumonia. All cases were validated by a check of the clinical records. The association between pneumococcal vaccination and the risk of each outcome was evaluated by means of multivariate Cox proportional hazard models, adjusted for age, sex, comorbidity, immunocompetence, and influenza vaccine status.

Results. Pneumococcal vaccination was associated with significant reductions in the risk of hospitalization for pneumonia (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.59–0.92) and in the overall pneumonia rate (HR, 0.79; 95% CI, 0.64–0.98). The incidence of invasive pneumococcal disease was low (64 cases per 100,000 person-years), and a considerable protective effect against invasive pneumococcal disease did not attain statistical significance (HR, 0.60; 95% CI, 0.22–1.65). However, the vaccine showed a significant effectiveness of 45% to prevent pneumococcal pneumonia (HR, 0.55; 95% CI, 0.34–0.88). Finally, vaccination was associated with a significant 59% reduction in the risk of death due to pneumonia among vaccinated subjects (HR, 0.41; 95% CI, 0.23–0.72)

Conclusions. These results indicate that the 23-valent PPV effectively prevented pneumococcal pneumonia (with or without bacteremia) and decreased the rates of overall pneumonia and of mortality due to pneumonia in older adults, providing new arguments for systematic vaccination in the elderly population.

The 23-valent polysaccharide pneumococcal vaccine (PPV) is currently recommended for use in elderly persons and in persons at high risk of infection [1, 2]. However, despite numerous studies, its effectiveness in preventing noninvasive pneumococcal infection and other clinically relevant medical outcomes remains unclear.

Several meta-analyses have evaluated this problem, and despite inconclusive results, it has generally been observed that the 23-valent PPV is effective for the prevention of invasive pneumococcal disease (IPD) [3–6]. In a recent study in the Cochrane Review, the 23-valent PPV was not found to be effective in preventing either pneumonia or death among elderly or high-risk subjects; the researchers concluded that only observational studies have shown a significant efficacy in preventing IPD [5]. In a recent review, Fedson and Liss [7] concluded that the results in prospective clinical trials and meta-analyses have been inconclusive, but that they should not be regarded as negative, because many trials have focused on unrepresentative populations, and others have lacked statistical power or have had serious methodological problems.

The latest studies have not clarified the controversy regarding the effectiveness of this vaccine [8–12]. In a large retrospective cohort study, Jackson et al. [8] found an efficacy rate of 44% against pneumococcal bacteremia in older adults, but they also observed an unexplained 14% increase in the risk of hospitalization for pneumonia among vaccinated subjects. Two recent case-control studies have reported contradictory results. Benin et al. [11] did not find any significant protective effect of the 23-valent PPV against IPD in Navajo adults (a group with a high incidence of pneumococcal disease), whereas Dominguez et al. [12] found an efficacy rate of 72% against IPD in elderly Spanish subjects.

In Catalonia, a region in the northeast of Spain with a population of 6 million people, free pneumococcal vaccination of all elderly subjects was introduced and began to be recommended in October 1999. This study was planned for 3 years, and it commenced on 1 January 2002 [13]. An interim analysis, which covered the first year of the study, was reported previously [14]. In the present study, we have assessed the vaccine's effectiveness in preventing IPD, pneumococcal pneumonia, all-cause pneumonia, and death in elderly people who lived in the community during the period from January 2002 through April 2005.

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Methods

Design, setting, and study population. We conducted a prospective cohort study that included all community-dwelling subjects assigned to 1 of 8 primary health care centers (PHCCs) in Tarragona, Catalonia, Spain (n = 11,241), who were aged ⩾65 years at the time of the study's start (1 January 2002). During the period from October 1999 through December 2001, family physicians at 8 participating PHCCs recommended pneumococcal vaccination for all persons aged ⩾65 years. During this period, no specific campaign was undertaken, and the 23-valent PPV was offered free of charge when elderly subjects visited the PHCC during the annual influenza vaccination campaigns (October–November) or at any other visit throughout the rest of the year. All cohort members were observed from the start of the study until enrollment at the PHCC ceased, until the first occurrence of each specific outcome, or until the end of the study (30 April 2005). The study was conducted in accordance with the general principles for observational studies set out by the Catalan Health Institute (Tarragona).

Data sources. All participating PHCCs have an institutional database with registries of immunizations, laboratory tests, medication prescriptions, and diagnoses associated with chronic diseases, outpatient visits, and hospitalizations coded according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9). This institutional database (which has been in place since 1998) and the computerized clinical records for each cohort member were used to identify whether the individual had received pneumococcal and influenza vaccinations and to identify the presence of comorbidity. The hospital admission discharge diagnosis databases and the medical records from 3 participating reference hospitals (Joan XXIII, Santa Tecla, and Pius Hospital) were used to identify and validate primary end points. Isolates were sent to the National Center of Microbiology (Madrid, Spain) for serotyping.

Outcome measure and definitions. The primary outcomes were IPD, community-acquired pneumonia (CAP), pneumococcal pneumonia, and death due to pneumonia. Means of conventional diagnostic evaluation included blood culture, sputum culture, and serological testing of paired serum samples. The Streptococcus pneumoniae urinary antigen test (Binax-NOW) has been used since 31 May 2003, as indicated by the attending physician.

IPD was defined as a the presence of S. pneumoniae on culture of blood samples, CSF samples, or samples from other normally sterile sites. CAP was defined as an acute respiratory illness with evidence of a new infiltrate on a chest radiograph. Pneumococcal pneumonia was defined as CAP in which S. pneumoniae was identified by blood culture, sputum culture, or urinary antigen test. Death due to pneumonia was considered to have occurred when the patient died ⩽30 days after receiving a diagnosis of pneumonia [15].

IPD and CAP were identified on the basis of ICD-9 discharge codes for bacteremia (038.0, 038.2, 041.0, 041.2, 320.1) or pneumonia (480–487.0). Laboratory records were also used for identified cases of pneumococcal infections not detected in ICD-9 discharge codes. Outpatient CAP was defined as a primary care or emergency visit (in which the subject was not hospitalized) with an ICD-9 code for pneumonia in the PHCC's databases. All cases of CAP (in both hospitalized patients and outpatients) were radiographically confirmed and validated by review of the medical record with the use of standardized data-collection instruments. A diagnosis of CAP was considered if, on conclusion of the medical record review, the physician reviewer verified this diagnosis and that it did not involve a readmission, a case of nosocomial pneumonia, or another diagnosis. The investigators who validated clinical data and those who performed microbiological procedures were unaware of the vaccination histories of the subjects.

Covariates. Covariates were age, sex, number of outpatient visits in the 24 months before the study's start, history of hospitalization for pneumonia in the previous 24 months, influenza vaccination status, presence of any comorbidity (e.g., chronic heart disease, diabetes mellitus, chronic lung disease, hypertension, and obesity), current smoking status, and immunological situation. Immunocompromise was a composite variable defined by the presence of any one of the following characteristics: cancer (solid organ or hematological neoplasia), chronic severe nephropathy (nephrotic syndrome, renal failure, or receipt of dialysis or a transplant), chronic severe liver disease (cirrhosis), anatomical or functional asplenia, AIDS, and receipt of long-term corticosteroid therapy (defined as 20 mg/day of prednisone) or another immunosuppressive medication [8, 16].

Statistical analysis. The incidence of each event was calculated in person-years, with the sum of the person-time contributed to each individual considered in the denominator. Multivariable Cox proportional hazard models, with time-varying covariates, were used to evaluate the association between having received the pneumococcal vaccine and the time of the first outcome during the study period.

Pneumococcal vaccination status was a time-varying covariate, and persons were considered to be vaccinated 14 days after vaccine administration. Annual influenza vaccine status was also a time-varying covariate, whereas the other covariates were defined at study entry. Persons who had received an influenza vaccine were considered to be vaccinated against influenza from 1 December in the current year of vaccination until the end of the next influenza campaign.

Multivariable Cox models began with all variables significant in the univariate analysis at the 25% level [17]. The proportional hazard assumptions were assessed by adding the covariate by log-time interactions to the model and plotting the scaled and smoothed Schoenfeld residuals obtained from main effects model, where possible [17]. The statistics package used was Stata/SE software, version 9.1 (Stata Corp.).

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Results

The 11,241 cohort members were observed for a total of 33,905 person-years, of which 17,401 person-years (51%) followed the 23-valent PPV. In total, 4986 subjects were vaccinated before the study started, whereas 4314 (87%) had received the 23-valent PPV during the previous 2 years. of the 6255 subjects who had not received the 23-valent PPV before entering the study, 1449 (23%) were vaccinated during the 40-month study period. These 1449 subjects contributed to the analysis, for a total of 4599 person-years (2312 person-years in the unvaccinated group and 2287 person-years in the vaccinated group). The baseline characteristics of the cohort members are shown in table 1.

Table 1
Table 1

Baseline characteristics of 11,241 cohort members, according to their pneumococcal vaccination status, before the start of the study.

During the total study period, IPD was observed in 22 subjects (1 of whom was not hospitalized), and CAP was observed in 473 subjects (355 of whom were hospitalized and 118 of whom were outpatients). The incidence of IPD was 0.64 cases per 1000 person-years (0.53 cases per 1000 person-years for bacteremic pneumococcal pneumonia), and it was 13.96 cases per 1000 person-years for overall pneumonia (10.48 hospitalizations per 1000 person-years for pneumonia and 3.48 outpatient cases of pneumonia per 1000 person-years). There were 1497 deaths due to all causes, among which 60 occurred within 30 days after the onset of pneumonia.

An etiological study was performed for 358 (75.7%) of the 473 patients with CAP. of 355 hospitalized patients with CAP, blood cultures were performed for 278 (78.3%), and sputum cultures were performed for 189 (53.1%). Urinary antigen tests were performed for 119 (25.2%) of all 473 patients with CAP, of whom 97 (81.5%) were hospitalized. S. pneumoniae was identified in 70 patients (by blood culture in 18, by sputum culture in 5, and by urinary antigen test in 47), and other etiological agents were identified in 61 patients.

The initial unadjusted analysis revealed higher rates of hospitalization and of overall pneumonia among vaccinated subjects, but it also revealed lower rates of IPD, pneumococcal pneumonia, and death due to pneumonia among these vaccinated subjects. The fatality rate was 12.7% for overall pneumonia (16.3% among unvaccinated persons and 9.8% among vaccinated persons; P = .023).

In the multivariable analysis, pneumococcal vaccination was associated with nonsignificant reductions in the risk of IPD due to vaccine-related serotypes (hazard ratio [HR], 0.61; 95% CI, 0.13–2.76), IPD due to all serotypes (HR, 0.60; 95% CI, 0.22–1.65), bacteremic pneumococcal pneumonia (HR, 0.45; 95% CI, 0.15–1.40) and nonbacteremic pneumococcal pneumonia (HR, 0.61; 95% CI, 0.35–1.06), as well as a significant protective effect against overall pneumococcal pneumonia (HR, 0.55; 95% CI, 0.34–0.88). Pneumococcal vaccination did not alter the risk of CAP due to other microorganisms (HR, 1.10; 95% CI, 0.61–1.99) or the risk of CAP due to nonidentified pathogens (HR, 0.88; 95% CI, 0.69–1.13).

Pneumococcal vaccination was associated with significant reductions in the risk of hospitalization for pneumonia (HR, 0.74; 95% CI, 0.59–0.92) and overall pneumonia (HR, 0.79; 95% CI, 0.64–0.98), but vaccination did not affect the risk of outpatient pneumonia (HR, 0.90; 95% CI, 0.59–1.37). Finally, pneumococcal vaccination was associated with a reduction in the rate of death due to pneumonia among vaccinated subjects (HR, 0.41; 95% CI, 0.23–0.72).

Table 2 shows the unadjusted rates and multivariable analysis results for pneumococcal infections. The values for different results for hospitalized patients and overall pneumonia and for death due to pneumonia or to all causes are shown in table 3. The covariate pneumococcal vaccine has proportional hazards in all the models. Footnotes in both tables indicate which predictor variables were statistically significant (P < .05) in each outcome. Table 4 shows the results of multivariable analyses according to influenza periods and influenza vaccine status at the start of the study.

Table 2
Table 2

Incidence and risk of invasive pneumococcal disease (IPD) and pneumococcal pneumonia in relation to pneumococcal vaccination status.

Table 3
Table 3

Incidence and risk of hospitalization for pneumonia, outpatient pneumonia, overall pneumonia, and death due to pneumonia or to any cause, according to pneumococcal vaccination status.

Table 4
Table 4

Multivariable analyses of pneumococcal vaccine effectiveness for influenza or noninfluenza periods, according to influenza vaccine status before the beginning of the study.

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Discussion

We undertook a long prospective study to evaluate the controversial effectiveness of the 23-valent PPV in older adults. Although we did not conduct a randomized, controlled trial, the large size of our study population, together with adjustment for important covariables in the multivariable analysis, provides an adequate basis for assessing the health effects of pneumococcal vaccination in the elderly population.

All outcome measures and definitions were based on defined criteria in classic meta-analyses [3, 15]. The study population was representative and large enough to evaluate most outcomes related to pneumococcal vaccination, but we lacked statistical power to assess events as uncommon as IPD.

Strengths of the study were the validation of outcome events and the use of survival analysis methods to estimate vaccine effectiveness when adjusted for important covariates such as comorbidity or influenza vaccine status. However, as with all observational studies, the possible influence of residual confounding on the estimates of vaccine effectiveness can not be completely excluded, because vaccination was not randomized.

In this study, the incidence of IPD (64 cases per 100,000 person-years) was within the range reported from developed countries [2]. The distribution of clinical syndromes and the proportion of cases of IPD caused by vaccine serotypes or vaccine-related serotypes are in agreement with data reported in previous studies [2, 12, 16]. Hospitalizations for pneumonia (10.5 hospitalizations per 1000 person-years), the pneumonia case-fatality rate (13%), and the death rate for all causes (43.4 deaths per 1000 inhabitants per year) are also in agreement with rates reported for noninstitutionalized adults aged >65 years [2, 8, 9, 12, 18]. We believe that these similar results support the validity of our methods.

In this study, although the effect did not reach statistical significance because of the limited number of cases, crude and adjusted rates point to a protective effect against IPD and bacteremic pneumococcal pneumonia. Our results fit with those obtained in retrospective studies of pneumococcal vaccination that have shown a rate of effectiveness of 40%–70% for the prevention of IPD [8, 12, 16, 19, 20].

We observed a significant efficacy rate (45%; 95% CI, 12%–66%) against overall pneumococcal pneumonia. This effectiveness was based on the ability of the 23-valent PPV to prevent as many bacteremic cases as nonbacteremic cases. A protective effect of the 23-valent PPV against pneumococcal pneumonia was reported in earlier trials among younger adults [21, 22] and institutionalized elderly subjects [23], but prospective clinical trials and meta-analyses have failed to demonstrate this effect among people aged >55 years [3–7].

Definitive pneumococcal pneumonia (defined as a positive blood culture result) is a specific outcome to evaluate the efficacy of the 23-valent PPV; however, this outcome had a low sensitivity for detection of the global effect of the vaccine, because 80% of cases of pneumococcal pneumonia do not involve bacteremia [2]. In contrast, the conventional diagnosis of presumptive pneumococcal pneumonia has low specificity, because isolation of S. pneumoniae from sputum specimens may represent colonization. We used the Binax-NOW urinary antigen test to detect nonbacteremic cases of pneumococcal pneumonia, and 48 of 53 cases of nonbacteremic pneumococcal pneumonia were diagnosed using this test. Several studies have evaluated this procedure, concluding that this test had acceptable sensitivity (60%–70%) and high specificity (82%–98%), even when unconcentrated urine samples are used [24, 25]. Considering only the cases of CAP that occurred after the Binax-NOW test was available (from May 2003 to April 2005), the Binax-NOW test was used for 45% of cases of CAP overall (42.5% of cases in nonvaccinated subjects and 46.8% of those in vaccinated subjects). Logistic regression analysis did not reveal any significant association between the use of the Binax-NOW test and pneumococcal vaccine status (OR, 0.92; 95% CI, 0.54–1.58) or for other factors predicting the use of the Binax-NOW test. Analysis restricted to the period of Binax-NOW testing did not reveal differences in the vaccine's effectiveness, compared with the overall study period (data available on request).

In this study, the 23-valent PPV was shown to have a significant efficacy rate (26%; 95% CI, 8%–41%) in reducing the risk of hospitalization for all-cause pneumonia and a rate of 21% (95% CI, 2%–34%) for the prevention of overall pneumonia. Although these 2 outcomes are not as specific as IPD or pneumococcal pneumonia, they can be used as a good measure of the vaccine's effectiveness [7].

This study has also documented a significant 59% reduction (95% CI, 28%–77%) in the risk of death due to pneumonia among vaccinated subjects. Excluding earlier trials [21, 22], prospective and retrospective studies have failed to demonstrate a protective effect for the 23-valent PPV against pneumonia or death in general community-dwelling individuals [3, 7]. In a retrospective cohort study, Nichol et al. [26] observed that the pneumococcal vaccination reduced the rate of hospitalizations for pneumonia by 47% among patients with chronic obstructive pulmonary disease. In a nonrandomized, large-scale intervention of elderly individuals in Stockholm, Sweden, Christenson et al. [9] observed an additive effect of influenza and pneumococcal vaccinations in reducing the mortality rate for hospitalized patients with pneumonia by 35%, but this effect was not significant for patients who had only received the 23-valent PPV. Our findings are consistent with those reported in an interim analysis covering the first 12-month study period; the analysis pointed to a reduction in the risk of hospitalization for pneumonia (HR, 0.80; 95% CI, 0.50–1.28) and overall pneumonia (HR, 0.86; 95% CI, 0.56–1.31) and also revealed a significant protective effect against death due to pneumonia (HR, 0.28; 95% CI, 0.09–0.83) [14].

We obtained information on annual influenza vaccinations for all cohort members. This was a strong point of this study, given that few studies have adjusted their results for this variable [8, 16]. In our study, the vaccinated group had greater influenza vaccination coverage than did the nonvaccinated group, and this was a confounder in some Cox models. To decrease the possible bias linked with influenza vaccine effects [27], we performed supplementary analyses that are based on influenza vaccine status when the study started, and we observed that pneumococcal vaccination was associated with a significant reduction in the risk of hospitalization for pneumonia among subjects who had not been vaccinated against influenza (HR, 0.65; 95% CI, 0.43–0.99). Specific analysis confined to influenza seasons showed that pneumococcal vaccination was associated with significant reductions in the risk of pneumococcal pneumonia (HR, 0.39; 95% CI, 0.21–0.74), hospitalization for pneumonia (HR, 0.69; 95% CI, 0.49–0.97), and death due to pneumonia (HR, 0.44; 95% CI, 0.20–0.98).

The effectiveness of the 23-valent PPV is controversial. The Cochrane Collaboration reported a rate of vaccine effectiveness of 53% (95% CI, 41%–63%) against IPD, but it concluded that the vaccine did not prove to have a significative effect in preventing either pneumonia (95% CI, -15 to 20%) or death (95% CI, -9% to 12%) [5]. In contrast, Fedson et al. [2, 7] concluded that none of the published meta-analyses have contained a sufficient number of person-years of observation to reach any reliable conclusion about the efficacy of the 23-valent PPV to prevent pneumonia or death.

If we consider that 30%–50% of overall cases of pneumonia could be caused by S. pneumoniae [2], our findings are epidemiologically plausible and support the effectiveness of the 23-valent PPV for prevention of pneumococcal pneumonia (including nonbacteremic cases), hospitalization for all-cause pneumonia, overall pneumonia, and death due to pneumonia.

Considering the low incidence of IPD (∼50 cases per 100,000 elderly person–years) [2], the 23-valent PPV could be more efficient in avoiding 1 case of pneumococcal pneumonia, 1 hospitalization for pneumonia, or 1 death due to pneumonia than 1 case of IPD. Our findings provide important information and could have implications in cost-effectiveness analyses and public policy for pneumococcal vaccination in the general elderly population. Some studies have shown that pneumococcal vaccination appears to be cost-effective for high-risk or elderly subjects, although the vaccine may only be effective for preventing IPD [28, 29], but these results depend highly on the uncertainties around vaccine efficacy estimates [29]. Additional benefits of the 23-valent PPV, as we have found in this study, could have a greater effect on vaccine efficacy in elderly people.

An increasing number of countries are adopting pneumococcal conjugate vaccination of infants and count on a future reduction in the number of cases of IPD in older adults. However, it must not be forgotten that the decrease in the rate of IPD after the introduction of conjugate vaccine was lower in elderly people (-18%) than in young adults (-32%) [30]; in addition, the immunogenicity of the current conjugate vaccines is worse than that for the polysaccharide vaccine in adults [31].

We conclude that the 23-valent PPV should be recommended for all subjects aged ⩾65 years. The greatest burden of infection and death due to pneumonia falls on this population group, and they can obtain an important benefit from the vaccination.

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Evan-65 Study Group

A. Vila-Córcoles, X. Ansa, A. Gómez, J. Fort, M. Piqueras, J. Grifoll, J. L. Pinyol, and D. Montanyes (Primary Care Service of Tarragona-Valls); N. Sarrá, J. M. Roca, M. Grivé, and R. Antón (Primary Care Center of Bonavista–La Canonja); N. Saún, B. Rull, C. M. Fuentes, E. Satué, M. J. Solís, M. C. DeDiego, B. Fernández, V. Silvestre, M. A. Puig, and X. Bria (Primary Care Center of Torreforta–La Granja); I. Noguera, O. Ochoa-Gondar, M. Herreros, and F. Grifoll (Primary Care Center of Sant Pere i Sant Pau); C. Llor, F. Bobé, M. Maxenchs, and M. Perez-Bauer (Primary Care Center of Tarraco); J. Balsells, E. Martín, L. Clotas, and A. Serrano (Primary Care Center of Sant Salvador); L. Palacios, F. Gallego, C. Ferrández, and E. Salsench (Primary Care Center of Salou); F. Ester, S. Montserrat, and G. Cando (Primary Care Center of Morell); M. Alvarez, I. Hospital, I. Guinea, M. M. Juarez, C. Bayona, D. Llovet, and O. Esteso (Primary Care Center of Valls); A. Vilanova, F. Gómez-Bertomeu, J. M. Santamaria, and A. García-Fuertes (Hospital Joan XXIII, Tarragona); X. Raga, X. Clivillé, and M. C. Daufí (Hospital Santa Tecla, Tarragona); and T. Benet, J. M. Villó (Pius Hospital, Valls).

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Acknowledgments

We would like to thank all members of EVAN-65 Study Group for their collaboration in this project. We also thank the medical staffs of the participating hospitals and the microbiological laboratories that participated and that sent isolates for serotyping to the National Center of Microbiology of the Instituto de Salud Carlos III (Madrid). We thank Timothy Bowring for his help in the production of this article.

Financial support. Health Research Fund (FIS) of the Spanish Ministry of Health and Consumer Affairs (expedient PI-02117).

Potential conflicts of interest. All authors: no conflicts.

  • Received April 19, 2006.
  • Accepted June 1, 2006.
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  1. Clin Infect Dis. (2006) 43 (7): 860-868. doi: 10.1086/507340
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