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Post hoc analysis of the efficacy of the 13-valent pneumococcal conjugate vaccine against vaccine-type community-acquired pneumonia in at-risk older adults
Vaccine 36 (2018) 1477–1483
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Post hoc analysis of the efficacy of the 13-valent pneumococcal conjugate vaccine against vaccine-type community-acquired pneumonia in at-risk older adults José A. Suaya a,⇑, Qin Jiang b, Daniel A. Scott c, William C. Gruber c, Chris Webber c, Beate Schmoele-Thoma d, Cassandra K. Hall-Murray b, Luis Jodar b, Raul E. Isturiz b a
Pfizer Vaccines Medicines Development & Scientific and Clinical Affairs, New York, NY, USA Pfizer Vaccines Medicines Development & Scientific and Clinical Affairs, Collegeville, PA, USA c Pfizer Vaccines Clinical Research and Development, Pearl River, NY, USA d Pfizer Vaccines Clinical Research and Development, Berlin, Germany b
a r t i c l e
i n f o
Article history: Received 8 September 2017 Received in revised form 12 January 2018 Accepted 17 January 2018 Available online 9 February 2018 Keywords: Community-acquired pneumonia PCV13 Vaccine efficacy Older adults At risk Chronic conditions
a b s t r a c t Background: Individuals with certain chronic medical conditions are at higher risk of developing pneumonia and pneumococcal disease than those without. Using data from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), this post hoc analysis assessed the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged 65 years with at-risk conditions. Methods: The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) was a doubleblind, parallel-group, randomized, placebo-controlled study in the Netherlands in which adults aged 65 years received either PCV13 or placebo. Outcomes of interest were identified using prespecified clinical criteria, radiographic confirmation, routine microbiologic testing, and a serotype-specific urinary antigen detection assay. Methods: In this post hoc analysis, participants were classified by at-risk status based on self-reporting of any of the following chronic medical conditions: heart disease, lung disease, asthma, diabetes, liver disease, and smoking. The objective of this analysis was to assess PCV13 vaccine efficacy (VE) against a first episode of vaccine-serotype community-acquired pneumonia (VT-CAP) in at-risk participants. Results: Of the 84,496 adults enrolled in the study, 41,385 (49.2%) were considered at risk owing to chronic medical conditions. Of the 139 VT-CAP cases, 115 (82.7%) occurred in these participants. VE of PCV13 against a first episode of VT-CAP among participants with at-risk conditions was 40.3% (95.2% CI: 11.4%, 60.2%). Average duration of follow-up since vaccination was 3.95 years for at-risk participants; protection did not wane over the study period. Conclusions: This post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) showed significant and persistent efficacy of PCV13 against VT-CAP in at-risk older adults. Conclusions: ClinicalTrials.gov identifier: NCT00744263. Ó 2018 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
Abbreviations: ACIP, Advisory Committee on Immunization Practices; CAP, community-acquired pneumonia; COPD, chronic obstructive pulmonary disease; IPD, invasive pneumococcal disease; IR, incidence rate; IRR, incidence rate ratio; mITT, modified intention-to-treat; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; PY, person-years; Sp-CAP, community-acquired pneumonia caused by Streptococcus pneumoniae; VE, vaccine efficacy; VT-CAP, PCV13 vaccine-serotype community-acquired pneumonia. ⇑ Corresponding author at: Global Pneumococcal Vaccines, Vaccines Medical Development and Medical/Scientific Affairs, Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. E-mail addresses: [email protected] (J.A. Suaya), [email protected] (Q. Jiang), [email protected] (D.A. Scott), [email protected] (W.C. Gruber), Chris. [email protected] (C. Webber), [email protected] (B. Schmoele-Thoma), [email protected] (C.K. Hall-Murray), [email protected] (L. Jodar), [email protected] (R.E. Isturiz). https://doi.org/10.1016/j.vaccine.2018.01.049 0264-410X/Ó 2018 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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1. Introduction Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality in adults worldwide [1]; Streptococcus pneumoniae is among the most frequently isolated causative pathogens [2,3]. There are 2 pneumococcal vaccines currently licensed and recommended for use in adults in the United States [4] and many other countries [5]: a 13-valent pneumococcal conjugate vaccine (PCV13) and a 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV13 contains capsular polysaccharides from 13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) individually conjugated to nontoxic diphtheria toxin cross-reactive material 197 protein [6], whereas PPSV23 contains 23 nonconjugated capsular polysaccharides, 12 in common with PCV13 [7]. The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) was conducted according to accelerated approval pathway requirements of the US Food and Drug Administration to measure PCV13 efficacy in older adults [8]. It was a doubleblind, randomized, clinical study of 84,496 adults aged 65 years in the Netherlands [9]. Participants were randomized to receive either PCV13 or placebo from September 2008 to January 2010 and were followed for a mean of 3.97 years. Per-protocol analysis of the study demonstrated a 45.6% vaccine efficacy (VE; 95.2% CI: 21.8%, 62.5%) against first episodes of PCV13 vaccine-serotype CAP (VT-CAP; primary objective) [9]. On the basis of the findings from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), the US Advisory Committee on Immunization Practices (ACIP) now recommends routine sequential use of both PCV13 and PPSV23 in adults aged 65 years [8]. ACIP also recommends that adults aged 19 years with immunocompromising conditions or anatomic or functional asplenia receive sequential PCV13 and PPSV23 vaccinations on the combined basis of high incidence of pneumococcal disease in these populations and positive results from PCV13 immunogenicity and cost-effectiveness studies [10]. Individuals of all ages with chronic, nonimmunocompromising conditions (termed ‘‘at risk” in some studies [11–13]) such as heart disease, lung disease (including chronic obstructive pulmonary disease [COPD] and asthma), diabetes, liver disease, and smoking (not further defined), many of which are highly prevalent in the adult population [14,15], are also at increased risk of developing pneumonia and pneumococcal disease [11–13,16–19]. When atrisk individuals do develop CAP, their episodes are more costly than for individuals without known risk or in the overall population [19,20], and their case fatality rate exceeds that of individuals with lower risk [21]. Although determining the etiology of adult CAP is challenging, S pneumoniae is among the most commonly identified pathogens in CAP, accounting for 13% of hospitalized CAP and approximately 35% of CAP with identified pathogens in the United States [2] and Europe [1], respectively. Thus, preventing adult pneumococcal CAP (Sp-CAP) is of critical importance. Because at-risk adults aged <65 years in the United States are currently recommended to receive PPSV23 alone [10], the performance of PCV13 in these populations is of public health interest. To better characterize VE in at-risk individuals, as well as to address a specific request from ACIP, we conducted a post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) among the subpopulation with at-risk conditions.
Briefly, it was a double-blind, parallel-group, randomized, placebo-controlled trial that enrolled 84,496 immunocompetent adults aged 65 years in the Netherlands with no history of pneumococcal vaccination. Participants were randomized to receive a single dose of either PCV13 or placebo. The study’s primary objective was to demonstrate PCV13 efficacy against a first episode of VT-CAP in the per protocol population efficacy analysis. VT-CAP was determined by the presence of 2 prespecified clinical criteria, chest radiography findings suggestive of CAP, and a positive VT-specific urinary antigen test or isolation of VT–S pneumoniae from blood or another sterile site. 2.2. Objectives of post hoc analysis The main objective of the current post hoc analysis was to assess PCV13 VE against a first episode of VT-CAP in at-risk participants (defined below) based on the per protocol population efficacy analysis, consistent with the original study [9]. Because cases and VE for the overall population were reported previously [9], PCV13 VE in participants without known risk is also provided for contextual purposes. Sensitivity analyses included calculating PCV13 VE against a first episode of VT-CAP in at-risk participants based on the modified intention-to-treat (mITT) population efficacy analysis and PCV13 VE against all episodes of VT-CAP. 2.3. Populations for analysis Consistent with the original study [9], the mITT population included study participants who (1) were eligible and (2) had an episode of CAP with symptoms’ onset 14 days after vaccination. The per protocol population included participants in the mITT population but excluded CAP episodes that had onset of symptoms following the receipt of any nonstudy pneumococcal vaccine or after diagnoses of any of the following conditions: immunosuppression or immunodeficiency, postobstructive pneumonia (excluding chronic obstructive pulmonary disease [COPD]), bronchial obstruction caused by primary lung cancer, another metastatic lung cancer, acquired immunodeficiency syndrome, confirmed or suspected pneumonia caused by Pneumocystis jiroveci, or active tuberculosis. 2.4. Classification of at-risk population Before receiving the study vaccine, all participants were asked to complete a questionnaire with the following screening list of medical conditions: heart disease, lung disease, asthma, diabetes with or without insulin use, liver disease, smoking, and history of splenectomy. Self-identified medical conditions were not verified by medical record review. Only immunocompetent older adults were enrolled [9], and the current analysis also excluded those with history of splenectomy, those not responding to any of the screening questions, or those not eligible. Participants were classified as at risk if they had 1 of the medical conditions listed above, other than splenectomy. None of the risk factors included are considered immunocompromising or high-risk conditions according to ACIP [10]. Participants without any reported at-risk condition were classified as ‘‘without known risk.” 2.5. Analyses
2. Methods 2.1. Study design The design of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) has been previously reported [9].
The case definitions of VT-CAP were the same as those used in the original study [9]. For purposes of contextualizing the setting and study period, VT epidemiology of pneumococcal CAP was described among individuals in the placebo group in terms of risk group and proportion of first episodes of Sp-CAP caused by PCV13
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3.3. VE for VT-CAP
vaccine serotypes (VT-CAP). Additionally, incidence rates (IR) of VT-CAP per 100,000 person-years were calculated by risk status and vaccination group. For IR calculations, each participant’s follow-up duration started from the day of vaccination and ended with the date when the subject concluded his/her participation in the study (eg, due to death, participant leaving the general practitioner’s practice or moving out of the catchment area, or selfwithdrawal) or the date of study discontinuation, whichever was earlier. The follow-up duration of each study participant was based on periodic contact from the coordinating center to the participants’ physicians. The total person-years of follow-up were aggregated by vaccine group and risk status. Finally, VE was estimated as 1-incidence rate ratio (IRR), where IRR is the incidence rate ratio comparing the PCV13 group with the placebo group. Exact 2-sided 95.2% CIs were calculated using the ClopperPearson method with alpha adjustment for interim analysis, reflecting the study overall analysis [9]. SASÒ version 9.4 (SAS Institute, Cary, NC) was used to perform all analyses.
Based on the per protocol analysis, for a first episode of VT-CAP, PCV13 VE in at-risk participants was 40.3% (95.2% CI: 11.4%, 60.2%); in participants without known risk, it was 66.7% (95.2% CI: 11.8%, 89.3%). Using our method of calculating VE, VE in overall study participants was 45.6% (95.2% CI: 21.9%, 62.5%). For all episodes of VT-CAP, PCV13 VE estimates were 36.5% (95.2% CI: 6.9%, 57.1%) in at-risk participants, 66.7% (95.2% CI: 11.8%, 89.3%) in those without known risk, and 42.4% (95.2% CI: 18.2%, 59.9%) in the overall study population (Table 3). Based on the mITT analysis, for a first episode of VT-CAP, PCV13 VE in at-risk participants was 32.5% (95.2% CI: 3.9%, 53.0%); in participants without known risk, it was 63.7% (95.2% CI: 14.7%, 86.1%). VE in overall study participants was 39.1% (95.2% CI: 15.9%, 56.2%). For all episodes of VT-CAP, PCV13 VE estimates were 31.8% (95.2% CI: 4.0%, 51.9%) in at-risk participants, 65.3% (95.2% CI: 19.0%, 86.7%) in those without known risk, and 38.8% (95.2% CI: 16.2%, 55.5%) in the overall study population (Table 3).
3. Results
3.4. Duration of protection
3.1. Study participants
Fig. 1 displays case accrual plots for first episodes of VT-CAP. Overall case accumulation in at-risk participants was higher than in participants without known risk in both the vaccine and placebo groups; this was expected due to higher CAP risk among these individuals. Vaccine efficacy did not appear to wane over the study period.
Of the 84,496 study participants [9], 432 were excluded from the post hoc analysis (Table 1) for any of the following hierarchical (ie, not mutually exclusive) reasons: 368 on the basis of ineligibility, 73 with history of splenectomy, and 2 with incomplete medical condition forms. The current analysis included 41,385 at-risk participants and 42,679 participants without known risk. Table 2 gives additional baseline characteristics of study participants and prevalence of each self-identified medical condition; these were similar in both vaccine and placebo groups among at-risk participants. 3.2. Epidemiology of VT-CAP among placebo group participants Among participants in the placebo group, 80.0% (72/90) of first episodes of VT-CAP occurred in at-risk participants (Table 3). VTCAP incidence in at-risk participants was 4.2 times higher than in participants without known risk (88.2 vs 21.1 episodes per 100,000 person-years). Similar findings were observed for all episodes of VT-CAP, ie, 80.4% (74/92) of all episodes in the placebo group were in at-risk participants, and VT-CAP incidence in atrisk participants was 4.3 times higher than in without-knownrisk participants (90.6 vs 21.1 episodes per 100,000 person-years). VT-CAP accounted for 62.1% (72/116) and 61.2% (74/121) of first episodes and all episodes of Sp-CAP, respectively, in at-risk participants in the placebo group (not shown in table).
4. Discussion This post hoc analysis showed statistically significant estimates of PCV13 efficacy compared with placebo against first and all episodes of VT-CAP in participants self-identified as having chronic medical conditions. As expected, because most first episodes of VT-CAP occurred in at-risk individuals, the VE estimates in this group were generally similar to those calculated for the entire study population [9]. These findings provide additional evidence for decision-making regarding the benefits of potential vaccination strategies in the at-risk population. PCV13 protection continued over the duration of the study (ie, an average of 3.95 years in atrisk participants and 4.00 years in participants without known risk), as observed for the entire study population [9]. Another recent post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) found that PCV13 VE did not wane over the 5-year study duration [22]. The chronic conditions included in the at-risk category are very prevalent in adult populations across age groups worldwide, which
Table 1 Population attrition and risk classification. Participants, n (%)
Excluded from this post hoc analysis*,y Did not meet study inclusion criteria History of splenectomy Incomplete medical condition form Included in this post hoc analysisà At risk§ Without known risk
PCV13 (n = 42,240)
Placebo (n = 42,256)
Total (N = 84,496)
221 (0.5) 186 (84.2) 41 (18.6) 1 (0.5) 42,019 (99.5) 20,680 (49.2) 21,339 (50.8)
211 (0.5) 182 (86.3) 32 (15.2) 1 (0.5) 42,045 (99.5) 20,705 (49.2) 21,340 (50.8)
432 (0.5) 368 (85.2) 73 (16.9) 2 (0.5) 84,064 (99.5) 41,385 (49.2) 42,679 (50.8)
PCV13 = 13-valent pneumococcal conjugate vaccine. * The count in this row is used as a denominator for the percentages for the 3 rows below. y Exclusion criteria were not mutually exclusive. à The count in this row is used as a denominator for the percentages for the 2 rows below. § Conditions included in this category were heart disease, lung disease, asthma, diabetes with or without insulin use, liver disease, and smoking.
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Table 2 Baseline characteristics of participants stratified by risk classification. At risk (n = 41,385)
Without known risk (n = 42,679)
All (N = 84,064)
PCV13 (n = 20,680)
Placebo (n = 20,705)
PCV13 (n = 21,339)
Placebo (n = 21,340)
Sex, n (%) Female Male
8313 (40.2) 12,367 (59.8)
8095 (39.1) 12,610 (60.9)
10,400 (48.7) 10,939 (51.3)
10,292 (48.2) 11,048 (51.8)
37,100 (44.1) 46,964 (55.9)
Race, n (%) White Nonwhite Missing
20,337 (98.3) 339 (1.6) 4 (0.0)
20,369 (98.4) 329 (1.6) 7 (0.0)
21,048 (98.6) 286 (1.3) 5 (0.0)
21,042 (98.6) 295 (1.4) 3 (0.0)
82,796 (98.5) 1249 (1.5) 19 (0.0)
Age at enrolment, y Mean (SD) Median Min–max <75, n (%) 75–<85, n (%) 85, n (%)
73.1 (5.8) 72.0 65–101.1 13,678 (66.1) 6200 (30.0) 802 (3.9)
73.1 (5.8) 72.0 65–99.5 13,654 (65.9) 6275 (30.3) 776 (3.7)
72.5 (5.6) 71.2 65–100.3 15,202 (71.2) 5452 (25.5) 685 (3.2)
72.4 (5.5) 71.1 65–96.1 15,277 (71.6) 5412 (25.4) 651 (3.1)
72.8 (5.7) 71.6 65–101.1 57,811 (68.8) 23,339 (27.8) 2914 (3.5)
Self-reported medical condition, n (%) Asthma 2008 (9.7) Diabetes 5211 (25.2) Heart disease 10,642 (51.5) Liver disease 203 (1.0) Lung disease 4224 (20.4) Smoking 5175 (25.0)
2094 (10.1) 5303 (25.6) 10,657 (51.5) 199 (1.0) 4324 (20.9) 5147 (24.9)
0 0 0 0 0 0
0 0 0 0 0 0
4102 (4.9) 10,514 (12.5) 21,299 (25.3) 402 (0.5) 8548 (10.2) 10,322 (12.3)
(0) (0) (0) (0) (0) (0)
(0) (0) (0) (0) (0) (0)
PCV13 = 13-valent pneumococcal conjugate vaccine.
Table 3 PCV13 VT-CAP incidence rates and vaccine efficacy. At risk (n = 41,385)
PY Mean follow-up, y Per protocol analysis First episode of VT-CAP IR (per 100,000 PY) PCV13 VE* [95.2% CI],% All episodes of VT-CAP IR (per 100,000 PY) PCV13 VE* [95.2% CI],%
All (N = 84,064)
PCV13 (n = 20,680)
Placebo (n = 20,705)
PCV13 (n = 21,339)
Placebo (n = 21,340)
PCV13 (n = 42,019)
Placebo (n = 42,045)
81,676 3.95
81,668 3.94
85,408 4.00
85,318 4.00
167,084 3.98
166,985 3.97
43 52.7
72 88.2
6 7.0
18 21.1
49 29.3
90 53.9
40.3 [11.4, 60.2] 47 57.5
74 90.6
66.7 [11.8, 89.3] 6 7.0
36.5 [6.9, 57.1]
Modified intention-to-treat analysis First episode of VT-CAPà 56 IR (per 100,000 PY) 68.6 PCV13 VE* [95.2% CI],% All episodes of VT-CAPà IR (per 100,000 PY) PCV13 VE* [95.2% CI],%
Without known risk (n = 42,679)
53 31.7
66.7 [11.8, 89.3] 83 101.6
8 9.4
32.5 [3.9, 53.0]
60 73.5
18 21.1
45.6 [21.9, 62.5]y
22 25.8
42.4 [18.2, 59.9]y 64 38.3
63.7 [14.7, 86.1] 88 107.8
31.8 [4.0, 51.9]
8 9.4
23 27.0 65.3 [19.0, 86.7]
92 55.1
105 62.9 39.1 [15.9, 56.2]
68 40.7
111 66.5 38.8 [16.2, 55.5]
IR = incidence rate; IRR = IR ratio; PCV13 = 13-valent pneumococcal conjugate vaccine; PY = person-years; VE = vaccine efficacy; VT-CAP = vaccine-serotype communityacquired pneumonia. * VE was estimated as 1-IRR, where IRR compared the PCV13 group with the placebo group. y VE estimates for the overall population were previously reported by Bonten et al., Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults, N Engl J Med 372 (2015) 1114–25 [9]. However, VE was calculated differently for the current study (ie, as 1-IRR), and the 95.2% CIs in the per protocol analysis therefore differ slightly from those reported by Bonten et al. à Because of population exclusions for the current study and the different method of calculating VE, the number of cases and corresponding point estimates and confidence intervals for the overall population in the modified intention-to-treat analysis differ from those in Bonten et al. [9].
is important because the risk of developing a first episode of VT-CAP in at-risk participants was >4 times greater than in participants without known risk. For example, among US Medicare beneficiaries aged 65 years in 2010, 34%, 28%, and 12% had ischemic heart disease, diabetes, and COPD, respectively [15]. Furthermore,
>60% of US adults aged 65 years had 2 or more chronic conditions in 2012 [14], and individuals with multiple comorbid conditions are at even higher risk of pneumonia and IPD than those with a single chronic condition [11–13,16,18]. Among younger US adults, 12% of those aged 45 to 64 years have diabetes [23], amounting
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Cumulative First Episodes of VT-CAP, n
A 80 Placebo (At Risk)
70
PCV13 (At Risk)
60 50 40 30 20 10 0 0
1
2
3
4
5
4
5
Time Postvaccination, y Cumulative First Episodes of VT-CAP, n
B 80 Placebo (Without Known Risk)
70
PCV13 (Without Known Risk)
60 50 40 30 20 10 0 0
1
2
3
Time Postvaccination, y Fig. 1. Cumulative first episodes of VT-CAP in the (A) at-risk and (B) withoutknown-risk populations plotted against time since vaccination. PCV13 = 13-valent pneumococcal conjugate vaccine; VT-CAP = vaccine-serotype community-acquired pneumonia.
to 10 million individuals alone [24]. Moreover, in 2012, 26.5% and 62.9% of adults aged 18 to 44 and 45 to 64 years, respectively, had 1 of 10 chronic conditions (hypertension, coronary heart disease, stroke, diabetes, cancer, arthritis, hepatitis, weak or failing kidneys, asthma, and COPD), amounting to >80 million affected individuals [14]; >25% had 2 of these conditions, with higher age generally associated with an increasing number of comorbidities [14]. The prevalence of chronic medical conditions is also high in other countries. For example, in 2015, diabetes prevalence among adults aged 20 to 79 years was 7.6% in Japan [25] and 10.6% in Germany [26]. Among the 96 million adults aged 65 years living in the European Union in 2015 [27], a broad but conservative estimate of COPD prevalence is 10% [28]. Thus, there is a substantial need for protection against pneumococcal disease among these at-risk individuals. Pneumococcal conjugate vaccines induce solid functional antibody responses in at-risk individuals. A 2012 study demonstrated that 7-valent PCV elicited higher serotype-specific antibody levels and opsonophagocytic activity (OPA) killing compared with PPSV23 in patients with COPD; this advantage persisted >2 years [29]. A 2017 study on the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated that PCV13 vaccination elicited significant and lasting increases in OPA titers and immunoglobulin G concentrations for all 13 serotypes for subjects with and without comorbidities alike [30]. A post hoc analysis of 3 other previously published studies found that, compared with
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PPSV23, PCV13 elicited higher OPA titers and greater geometric mean fold ratios from prevaccination to postvaccination for most PCV13 serotypes in adults aged 50 years with cardiovascular disease, pulmonary disease, and diabetes [31]. OPA titers were similar between these adults and those not at risk, regardless of age group (50–59, 60–64, and 70 years). A recent post hoc analysis of available immunogenicity data based on a standardized OPA assay in adults aged 18 to 64 years [32–34] showed that OPA titers 1 month following PCV13 vaccination were similar in subjects with or without underlying chronic medical conditions, including heart disease, liver disease, lung disease, kidney disease, diabetes, and smoking [35]. Additionally, OPA titers in subjects aged 18 to 64 years with these comorbidities were similar to or higher than those from adults aged 65 years in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) [9], for whom efficacy has been established. Relatedly, one of the studies evaluated in the post hoc analysis demonstrated that younger adults overall had more robust immune responses to PCV13 than older adults [32]. Collectively, these results provide evidence that PCV13 is immunogenic in adults both with and without underlying chronic medical conditions and suggest that our findings regarding PCV13 efficacy against VT-CAP in at-risk older adults may be extended to at-risk adults aged <65 years, individuals who also have increased risk of pneumonia [11,13,18]. Vaccination recommendations vary worldwide based on age, risk factors, and pneumococcal vaccines recommended [5]. The current results may support vaccination of at-risk individuals for whom, despite lower VE estimates but given the higher incidence of VT-CAP in this group, PCV13 vaccination would be more efficient than for individuals without known risk. On the other hand, vaccinating the general population, rather than only at-risk individuals, can result in larger public health gains, although this strategy would require additional budget allocation. Consequently, a combined vaccination strategy (ie, age-based vaccination of older adults, who have a higher overall incidence of CAP than younger adults, and risk-based vaccination of younger adults, whose incidence of CAP is often comparable with the overall older adult population [13]) may be one strategy to maximize the public health impact of PCV13. As has been recommended for older adults, sequential use of PCV13 followed by PPSV23 may optimize protection, based on the robust efficacy of PCV13 against vaccine-type CAP and IPD as demonstrated in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) and the proportion of IPD covered by the unique serotypes in PPSV23 [8]. Nevertheless, pneumococcal vaccination strategies in adults would depend on the unique characteristics of a given country, such as the epidemiology and cost of VT-CAP, size of the population to vaccinate, type of recommendation, projected public health impact, cost of vaccines, cost-effectiveness, access to vaccines, and other programmatic considerations. Another recent post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) explored whether the PCV13 VE for a first episode of VT-CAP was modified by the presence of selected individual at-risk chronic medical conditions, such as lung disease, heart disease, diabetes mellitus, and smoking [36]. These conditions were retrospectively identified by a combination of self-reports and a review of medical records at the time of patient enrollment. Only diabetes mellitus was identified as a significant effect modifier, with higher VE calculated in this group. This analysis was subject to several potential shortcomings. Importantly, the original study was not designed to assess VE at the level of individual risk factor groups. Other limitations include the use of multiple comparisons without multiplicity adjustments and the lack of an established or plausible biological explanation as to why diabetes might serve as a positive-effect
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modifier. Nevertheless, the VE estimated for any at-risk condition (which included asplenia) was consistent with the overall estimate and confidence bounds from the current analysis (45.3% [95% CI: 19.9%, 62.6%]). Our analysis has both strengths and limitations. Analyses were restricted to at-risk participants as a group rather than by individual self-reported chronic conditions, an approach that diminished statistical issues associated with multiple comparisons. Despite the fact that only approximately half of participants were classified as at-risk, the VT-CAP first episodes from these participants contributed a majority (83%) of the overall study cases, which provided additional support for the significant vaccine efficacy observed in the at-risk population. Among the limitations, our analysis lacked participants with immunocompromising conditions (to remain consistent with the original study [9]), although such individuals are usually considered high risk rather than at risk for developing pneumococcal diseases [11–13]. Because of the post hoc nature of our analysis (ie, stratification of the study participants by risk status was not specified before the start of the trial), the results are exploratory; nevertheless, the findings were consistent with results from the overall study [9]. As our study assessed a number of risk factors combined in the at-risk group, no biological explanation for the VE estimates can be drawn because these estimates could result from diverging VE estimates for each individual risk factor. Lastly, medical conditions were self-reported and were not verified by a review of medical records. Although research suggests that self-reports of chronic conditions generally correlate with formally diagnosed disease [37], a previous analysis found that they were less reliable for respiratory disease in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) population [36]. In summary, this post hoc analysis assessed the robustness of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) results for the at-risk population, which represented about 50% of study participants. Results showed robust and significant PCV13 VE against first and all episodes of VT-CAP in these individuals, and PCV13-induced protection did not wane over the course of the study. Funding This research was funded by Pfizer (www.Pfizer.com). Role of the sponsor Pfizer was involved with study concept and design, analysis and interpretation of the data, and drafting of the manuscript. Conflict of interest statement All authors are employees of and may hold stock in Pfizer Inc. Author contributions JAS, REI, LJ, WCG, DAS, BS-T, CW, and QJ were involved in crafting the study concept and design. JAS, REI, LJ, DAS, BS-T, and CW were involved in data acquisition. JAS, CKH-M, and QJ participated in data analysis and interpretation. All authors participated in drafting and/or critically revising the manuscript. All authors approved the final version of the manuscript for submission. Acknowledgements Editorial support for development of this manuscript was provided by Judith Kandel, PhD, at Complete Healthcare Communica-
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Post hoc analysis of the efficacy of the 13-valent pneumococcal conjugate vaccine against vaccine-type community-acquired pneumonia in at-risk older adults José A. Suaya a,⇑, Qin Jiang b, Daniel A. Scott c, William C. Gruber c, Chris Webber c, Beate Schmoele-Thoma d, Cassandra K. Hall-Murray b, Luis Jodar b, Raul E. Isturiz b a
Pfizer Vaccines Medicines Development & Scientific and Clinical Affairs, New York, NY, USA Pfizer Vaccines Medicines Development & Scientific and Clinical Affairs, Collegeville, PA, USA c Pfizer Vaccines Clinical Research and Development, Pearl River, NY, USA d Pfizer Vaccines Clinical Research and Development, Berlin, Germany b
a r t i c l e
i n f o
Article history: Received 8 September 2017 Received in revised form 12 January 2018 Accepted 17 January 2018 Available online 9 February 2018 Keywords: Community-acquired pneumonia PCV13 Vaccine efficacy Older adults At risk Chronic conditions
a b s t r a c t Background: Individuals with certain chronic medical conditions are at higher risk of developing pneumonia and pneumococcal disease than those without. Using data from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), this post hoc analysis assessed the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged 65 years with at-risk conditions. Methods: The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) was a doubleblind, parallel-group, randomized, placebo-controlled study in the Netherlands in which adults aged 65 years received either PCV13 or placebo. Outcomes of interest were identified using prespecified clinical criteria, radiographic confirmation, routine microbiologic testing, and a serotype-specific urinary antigen detection assay. Methods: In this post hoc analysis, participants were classified by at-risk status based on self-reporting of any of the following chronic medical conditions: heart disease, lung disease, asthma, diabetes, liver disease, and smoking. The objective of this analysis was to assess PCV13 vaccine efficacy (VE) against a first episode of vaccine-serotype community-acquired pneumonia (VT-CAP) in at-risk participants. Results: Of the 84,496 adults enrolled in the study, 41,385 (49.2%) were considered at risk owing to chronic medical conditions. Of the 139 VT-CAP cases, 115 (82.7%) occurred in these participants. VE of PCV13 against a first episode of VT-CAP among participants with at-risk conditions was 40.3% (95.2% CI: 11.4%, 60.2%). Average duration of follow-up since vaccination was 3.95 years for at-risk participants; protection did not wane over the study period. Conclusions: This post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) showed significant and persistent efficacy of PCV13 against VT-CAP in at-risk older adults. Conclusions: ClinicalTrials.gov identifier: NCT00744263. Ó 2018 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
Abbreviations: ACIP, Advisory Committee on Immunization Practices; CAP, community-acquired pneumonia; COPD, chronic obstructive pulmonary disease; IPD, invasive pneumococcal disease; IR, incidence rate; IRR, incidence rate ratio; mITT, modified intention-to-treat; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; PY, person-years; Sp-CAP, community-acquired pneumonia caused by Streptococcus pneumoniae; VE, vaccine efficacy; VT-CAP, PCV13 vaccine-serotype community-acquired pneumonia. ⇑ Corresponding author at: Global Pneumococcal Vaccines, Vaccines Medical Development and Medical/Scientific Affairs, Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. E-mail addresses: [email protected] (J.A. Suaya), [email protected] (Q. Jiang), [email protected] (D.A. Scott), [email protected] (W.C. Gruber), Chris. [email protected] (C. Webber), [email protected] (B. Schmoele-Thoma), [email protected] (C.K. Hall-Murray), [email protected] (L. Jodar), [email protected] (R.E. Isturiz). https://doi.org/10.1016/j.vaccine.2018.01.049 0264-410X/Ó 2018 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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1. Introduction Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality in adults worldwide [1]; Streptococcus pneumoniae is among the most frequently isolated causative pathogens [2,3]. There are 2 pneumococcal vaccines currently licensed and recommended for use in adults in the United States [4] and many other countries [5]: a 13-valent pneumococcal conjugate vaccine (PCV13) and a 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV13 contains capsular polysaccharides from 13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) individually conjugated to nontoxic diphtheria toxin cross-reactive material 197 protein [6], whereas PPSV23 contains 23 nonconjugated capsular polysaccharides, 12 in common with PCV13 [7]. The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) was conducted according to accelerated approval pathway requirements of the US Food and Drug Administration to measure PCV13 efficacy in older adults [8]. It was a doubleblind, randomized, clinical study of 84,496 adults aged 65 years in the Netherlands [9]. Participants were randomized to receive either PCV13 or placebo from September 2008 to January 2010 and were followed for a mean of 3.97 years. Per-protocol analysis of the study demonstrated a 45.6% vaccine efficacy (VE; 95.2% CI: 21.8%, 62.5%) against first episodes of PCV13 vaccine-serotype CAP (VT-CAP; primary objective) [9]. On the basis of the findings from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), the US Advisory Committee on Immunization Practices (ACIP) now recommends routine sequential use of both PCV13 and PPSV23 in adults aged 65 years [8]. ACIP also recommends that adults aged 19 years with immunocompromising conditions or anatomic or functional asplenia receive sequential PCV13 and PPSV23 vaccinations on the combined basis of high incidence of pneumococcal disease in these populations and positive results from PCV13 immunogenicity and cost-effectiveness studies [10]. Individuals of all ages with chronic, nonimmunocompromising conditions (termed ‘‘at risk” in some studies [11–13]) such as heart disease, lung disease (including chronic obstructive pulmonary disease [COPD] and asthma), diabetes, liver disease, and smoking (not further defined), many of which are highly prevalent in the adult population [14,15], are also at increased risk of developing pneumonia and pneumococcal disease [11–13,16–19]. When atrisk individuals do develop CAP, their episodes are more costly than for individuals without known risk or in the overall population [19,20], and their case fatality rate exceeds that of individuals with lower risk [21]. Although determining the etiology of adult CAP is challenging, S pneumoniae is among the most commonly identified pathogens in CAP, accounting for 13% of hospitalized CAP and approximately 35% of CAP with identified pathogens in the United States [2] and Europe [1], respectively. Thus, preventing adult pneumococcal CAP (Sp-CAP) is of critical importance. Because at-risk adults aged <65 years in the United States are currently recommended to receive PPSV23 alone [10], the performance of PCV13 in these populations is of public health interest. To better characterize VE in at-risk individuals, as well as to address a specific request from ACIP, we conducted a post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) among the subpopulation with at-risk conditions.
Briefly, it was a double-blind, parallel-group, randomized, placebo-controlled trial that enrolled 84,496 immunocompetent adults aged 65 years in the Netherlands with no history of pneumococcal vaccination. Participants were randomized to receive a single dose of either PCV13 or placebo. The study’s primary objective was to demonstrate PCV13 efficacy against a first episode of VT-CAP in the per protocol population efficacy analysis. VT-CAP was determined by the presence of 2 prespecified clinical criteria, chest radiography findings suggestive of CAP, and a positive VT-specific urinary antigen test or isolation of VT–S pneumoniae from blood or another sterile site. 2.2. Objectives of post hoc analysis The main objective of the current post hoc analysis was to assess PCV13 VE against a first episode of VT-CAP in at-risk participants (defined below) based on the per protocol population efficacy analysis, consistent with the original study [9]. Because cases and VE for the overall population were reported previously [9], PCV13 VE in participants without known risk is also provided for contextual purposes. Sensitivity analyses included calculating PCV13 VE against a first episode of VT-CAP in at-risk participants based on the modified intention-to-treat (mITT) population efficacy analysis and PCV13 VE against all episodes of VT-CAP. 2.3. Populations for analysis Consistent with the original study [9], the mITT population included study participants who (1) were eligible and (2) had an episode of CAP with symptoms’ onset 14 days after vaccination. The per protocol population included participants in the mITT population but excluded CAP episodes that had onset of symptoms following the receipt of any nonstudy pneumococcal vaccine or after diagnoses of any of the following conditions: immunosuppression or immunodeficiency, postobstructive pneumonia (excluding chronic obstructive pulmonary disease [COPD]), bronchial obstruction caused by primary lung cancer, another metastatic lung cancer, acquired immunodeficiency syndrome, confirmed or suspected pneumonia caused by Pneumocystis jiroveci, or active tuberculosis. 2.4. Classification of at-risk population Before receiving the study vaccine, all participants were asked to complete a questionnaire with the following screening list of medical conditions: heart disease, lung disease, asthma, diabetes with or without insulin use, liver disease, smoking, and history of splenectomy. Self-identified medical conditions were not verified by medical record review. Only immunocompetent older adults were enrolled [9], and the current analysis also excluded those with history of splenectomy, those not responding to any of the screening questions, or those not eligible. Participants were classified as at risk if they had 1 of the medical conditions listed above, other than splenectomy. None of the risk factors included are considered immunocompromising or high-risk conditions according to ACIP [10]. Participants without any reported at-risk condition were classified as ‘‘without known risk.” 2.5. Analyses
2. Methods 2.1. Study design The design of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) has been previously reported [9].
The case definitions of VT-CAP were the same as those used in the original study [9]. For purposes of contextualizing the setting and study period, VT epidemiology of pneumococcal CAP was described among individuals in the placebo group in terms of risk group and proportion of first episodes of Sp-CAP caused by PCV13
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3.3. VE for VT-CAP
vaccine serotypes (VT-CAP). Additionally, incidence rates (IR) of VT-CAP per 100,000 person-years were calculated by risk status and vaccination group. For IR calculations, each participant’s follow-up duration started from the day of vaccination and ended with the date when the subject concluded his/her participation in the study (eg, due to death, participant leaving the general practitioner’s practice or moving out of the catchment area, or selfwithdrawal) or the date of study discontinuation, whichever was earlier. The follow-up duration of each study participant was based on periodic contact from the coordinating center to the participants’ physicians. The total person-years of follow-up were aggregated by vaccine group and risk status. Finally, VE was estimated as 1-incidence rate ratio (IRR), where IRR is the incidence rate ratio comparing the PCV13 group with the placebo group. Exact 2-sided 95.2% CIs were calculated using the ClopperPearson method with alpha adjustment for interim analysis, reflecting the study overall analysis [9]. SASÒ version 9.4 (SAS Institute, Cary, NC) was used to perform all analyses.
Based on the per protocol analysis, for a first episode of VT-CAP, PCV13 VE in at-risk participants was 40.3% (95.2% CI: 11.4%, 60.2%); in participants without known risk, it was 66.7% (95.2% CI: 11.8%, 89.3%). Using our method of calculating VE, VE in overall study participants was 45.6% (95.2% CI: 21.9%, 62.5%). For all episodes of VT-CAP, PCV13 VE estimates were 36.5% (95.2% CI: 6.9%, 57.1%) in at-risk participants, 66.7% (95.2% CI: 11.8%, 89.3%) in those without known risk, and 42.4% (95.2% CI: 18.2%, 59.9%) in the overall study population (Table 3). Based on the mITT analysis, for a first episode of VT-CAP, PCV13 VE in at-risk participants was 32.5% (95.2% CI: 3.9%, 53.0%); in participants without known risk, it was 63.7% (95.2% CI: 14.7%, 86.1%). VE in overall study participants was 39.1% (95.2% CI: 15.9%, 56.2%). For all episodes of VT-CAP, PCV13 VE estimates were 31.8% (95.2% CI: 4.0%, 51.9%) in at-risk participants, 65.3% (95.2% CI: 19.0%, 86.7%) in those without known risk, and 38.8% (95.2% CI: 16.2%, 55.5%) in the overall study population (Table 3).
3. Results
3.4. Duration of protection
3.1. Study participants
Fig. 1 displays case accrual plots for first episodes of VT-CAP. Overall case accumulation in at-risk participants was higher than in participants without known risk in both the vaccine and placebo groups; this was expected due to higher CAP risk among these individuals. Vaccine efficacy did not appear to wane over the study period.
Of the 84,496 study participants [9], 432 were excluded from the post hoc analysis (Table 1) for any of the following hierarchical (ie, not mutually exclusive) reasons: 368 on the basis of ineligibility, 73 with history of splenectomy, and 2 with incomplete medical condition forms. The current analysis included 41,385 at-risk participants and 42,679 participants without known risk. Table 2 gives additional baseline characteristics of study participants and prevalence of each self-identified medical condition; these were similar in both vaccine and placebo groups among at-risk participants. 3.2. Epidemiology of VT-CAP among placebo group participants Among participants in the placebo group, 80.0% (72/90) of first episodes of VT-CAP occurred in at-risk participants (Table 3). VTCAP incidence in at-risk participants was 4.2 times higher than in participants without known risk (88.2 vs 21.1 episodes per 100,000 person-years). Similar findings were observed for all episodes of VT-CAP, ie, 80.4% (74/92) of all episodes in the placebo group were in at-risk participants, and VT-CAP incidence in atrisk participants was 4.3 times higher than in without-knownrisk participants (90.6 vs 21.1 episodes per 100,000 person-years). VT-CAP accounted for 62.1% (72/116) and 61.2% (74/121) of first episodes and all episodes of Sp-CAP, respectively, in at-risk participants in the placebo group (not shown in table).
4. Discussion This post hoc analysis showed statistically significant estimates of PCV13 efficacy compared with placebo against first and all episodes of VT-CAP in participants self-identified as having chronic medical conditions. As expected, because most first episodes of VT-CAP occurred in at-risk individuals, the VE estimates in this group were generally similar to those calculated for the entire study population [9]. These findings provide additional evidence for decision-making regarding the benefits of potential vaccination strategies in the at-risk population. PCV13 protection continued over the duration of the study (ie, an average of 3.95 years in atrisk participants and 4.00 years in participants without known risk), as observed for the entire study population [9]. Another recent post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) found that PCV13 VE did not wane over the 5-year study duration [22]. The chronic conditions included in the at-risk category are very prevalent in adult populations across age groups worldwide, which
Table 1 Population attrition and risk classification. Participants, n (%)
Excluded from this post hoc analysis*,y Did not meet study inclusion criteria History of splenectomy Incomplete medical condition form Included in this post hoc analysisà At risk§ Without known risk
PCV13 (n = 42,240)
Placebo (n = 42,256)
Total (N = 84,496)
221 (0.5) 186 (84.2) 41 (18.6) 1 (0.5) 42,019 (99.5) 20,680 (49.2) 21,339 (50.8)
211 (0.5) 182 (86.3) 32 (15.2) 1 (0.5) 42,045 (99.5) 20,705 (49.2) 21,340 (50.8)
432 (0.5) 368 (85.2) 73 (16.9) 2 (0.5) 84,064 (99.5) 41,385 (49.2) 42,679 (50.8)
PCV13 = 13-valent pneumococcal conjugate vaccine. * The count in this row is used as a denominator for the percentages for the 3 rows below. y Exclusion criteria were not mutually exclusive. à The count in this row is used as a denominator for the percentages for the 2 rows below. § Conditions included in this category were heart disease, lung disease, asthma, diabetes with or without insulin use, liver disease, and smoking.
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Table 2 Baseline characteristics of participants stratified by risk classification. At risk (n = 41,385)
Without known risk (n = 42,679)
All (N = 84,064)
PCV13 (n = 20,680)
Placebo (n = 20,705)
PCV13 (n = 21,339)
Placebo (n = 21,340)
Sex, n (%) Female Male
8313 (40.2) 12,367 (59.8)
8095 (39.1) 12,610 (60.9)
10,400 (48.7) 10,939 (51.3)
10,292 (48.2) 11,048 (51.8)
37,100 (44.1) 46,964 (55.9)
Race, n (%) White Nonwhite Missing
20,337 (98.3) 339 (1.6) 4 (0.0)
20,369 (98.4) 329 (1.6) 7 (0.0)
21,048 (98.6) 286 (1.3) 5 (0.0)
21,042 (98.6) 295 (1.4) 3 (0.0)
82,796 (98.5) 1249 (1.5) 19 (0.0)
Age at enrolment, y Mean (SD) Median Min–max <75, n (%) 75–<85, n (%) 85, n (%)
73.1 (5.8) 72.0 65–101.1 13,678 (66.1) 6200 (30.0) 802 (3.9)
73.1 (5.8) 72.0 65–99.5 13,654 (65.9) 6275 (30.3) 776 (3.7)
72.5 (5.6) 71.2 65–100.3 15,202 (71.2) 5452 (25.5) 685 (3.2)
72.4 (5.5) 71.1 65–96.1 15,277 (71.6) 5412 (25.4) 651 (3.1)
72.8 (5.7) 71.6 65–101.1 57,811 (68.8) 23,339 (27.8) 2914 (3.5)
Self-reported medical condition, n (%) Asthma 2008 (9.7) Diabetes 5211 (25.2) Heart disease 10,642 (51.5) Liver disease 203 (1.0) Lung disease 4224 (20.4) Smoking 5175 (25.0)
2094 (10.1) 5303 (25.6) 10,657 (51.5) 199 (1.0) 4324 (20.9) 5147 (24.9)
0 0 0 0 0 0
0 0 0 0 0 0
4102 (4.9) 10,514 (12.5) 21,299 (25.3) 402 (0.5) 8548 (10.2) 10,322 (12.3)
(0) (0) (0) (0) (0) (0)
(0) (0) (0) (0) (0) (0)
PCV13 = 13-valent pneumococcal conjugate vaccine.
Table 3 PCV13 VT-CAP incidence rates and vaccine efficacy. At risk (n = 41,385)
PY Mean follow-up, y Per protocol analysis First episode of VT-CAP IR (per 100,000 PY) PCV13 VE* [95.2% CI],% All episodes of VT-CAP IR (per 100,000 PY) PCV13 VE* [95.2% CI],%
All (N = 84,064)
PCV13 (n = 20,680)
Placebo (n = 20,705)
PCV13 (n = 21,339)
Placebo (n = 21,340)
PCV13 (n = 42,019)
Placebo (n = 42,045)
81,676 3.95
81,668 3.94
85,408 4.00
85,318 4.00
167,084 3.98
166,985 3.97
43 52.7
72 88.2
6 7.0
18 21.1
49 29.3
90 53.9
40.3 [11.4, 60.2] 47 57.5
74 90.6
66.7 [11.8, 89.3] 6 7.0
36.5 [6.9, 57.1]
Modified intention-to-treat analysis First episode of VT-CAPà 56 IR (per 100,000 PY) 68.6 PCV13 VE* [95.2% CI],% All episodes of VT-CAPà IR (per 100,000 PY) PCV13 VE* [95.2% CI],%
Without known risk (n = 42,679)
53 31.7
66.7 [11.8, 89.3] 83 101.6
8 9.4
32.5 [3.9, 53.0]
60 73.5
18 21.1
45.6 [21.9, 62.5]y
22 25.8
42.4 [18.2, 59.9]y 64 38.3
63.7 [14.7, 86.1] 88 107.8
31.8 [4.0, 51.9]
8 9.4
23 27.0 65.3 [19.0, 86.7]
92 55.1
105 62.9 39.1 [15.9, 56.2]
68 40.7
111 66.5 38.8 [16.2, 55.5]
IR = incidence rate; IRR = IR ratio; PCV13 = 13-valent pneumococcal conjugate vaccine; PY = person-years; VE = vaccine efficacy; VT-CAP = vaccine-serotype communityacquired pneumonia. * VE was estimated as 1-IRR, where IRR compared the PCV13 group with the placebo group. y VE estimates for the overall population were previously reported by Bonten et al., Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults, N Engl J Med 372 (2015) 1114–25 [9]. However, VE was calculated differently for the current study (ie, as 1-IRR), and the 95.2% CIs in the per protocol analysis therefore differ slightly from those reported by Bonten et al. à Because of population exclusions for the current study and the different method of calculating VE, the number of cases and corresponding point estimates and confidence intervals for the overall population in the modified intention-to-treat analysis differ from those in Bonten et al. [9].
is important because the risk of developing a first episode of VT-CAP in at-risk participants was >4 times greater than in participants without known risk. For example, among US Medicare beneficiaries aged 65 years in 2010, 34%, 28%, and 12% had ischemic heart disease, diabetes, and COPD, respectively [15]. Furthermore,
>60% of US adults aged 65 years had 2 or more chronic conditions in 2012 [14], and individuals with multiple comorbid conditions are at even higher risk of pneumonia and IPD than those with a single chronic condition [11–13,16,18]. Among younger US adults, 12% of those aged 45 to 64 years have diabetes [23], amounting
J.A. Suaya et al. / Vaccine 36 (2018) 1477–1483
Cumulative First Episodes of VT-CAP, n
A 80 Placebo (At Risk)
70
PCV13 (At Risk)
60 50 40 30 20 10 0 0
1
2
3
4
5
4
5
Time Postvaccination, y Cumulative First Episodes of VT-CAP, n
B 80 Placebo (Without Known Risk)
70
PCV13 (Without Known Risk)
60 50 40 30 20 10 0 0
1
2
3
Time Postvaccination, y Fig. 1. Cumulative first episodes of VT-CAP in the (A) at-risk and (B) withoutknown-risk populations plotted against time since vaccination. PCV13 = 13-valent pneumococcal conjugate vaccine; VT-CAP = vaccine-serotype community-acquired pneumonia.
to 10 million individuals alone [24]. Moreover, in 2012, 26.5% and 62.9% of adults aged 18 to 44 and 45 to 64 years, respectively, had 1 of 10 chronic conditions (hypertension, coronary heart disease, stroke, diabetes, cancer, arthritis, hepatitis, weak or failing kidneys, asthma, and COPD), amounting to >80 million affected individuals [14]; >25% had 2 of these conditions, with higher age generally associated with an increasing number of comorbidities [14]. The prevalence of chronic medical conditions is also high in other countries. For example, in 2015, diabetes prevalence among adults aged 20 to 79 years was 7.6% in Japan [25] and 10.6% in Germany [26]. Among the 96 million adults aged 65 years living in the European Union in 2015 [27], a broad but conservative estimate of COPD prevalence is 10% [28]. Thus, there is a substantial need for protection against pneumococcal disease among these at-risk individuals. Pneumococcal conjugate vaccines induce solid functional antibody responses in at-risk individuals. A 2012 study demonstrated that 7-valent PCV elicited higher serotype-specific antibody levels and opsonophagocytic activity (OPA) killing compared with PPSV23 in patients with COPD; this advantage persisted >2 years [29]. A 2017 study on the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated that PCV13 vaccination elicited significant and lasting increases in OPA titers and immunoglobulin G concentrations for all 13 serotypes for subjects with and without comorbidities alike [30]. A post hoc analysis of 3 other previously published studies found that, compared with
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PPSV23, PCV13 elicited higher OPA titers and greater geometric mean fold ratios from prevaccination to postvaccination for most PCV13 serotypes in adults aged 50 years with cardiovascular disease, pulmonary disease, and diabetes [31]. OPA titers were similar between these adults and those not at risk, regardless of age group (50–59, 60–64, and 70 years). A recent post hoc analysis of available immunogenicity data based on a standardized OPA assay in adults aged 18 to 64 years [32–34] showed that OPA titers 1 month following PCV13 vaccination were similar in subjects with or without underlying chronic medical conditions, including heart disease, liver disease, lung disease, kidney disease, diabetes, and smoking [35]. Additionally, OPA titers in subjects aged 18 to 64 years with these comorbidities were similar to or higher than those from adults aged 65 years in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) [9], for whom efficacy has been established. Relatedly, one of the studies evaluated in the post hoc analysis demonstrated that younger adults overall had more robust immune responses to PCV13 than older adults [32]. Collectively, these results provide evidence that PCV13 is immunogenic in adults both with and without underlying chronic medical conditions and suggest that our findings regarding PCV13 efficacy against VT-CAP in at-risk older adults may be extended to at-risk adults aged <65 years, individuals who also have increased risk of pneumonia [11,13,18]. Vaccination recommendations vary worldwide based on age, risk factors, and pneumococcal vaccines recommended [5]. The current results may support vaccination of at-risk individuals for whom, despite lower VE estimates but given the higher incidence of VT-CAP in this group, PCV13 vaccination would be more efficient than for individuals without known risk. On the other hand, vaccinating the general population, rather than only at-risk individuals, can result in larger public health gains, although this strategy would require additional budget allocation. Consequently, a combined vaccination strategy (ie, age-based vaccination of older adults, who have a higher overall incidence of CAP than younger adults, and risk-based vaccination of younger adults, whose incidence of CAP is often comparable with the overall older adult population [13]) may be one strategy to maximize the public health impact of PCV13. As has been recommended for older adults, sequential use of PCV13 followed by PPSV23 may optimize protection, based on the robust efficacy of PCV13 against vaccine-type CAP and IPD as demonstrated in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) and the proportion of IPD covered by the unique serotypes in PPSV23 [8]. Nevertheless, pneumococcal vaccination strategies in adults would depend on the unique characteristics of a given country, such as the epidemiology and cost of VT-CAP, size of the population to vaccinate, type of recommendation, projected public health impact, cost of vaccines, cost-effectiveness, access to vaccines, and other programmatic considerations. Another recent post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) explored whether the PCV13 VE for a first episode of VT-CAP was modified by the presence of selected individual at-risk chronic medical conditions, such as lung disease, heart disease, diabetes mellitus, and smoking [36]. These conditions were retrospectively identified by a combination of self-reports and a review of medical records at the time of patient enrollment. Only diabetes mellitus was identified as a significant effect modifier, with higher VE calculated in this group. This analysis was subject to several potential shortcomings. Importantly, the original study was not designed to assess VE at the level of individual risk factor groups. Other limitations include the use of multiple comparisons without multiplicity adjustments and the lack of an established or plausible biological explanation as to why diabetes might serve as a positive-effect
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modifier. Nevertheless, the VE estimated for any at-risk condition (which included asplenia) was consistent with the overall estimate and confidence bounds from the current analysis (45.3% [95% CI: 19.9%, 62.6%]). Our analysis has both strengths and limitations. Analyses were restricted to at-risk participants as a group rather than by individual self-reported chronic conditions, an approach that diminished statistical issues associated with multiple comparisons. Despite the fact that only approximately half of participants were classified as at-risk, the VT-CAP first episodes from these participants contributed a majority (83%) of the overall study cases, which provided additional support for the significant vaccine efficacy observed in the at-risk population. Among the limitations, our analysis lacked participants with immunocompromising conditions (to remain consistent with the original study [9]), although such individuals are usually considered high risk rather than at risk for developing pneumococcal diseases [11–13]. Because of the post hoc nature of our analysis (ie, stratification of the study participants by risk status was not specified before the start of the trial), the results are exploratory; nevertheless, the findings were consistent with results from the overall study [9]. As our study assessed a number of risk factors combined in the at-risk group, no biological explanation for the VE estimates can be drawn because these estimates could result from diverging VE estimates for each individual risk factor. Lastly, medical conditions were self-reported and were not verified by a review of medical records. Although research suggests that self-reports of chronic conditions generally correlate with formally diagnosed disease [37], a previous analysis found that they were less reliable for respiratory disease in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) population [36]. In summary, this post hoc analysis assessed the robustness of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) results for the at-risk population, which represented about 50% of study participants. Results showed robust and significant PCV13 VE against first and all episodes of VT-CAP in these individuals, and PCV13-induced protection did not wane over the course of the study. Funding This research was funded by Pfizer (www.Pfizer.com). Role of the sponsor Pfizer was involved with study concept and design, analysis and interpretation of the data, and drafting of the manuscript. Conflict of interest statement All authors are employees of and may hold stock in Pfizer Inc. Author contributions JAS, REI, LJ, WCG, DAS, BS-T, CW, and QJ were involved in crafting the study concept and design. JAS, REI, LJ, DAS, BS-T, and CW were involved in data acquisition. JAS, CKH-M, and QJ participated in data analysis and interpretation. All authors participated in drafting and/or critically revising the manuscript. All authors approved the final version of the manuscript for submission. Acknowledgements Editorial support for development of this manuscript was provided by Judith Kandel, PhD, at Complete Healthcare Communica-
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