13-Valent Pneumococcal Conjugate Vaccine Immunogenicity in

ABSTRACTIntroduction: The CAPiTA study, which was a randomized, double-blind clinical trial in 84,496 participants 65 years of age and older in the Netherlands, demonstrated efficacy against first episodes of vaccine type (VT) community-acquired pneumonia (CAP) and first episodes of VT-IPD. Results of the primary and secondary endpoints have been previously reported.

Methods: A subset of the subjects (2011) was enrolled utilizing home-based visits in a single region in the Netherlands. Blood samples for immunogenicity analysis were taken at baseline before vaccination, one month, 12 months, and 24 months after vaccination. Serotype-specific opsonophagocytic activity (OPA) titers and anticapsular polysaccharide immunoglobulin G (IgG) concentrations (µg/mL) were measured at each of these time points for all 13 PCV13 serotypes and compared to placebo.

Results: For both OPA and IgG, there were significant increases in antibody levels for all serotypes after one month after vaccination compared to before vaccination with PCV13. One month after vaccination the ratios for OPA geometric mean titers (GMTs) of PCV13 to placebo ranged from 4.4 (serotype 9V) to 62.6 (serotype 4); after 12 months the ratios ranged from 2.2 (serotype 9V) to 13.9 (serotype 4) and after 24 months from 1.6 (serotype 9V) to 8.0 (serotype 4).

One month after vaccination, the ratios for IgG geometric mean concentrations (GMCs) of PCV13 to placebo ranged from 2.97 (serotype 3) to 12.12 (serotype 18C); after 12 months, the ratios ranged from 1.66 (serotype 3) to 5.72 (serotype 18C) and after 24 months, from 1.56 (serotype 3) to 4.76 (serotype 18C).

The ratios for both OPA GMTs and IgG GMCs in the age subgroups ≥65 to <70 years, ≥70 to <80 years, and ≥80 years followed a similar pattern, indicating that measurable antibody responses extended out at least two years after vaccination for all age groups.

Conclusions: The observed immune responses support the demonstrated efficacy of PCV13 against VT-CAP and VT-IPD in adults 65 years and older. Both binding IgG antibodies and functional OPA antibodies persisted at least two years after vaccination at levels above baseline.

(Funded by Pfizer Inc.; ClinicalTrials.gov number, NCT00744263.)

OBJECTIVES• To assess the immune responses to 13-valent pneumococcal conjugate vaccine (PCV13)

compared with placebo by age group before vaccination and approximately 1, 12, and 24 months after study vaccine administration by serotype-specific opsonophagocytic activity (OPA) titers and serum immunoglobulin G (IgG) responses for all subjects in the immunogenicity subset and within different age and gender groups

METHODS

Study Design

• This was a parallel, randomized, placebo-controlled, double-blind, single-center trial in which subjects were randomly assigned in a 1:1 ratio to receive either PCV13 or placebo as a single dose.

• Approximately 2000 of the approximately 85,000 subjects were recruited at home visits in a single region in the Netherlands and had 4 home visits for blood draws for immunogenicity assessments.

• Vaccination occurred at visit 1 (baseline), and blood samples were taken at baseline and 1, 12, and 24 months after vaccination (Figure 1).

Figure 1. Immunogenicity Study Design

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Key Inclusion and Exclusion Criteria for the Immunogenicity Subset

• Inclusion

– Men or women ≥65 years of age at time of vaccination

– Registered with a general practitioner referring subjects for the study

– Able to fulfill study requirements

– Ability to complete an e-diary

• Exclusion

– Previous pneumococcal vaccination

– Use of investigational vaccine or medication in past 30 days

– Resident in nursing home/long-term care facility

– Immune deficiency or suppression

– History of severe adverse reaction to a vaccine or component

– Contraindication to influenza vaccination, if influenza vaccine is to be administered

– Vaccination with influenza vaccine in the previous 7 days

– Contraindication to PCV13

Immunogenicity Analyses

• Serum OPAs for the 13 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) were determined for all subjects in the immunogenicity subset for each blood sample.

– This was by microcolony assay using a titer achieving 50% killing as the endpoint.

– Results were reported as antibody titers.

• Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of VT anticapsular pneumococcal binding IgG, and results were expressed as μg/mL.

– For the 13 serotypes contained in PCV13, the serotype-specific IgG concentrations were logarithmically transformed for analysis.

– Within each vaccine group and for each antibody concentration separately, geometric means of the IgG antibody concentrations at all visits (prevaccination and 1, 12, and 24 months after vaccination) were calculated.

– Similar procedures were used for OPA.

13-Valent Pneumococcal Conjugate Vaccine Immunogenicity in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA)

A. van Deursen,1 C. Webber,2 M. Patton,2 D. Scott,3 M. Sidhu,4 W. Drews,5 M. Bonten6 on behalf of the CAPiTA Study Team1Department of Immunology, Wilhelmina Children’s Hospital, UMC Utrecht, Netherlands; 2Pfizer Vaccine Clinical Research, Maidenhead, UK; 3Pfizer Vaccine Clinical Research, Pearl River, NY, USA;

4High Throughput Clinical Testing, Pfizer Vaccine R&D, Pearl River, NY, USA; 5inVentiv Health Clinical, LLC, Austin, TX, USA; 6Julius Center for Health Sciences and Primary Care, UMC Utrecht, Netherlands

Presented at IDWeek 2014; October 8–12, 2014; Philadelphia, PA. This study was sponsored by Pfizer Inc.

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INTRODUCTION• Pneumococcal disease is a major global public health problem affecting all age

groups.1 The highest rates of pneumococcal disease occur in young children (the majority in developing countries) and in the elderly (particularly in industrialized countries).2 People older than 50 years of age, particularly those older than 65, and those of any age with certain underlying medical conditions such as chronic lung disease, are at increased risk for developing pneumococcal infection or experiencing severe disease and complications.3,4

• The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), a randomized, double-blind, placebo-controlled clinical trial in 84,496 participants 65 years of age and older in the Netherlands, demonstrated efficacy against first episodes of vaccine type (VT) community-acquired pneumonia (CAP) and first episodes of VT–invasive pneumococcal disease (IPD). Results of the primary and secondary endpoints as well as safety have been previously reported.5

CONCLUSIONS

• PCV13 was immunogenic, inducing IgG and functional antibody responses. The responses were similar for all age groups and serotypes across all evaluated time points.

• Over the 2-year follow-up period, levels of both IgG binding and functional antibody remained above baseline and were higher than levels in placebo recipients.

• The persistence of circulating antibody is consistent with data from the overall study population, where efficacy of VT-CAP, nonbacteremic noninvasive VT CAP, and VT-IPD did not appear to wane over the ~4 years of follow-up.5

REFERENCES

1. World Health Organization. Wkly Epidemiol Rec. 2008;83:373-384.

2. World Health Organization. Wkly Epidemiol Rec. 2007;82:93-104.

3. Butler JC. Epidemiology of pneumococcal disease. In: Tuomanen E, et al, eds. The Pneumococcus. Vol 10. 1st ed. Washington, DC: American Society for Microbiology; 2004:148-168.

4. Jackson LA. Pneumococcal polysaccharide vaccines. In: Plotkin S, et al, eds. Vaccines. 6 ed. Philadelphia: Saunders; 2012:542-572.

5. Bonten M, et al. Community Acquired Pneumonia Immunisation Trial in Adults (CAPiTA). Presented at: 9th International Symposium on Pneumococci and Pneumococcal Diseases; March 9-13, 2014; Hyderabad, India.

• 2011 subjects were enrolled.• Mean age was 72.5 years, with more men than women in both vaccine groups.• Race and age strata were balanced between the vaccine groups, as were patient-reported comorbidities.• Demographics of the immunogenicity population were representative of the overall study population.• The baseline characteristics and comorbid conditions are shown in Table 1.

Table 1. Baseline Characteristics and Patient-Reported Comorbidities (Evaluable Immunogenicity Population)

PCV13 n=981

Placebo n=974

Mean (SD) age, y(range)

72.6 (5.5) (65.1–92.3)

72.5 (5.6) (65.0–94.0)

Male, n (%) 520 (53.0) 543 (55.7) Female, n (%) 461 (47.0) 431 (44.3) White, n (%) 970 (98.9) 961 (98.7)Nonwhite, n (%) 11 (1.1) 13 (1.3)Age, y, n (%)

≥65 and <70 395 (40.3) 413 (42.4) ≥70 and <80 474 (48.3) 447 (45.9)≥80 112 (11.4) 114 (11.7) <75 years of age 679 (69.2) 685 (70.3) ≥75 years of age 302 (30.8) 289 (29.7)

Patient-reported comorbidities, %Any 42.8 39.4Asthma* 5.1 4.6Diabetes mellitus: insulin use* 2.2 2.3Diabetes mellitus: no insulin use* 9.7 9.3Heart disease* 23.2 22.2Liver disease* 0.5 0.4Lung disease* 10.4 10.1Splenectomy* 0.1 0.1Smoking (%) 7.7 11.2

*Not mutually exclusive.

Opsonophagocytic Activity

• The OPA GMTs were similar in the 2 vaccine groups before vaccination. The OPA GMTs to each of the 13 serotypes increased after vaccination in the PCV13 subjects, then decreased by 12 and 24 months after vaccination, but remained higher than both the prevaccination OPA GMTs (Figure 2), and the corresponding OPA GMTs in the placebo group at each postvaccination time point.

• The OPA geometric means (GMs; not shown) in the PCV13 group were statistically significantly greater than the OPA GMRs in the placebo group at each postvaccination time point and for each serotype.

• Reverse cumulative distribution curves show that OPA titers remained higher than placebo at all evaluated time points and for all serotypes (Figure 3).

Figure 2. OPA GMTs of PCV13 at Baseline and 1, 12, and 24 Months Postvaccination (Evaluable Population, PCV13 Group Only)

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PCV13 - Before VaccinationPCV13 - 1 Month After VaccinationPCV13 - 12 Months After VaccinationPCV13 - 24 Months After VaccinationPlacebo - Before VaccinationPlacebo - 1 Month After VaccinationPlacebo - 12 Months After VaccinationPlacebo - 24 Months After Vaccination

OPA Responses by Age

• OPA GMTs were measured at each time point by age group: ≥65 to <70; ≥70 to <80, and ≥80 years of age.

• For all ages and time points, OPA GMTs for the PCV13 subjects remained above baseline and above placebo, indicating persistence of antibody response over the 2-year period (Figure 4).

Figure 4. Antibody Response (OPA Titer) Curves Prevaccination (Baseline) and Postvaccination (Months 1, 12, and 24) in Adults Who Received PCV13

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IgG Antibody

• The IgG geometric mean concentrations (GMCs) were similar in the 2 vaccine groups before vaccination. The IgG GMCs to each of the 13 serotypes increased after vaccination in the PCV13 subjects, then decreased by 12 and 24 months after vaccination, but remained higher than both the prevaccination IgG GMCs and the corresponding IgG GMCs in the placebo group at each postvaccination time point.

• Reverse cumulative distribution curves demonstrate a clear separation of IgG PCV13 from placebo at all time points and for all serotypes (Figure 5). This is applicable for all serotypes across all time points.

Figure 5. Reverse Cumulative Distribution Curves for IgG Antibody Concentrations for All Serotypes and for All Evaluated Time Points (Evaluable Population)

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PCV13 - Before VaccinationPCV13 - 1 Month After VaccinationPCV13 - 12 Months After VaccinationPCV13 - 24 Months After VaccinationPlacebo - Before VaccinationPlacebo - 1 Month After VaccinationPlacebo - 12 Months After VaccinationPlacebo - 24 Months After Vaccination

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Correlation of OPA Responses With IgG Responses

• The IgG and OPA results showed higher correlation for the PCV13 group compared with the placebo group within each serotype and each postvaccination time point.

• All of these differences were statistically significant except for serotype 6A (at each postvaccination time point) and serotype 6B (at 1 and 12 months after vaccination). – Scatterplots of a representative example, serotype 7F, are presented in Figure 6.

Figure 6. IgG OPA Correlation Plot of Serotype 7F for 1, 12, and 24 Months Postvaccination

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RESULTS

For additional information, please contact:

Dr. Anna M. van DeursenDepartment of Immunology

Wilhelmina Children’s HospitalUMC UtrechtNetherlands

Email: [email protected]

Documents

13-Valent Pneumococcal Conjugate Vaccine Immunogenicity in