Pneumonia, Aging
Conditions
Keywords
Genomics, Epigenomics, Pneumococcal vaccine, Elderly
Brief summary
This is a prospective, single-site, randomized, then open-label study designed to develop a detailed transcriptional and epigenetic profile of the immune response to pneumococcal vaccination with conjugated and non-conjugated polysaccharide vaccines in the senescent immune system of older adults. In this study, 40 healthy adults ages 60 and older that have never received pneumococcal vaccination, will be randomized in a 1:1 ratio to receive Prevnar-13 (Pfizer), a conjugated 13-valent vaccine or Pneumovax 23 (Merck), a non-conjugated 23-valent vaccine. Following randomized assignment of vaccine, the study will be open-label. Six (6) study visits will occur over about 70 days, with an optional 7th visit for participants to receive a second vaccination with the other pneumococcal vaccine one to two years after randomization. Participants will provide blood samples for transcriptional, epigenetic and biological analyses pre- and post-vaccination.
Detailed description
This prospective, single-site, randomized, then open-label study is designed to develop a detailed transcriptional and epigenetic profile of the immune response to pneumococcal vaccination with conjugated and non-conjugated polysaccharide vaccines in the senescent immune system of older adults. This knowledge may lead to development of more effective vaccines through increased understanding of the effects of immunosenescence on mechanisms of immune response to pneumococcal vaccination in older adults elderly. Forty (40) healthy adults ages 60 and older that have never received pneumococcal vaccination, will be randomized in a 1:1 ratio to receive Prevnar-13 (Pfizer), a conjugated 13-valent vaccine or Pneumovax 23 (Merck), a non-conjugated 23-valent vaccine. Following randomized assignment of vaccine, the study will be open-label. The study sample will be drawn from the population of healthy older participants in the catchment area of UConn Health in Farmington, CT. The first six (6) study visits are planned to occur over 67 days at Days -7, 0, 1, 10, 28 (±3 d) and 60 (± 5d). Participants will provide blood samples for transcriptional, epigenetic and biological analyses pre- and post-vaccination. One to two years after receiving the randomly-assigned vaccination, participants may opt to receive administration of a second pneumococcal vaccine with the vaccine that they did not receive by random assignment at Visit 2 (Day 0). This second vaccine will be provided at no charge to the participant. Administration of this vaccine will occur at an optional Visit 7 for participants who choose to receive the second vaccine and will be scheduled at the participant's convenience one-two years after receiving the first pneumococcal vaccine. If the participant opts to receive the second vaccine within the study and attends optional Visit 7, blood samples for genomic and biologic analysis will be collected at the visit.
Interventions
BIOLOGICALPneumococcal 13valent Conj Vaccine Diphtheria CRM197 Protein
One to two years after receiving the randomly-assigned vaccination, participants may opt to receive administration of a second pneumococcal vaccine with Pneumovax 23
BIOLOGICALPneumococcal Vaccine Polyvalent
One to two years after receiving the randomly-assigned vaccination, participants may opt to receive administration of a second pneumococcal vaccine with Prevnar-13
Sponsors
UConn Health
University of Alabama at Birmingham
The Jackson Laboratory
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Randomized assignment to group will be in a 1:1 ratio utilizing block randomization in blocks of 10 to receive Prevnar-13 or Pneumovax 23. Following randomized assignment of vaccine, the study will be open-label.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Able and willing to provide written informed consent * Male or Female, 60 years of age or older * Willing to receive pneumococcal vaccination with Prevnar 13 (Wyeth/ Pfizer) or Pneumovax 23 (Merck), as randomly assigned. * Available to attend 6 study visits over 67 days (Visit 7 is optional at Day 365-720).
Exclusion criteria
* Previous pneumococcal vaccination with Prevnar 13 or Pneumovax 23. * History of anaphylactic/anaphylactoid or severe allergic reaction to any component of Pneumovax 23, Prevnar 13 or any diphtheria toxoid-containing vaccine. * Established diagnosis of diabetes * History of receiving Zostavax (shingles vaccine) within previous 4 weeks. (Study entry may be delayed to satisfy a 28-day interval between vaccinations) * Known history of any of the following co-morbid conditions: * Malignancy (participants without a recurrence in the last 5 years will be allowed) * Congestive Heart Failure * Cardiovascular Disease (unstable ≤ 6 months\*) * Kidney disease * Renal failure * Impaired hepatic function * Autoimmune disease such as: Rheumatoid Arthritis, systemic lupus erythematosus (SLE), Inflammatory Bowel Disease, etc. * Use of medicines during past 6 months known to alter immune response such as high-dose corticosteroids * HIV, AIDS or other Immunodeficiency * Recent (≤ 3 months) trauma or surgery * Current substance and/or alcohol abuse \* Unstable disease is defined as a change in therapy or hospitalization for worsening disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pneumococcal-specific Antibody Responses | 70 days | To vaccinate healthy older participants with pneumococcal vaccines, collect longitudinal blood samples and assess pneumococcal-specific antibody responses. The unit of measurement used is log2 titer defined as a measure to quantify the overall strength of responses using the sum of all serotype responses. Data shown below is from longitudinal study timepoints (pre and post) first pneumococcal vaccine. At study endpoint, Visit 7, a second pneumococcal vaccine was administered and no further sample collection visits were conducted as proposed in the study design. |
| Pneumococcal-specific Antibody Responses - Fold Change Post First Vaccination | 70 days | Fold change between the baseline and post first vaccination titers was calculated for each pneumococcal vaccine cohort. Data shown below is from longitudinal study timepoints (pre and post) first pneumococcal vaccine. At study endpoint, Visit 7, a second pneumococcal vaccine was administered and no further sample collection visits were conducted as proposed in the study design. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Genes Upregulated Following Vaccination With PCV13 or PPSV23 | 10 days post first vaccination | RNA-seq and ATAC-seq to enable quantitative assessment of both coding RNA's and ncsRNA's as well as to resolve the epigenetic landscape of immune cells in the context of vaccine responses. We assessed the number of genes upregulated post first vaccination \[PCV13 or PPSV23\]. Data shown below is from longitudinal study timepoints (pre and post) first pneumococcal vaccine. At study endpoint, Visit 7, a second pneumococcal vaccine was administered and no further sample collection visits were conducted as proposed in the study design. |
| Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | baseline and 10 days post first vaccination | Measure of functional status of immune cells in older participants following administration of a single pneumococcal vaccine, Prevnar13 or Pneumovax23, at baseline and 10 days post first vaccination. Data shown below is from longitudinal study timepoints (pre and post) first pneumococcal vaccine. At study endpoint, Visit 7, a second pneumococcal vaccine was administered and no further sample collection visits were conducted as proposed in the study design. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prevnar 13 Prevnar 13 (Pneumococcal 13valent Conj Vaccine Diphtheria CRM197 Protein) will be administered at the single 0.5 ml dose, by intramuscular injection with routine clinical care.
Pneumococcal 13valent Conj Vaccine Diphtheria CRM197 Protein: One to two years after receiving the randomly-assigned vaccination, participants may opt to receive administration of a second pneumococcal vaccine with Pneumovax 23 | 19 |
| Pneumovax 23 Pneumovax 23 (Pneumococcal Vaccine Polyvalent) will be administered at the single 0.5ml dose, by intramuscular injection with routine clinical care.
Pneumococcal Vaccine Polyvalent: One to two years after receiving the randomly-assigned vaccination, participants may opt to receive administration of a second pneumococcal vaccine with Prevnar-13 | 20 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Participant did not complete the last study visit due to hospitalization unrelated to the vaccine | 1 | 0 |
Baseline characteristics
| Characteristic | Prevnar 13 | Pneumovax 23 | Total |
|---|---|---|---|
| Age, Continuous | 67.52 years STANDARD_DEVIATION 7.15 | 69.25 years STANDARD_DEVIATION 9.25 | 68.40 years STANDARD_DEVIATION 7.8 |
| BMI | 24.83 kg/m^2 STANDARD_DEVIATION 3.77 | 27.16 kg/m^2 STANDARD_DEVIATION 5.94 | 26.13 kg/m^2 STANDARD_DEVIATION 5.04 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 20 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 19 Participants | 37 Participants |
| Sex: Female, Male Female | 9 Participants | 10 Participants | 19 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 20 |
| other Total, other adverse events | 1 / 19 | 0 / 20 |
| serious Total, serious adverse events | 0 / 19 | 0 / 20 |
Outcome results
Primary
Pneumococcal-specific Antibody Responses
To vaccinate healthy older participants with pneumococcal vaccines, collect longitudinal blood samples and assess pneumococcal-specific antibody responses. The unit of measurement used is log2 titer defined as a measure to quantify the overall strength of responses using the sum of all serotype responses. Data shown below is from longitudinal study timepoints (pre and post) first pneumococcal vaccine. At study endpoint, Visit 7, a second pneumococcal vaccine was administered and no further sample collection visits were conducted as proposed in the study design.
Time frame: 70 days
Population: 39 healthy volunteers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prevnar 13 | Pneumococcal-specific Antibody Responses | Baseline | 72.1 log2 titer | Standard Deviation 19.4 |
| Prevnar 13 | Pneumococcal-specific Antibody Responses | Post first vaccination | 128.9 log2 titer | Standard Deviation 19.5 |
| Pneumovax 23 | Pneumococcal-specific Antibody Responses | Baseline | 79.4 log2 titer | Standard Deviation 18.6 |
| Pneumovax 23 | Pneumococcal-specific Antibody Responses | Post first vaccination | 120.9 log2 titer | Standard Deviation 15 |
Primary
Pneumococcal-specific Antibody Responses - Fold Change Post First Vaccination
Fold change between the baseline and post first vaccination titers was calculated for each pneumococcal vaccine cohort. Data shown below is from longitudinal study timepoints (pre and post) first pneumococcal vaccine. At study endpoint, Visit 7, a second pneumococcal vaccine was administered and no further sample collection visits were conducted as proposed in the study design.
Time frame: 70 days
Population: 39 healthy volunteers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prevnar 13 | Pneumococcal-specific Antibody Responses - Fold Change Post First Vaccination | 55.6 Fold Change | Standard Deviation 25.5 |
| Pneumovax 23 | Pneumococcal-specific Antibody Responses - Fold Change Post First Vaccination | 41.6 Fold Change | Standard Deviation 18.8 |
Secondary
Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23
Measure of functional status of immune cells in older participants following administration of a single pneumococcal vaccine, Prevnar13 or Pneumovax23, at baseline and 10 days post first vaccination. Data shown below is from longitudinal study timepoints (pre and post) first pneumococcal vaccine. At study endpoint, Visit 7, a second pneumococcal vaccine was administered and no further sample collection visits were conducted as proposed in the study design.
Time frame: baseline and 10 days post first vaccination
Population: A longitudinal analysis of different cell populations in whole blood samples was performed using flow cytometry at various time points. The number of plasmablasts and ICOS+ Tfh cells at baseline and post first vaccination at day 10 are reported below.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prevnar 13 | Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | Plasmablasts cell count at baseline | 0.4 cells/microliter | Standard Deviation 0.4 |
| Prevnar 13 | Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | Plasmablasts cell count at Day 10 post first vaccination | 0.7 cells/microliter | Standard Deviation 0.8 |
| Prevnar 13 | Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | ICOS+Tfh cell count at baseline | 4.1 cells/microliter | Standard Deviation 3.8 |
| Prevnar 13 | Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | ICOS+Tfh cell count at Day 10 post first vaccination | 8.8 cells/microliter | Standard Deviation 7.6 |
| Pneumovax 23 | Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | ICOS+Tfh cell count at Day 10 post first vaccination | 6.8 cells/microliter | Standard Deviation 3.9 |
| Pneumovax 23 | Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | Plasmablasts cell count at baseline | 0.5 cells/microliter | Standard Deviation 0.3 |
| Pneumovax 23 | Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | ICOS+Tfh cell count at baseline | 4.1 cells/microliter | Standard Deviation 2.4 |
| Pneumovax 23 | Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23 | Plasmablasts cell count at Day 10 post first vaccination | 1.6 cells/microliter | Standard Deviation 2.5 |
Secondary
Number of Genes Upregulated Following Vaccination With PCV13 or PPSV23
RNA-seq and ATAC-seq to enable quantitative assessment of both coding RNA's and ncsRNA's as well as to resolve the epigenetic landscape of immune cells in the context of vaccine responses. We assessed the number of genes upregulated post first vaccination \[PCV13 or PPSV23\]. Data shown below is from longitudinal study timepoints (pre and post) first pneumococcal vaccine. At study endpoint, Visit 7, a second pneumococcal vaccine was administered and no further sample collection visits were conducted as proposed in the study design.
Time frame: 10 days post first vaccination
Population: To compare the transcriptional responses induced by vaccines on circulating PBMCs we generated RNA-seq data from 31 responders out of 39 total donors. We selected the topmost strong and weak responders from each participant arm (15 participants in Prevnar 13 arm, 16 participants in Pneumovax 23 arm) to generate RNA-seq data. The aim was to identify specific RNA transcriptional signatures of responsivity vs non-responsivity to the first administered pneumococcal vaccine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prevnar 13 | Number of Genes Upregulated Following Vaccination With PCV13 or PPSV23 | 26 Number of upregulated genes at day 10 |
| Pneumovax 23 | Number of Genes Upregulated Following Vaccination With PCV13 or PPSV23 | 42 Number of upregulated genes at day 10 |