Genomics and Epigenomics of the Elderly Response to Pneumococcal Vaccines

• Sponsor: The Jackson Laboratory (Other)
• Overall Status: Completed
• CT.gov ID: NCT03104075
• Collaborator: UConn Health (Other), University of Alabama at Birmingham (Other)
• Enrollment: 40
• Location: 1
• Arms: 2
• Actual Duration (Months): 40.4
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia; Aging	Biological: Pneumococcal 13valent Conj Vaccine Diphtheria CRM197 Protein; Biological: Pneumococcal Vaccine Polyvalent	Phase 4

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

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.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.
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Genomics and Epigenomics of the Elderly Response to Pneumococcal Vaccines
• Actual Study Start Date: Apr 17, 2017
• Actual Primary Completion Date: Dec 5, 2019
• Actual Study Completion Date: Aug 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Biological: 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; Other Names: Prevnar 13
Active Comparator: Pneumovax 23 Pneumovax 23 (Pneumococcal Vaccine Polyvalent) will be administered at the single 0.5ml dose, by intramuscular injection with routine clinical care.	Biological: 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; Other Names: Pneumovax 23

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UConn Center On Aging	Farmington	Connecticut	United States	06030

Sponsors and Collaborators

• The Jackson Laboratory
• UConn Health
• University of Alabama at Birmingham

Investigators

• Principal Investigator: George Kuchel, M.D. F.R.C.P, UConn Center on Aging

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 9, 2019
• Informed Consent Form - Jun 18, 2018

More Information

Publications

None provided.

• Responsible Party: JACQUES BANCHEREAU, Director Immunological Sciences, The Jackson Laboratory
• ClinicalTrials.gov Identifier: NCT03104075
• Other Study ID Numbers: 16-071J-1
• First Posted: Apr 7, 2017
• Last Update Posted: Dec 7, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by JACQUES BANCHEREAU, Director Immunological Sciences, The Jackson Laboratory: Genomics; Epigenomics; Pneumococcal vaccine; Elderly
• Additional relevant MeSH terms: Pneumonia; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine

Study Results

Participant Flow

Arm/Group Title	Prevnar 13	Pneumovax 23
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	20	20
COMPLETED	19	20
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Prevnar 13	Pneumovax 23	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	19	20	39
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.52 (7.15)	69.25 (9.25)	68.40 (7.80)
Sex: Female, Male (Count of Participants)
Female	9 47.4%	10 50%	19 48.7%
Male	10 52.6%	10 50%	20 51.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	19 100%	20 100%	39 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 5.3%	1 5%	2 5.1%
White	18 94.7%	19 95%	37 94.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.83 (3.77)	27.16 (5.94)	26.13 (5.04)

Outcome Measures

1. Primary Outcome

Title	Pneumococcal-specific Antibody Responses
Description	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

Outcome Measure Data

Analysis Population Description

39 healthy volunteers

Arm/Group Title	Prevnar 13	Pneumovax 23
Arm/Group Description	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. [Data analyzed and shown below for the first vaccine i.e. Prevnar 13] 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. [Second vaccine i.e. Pneumovax 23 administered at study endpoint (Visit 7), no further data collected post-second vaccination]	Pneumovax 23 (Pneumococcal Vaccine Polyvalent) will be administered at the single 0.5ml dose, by intramuscular injection with routine clinical care. [Data analyzed and shown below for the first vaccine i.e. Pneumovax 23] 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. [Second vaccine i.e. Prevnar 13 administered at study endpoint (Visit 7), no further data collected post-second vaccination]
Measure Participants	19	20
Baseline	72.1 (19.4)	79.4 (18.6)
Post first vaccination	128.9 (19.5)	120.9 (15.0)

2. Primary Outcome

Title	Pneumococcal-specific Antibody Responses - Fold Change Post First Vaccination
Description	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

Outcome Measure Data

Analysis Population Description

39 healthy volunteers

Arm/Group Title	Prevnar 13	Pneumovax 23
Arm/Group Description	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. [Data analyzed and shown below for the first vaccine i.e. Prevnar 13] 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. [Second vaccine i.e. Pneumovax 23 administered at study endpoint (Visit 7), no further data collected post-second vaccination]	Pneumovax 23 (Pneumococcal Vaccine Polyvalent) will be administered at the single 0.5ml dose, by intramuscular injection with routine clinical care. [Data analyzed and shown below for the first vaccine i.e. Pneumovax 23] 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. [Second vaccine i.e. Prevnar 13 administered at study endpoint (Visit 7), no further data collected post-second vaccination]
Measure Participants	19	20
Mean (Standard Deviation) [Fold Change]	55.6 (25.5)	41.6 (18.8)

3. Secondary Outcome

Title	Number of Genes Upregulated Following Vaccination With PCV13 or PPSV23
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Prevnar 13	Pneumovax 23
Arm/Group Description	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. [Data analyzed and shown below for the first vaccine i.e. Prevnar 13] 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. [Second vaccine i.e. Pneumovax 23 administered at study endpoint (Visit 7), no further data collected post-second vaccination]	Pneumovax 23 (Pneumococcal Vaccine Polyvalent) will be administered at the single 0.5ml dose, by intramuscular injection with routine clinical care. [Data analyzed and shown below for the first vaccine i.e. Pneumovax 23] 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. [Second vaccine i.e. Prevnar 13 administered at study endpoint (Visit 7), no further data collected post-second vaccination]
Measure Participants	15	16
Number [Number of upregulated genes at day 10]	26	42

4. Secondary Outcome

Title	Alterations to APCs, Tfh Cells or B Cells in Response to PCV13 and PPSV23
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Prevnar 13	Pneumovax 23
Arm/Group Description	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. [Data analyzed and shown below for the first vaccine i.e. Prevnar 13] 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. [Second vaccine i.e. Pneumovax 23 administered at study endpoint (Visit 7), no further data collected post-second vaccination]	Pneumovax 23 (Pneumococcal Vaccine Polyvalent) will be administered at the single 0.5ml dose, by intramuscular injection with routine clinical care. [Data analyzed and shown below for the first vaccine i.e. Pneumovax 23] 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. [Second vaccine i.e. Prevnar 13 administered at study endpoint (Visit 7), no further data collected post-second vaccination]
Measure Participants	19	20
Plasmablasts cell count at baseline	0.4 (0.4)	0.5 (0.3)
Plasmablasts cell count at Day 10 post first vaccination	0.7 (0.8)	1.6 (2.5)
ICOS+Tfh cell count at baseline	4.1 (3.8)	4.1 (2.4)
ICOS+Tfh cell count at Day 10 post first vaccination	8.8 (7.6)	6.8 (3.9)

Adverse Events

Time Frame	Data were collected on participants during the 2017-2018 vaccination seasons. Blood samples obtained 7 days prior to vaccination and Day 1, 10, 28, 60 post-vaccination.
Adverse Event Reporting Description	AEs were collected on participants throughout the duration of the study. None of the AEs were related to the vaccine. One participant had a vasovagal syncope episode due to blood draw.
Arm/Group Title	Prevnar 13		Pneumovax 23
Arm/Group Description	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.		Pneumovax 23 (Pneumococcal Vaccine Polyvalent) will be administered at the single 0.5ml dose, by intramuscular injection with routine clinical care.
All Cause Mortality
	Prevnar 13		Pneumovax 23
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/20 (0%)
Serious Adverse Events
	Prevnar 13		Pneumovax 23
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Prevnar 13		Pneumovax 23
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/20 (0%)
General disorders
Vasovagal Syncope	1/19 (5.3%)	1	0/20 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.