Effects of Aging on Primary and Secondary Vaccine Responses in a 15-Year Longitudinal Cohort

Study Overview
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Brief Summary
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The purpose of this study is to use an existing, unique clinical cohort: the longitudinal cohort of younger (21-40 years) and elderly (>65 years) subjects whose yearly influenza vaccine responses have been studied extensively since 2007, to gain molecular and cellular mechanistic insights into the impaired vaccine responses in the elderly.

Detailed Description
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This is a phase I mechanistic study of sixty 21-40 and >65 year old adult volunteers who previously participated in vaccine studies with our program. All participation is by invitation only. The volunteers will be enrolled into two groups. Group A: Up to 30 healthy adult volunteers age 21-40 who will be given seasonal quadrivalent inactivated influenza vaccine (IIV4) prior to flu season for each of 5 years. They will also be given an inactivated Hepatitis A vaccine in the spring of years 1 and 2. Each volunteer will complete a total of 4 visits for each immunization: Day 0 (pre-immunization), Day 6-8, Day 12-15, and Day 26-30 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). A subset of this group will be randomized to receive either a Typhoid Vi Polysaccharide Vaccine or Typhoid Vaccine Live Oral Ty21a vaccine in year 3. Each volunteer will complete a total of 4 visits for this immunization: Day 0 (pre-immunization), Day 6-8 post completion of injection or final oral dose, Day 12-15 and Day 26-30 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). Group B: Up to 30 healthy adult volunteers age 65 plus who will be randomized and given seasonal trivalent high dose inactivated influenza vaccine (IIV3) or trivalent adjuvanted trivalent inactivated influenza vaccine (Fluad) prior to flu season for each of 5 years. They will also be given an inactivated Hepatitis A vaccine in the spring of years 1 and 2 and aTyphoid Vi Polysaccharide Vaccine in year 3. Each volunteer will complete a total of 4 visits for each immunization: Day 0 (pre-immunization), Day 6-8, Day 12-15, and Day 26-30 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). A subset of subjects (with a target of 10 younger and 10 older subjects depending on health), will undergo bone marrow aspirates one or two years after typhoid vaccination.

Official Title
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Effects of Aging on Primary and Secondary Vaccine Responses in a 15-Year Longitudinal Cohort

Conditions
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Influenza, Hepatitis A, Typhoid, Healthy Adults

Intervention / Treatment
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* Biological: Fluzone® quadrivalent
* Biological: Fluzone High Dose
* Biological: Fluad
* Biological: Vaqta
* Biological: Typhim Vi
* Biological: Vivotif


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study. Prior participant in either the Ellison cohort or another Stanford vaccine study with archived samples. Male or female, aged 18-40 years or 65 years and older. In good general health as evidenced by medical history. Exclusion Criteria: Prior off-study vaccination with the current season influenza vaccine for influenza vaccinations. Allergy to egg or egg products Allergy to vaccine components, including thimerosal Active systemic or serious concurrent illness, including febrile illness on the day of vaccination Receipt of blood or blood products within the past 6 months of any study vaccination or planned receipt of blood products prior to completion of Day 28 post-immunization visit. Receipt of inactivated vaccine 14 days prior to study vaccination or planned vaccination prior to Day 28 after study vaccination. Receipt of live, attenuated vaccine within 60 days of study vaccination or planned vaccination prior to Day 28 after study vaccination. Donation of the equivalent of a unit of blood within 6 weeks prior to enrollment or planned blood donation prior to Day 28 after study vaccination. Use of investigational agents within 30 days prior to enrollment or planned use of investigational agents prior to completion of all study visits. Need for allergy immunizations (that cannot be postponed) between Days 0 and 28 post-immunization. Pregnant or lactating woman for all but influenza vaccine. A woman who is pregnant or breastfeeding may be evaluated by the Protocol Director to determine if influenza vaccination would affect volunteer safety and may be included at the discretion of the investigator. Blood sample collection will be adjusted as necessary for volunteer safety (e.g. blood collection volume for a pregnant woman would follow the minimal risk guidelines of 50 ml in an 8 week period and collection may not occur more frequently than 2 times per week). Any condition, which, in the opinion of the investigator, might interfere with volunteer safety, study objectives or the ability of the participant to understand or comply with the study protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A IIV4<br>Group A: Up to 30 healthy volunteers 18-40 years old, will be given seasonal quadrivalent inactivated influenza vaccine (IIV4) Fluzone® Quadrivalent vaccine. Each volunteer will complete a total of 4 visits: Day 0 (pre-immunization), Day 6-8, Day 12-16, and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Fluzone® quadrivalent<br>* IIV4 vaccine will be administered as a 0.5 mL dose, with a sterile, disposable syringe and needle by intramuscular (IM) injection into the deltoid muscle.<br>* Other names: IIV4 inactivated influenza vaccine;|
| Experimental: Group B High Dose IIV3<br>Group B: Up to 15 healthy volunteers 65 plus years old, will be given seasonal high dose trivalent inactivated influenza vaccine (Fluzone High Dose) Fluzone® high dose vaccine. Each volunteer will complete a total of 4 visits: Day 0 (pre-immunization), Day 6-8, Day 12-16, and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Fluzone High Dose<br>* High Dose IIV3 vaccine will be administered as a 0.5 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>* Other names: High Dose Trivalent, inactivated influenza vaccine (TIV);|
| Experimental: Group B Fluad<br>Group B: Up to 15 healthy volunteers 65 plus years old, will be given seasonal adjuvanted trivalent inactivated influenza vaccine Fluad®. Each volunteer will complete a total of 4 visits: Day 0 (pre-immunization), Day 6-8, Day 12-16, and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Fluad<br>* Fluad vaccine will be administered as a 0.5 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>* Other names: Adjuvanted Trivalent, inactivated influenza vaccine;|
| Experimental: Group A Hepatitis A (HepA)<br>Group A: Up to 30 healthy volunteers 18-40 years old, will be given inactivated Hepatitis A vaccine Vaqta® in year 1 of the study and a booster 12 months post primary Vaqta vaccination. Each volunteer will complete a total of 4 visits per vaccination: Day 0 (pre-immunization), Day 6-8, Day 12-16, and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Vaqta<br>* Vaqta vaccine will be administered as a 1 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>* Other names: Inactivated Hepatitis A Vaccine;|
| Experimental: Group B Hepatitis A<br>Group B: Up to 30 healthy volunteers 65 plus years old, will be given inactivated Hepatitis A vaccine Vaqta® in year 1 of the study and a booster 12 months post primary Vaqta vaccination. Each volunteer will complete a total of 4 visits per vaccination: Day 0 (pre-immunization), Day 6-8, Day 12-16, and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Vaqta<br>* Vaqta vaccine will be administered as a 1 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>* Other names: Inactivated Hepatitis A Vaccine;|
| Experimental: Group A Typhoid VI<br>Group A: Up to 15 healthy volunteers 18-40 years old, will be randomized to either Typhoid Vi Polysaccharide Vaccine (Typhoid VI), Typhim Vi®, or Typhoid Vaccine Live Oral Ty21a, Vivotif®. This arm represents those randomized to Typhoid VI. Each volunteer will complete a total of 4 visits: Day 0 (pre-immunization), Day 6-8, Day 12-16, and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Typhim Vi<br>* Typhim Vi vaccine will be administered as a 0.5 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>* Other names: Typhoid Vi Polysaccharide Vaccine;|
| Experimental: Group A Oral Typhoid<br>Group A: Up to 15 healthy volunteers 18-40 years old, will be randomized to either Typhoid Vi Polysaccharide Vaccine, Typhim Vi®, or Typhoid Vaccine Live Oral Ty21a, Vivotif® (Oral Typhoid). This arm represents those randomized to Oral Typhoid. Each volunteer will complete a total of 4 visits: Day 0 (pre-immunization), Day 6-8 (from date of last oral dose), Day 12-16, and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Vivotif<br>* One capsule is to be swallowed approximately 1 hour before a meal with a cold or luke-warm [temperature not to exceed body temperature, e.g., 37 °C (98.6 °F)] drink on alternate days, e.g., days 1, 3, 5 and 7.<br>* Other names: Typhoid Vaccine Live Oral Ty21a;|
| Experimental: Group B Typhoid VI<br>Group B: Up to 30 healthy volunteers 65 plud years old, will be given Typhoid Vi Polysaccharide Vaccine (Typhoid VI), Typhim Vi® vaccine. Each volunteer will complete a total of 4 visits: Day 0 (pre-immunization), Day 6-8, Day 12-16, and Day 28+ 7 (post-immunization). All visits will consist of drawing blood for study assays and monitoring for serious adverse events (SAEs). | Biological: Typhim Vi<br>* Typhim Vi vaccine will be administered as a 0.5 mL dose, with a sterile, disposable syringe and needle by IM injection into the deltoid muscle.<br>* Other names: Typhoid Vi Polysaccharide Vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hemagglutination inhibition assay (HAI) titers | HAI titers measured at Days 0 and 28 for influenza. | Day 0 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| related AEs occurring during the 28 days post vaccination | related AEs occurring during the 28 days post vaccination for each of the vaccination types (Influenza, Hepatitis A, Typhoid) | Day 0 to Day 28 post-each immunization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inactivated Hepatitis A vaccine, Inactivated, trivalent high-dose influenza vaccine, Typhoid Vi Polysaccharide Vaccine, Typhoid Vaccine Live Oral Ty21a, Influenza Vaccine, Adjuvanted, Inactivated, quadrivalent influenza vaccine