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.

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.

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Prior participant in either the Ellison cohort or another Stanford vaccine study with archived samples.
4. Male or female, aged 18-40 years or 65 years and older.
5. In good general health as evidenced by medical history.

Exclusion Criteria:

1. Prior off-study vaccination with the current season influenza vaccine for influenza vaccinations.
2. Allergy to egg or egg products
3. Allergy to vaccine components, including thimerosal
4. Active systemic or serious concurrent illness, including febrile illness on the day of vaccination
5. 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.
6. Receipt of inactivated vaccine 14 days prior to study vaccination or planned vaccination prior to Day 28 after study vaccination.
7. Receipt of live, attenuated vaccine within 60 days of study vaccination or planned vaccination prior to Day 28 after study vaccination.
8. 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.
9. Use of investigational agents within 30 days prior to enrollment or planned use of investigational agents prior to completion of all study visits.
10. Need for allergy immunizations (that cannot be postponed) between Days 0 and 28 post-immunization.
11. 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).
12. 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.

The NIH Human Immunology Project Consortium (HIPC) data repositories (ImmPORT) may store the results of the research assays results. Genetic data that is developed in this study may be made available to other researchers through the National Center for Biotechnology Information (NCBI) databases. Results from research assays will be labeled with a unique identification code and the volunteer identity (except for age) will not be disclosed.

De-identified data will be loaded into ImmPort following completion of all data analysis

De-identified data will be publicly available through ImmPort