PHAR 504 EXAM III Lecture Review

(10/16) Wenzler Lecture: Principles of Immunization The decision to administer a vaccine involves: (1) Risk of Disease, (2) Benefit of Vaccine, (3) Risk of Vaccine

- While no vaccine is 100% effective, most provide 80%+ protection, Benefit:Risk changes over time - AE: Rare, and usually mild and non-life threatening, see “Complications” under “Immune Response” below

Vaccination Types - Live/Attenuated: Low initial dose with High cumulative dose, Stimulates an immune response

o MoA: Organisms with a modified decreased virulence replicate within recipient cells, thus inducing higher cumulative dosing/antigenicity that increases logarithmically until controlled by the immune system

o Efficacy: Confers lifelong immunity, though it is prone to waning over the long-term o Development: Use serial passage in tissue cell culture line to ßvirulence & maintain immunogenicity

- Inactivated/Detoxified: High initial dose, same cumulative dose, does not stimulate an immune response o MoA: Inactivated vaccine does not replicate and antigenicity is limited to the administration o Efficacy: Generally does not produce permanent immunity with 1 dose, will require repeated vaccinations

and boosters to maintain high levels of Ab (Examples: Tdap, Rabies, Typhoid) § Exception: Polio and Hep B à there are not standard recommendations for boosters, check titers

o Development: Generated in bacteria following concentration, purification, and inactivation. § More recent techniques involve using recombinant techniques and polymers (sustained-release)

o Special: Benefit ALWAYS outweighs the risks Determinants of Immunogenicity

- Chemical and Physical States of the Ag - Recipient Characteristics: Genetics, Physical Condition

o Disclaimer: If the person is sick, indeed, the vaccination may result in decreased efficacy. However, since the benefits outweigh the risks, the person should still receive the immunization. Potential exceptions include the big boy vaccines that aren’t given annually – in which case you’ll want optimal efficacy

o That being said, no the patient won’t die if they receive a vaccine while sick so they can calm tf down - Antigen Presentation: RoA, Dose, Timing of dose, Adjuvants

o RoA: Determines the breadth of the response. § IM/SC confer predominantly systemic IgG response § Oral/Intranasal produce local IgA responses with minimal IgG

o Dose: Determines the extent of the immune response. Dose-response relationship will plateau o Adjuvants: Used to help stimulate immune responses. The only FDA approved adjuvant is Aluminum

Hydroxide, a PAMP used to stimulate T and B cells. Europe uses emulsion oils - T-lymphocyte-dependent immune response: This is ideal and the mechanism for the majority of vaccines

o Induces immunologic memory, and repeat administration will boost the effect o Provides immunogenicity to all age groups!

- T-lymphocyte-independent immune response: This works as well, but not sure why you’d want to use it o Does not induce immunologic memory and cannot be boosted. Poor efficacy in youth and infants o Poor efficacy can be overcome via linkage to a carrier protein, such as pneumococcal, meningococcal

which use capsid particles. Immune Response: Per Wenzler: “Altogether, we unfortunately still do not know exactly how vaccinations work”

- Innate: The rapid and nonspecific response. Mediated by NK cells (virus), Complement (Bacteria), and DC/Macrophages (foreign particulates and microorganisms)

o MoA: Mobilized by APC recognition of PAMPs in the organism or adjuvant - Adaptive: Slower but specific to foreign Ag. It is mediated by APCs and T/B Lymphocytes. This is the immune

response that we are interested in, and is the underlying principle of vaccination o MoA: Results in long-term immune memory, protecting host against subsequent challenge

- Temporal (time) Response: Protection generally conferred in ~2 weeks o Circulating Ab appear in 7-10 days, IgM first then IgG. Titers peak in 2-6 weeks then decrease o Subsequent exposure to same Ag will involve a heightened humoral and cell-mediated response (4-5days)

- Measuring the Response: This refers to methods employed to gauge responsiveness o Serum Ab monitoring: Determines the humoral responsiveness by measuring appearance and [Ab].

§ Absence of measurable Ab does not mean lack of protection (wanes over time) § Presence of Ab is not always sufficient, should know the particular concentration

o Opsonophagocytic Activity: assay of choice. Serum from pt is exposed to different titers of vaccine to evaluate responsiveness and the level at which the pt stops responding

o Measuring Cell-mediated immunity: Impractical in most settings, limited to the govt. - Complications: There are rare vaccine-related adverse effects to be aware of, and myths to debunk

o AE: There exists a few associated adverse effects among some vaccinations § MMR – Thrombocytopenia Rubella – Acute Arthritis § Diphtheria – Brachial Neuritis All Vaccines: Carry risk of Anaphylaxis

o Overwhelm the infant immune system: PROVEN INCORRECT – “Infant immune system can tolerate 10,000 vaccines at once” - Wenzler

o Chronic Allergic or Autoimmune Disorders: PROVEN INCORRECT o Autism: Well-documented, highly accurate and.. PROVEN INCORRECT!

Vaccine Development: Similar to other drugs, vaccines require approval following 4 development phases - Pre-clinical: Animal Models – to demonstrate the production of Ab and safety - Phase I: Demonstrate Ab protection and safety in humans - Phase II: Clinical trials to select optimal schedule and further safety - Phase III: Efficacy - à Upon approval, vaccines need not repeat this process, even if the components change.

Advisory Committee on Immunization Practices (ACIP): Provide annual updated recommendations on vaccines FLU/INFLUENZA Vaccinations: The Flu season is November-May, Peaking in February, vaccinate until end of March

- Development: There are currently 3 different procedures by which (inactivated) influenza vaccines are developed o (1): Egg-based vaccines (Most common!) […has Egg] o (2): Cell culture-based vaccine produce in marine darby canine kidney cells [May have egg] o (3): Recombinant Vaccine produced via reverse genetics in insect cell lines [NO Eggs]

- Overall, the inactivated influenza vaccines are composed of split influenza viruses and/or purified surface Ag. o Trivalent: Contains 2 A viruses (H1N1, H3N2) and 1 B strain. o Quadrivalent: Trivalent + 1 more B strain o High Dose: This is only an Age-based vaccination. 65yo+

- Annual Changes: Due to antigen drift, the vaccine components vary from year to year depending on the current influenza strains in circulation

- Why is it important to have non-egg based methods to make vaccines? o (1) To avoid allergy contraindications (Egg protein is removed, but company ‘CYA’ “may contain eggs”) o (2) In the unfortunate case of an insane pandemic/KFC that wipes out all the chickens, need a backup

VACCINE: Inactivated Influenza: IM The more prevalent flu-vaccine and currently only accepted version - Administration: IM, Everyone over 6mo - Efficacy: 60% effective in preventing influenza (<65yo), Decreased immunity <2, >40

o Even if you still get infected, your flu-symptoms will be reduced compared to anti-vaxxers o For influenza cases, reduces 50% hospitalizations, 80% deaths

- ContraX: The only contraindication is during Induction or Consilidation Chemotherapy VACCINE: Live/Attenuated Influenza: ACIP no longer recommends this vaccination

- Administration: Intranasal, recommended for ages 2-49 - Efficacy: Only 45% effective, compared to inactivated version 60% effective - MoA: Small degree of viral replication (Viremia), eventually produces a localized IgA immune response - ContraX: Preggers, Egg allergy, conditions that could result in complication, close contact with immunocomp

VACCINE: Pneumococcal Conjugate Vaccine (PCV): IM. Inactivated Soluble Capsular material + Protein Carrier - Administration: ACIP: Everyone 65+ should get PCV13 in series with PPSV23 8 weeks later

o ACIP: All adults 50yo+ with 1+ risk factor should receive PCV13 in series with PPSV23 8 weeks later § Risk factors: Renal Failure, asplenia, CSF leak, cochlear implants, immunocompromised

- Efficacy: While it is only ~30% effective in preventing CAP (community acquired pneumonia), it is highly effective (80-97%) at preventing invasive infections – of which are the more severe.

- PCV7: 7-valent, Released in 2000, used in infants and young children - PCV13: 13-valent, Released in 2010. Administered as 4 dose series (2,4,6 months, with booster at 12-15 months) - MoA: Pneumococcal capsular polysaccharide is covalently linked to a protein carrier to help induce a T-cell-

dependent response, such that immunological memory is established - AE: Mild fever is common

VACCINE: Pneumococcal Polysaccharide Vaccine (PPSV23): IM Aka “Pneumovax” and the “Polysaccharide” - Administration: Vaccination of everyone >2yo. Especially adults at high risk for respiratory tract infections

o 65yo: Revaccinate after age 65 if given before age 65. (Albeit 5 years separation) o Suggested for: CV, Chronic Pulmonary Disease, Asplenia, Cancer, Liver Disease, Renal Failure,

Immunocompromised, Smoke cigs, >65yo - Efficacy: Very effective against pneu bacteremia, though not necessarily effective against non-bacteremic pneu

- Released in 1983, covers 23 serotypes of S. pneumoniae. Works against pneumococcal bacteremia - MoA: Produces a T-Cell independent response, thus there is no immunological memory. It is used as a booster to

PCV7 and PCV13 Special Immunization Circumstances:

- Travel: Review compliance with routinely recommended immunizations, cdc.gov/travel o Yellow Fever Vax is needed for Africa and Asia…there’s a bunch, just ask or look it up

- Occupational Exposure: Required for healthcare providers: HepB MMR, Influenza ,Varicella, Tdap - Pregnancy: Pregnant patients are considered immunocompromised due to low T cell counts. Should get Tdap and

Inactivated Influenza. Otherwise, consult MD about benefit:risk of others - Immunocompromised: AVOID LIVE/ATTENUATED! Family members/close contacts should be vaccinated on

your behalf LAW: Illinois pharmacists are required to report to vaccination registry

- Illinois Pharmacists can administer any vaccine to any patient >10yo (exception HPV >14yo) (10/20) Lecture Jaki: Medicinal Chemistry and Pharmacology of Allergy and Pulmonary Drugs FYI: The lungs are not symmetric; the left is slightly smaller because we gotta make room for the heart. You can live with just 1 ‘wing’ (one lung), you’ll just have SoB and more room for that big heart of yours ;) Lung Functionality: Alveoli (buncha grapes) are tightly wrapped in capillaries to help facilitate gas exchange. Their flexibility is conferred by elastin proteins CONDITION: Asthma: An immune reaction mediated by irritants in the air as well as allergens. This leads to swelling of the bronchioles, causing the mucus to become trapped. This overall reduction in the amount of air flow in the lungs may cause coughing, shortness of breath, and even lead to infection (due to reduced clearance of mucus+captured irritant)

- NK Cells release cytokines in response to the allergens to induce inflammation CONDITION: Chronic Obstructive Pulmonary Disease (COPD): Exacerbation of chronic bronchitis+Emphysema

- Sx: Bronchoconstriction, inflammation, mucus, cough - Smoker’ Cough: Early stage COPD – a dry cough in the morning - Chronic Bronchitis: Abundance of mucus produced clogs the bronchioles. Though mucus is normally produced

by the lung, but when exposed to irritants the wings may become infected and/or inflamed o Cx: Extended exposure to cigarette smoke

- Emphysema: Late stage COPD. Dangerous, and potentially fatal, it is irreversible lung damage. o Patho: Often due to cigarette smoke, there exists an imbalance between the production of neutrophil

elastase and a-1-antitrypsin, causing the dissolution/destruction of the elastin protein in the walls of the alveoli. Destruction of these inner walls causes severe respiration difficulty, due to the loss of elasticity and prolonged exhalation time (small volume of gas exchanged per breath)

o Tx: Irreversible, but you can decrease your symptoms by improving your lung volume through exercise - Treatment of COPD is utilizes drug therapy to target the symptoms of respiratory disorders