Part 1: The Basics of Immunization and VaccinesPharMEDium Lunch and Learn Series
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Part 1: The Basics of Immunization and Vaccines
December 8, 2017
Featured Speaker: Michael E. Klepser, PharmD, FCCP, FIDPProfessor of Pharmacy PracticeFerris State UniversityCollege of PharmacyBig Rapids, Michigan
LUNCH AND LEARN
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CE Activity Information & Accreditation
ProCE, Inc. (Pharmacist and Tech CE)
1.0 contact hour
Funding: This activity is self‐funded through PharMEDium.
It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Klepser is an Advisory Board Member for Melinta Therapeutics and Nabriva, a Consultant for Arkray Diagnostics and PTS Diagnostics, and a Content Developer for NACDS.
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Part 1: The Basics of Immunization and Vaccines
Michael E. Klepser, PharmD, FCCP, FIDP
Professor
Ferris State University
College of Pharmacy
Part 1: The Basics of Immunization and VaccinesPharMEDium Lunch and Learn Series
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Learning Objectives
At the conclusion of this presentation, participants will be able to:
1. Describe the differences among various vaccines.
2. Explain how vaccine effectiveness is measured.
3. Discuss the role of adjuvants in vaccines.4. List common side effects and precautions
associated with vaccine administration.5. Discuss Healthy People 2020 with respect to
immunization targets.
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History of Immunizations
• The transfer of pus from smallpox lesions from an infected individual to a non-infected one was practiced since the 1600s.
• Edward Jenner took pus from a cowpox lesion and vaccinated James Phipps in 1796.
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History of Immunizations
• The transfer of pus from smallpox lesions from an infected individual to a non-infected one was practiced since the 1600s.
• Edward Jenner took pus from a cowpox lesion and vaccinated James Phipps in 1796.The word vaccine comes from the Latin noun vacca which means cow.
Since Jenner used cowpox material for injections they were called vaccines.
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History of Vaccines
• Louis Pasteur developed the first laboratory manufactured vaccines.
• Most vaccines used today were developed in the 20th century or later.
• Currently there are vaccines available in the United States against 25 infectious conditions.
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Currently Approved Vaccines in the United States
• Adenovirus (military only)• Anthrax• Diphtheria• Hepatitis A• Hepatitis B• H. influenzae type b• Human Papillomavirus• Influenza• Japanese Encephalitis• Measles• Meningococcal• Mumps
• Pertussis• Pneumococcal• Polio• Rabies• Rotavirus• Rubella• Shingles• Smallpox• Tetanus• Tuberculosis• Typhoid Fever• Varicella• Yellow Fever
Red = Part of child and/or adult recommended schedules
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Timeline of Vaccine Development
Source: http://pediatrics.aappublications.org/content/pediatrics/132/5/898/F4.large.jpg
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Impact of Vaccines on World Health
Source: Vaccine 2013. 18;31 (Suppl 2):B61‐72.
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Immunologic Basics of Vaccinations
• Following exposure to an antigen the body develops an immune response to protect itself.
• Immune responses are divided into:– Innate immune responses
– Adaptive immune responses
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Immunologic Basics of Immunization
Innate responses• Rapid and nonspecific• First line of defense• Mediated by:
– Natural killer cells • Recognize and kill virally
infected cells
– Complement• Activated by components
of bacteria
– Phagocytes• Macrophages and
dendritic cells• Ingest foreign particles
Adaptive responses• Specific
• Develops over days
• Long-term immune memory
• Stimulated through immunization
• Mediated by:– T lymphocytes
– B lymphocytes
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T Lymphocytes
• Subtype of white blood cell• Part of cell-mediated immunity• Types:
– T helper cells: help other WBC in immunologic process (CD4+ T cells)
• Th1 cells: lead to cell-mediated responses
• Th2 cells: produce IL-4 and IL-5 which cause B cells to differentiate into antibody-secreting plasma cells
– Cytotoxic cells: destroy virus-infected and tumor cells (CD8+ T cells)
– Memory T cells: long-lived and can quickly respond to a stimulus
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B Lymphocytes
• Subtype of white blood cell
• Part of humoral-mediated immunity
• Types:– Plasma cells: Long-lived, non-
proliferating antibody secreting cells
– Memory B cells: circulate throughout the body and initiate a stronger, more rapid antibody response if they detect the antigen that had activated their parent B cell
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Antibodies
• Y-shaped protein produced by plasma cells
• Recognize antigens and bind to pathogen to tag it for attack by the immune system or neutralize the target by blocking invasion or impacting survival
• Also called immunoglobulins (Ig)– IgM: Secreted in the early stages of a
immune response
– IgG: Provides the majority of antibody-based immunity
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Summary of Key Steps in Generation of Protective Immunity
a. Antigen processing
b. Antigen activation of B cells and complement
c. Activation of antigen presenting cells (APC)
d. Activation of T helper cells
e. T cell-B cell collaboration results in generation of plasma cells and memory B cells
Source: https://www.researchgate.net/figure/47430035_fig2_Figure-1-Key-steps-during-the-generation-of-protective-immune-responsesa-Antigen
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Immunologic Basics of Immunization
• On first exposure to a vaccine, a primary response is induced and circulating antibodies will appear in 7-10 days.– IgM appear early and have low affinity
– IgG appear later and have high affinity
• Antibody titers peak in 2-6 weeks and then decline
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Antibodies
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Immunologic Basics of Immunization
• After a second exposure to a vaccine, a heightened humoral or cell-mediated response is observed.
• Typically occur within 4-5 days
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Antibodies
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Determinants of Immunogenicity
• Characteristics of the antigen
• Genetic characteristics of the recipient
• Physiologic state of the recipient– Age, nutritional status, sex, pregnancy status,
stress, infections, immune status
• Manner in which the antigen is presented– Route of administration, number of doses, timing
of doses, presence of adjuvants, conjugation
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Response to Vaccines
• Serologic response– Response to vaccines, seroconversion, gauged
by measuring the appearance and concentration of antibodies.
• Only assesses humoral immunity
– Duration of immunity is assessed by persistence of antibodies.
• May not be reliable
– Opsonophagocytic activity is used to assess functional antibodies.
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Response to Vaccines
• Clinical protection– Vaccine effectiveness
• Calculate the risk of disease among vaccinated and unvaccinated persons and determine reduction in risk.
Vaccine Effectiveness
=Risk among unvaccinated group – Risk among vaccinated group
Risk among unvaccinated group
• Recommended vaccine effectiveness for universal use of a vaccine in children is defined as > 80% following a primary series.
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Improving Response to Vaccines
• An adjuvant is a substance used in combination with an antigen to produce a more robust immune response.– Depot effect
– Up-regulation of cytokines and chemokines
– Cellular recruitment at injection site
– Increased antigen uptake and presentation of antigen presenting cells (APC) which express pattern recognition receptors (PRR)
– Activation of inflammasomes
Source: http://www.invivogen.com/images/Adjuvant-mechanism.jpg
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Types of Adjuvants
• Alum– Results in a depot effect and activates antigen
presenting cells (APC)• Provoke strong Th2 (humoral) response
• Poor modulation of Th1 (cellular) response
• Emulsions– Results in a depot effect and induces major
histocompatibility complex (MHC) response• Provoke strong Th2 response
• Mixed Th1 response
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Types of Adjuvants
• Pattern Recognition Receptor (PRR) Ligands– Pattern recognition receptors
• Expressed by cells of the innate immune system – Dendritic cells, macrophages, monocytes, and neutrophils
• Detect molecules, pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens.
• Mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.
• Examples:– Membrane bound: Toll-like receptors (TLR), C-type lectin receptors
(CLR)
– Cytoplasmic: NOD-like receptors (NLR), RIG-I-like receptors (RLR)
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Types of Adjuvants
• Pattern Recognition Receptor (PRR) Ligands– Facilitate antigen binding
to PRR.
– Induce innate immunity by targeting antigen presenting cells (APC) and subsequently influencing adaptive immunity.
– Stimulate Th1 and Th2 responses.
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Improving Response to Vaccines
• Conjugates– B cell response to a capsular polysaccharide is T cell
independent, meaning that B cells can produce antibodies without T cell stimulation.
• Polysaccharides cannot be loaded onto the MHC complex of antigen presenting cells (APC) because MHC can only bind peptides.
Source: https://www.researchgate.net/profile/Peter_Beverley/publication/24005221/figure/fig1/AS:279063995404374@1443545449920/Figure-1-The-immune-response-to-polysaccharide-and-protein-polysaccharide-conjugate.png
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Improving Response to Vaccines
• Conjugates• A highly antigenic protein
that is attached to a poor antigen like a capsular polysaccharide.
• A conjugated vaccine is able to be presented on the MHC molecule and the T cell can be activated.
– Stimulates a more vigorous immune response and promotes a more rapid and long-lasting immunologic memory.
Source: https://www.researchgate.net/profile/Peter_Beverley/publication/24005221/figure/fig1/AS:279063995404374@1443545449920/Figure-1-The-immune-response-to-polysaccharide-and-protein-polysaccharide-conjugate.png
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Examples of Conjugated Vaccines
• Pneumococcal
• Haemophilus influenzae type b
• Meningococcal
Source: Clutterbuck EA. JID 2015; 205: 1408-16.
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Types of Vaccines
Live Attenuated Vaccines
• Contained live but weakened bacteria or virus
• Risk of causing disease
• Stimulate an immune response similar to the actual disease
• Durable immunity
Inactivated Vaccines
• Contain killed whole microbes, toxoids, or antigenic subunits
• Cannot cause active disease
• Immunity tends to wane
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Live Vaccines
• Made by passing the pathogen through a series of cell cultures to diminish the pathogenicity.
• Examples:– Measles, mumps, rubella
– Rotavirus
– Small pox
– Varicella
– Yellow fever
– Zoster (Zostavax)
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Inactivated/Killed Vaccines
• Made exposing the pathogen to heat or chemicals such as formaldehyde or formalin.– Destroys the ability to replicate but keeps it intact
to stimulate the immune system.
• Examples:– Hepatitis A
– Polio
– Rabies
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Toxoid Vaccines
• Inactivating the toxin with heat or chemicals such as formaldehyde or formalin.– Destroys the ability to cause symptoms but keeps
it intact to stimulate the immune system.
• Examples:– Diphtheria
– Tetanus
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Subunit Vaccines
• Contain fractions of the pathogen that provoke a response from the immune system.
• Examples:– Haemophilus influenzae type b
– Hepatitis B
– Human papillomavirus
– Meningococcal
– Pertussis
– Pneumococcal
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Vaccine Components
• Antigen
• Suspending fluid
• Preservatives, stabilizers, and antibiotics– Inhibit or prevent bacterial growth
• Thiomerosal is a mercury-based preservative. Now removed from most childhood vaccines.
– Stabilize the antigen
• Adjuvants
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General Rule for Administration of Vaccines
Antigen combination Recommended minimum interval between doses
Two or more inactivated Simultaneously or at any interval
Inactivated and live Simultaneously or at any interval
Two or more live 28-day minimum interval, if not administered simultaneously
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General Rule for Administration of Vaccines
• Exceptions to the rule:– Do not administer conjugated pneumococcal vaccine
with the conjugated meningococcal vaccine to asplenic patients. Results in decreased response to the pneumococcal vaccine. Recommendation is to administer the pneumococcal vaccine followed by the meningococcal vaccine 4-weeks later.
– Do not administer the different pneumococcal vaccines (PCV13 and PPSV) together. There is a better immune response when PCV13 is administered first.
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General Rule for Administration of Vaccines
• Exceptions to the rule:– Oral typhoid and rotavirus vaccines may be
administered with or at any interval before or after any other inactivated or live injectable vaccines.
Source: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/timing.html#t-03
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Routes of Vaccine Administration
• Intramuscular and subcutaneous administration results in primarily an IgG response.– Intradermal administration may be
more efficient and require less antigen to be administered. Possibly related to direct antigen delivery to the draining lymph nodes.
• Oral and nasal delivery produce a local IgA and general IgG response.
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Precautions with Administering Vaccines
• Allergic reaction to antigens or other vaccine components.
• Immunocompromised patients– Poor response
– Possibility of not controlling replication (live)
• Coadministration with antibiotics, antivirals, or immunoglobulins (live)
• Pregnancy
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Monitoring Vaccine Side Effects
• Observed during clinical trials– Only detects adverse events that occur relatively
frequently (1 per 1,000 doses or higher).
• Post-marketing– Vaccine Adverse Event Reporting System (VAERS)
• An early warning system to detect possible safety issues with U.S. vaccines by collecting information about adverse events that occur after vaccination.
– Vaccine Safety Datalink (VSD)• Conducts vaccine safety studies based on questions or
concerns raised from the medical literature and reports to the VAERS.
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Vaccine Side Effects
• Vaccines stimulate an immune response– Fever and aches are common
• Vary with vaccine– Range from mild injection site reactions to death
– Vaccines with highest risk of severe adverse reactions:
• Small pox, Yellow fever
– Guillain-Barre Syndrome• Rapid-onset muscle weakness caused by the immune
system damaging the peripheral nervous system.
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Vaccine Recommendations
• Advisory Committee on Immunization Practices (ACIP)– Composition
• 15 voting members, 8 ex officio members from federal agencies, and 30 non-voting liaisons
– Purpose is to develop recommendations on the use of vaccines in the civilian population of the United States.
• Publish annual immunization schedules
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Evolution of Immunizations
• Pediatric schedule - 1995
Source: https://www.cdc.gov/vaccines/hcp/acip-recs/recs-by-date.html
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Evolution of Immunizations
• Pediatric schedule - 2016
Source: https://www.cdc.gov/vaccines/hcp/acip-recs/recs-by-date.html
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Evolution of Immunizations
• Adult schedule – 2002
Source: https://www.cdc.gov/vaccines/hcp/acip-recs/recs-by-date.html
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Evolution of Immunizations
• Adult schedule – 2016
Source: https://www.cdc.gov/vaccines/hcp/acip-recs/recs-by-date.html
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Evolution of Immunizations
• Numbers of vaccines recommended have increased.
• Populations recommended to receive immunizations have increased.
• Immunization schedules have become more complicated.
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Vaccine Goals
• Health goals for the United States are set each decade by the Department of Health and Human Services.– Aims to reach four overarching goals: Attain high-
quality, longer lives free of preventable disease, disability, injury, and premature death.
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Healthy People 2020 Vaccination Goals
Pneumococcal vaccine: 90% of adults > 65 years of age
https://www.healthypeople.gov/2020/topics-objectives/topic/immunization-and-infectious-diseases/objectives
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Healthy People 2020 Vaccination Goals
Influenza vaccine: 70% of adults
https://www.healthypeople.gov/2020/topics-objectives/topic/immunization-and-infectious-diseases/objectives
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Healthy People 2020 Vaccination Goals
Zoster vaccine: 30% of adults > 60 years of age
https://www.healthypeople.gov/2020/topics-objectives/topic/immunization-and-infectious-diseases/objectives
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Healthy People 2020 Vaccination Goals
• Select goals– HPV vaccine: 80% of females aged 10-15 years of
age who have received 3 doses of vaccine
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Summary
• Vaccines stimulate cellular and humoral immunity through B and T cell mediated processes.
• Vaccine effectiveness is affected by numerous host and vaccine factors.
• Vaccine administration schedules are growing more complicated.