2.1 Immunizing Agents

Active Immunizing Agent Classes

Vaccines: Inactivated, Live attenuated

Toxoids

Passive Immunizing Agent Classes

Immunoglobulins

Antitoxins

Vaccine Components

Antigen (All vaccines will contain some kind of antigen to elicit an immune response)

Adjuvants

Preservatives*

Stabilizers

Buffers

Antibiotics

Adjuvants definition and examples

Substance added to a vaccine to enhance the immune system's response

induce inflammatory factors to injection site – helps immune response

May cause injection site reactions

Examples: • Aluminum salts (aluminum hydroxide, aluminum phosphate) • AS04 • MF59

Live vaccines do not use adjuvants

Preservatives Definition and Examples

Used in vaccines to prevent bacterial or fungal contamination

Required for vaccines in multi-dose vial

Examples: Phenol • Phenoxyethanol • Thimerosal

Thiomersal, is it safe?

Yes

No longer in vaccines in Canada since 2001

methylmercury is unsafe (neurologic problems, found in fish)

Thiomersal is based on ethyl mercury which is easily broken down and excreted from tissues

Autism Link to MMR vaccine: Why it is wrong

30 kids, chose kids on the spectrum of autism already (would have been diagnosed when turned 12)

Works for 2 companies with RFK Jr. 

Additives in vaccines which support growth and purification

Antibiotics - neomycin, streptomycin, polymyxin B

Egg proteins – mostly eliminated due to purification processes

Formaldehyde – to deactivate/denature proteins

Lactose, gelatin, human and bovine serum albumin as growth support agents

Most of additives removed during manufacturing – trace or residual amounts may remain:

May be concern if anaphylactic reaction risk or if culture does not allow cow products (bovine)

Live-attenuated vaccines include

Measles, mumps, rubella

Varicella (chickenpox)

Rotavirus

Yellow fever

Inactivated/Killed Vaccines Include

Polio (IPV)

Hepatitis A

Rabies

Subunit/Conjugate Vaccines Include

Pertussis

Pneumococcal

Meningococcal

Zoster (shingles)

mRNA vaccines (COVID)

Hepatitis B

Influenza (infection)

Haemophilis influenza type b (Hib)

Human papillomavirus (HPV)

Toxoid (Inactivated Toxin) Include

Diphtheria

Tetanus

Live-Attenuated Vaccines: How they work

Attenuated strains which replicate in host:

• Attenuation means the virus or bacterium has been weakened to reduce virulence so it cannot cause disease in healthy people

Act like natural infection:

• Live vaccines are the closest to actual infection and therefore elicit good, strong, long-lasting immune responses

Live Attenuated Vaccines Advantages

Single dose often sufficient to induce long lasting immunity

Strong immune response evoked

Local and systemic immunity produced

Live Attenuated Vaccines Disadvantages

Potential to revert to virulence

Caution/contraindicated in immunosuppressed patients

Interference by passive antibody, potentially other live vaccines

Poor stability

Potential for contamination with adventitious viruses

Live Attenuated Vaccines AEs

Side effects often mimic the disease.

MMR – fever and rash can occur 7-12 days following immunization

Vaccine is sensitive to exposure to heat and light.

Shake/swirl gently until pellet completely dissolved (no bubbles)

Inactivated/Killed Vaccines: How they Work

Uses a killed version of the organism that causes the disease:

• Treating pathogens with chemicals, heat, or radiation to kill them

• Body reacts to several different antigens simultaneously

Inactivated/Killed Vaccines Advantages

Stable

Constituents clearly defined

Unable to cause the infection

Inactivated/Killed Vaccines Disadvantages

Often need several doses

Local reactions common

Adjuvant needed

keeps vaccine at injection site

activates antigen presenting cells

Shorter lasting immunity generally

Inactivated/Killed Vaccines Expected Reactions

Typically occur within 48 hours:

fever • irritability • drowsiness • local pain and swelling • vomiting

Split/Subunit Vaccines: What are they?

A vaccine that contains purified specific pieces of a virus or bacteria chosen specifically to elicit an immune response:

• Produced in a variety of different ways

  • Purification of a split/killed vaccine

  • Production of a specific Ag (Hepatits B)

• Largest category of vaccines

• Instead of the entire microbe, contain only antigens that best stimulate the immune system.

• Typically, adverse reactions are lower as the vaccine contains only essential antigens.

Split/Subunit Vaccines Advantages

Stable

Constituents clearly defined

Unable to cause the infection

Split/Subunit Vaccines Disadvantages

Often need several doses

Local reactions common

Adjuvant needed

keeps vaccine at injection site

activates antigen presenting cells

Shorter lasting immunity generally

Split/Subunit Vaccines Expected Reactions

Typically occur within 48 hours:

fever • irritability • drowsiness • local pain and swelling • vomiting

Subunit – Polysaccharide Vaccines: What do they do

Protect against certain encapsulated bacteria (e.g., pneumococcal)

Capsule contains polysaccharides that surround the cell and can be removed from the cell

T-cell independent immunogens:

• Proteins need to be present to illicit proteolytic digestion and presentation to T-cells

• Tend to produce weak vaccines (Dont use in kids because they dont work)

Subunit – Polysaccharide Vaccines Advantages

Stable • Constituents clearly defined • Unable to cause the infection

Subunit – Polysaccharide Vaccines Disadvantages

No boosting effect from extra doses

Need repeat doses to maintain protection

Local reactions very common (Local lump (golf ball) which doesn't hurt, lasts a couple of weeks)

Shorter lasting immunity generally

Subunit – Polysaccharide Vaccines EXPECTED REACTIONS

Typically occur within 48 hours:

• fever • irritability • drowsiness • local pain and swelling • vomiting • may cause localized swelling or lump

Subunit – Conjugated Polysaccharide: How do they Work?

Attaching (linking) the polysaccharide antigen to a protein carrier creates a more effective immunogen

Elicits both T and B cell immune response

Examples: Hib, meningococcal, pneumococcal (Prevnar)

Subunit – Conjugated Polysaccharide Advantages

Stable • Constituents clearly defined • Unable to cause the infection • Better response than polysaccharide alone

Subunit – Conjugated Polysaccharide Disadvantages

No boosting effect from extra doses • Need repeat doses to maintain protection • Local reactions very common • Shorter lasting immunity generally

Subunit – Conjugated Polysaccharide EXPECTED REACTIONS

Typically occur within 48 hours: • fever • irritability • drowsiness • local pain and swelling

vomiting

Toxoid Vaccines: How do they work

Uses a chemically treated/modified toxin that the body reacts to.

• Giving protection to a toxin produced by a bacteria, fungus etc.

• Require multiple doses for immunity

• Likely need boosters as protection wanes over time

Antigens derived from toxins

• Often dose of toxin to cause effect is significantly lower than dose to cause immune response

Detoxified without destroying their effectiveness as an antigen

Generally combined with aluminum salts or attach to immunogenic protein to enhance immunogenicity

Immune response generates Ab that neutralize the virulent toxins associated with the disease:

• Do not prevent infection or reinfection of the organism

Examples: diphtheria, tetanus

Toxoid Vaccines Advantages

Stable • Constituents clearly defined • Unable to cause the infection

Toxoid Vaccines Disadvantages

No boosting effect from extra doses • Need repeat doses to maintain protection • Local reactions common • Shorter lasting immunity generally • Do not prevent infection or reinfection just prevent effect of toxoid/toxin

Toxoid Vaccines EXPECTED REACTIONS

Typically occur within 48 hours: • fever • irritability • drowsiness • local pain and swelling • vomiting

Nucleic Acid Vaccines: How do they work

Use genetic material for a specific Ag from a disease-causing virus to trigger protective immunity against it

Take advantage of the MHC-I receptor use to stimulate CD8 cells which are so important in viral infections

Nucleic Acid Vaccines: Two Types and Hurdles

• These types of vaccines include both mRNA and DNA type vaccines

• Both present significant technical hurdles due to stability issues outside of the cell

• Both also face hurdles of acceptance from the public who misunderstand how they work

• These will likely represent the most significant advances of vaccine technology in the 21st century

Nucleic Acid Vaccines – DNA Vaccines: When first developed, how they work

• First developed in the 1990’s

• Can produce robust immune responses to very specific targets and can be used in the immune compromised

• DNA plasmid taken up by cells then cross the nuclear membrane to be encoded to mRNA:

  • mRNA vaccines have the advantage of less likely being encoded into the genome by accident

  • DNA vaccines have the advantage of crossing into cells more readily

• More common and accepted in veterinary medicine

• First DNA vaccine for human use, the Indian ZyCovD vaccine against SARS-CoV-2, was approved in 2021

Nucleic Acid Vaccines – DNA Vaccines Advantages

• Very specific non-variable Ag targeting

• Cancer treatment vaccines?

• Constituents clearly defined

• Unable to cause the infection

• Take advantage of MHC-I receptors

• Future benefits in cancer targeted vaccines

• Potential longer lasting stimulation of immune response (plasmids can last months at site)

• Higher efficacy ~95%

Nucleic Acid Vaccines – DNA Vaccines Disadvantages

Local reactions common

Strict cold chain requirements often requiring freezing

Widespread misunderstanding of how these vaccines work limits current uptake •

Concerns over genome integration

Nucleic Acid Vaccines – DNA Vaccines EXPECTED REACTIONS

Typically occur within 48 hours but tend to be more intense than usual inactivated vaccines:

fever • irritability • drowsiness • local pain and swelling • vomiting

Nucleic Acid Vaccines -m: first developed, how they work

• First started development in the 1980’s

• Gene-based vaccine

• Carry the genetic instructions for the host’s cells to make the antigen which more closely mimics a natural infection

  • Essentially getting our cells to produce the subunit or protein of interest

    • for coronaviruses – the antigen of interest is the surface spike protein

    • researchers knew to focus on coronavirus spike protein based on research from SARS and MERS from the 1980 and 1990’s

• Prior to COVID-19, potential mRNA vaccines against SARS, MERS, rabies, influenza, Zika and a few other viruses have been studied in small early phase trials

Nucleic Acid Vaccines – mRNA Vaccines Advantages

• Lower cost and ease of production (not grown in eggs or cells)

• No risk of preexisting immunity which can limit effectiveness (compared to viral vector vaccines)

• May allow in future for one vaccine to target multiple diseases

• Higher efficacy ~95%

Nucleic Acid Vaccines – mRNA Vaccines Disadvantages

Stabilize/protect mRNA

Long-term efficacy and safety (e.g., very rare or long-term side effects)

Strict cold chain requirements often requiring freezin

Nucleic Acid Vaccines – mRNA Vaccines EXPECTED REACTIONS

Typically occur within 48 hours but tend to be more intense than usual inactivated vaccines:

• fever • irritability • drowsiness • local pain and swelling • vomiting

• Although myocarditis has occurred with COVID mRNA vaccines this is likely a result of the spike protein rather than the vaccine as it is seen in wild type infections as well as other vaccines

Reassortment Live Vaccine: what is it?

Mixing gene segments from a weakened (attenuated) "master donor virus" (MDV) with those from a currently circulating wild-type virus to create a safe yet effective hybrid vaccine strain.

Examples: Influenza/adenovirus vaccine, Bovine rotavirus

Reassortment Live Vaccine Advantages

• Lower cost and ease of production (not grown in eggs or cells)

• Like mRNA and DNA vaccines offers superior viral response

• Smaller dose required for effect

• Mimics wild type infection

Reassortment Live Vaccine Disadvantages

Risk of co-infection resulting in a new strain

Not useful in immunocompromised

Potential risk of transmission to non-vaccinated

Strict cold chain requirements •

isk of pre-existing immunity that reduces effectiveness (e.g. adenovirus common)

Reassortment Live Vaccine EXPECTED REACTIONS

Typically occur within 48 hours and vary by vaccine design

• e.g. LAIV is intranasal and tends to have more cold-like symptoms.

General side effects:

fever • irritability • drowsiness • local pain and swelling • vomiting

Combination Vaccines: what is it?

Refers to a vaccine that includes antigens for the prevention of more than one vaccine-preventable disease (e.g. measlesmumps-rubella)

Combination Vaccine Advantages

• Reduces the number of injections

• Improves adherence to immunization schedules

• Facilitates the uptake of new vaccine

• Reduces costs

Combination Vaccines Disadvantages

• If have a reaction to a dose you do not know what vaccine may have caused the reaction.

• May actually lower uptake or acceptance by some groups

Primary failure

An individual fails to make an adequate immune response to the initial vaccination (e.g. in about 10% of measles and mumps vaccine recipients)

Secondary failure

An individual makes an adequate immune response initially but then immunity wanes over time (a feature of most inactivated vaccines, hence the need for boosters in some cases)

Interval Between Vaccine Doses

If vaccines are given too close together it can result in less-than- optimal response:

• Longer intervals between doses of schedule is usually fine and may actually improve immune response

In general, inactivated vaccines can be administered at the same time or any time before or after other inactivated vaccines or live vaccines

Live vaccines must be administered at the same visit or separated by a period of at least 4 weeks