Immune memory and advancements in vaccinology

What is the earliest documented immunization practice mentioned, and where did it originate?

: Variolation, originating from ancient China around 1000 C.E

How was variolation performed?

A: Dried, pulverized pustules from smallpox patients were blown into the nostrils of uninfected individuals

What was the primary goal of variolation?

To protect against smallpox

What was a major flaw in the variolation process?

A: Sometimes live virions were used, causing unintended infection and spread

What are three key characteristics desired in a vaccine?

A: Safe, Effective, Durable.

Who is considered the founder of modern vaccinology?

A: Edward Jenner.

What observation led Edward Jenner to his discovery?

A: Milkmaids who contracted cowpox seemed immune to smallpox

How did Jenner first test his hypothesis?

A: He inoculated a boy with material from a cowpox lesion and later exposed him to smallpox material; the boy did not get sick

What is the mechanism behind Jenner's successful vaccination?

A: Immunity against cowpox virus provided cross-immunity against the antigenically similar smallpox virus.

What does the term "vaccine" originate from?

The Latin word for cow, "Vacca

Cowpox virus and Variola (smallpox) virus belong to which virus family and genus?

: Family: Poxviridae, Genus: Orthopoxvirus

: What major global health success was achieved through vaccination, and when was it declared?

A: The eradication of smallpox, declared by the WHO in 1980

Q: What is the Basic Reproduction Number (R0)?

: The average number of people one infected person will transmit a pathogen to in a fully susceptible population.

Q: What factors influence R0?

A: Environmental factors, human behavior, pathogen characteristics (e.g., transmission mode, shedding).

Q: Give examples of factors that can increase the R0 for the same pathogen over time.

A: Decreased vaccine availability/efficacy, vaccine hesitancy, selective pressures leading to more transmissible variants

Q: What makes pathogens like measles highly contagious (high R0)?

A: Factors like efficient aerosol transmission, aerosol kinetics (suspension time), low inoculum dose required, and high viral shedding.

Q: What is Herd Immunity?

A: When a sufficient proportion of a population is immune, hindering pathogen spread and protecting non-immune individuals.

Q: How does R0 relate to the level of vaccination needed for herd immunity?

A: A higher R0 requires a greater percentage of the population to be immune to achieve herd immunity.

Q: What is mass vaccination?

A: Vaccinating everyone eligible within a population

Q: What is ring vaccination?

A: Vaccinating individuals most likely exposed (contacts and contacts of contacts).

Q: State one advantage and one disadvantage of mass vaccination

A: Advantage: Broad coverage/rapid immunity. Disadvantage: Resource intensive/potential booster needs.

: State one advantage and one disadvantage of ring vaccination.

A: Advantage: Targeted/resource efficient. Disadvantage: Requires robust surveillance/ineffective if asymptomatic spread is prevalent.

Q: List three factors related to perception that affect vaccine uptake

A: Perception of disease deadliness, visible impact (disfigurement), perception of risk (mild symptoms/feeling invulnerable), myopic views (self vs. vulnerable populations), side effects

Q: How did the MMR-Autism myth affect measles cases in the USA?

A: After the myth started, vaccine uptake likely decreased, contributing to a resurgence in measles cases following its elimination

Q: Why is vaccination necessary even if natural infection can provide immunity? List two reasons

A: To protect immune-naïve/vulnerable individuals, prevent healthcare system overwhelm, avoid unnecessary deaths/debilitation, and prevent unknown long-term consequences of infection (e.g., neurological issues).

Q: Describe the kinetics of the adaptive immune response upon first encountering a pathogen.

A: It's delayed, requiring time for priming of specific T and B cells before they can act at the site of infection

Q: What determines the antigen specificity of adaptive immunity?

A: The T cell receptor (TCR) and B cell receptor (BCR)

Q: Briefly outline the steps from antigen encounter to T cell response at the infection site

A: APCs(Antigen-Presenting Cells) acquire antigen, traffic to lymph nodes, prime T cells, specific T cells proliferate, migrate to the infection site, and execute effector functions

What happens to most pathogen-specific T cells after an infection is cleared?

They undergo apoptosis (contraction phase).

What happens to the remaining small population of pathogen-specific T cells after contraction?

A: They establish a pool of memory T cells

Q: What is the key advantage of memory T cells upon pathogen re-exposure?

A: They re-expand rapidly without needing the initial priming step, providing faster protection

: Name the three main subtypes of memory T cells discussed.

A: Effector Memory T cells (Tem), Central Memory T cells (Tcm), and Tissue Resident Memory T cells (Trm)

Q: Where are Central Memory T cells (Tcm) primarily located, and what is their main function upon re-exposure?

A: Location: Secondary lymphoid organs. Function: Proliferate and differentiate into effector cells

Q: Where are Tissue Resident Memory T cells (Trm) located, and what is their key characteristic?

A: Location: Non-lymphoid tissues (like the skin, gut, lungs, and reproductive tract). Characteristic: Do not recirculate; provide immediate, localized protection

Q: Where are Effector Memory T cells (Tem) found, and what is their function upon antigen re-encounter?

A: Location: Circulate in blood and peripheral tissues. Function: Rapidly exert effector functions (e.g., cytokine production)

What is the role of short-lived plasma cells (activated B cells)?

A: Provide an immediate antibody response during the acute phase of infection by secreting large amounts of antibodies.

What are two key characteristics of memory B cells?

A: Often express class-switched immunoglobulins (IgG, IgA, IgE), exhibit somatic hypermutation for improved affinity, high proliferative capacity upon re-exposure.

Q: Where are long-lived plasma cells primarily found, and what is their function?

A: Location: Bone marrow (primarily). Function: Sustain long-term humoral immunity through continuous antibody secretion.

Q: What is an antigen?

A: Any molecule that can bind specifically to an antibody or T/B cell receptor

: What is an epitope?

A: The specific part of an antigen that is recognized and bound by an antibody or T/B cell receptor

Using SARS-CoV-2 as an example, name two viral components that can act as antigens.

A: Spike glycoprotein, Nucleocapsid protein, Membrane protein, Envelope protein.

How can antibodies neutralize a virus like SARS-CoV-2?

A: By binding to viral surface proteins (like Spike) and blocking interaction with host cell receptors, preventing infection

: How do cytotoxic T cells contribute to controlling viral infections?

They recognize viral antigens presented on MHC molecules on the surface of infected host cells and kill those cells

How is immunity established locally at tissue sites after infection?

A: Primed T cells migrate to tissues, and plasma cells either seed tissues locally or secrete antibodies from the bone marrow that enter tissues via circulation.

What forms the immunological basis for vaccines?

Adaptive immune memory (memory T cells, memory B cells, long-lived plasma cells).

List four broad categories of considerations in vaccine design and development

A: Immunological, Formulation, Manufacturing/Scalability, Population/Epidemiological, Economical/Logistical, Safety/Reactogenicity

What is a vaccine vector?

The delivery system used to introduce antigen(s) into a host to generate an adaptive immune response

How does the vector choice influence the immune response?

Affects antigen presentation pathways (MHC I vs MHC II), influences the breadth, magnitude, and longevity of the response, and its immunogenicity affects the need for boosters.

Q: What is pre-existing vector immunity, and how can it affect vaccination?

A: Immunity to the vaccine vector itself (from prior exposure/vaccination), which can clear the vector quickly, impairing vaccine immunogenicity and limiting boosting options with the same vector

Q: Why is antigen selection crucial in vaccine design?

A: The adaptive immune response targets specific antigens (epitopes); selecting the right antigens is key to generating protective immunity relevant to the pathogen's life cycle

Q: How can pathogen mutation affect vaccine efficacy, particularly for surface antigens?

A: Mutations can alter epitopes on antigens (like viral spike proteins), reducing the ability of vaccine-induced antibodies to recognize and neutralize the pathogen (immune evasion)

Q: What strategy can potentially improve vaccines against rapidly evolving pathogens like SARS-CoV-2?

A: Including multiple antigens, especially conserved ones (less tolerant to mutation), in the vaccine design.

Q: What is a live attenuated vaccine?

A: A vaccine containing a weakened form of the pathogen with reduced virulence but capable of limited replication

How is attenuation typically achieved for live vaccines?

Serial passaging in culture (leading to mutations) or using molecular biology techniques

State one major advantage of live attenuated vaccines

Mimic natural infection, generate robust cellular and humoral immunity, often provide long-lasting memory with fewer boosters

State one major disadvantage of live attenuated vaccines

Potential (rare) reversion to virulence, contraindications for immunocompromised individuals.

Give an example of a live attenuated vaccine.

MMR (Mumps, Measles, Rubella), BCG (Tuberculosis)

What is an inactivated vaccine?

A vaccine containing pathogens killed/inactivated by chemical or physical means, retaining antigenicity but unable to replicate.

State one advantage of inactivated vaccines.

Favorable safety profile (no reversion risk), can induce strong humoral responses

State one disadvantage of inactivated vaccines

Poorly immunogenic (weak cellular response), often require boosters, inactivation process might alter antigens

Give an example of an inactivated vaccine

Inactivated Polio Vaccine (IPV), some flu vaccines

What are recombinant subunit vaccines?

Vaccines containing purified pathogen components (like proteins or polysaccharides), often manufactured using recombinant DNA technology and formulated with adjuvants

What type of immunity is typically skewed towards with subunit vaccines (vaccine that contains purified parts of the pathogen that are antigenic)?

Humoral immunity (antibody production) (B cells, Helper T cells (CD4+))

Why are adjuvants often necessary for subunit vaccines?

The purified antigens themselves are often poorly immunogenic; adjuvants enhance the immune response

What is the function of a vaccine adjuvant?

To enhance the immunogenicity of a vaccine by stimulating the innate immune system, leading to better APC maturation, cytokine production, and adaptive priming

How do adjuvants improve adaptive immunity?

They promote robust CD4 and CD8 T cell responses, strong B cell/antibody responses, and long-lasting memory formation

What is "antigen sparing" in the context of adjuvants?

Adjuvants increase immunogenicity, meaning less antigen is needed per dose to achieve protection, allowing more doses to be produced from the same amount of antigen

What is an mRNA vaccine?

mRNA encoding a target antigen, encapsulated in a lipid nanoparticle (LNP) delivery system.

How do mRNA vaccines lead to an immune response?

The mRNA is taken up by host cells, translated into the target antigen protein (de novo synthesis), which then stimulates humoral and cellular immunity

State one advantage of mRNA vaccines

A: Significant de novo antigen expression leading to robust immune responses, potentially faster development/manufacturing cycles

State one disadvantage of mRNA vaccines

Require stringent cold storage, can have higher reactogenicity, complex/expensive manufacturing

Give an example of mRNA vaccines

Moderna and Pfizer SARS-CoV-2 vaccines

What is a viral-vectored vaccine?

An attenuated, often replication-deficient virus (like adenovirus) engineered to carry and express the gene for a target antigen from another pathogen

State one advantage of viral-vectored vaccines

Significant de novo (never before seen) antigen expression, capacity to infect host cells leads to robust humoral and cellular immunity, potential for mucosal delivery

State 3 disadvantages of viral-vectored vaccines

Pre-existing anti-vector immunity can impair efficacy and boosting, rare adverse events, potential contraindications for immunocompromised.

Give an example of a viral-vectored vaccine

Astrazeneca SARS-CoV-2 vaccine, Johnson & Johnson SARS-CoV-2 vaccine

How does the route of vaccination typically influence the location of the immune response?

The immune system tends to establish memory predominantly where the antigen is encountered

What type of immunity is robustly induced by intramuscular vaccination?

Systemic immunity (e.g., antibodies and T cells in the blood)

What type of immunity is often limited following intramuscular vaccination?

Mucosal immunity (at sites like the respiratory tract).

How can intramuscular vaccines protect against respiratory pathogens if they induce limited mucosal immunity?

Systemic antibodies can transudate into mucosal tissues, and circulating T cells can migrate to the site of infection, though local resident memory is not strongly established

What is a major advantage of respiratory mucosal vaccine delivery for respiratory pathogens?

It establishes tissue-resident adaptive immunity (Trm, Brm, secretory IgA) directly at the portal of entry/infection

Besides immune location, what is another practical advantage of mucosal vaccines (e.g., inhaled)?

They are needle-free.

What area of vaccinology is McMaster University considered a global leader in

Respiratory mucosal delivered vaccines, particularly inhaled aerosol delivery of adenoviral-vectored vaccines

How are vaccines typically prepared for inhaled aerosol delivery at McMaster?

Using a nebulizer to generate fine aerosolized droplets (e.g., 2-5µm) that can be inhaled deep into the lungs

Name two diseases for which McMaster has conducted clinical trials using adenoviral-vectored mucosal vaccines

Tuberculosis (TB) and COVID-19

When developing a new vaccine, what aspects of existing vaccines should be assessed first?

Efficacy, effectiveness, safety, manufacturing pipeline, storage conditions, cost, route of delivery

List three potential immunological limitations of existing vaccines that might warrant developing a new one

Poor humoral/cellular immunity, poor memory formation/waning immunity, tissue-restricted immunity, failure to address pathogen evolution/immune evasion

List two potential logistical or practical limitations of existing vaccines

High reactogenicity, complex manufacturing, stringent storage requirements, supply chain constraints, high cost

What was the primary antigen target for most first-generation COVID-19 vaccines?

The Spike glycoprotein of the ancestral SARS-CoV-2 strain

How did the emergence of SARS-CoV-2 variants like Omicron impact the efficacy of first-generation vaccines?

Mutations, particularly in the Spike protein, allowed variants to partially evade neutralizing antibodies generated by the original vaccines, reducing efficacy

What is the main strategy currently used to address new COVID-19 variants with vaccines?

Updating the vaccine to include the Spike antigen from the dominant circulating variant ("variant chasing").

Identify two key limitations of the first-generation intramuscular COVID-19 vaccines highlighted in the slides.

Limited antigen coverage (Spike-only) and limited induction of mucosal immunity

How does focusing solely on Spike immunity potentially contribute to viral adaptation?

It exerts selective pressure on the virus to mutate Spike for immune evasion.

What two main strategies did the McMaster group employ to design their next-generation COVID-19 vaccine?

1) Expand the antigenic repertoire (include multiple, conserved antigens beyond Spike). 2) Use a respiratory mucosal (inhaled) delivery route.  

Besides Spike, what other conserved SARS-CoV-2 antigens were included in the McMaster next-gen vaccine design?

A: Nucleocapsid protein and RNA-dependent RNA polymerase (RdRp)

Why target conserved antigens like Nucleocapsid and RdRp?

They are less likely to mutate (essential for the virus), potentially providing broader protection against variants, and are prominent T cell targets

Contrast the type of antibody response expected in the respiratory mucosa after intramuscular vs. inhaled vaccination

Intramuscular: Primarily monomeric IgG (transudated from blood). Inhaled: Multimeric secretory IgA and mucosal IgG.

Contrast the type of T cell response expected in the respiratory mucosa after intramuscular vs. inhaled vaccination.

Intramuscular: Limited/transient influx of circulating T cells. Inhaled: Establishment of multi-antigen specific tissue-resident memory T cells (Trm)

What type of B cell memory is expected in the respiratory mucosa following an inhaled vaccine?

Tissue-resident memory B cells.

What is the name of the Phase 2 clinical trial mentioned for the inhaled COVID-19 vaccine at McMaster?

AeroVax.