Lecture 14: Memory and Vaccines

Immunological Memory

• The adaptive immune system’s ability to retain recognition of a specific antigen after initial exposure.

• B- and T-cells that have the machinery to recognise a particular antigen are retained as memory cells.

  • These memory cells survive long-term after the infection is cleared.

• If the same antigen is encountered again, they enable a faster and stronger immune response.

Phases of Protective Immunity

• Protective immunity offers increased protection against pathogens that are encountered more than once.

• Follows a three-phase progression:

  1. Initial adaptive immune response – activates effector cells and produces antibodies.

  2. Protective immunity – high levels of circulating effector cells and antibodies above a protective threshold, making them readily detectable.

  3. Memory responses – over time, effector levels fall below the threshold, but protection is maintained by long-lived memory B and T cells that respond rapidly upon re-exposure.

Immune Response: First Vs Second Infection

• First Infection: Ab and T-cell response takes time to peak and then gradually tapers off.

• Second Infection: The Ab and T-cell response is much greater, with a steeper and higher peak, due to the memory of the immune system.

Features of Immunological Memory

• Primary adaptive response to infection is often slow and weak.

• Secondary exposure to the same pathogen: greater response

  • Secondary exposure is more rapid and better (has higher affinity and avidity of Abs) – has done the learning

Key Features Associated with Immune cells involved in memory, and Their Contribution to Immune Response

• Adaptive Immune System (Acquired Immunity):

  • Expansion of clones of cells with re-arranged antigen receptor genes specific to the primary antigen encountered.

    • T-cells with antigen-specific TcR

    • B-cells with antigen-specific BcR/Ig

• Enhanced Migration & Re-stimulation:

  • Increased adhesion molecules and rapid effector function allow for efficient circulation and movement to target sites for mounting an immune response.

• Survival:

  • Maintenance of memory clones, which are responsive to growth and survival cytokine signals, ensures their presence for future immune responses.

Generation of Memory B-Cells

• Increased numbers of antigen-specific memory B cells

• Already undergone antibody class switch and affinity maturation

• Can re-enter germinal centers during secondary immune responses to undergo additional somatic hypermutation and affinity maturation – helps produce more specific BCR

• Not yet differentiated into a plasma cell (possible though)

• Require help from CD4⁺ Th cells for secretion of Ab – don’t work in isolation

Maintenance of Memory T-Cells

• Activation-Induced Cell Death (AICD):

  • Most activated (effector) T-cells are programmed to die after an immune response.

  • AICD helps regulate the immune response by ensuring that T-cells do not over-respond and cause damage.

• Memory Cell Survival & Maintenance:

  • IL-15 and IL-7 are crucial for memory T-cell survival.

  • These cytokines promote homeostatic proliferation from stromal cells, ensuring the memory T-cells are maintained for future immune responses.

Memory T-Cells

• Express high levels of IL-7R for survival and genes like bcl-2 for cell longevity.

• High levels of adhesion molecule expression of CD44 to facilitate movement around the body.

• Low expression of CD69, a marker for effector cells, indicates a resting state.

• Memory cells located at the site of infection allow for a faster immune response without needing to travel.

Types of Memory T-Cells

• Tissue-resident memory cells: Located at the site of infection (e.g., lungs during a cold) for immediate response.

• Central memory cells: Adapted for recirculation through lymphoid tissue.

• Effector memory cells: Ready to rapidly enter inflamed tissues for a quick response.

  • Useful to have memory cells at the site of infection – don’t have to travel to evoke a response

Features of Naive vs Memory B-Cells

Immunological Memory – Spanish Flu

• 32/32 patients born before 1915 who had Spanish flu in 1918/1919 had serum antibodies that bound to H1N1 haemagglutinin protein.

  • Had 90 years of B-cell memory against the Spanish flu – potential for immune memory to be lifelong

• Memory B cells were isolated.

• 90 years of B cell memory!

• Studies have also shown persistence of memory to smallpox 75 years post-vaccine

Importance of Immune Memory

• It is a hallmark of adaptive and acquired immunity that allows for faster, stronger, and more specific immune responses upon re-exposure to pathogens.

• Without Memory, acquired, antigen-specific immunity would be less effective.

  • Memory helps prevent prolonged risk during the primary immune response, which can be slower and weaker.

• Acquired immune memory contributes to an increased healthy lifespan by offering quicker and more robust defences against recurring infections.

Protection From Immunisation and Vaccination

• Immunisation (Vaccination) provides immunity to a pathogen before naturally encountering it protecting against illness without suffering the disease.

• It prevents infection and its consequences (e.g., sickness or complications), generating immune memory for long-term protection.

• Vaccination vs. Natural Infection:

  • Natural infection involves risking illness, whereas vaccination gives you information about the infection without causing harm, generating immune memory, helping you live longer with better immunity.

Variolation

• Conducted for smallpox → Observations seen in the 1500s in Anceinet Iran, China, India

• It involves ‘bursting’ of pustules and taking its contents and using it as an inoculum to treat someone else

• Based on the idea that if the virus has been through an individual, then it had been weakened → would give an individual a weakened form of the virus (along with some immunity by passing on some Abs)

• Concept of vaccine predates the discovery of the immune system, determined from observations

Mary Wortley Montagu

• Introduced vaccination in 1717 to the UK → found out about the variolation process and brought it back to the UK

  • Risky → 1% death rate

Edward Jenner (1796)

• Developed the first smallpox vaccine using the cowpox virus (vaccinia).

• The word "vacca" is Latin for cow, reflecting the use of cowpox in the vaccine.

• Jenner's Observation:

  • Noticed that people who had cowpox were resistant to smallpox.

  • Used variolation (introducing the virus to a person) on a child, which successfully protected them from smallpox.

Luis Pasteur (1879)

• Developed vaccines based on preparations of weakened forms of pathogens- e.g. rabies and anthrax

  • Created weakened forms of a virus by passing them through different animals to create weaker/ attenuated viruses that could then be used to inoculate people

Modern Vaccines

• Modern vaccines have been highly successful:

• Work by generating protective antibodies & inducing T cell & B cell memory.

Vaccine Design

• Requires 2 components

  • Antigens: From the target pathogen, either provided directly or generated by the recipient’s body.

  • Infection Signal: Activates the host immune system to respond.

    • Live and attenuated vaccines naturally provide both antigens and an infection signal.

• Some vaccine platforms may require a boost to provide the infection signal - ADJUVANT

• Some vaccines require multiple boosters to produce the most effective immune response.

• 6 main designs in widespread use

Live Attenuated Infection Vaccines

• i. Related, less harmful infection:

  • Vaccinia (cowpox) is related to Variola (smallpox)

  • BCG bacteria (bovine tuberculosis) are related to Mycobacterium tuberculosis.

  • Highly effective, rarely found in nature, and dangerous to immunocompromised patients.

• ii. Live attenuated pathogen:

  • Sabin oral Polio, MMR, chickenpox

  • Highly effective, with some risk of disease in immunocompromised patients

Killed or Inactivated Infection Vaccines

• Salk Polio virus

• Lower risk of disease, but can occur due to improper activation

• May need boosters

Inactivating Viruses

• Inactivated crudely via

  • Heat

  • Chemicals e.g. formaldehyde, beta propiolactone

  • Radiation

• This preserves antigen structure, but the pathogen cannot replicate

Types of Modern Vaccines: Protein Subunit Vaccines

• Use purified or recombinant protein components from the pathogen (e.g., Hepatitis B, Novavax vaccine for SARS-Cov-2).

• These vaccines use the antigens that best stimulate the immune system.

• May be combined with boosting agents (like bacterial stimuli) to enhance the immune response.

  • This allows the virus to be administered in various forms, such as in vaccines for HiB meningitis.

Types of Modern Vaccines: Recombinant Viral-Vectored Vaccines

• Create a pathogen/virus that we haven’t been exposed to, e.g. non-pathogenic animal virus, and take out components and add in antigenic features that will stimulate a response to a virus

• Bioengineered virus to express target pathogen antigens in vivo

• widely investigated with good safety: e.g. Ebola vaccine

• Often use non-human virus as carrier, e.g. simian adenovirus is used in  AZ/Oxford Sars-Cov-2 vaccine

• Can cause reactivity to carrier virus, so cannot use the same carrier repeatedly = poor response

Types of Modern Vaccines: Virus Like Particles

• Highly effective, closely resembles live virus, but non-infectious – use of fake virus to transport components to the cells required

• can contain multiple antigenic components.

• e.g. Human papillomavirus (HPV) – Gardasil – helped to eradicate cervical cancer

Types of Nucleic Acid-Based mRNA Vaccines

• Can encode many antigens (even the whole genome of pathogens!)

• Antigen-encoding mRNA (or DNA) is complexed with a carrier such as lipid nanoparticles to be delivered into target cells

• The antigen will then be transiently expressed by those cells, causing an immune response.

• mRNA will naturally be degraded, not continually expressed

• Non-infectious and quick to manufacture and bulk up – good for booster shots

• Can be tricky to store as it requires cold chain – must have the infrastructure to transport and store

  • e.g. SARS-Cov-2 vaccine made by Moderna and

mRNA Vaccines

• Used for cancer – 2024 showed success in trails for lung cancer, melanoma, and other solid tumors as they’re easy to manipulate

Adjuvants

• “Helper” chemicals boost immune responses to an antigen

• Stimulate inflammation and antigen presentation to activate antigen-specific T cells

• e.g. Oil/Water emulsion, Alum (Aluminium Hydroxide), TLR ligands, liposomes

• Can increase immune responses, BUT can cause adverse immune pathology, including organ damage, septic shock, and autoimmunity.

Factors Affecing Vaccine Efficacy

• Depends on the individual’s MHC type; not all antigens are immunogenic in every person.

• Some pathogens mutate rapidly or go through multiple life cycle stages, making it difficult to target them effectively.

  • May be avoided using multivalent vaccines

Multivalent Vaccines

• Deliver a variety of antigenic epitopes with an adjuvant to trigger a range of protective immune responses

• May be useful for infections that mutate rapidly e.g. flu and viruses that cause common colds and COVID-19

Mucosal Vaccines

• Delivered through the nose or throat as a sniffable or inhalable formulation

• Designed to target specific tissue where a tissue-resident memory response is required - may be more effective in protecting against mucosal-based infections

  • May be more effective than conventional vaccines( systemic but not a tissue-targeted/ specific response)

• Potential virus blocking for e.g. respiratory viruses

• Potentially more durable i.e. long-term memory

• Used for e.g. flu and investigated now for COVID-19 with some countries using

Benefit of Mucosal Vaccine Delivery

• Combining vaccines with this delivery system can help target complex or difficult-to-target infections, such as RSV (Respiratory Syncytial Virus).

• Recent Example:

  • The recent roll-out of the RSV vaccine demonstrates the potential effectiveness

Why are some diseases difficult to target with a vaccine?

• Many diseases are caused by complex pathogens that have difficult-to-understand lifecycles, making it challenging to develop a vaccine.

• TB has a long latent phase, which makes it difficult to identify infected individuals and target them with a vaccine.

• The MMR vaccine is heat-sensitive and cannot be transported effectively to hot climates, limiting its accessibility.

Lack of an Effective Vaccine for TB and HIV

• Tuberculosis

  • Around a quarter of the global population is infected with TB.

  • There is no effective vaccine currently available for TB.

  • TB research is limited/ poor because TB often remains latent, due to granulomas formed by macrophages

• HIV and TB Coinfection:

  • Approximately 40 million people have HIV, and 25% of these individuals have latent TB.

  • 5–10% of people with latent TB will develop active TB (10.8 million cases).

  • Individuals with HIV have a 16-fold increase in the risk of developing active TB.

Why Do So Many Diseases Lack Vaccines

• Lack of understanding of the infection's life cycle or immune response to pathogen

  • In some cases, diseases have a complex life cycle with stage-specific immune responses (e.g., malaria).

• Poor models to study certain diseases.

  • Limited understanding of the immune response to the pathogen and its major antigens.

• Pathogens like HIV undergo frequent antigen variability, making it hard to create a universal vaccine.

• Lab Model Limitations: difficulties mimicking the human immune response in labs.

  • Animal models (e.g., monkeys) are restricted and raise ethical concerns.

• Transport/ lack of medical centres/ trained staff, e.g. poor infrastrucutre and storage issues, especially for vaccines requiring a cold chain.

• High costs of vaccines, make them inaccessible for many populations.

  • Even if vaccines are available, they may not be accessible to everyone due to financial or technological constraints.

Why is there a lack of research into certain diseases?

• Recent epidemics of neglected tropical diseases and zoonotic infections highlight the need for more research and infrastructure into these areas.

• Some diseases, like the Zika virus, lack enough funding for research.

• There is an increase in the number of zoonotic infections, which include diseases like Marburg virus.

Examples of Zoonotic Infections

• Ebola, Monkeypox, Bird Flu (H5N1), and SARS-Cov-2 are examples of diseases transmitted from animals to humans

One Health

• A concept that emphasises the interconnection between people, animals, plants, climate, and their shared environment to achieve optimal health outcomes.

Reasons for Rise in Vaccine Hesitancy and Decline in Vaccine Uptake

• Socioeconomic factors

• Social influences

• Trust

• Accessibility

• Confidence- in healthcare/technology etc

• Complacency- perception of risk is skewed

• Convenience- difficulties accessing services etc

• Communication-how accessible services/info

• Context- recognising cultural needs

6 Themes Surrounding Vaccine Trust

• 1. Control: the idea that we can take back control of our own bodies through alternative means– the idea of being natural

• 2. Parenting style: philosophies that shun mainstream medicine, opting for “natural” remedies.– the idea that nature is best (wellbeing market)

• 3. The Past: previous bad healthcare experiences or a bad experience around vaccination shape perceptions. = hesitancy; ill near the time of vaccine and have linked the two

• 4. Risk: misunderstandings about the risks of vaccination versus the risks of disease.

• 5. Fear of chemicals: the fear that the vaccine will introduce toxic chemicals – dialogue with the use of mercury in the vaccine

• 6. Distrust of government agencies and corporations

Population (Herd) Immunity

• A certain proportion of the population must be immune (through infection or vaccination) to protect others from a pathogen, especially those who cannot be vaccinated (e.g. due to age or allergies).

• Helps control the spread of infection and protects vulnerable individuals.

• Effectiveness depends on:

  • The virulence of the pathogen.

  • The susceptibility of the population.

• Example: The MMR vaccine requires a high level of __________ to be effective in preventing outbreaks.

Andrew Wakefield

• Hypothesised in 1998 that MMR was linked to autism. 

• His work was proven fraudulent, unethical, and the work was retracted, and he was disbarred

• His legacy persists, and the rise of vaccine hesitancy and the “anti-vax movement has contributed to a reduction in vaccine uptake

• Multiple studies have been conducted since (over 1 million children).

  • No study has replicated his findings

• Measles cases in Europe have risen 30-fold, and there have been alarms about growing numbers of cases in England

•  1 in 5 children are currently unprotected against measles, due to hesitancy and low vaccine uptake

• The World Health Organisation has said vaccine hesitancy is one of the 10 biggest global threats to health.

Measles Case Reugence

• Outbreaks in Ireland and the US – particularly in areas of low vaccination uptake

• Problematic as the MMR vaccine requires a large population to be vaccinated to achieve herd immunity

• Largely occurred in response to Andrew Wakefield

Misinformation

• False  or inaccurate information—getting the facts wrong

• Occurs accidentally - Social and general media play a critical role in its spread

Disinformation

• False information which is deliberately intended to mislead—intentionally misstating facts

  •   This can be a VERY lucrative initiative e.g. alt cures, sponsorship speaker fees

• Social and general media play a critical role in its spread

Disinformation Dozen

• 12 people are responsible for almost two-thirds of anti‑vaccine content circulating on social media platforms

Vaccine Messaging and Misinformation: Pro-Vaccine vs Anti-Vaccine

• Pro-vaccine groups have a simple message:
  → “Vaccines work and save lives.”

• Anti-vaccine narratives are more varied and emotionally driven, including:
  → Concerns about children’s health
  → advocate alternative medicine
  → Belief in conspiracy theories

• These messages fuel hesitancy and play into concerned narratives.

• Anti-vaccine content spreads more widely, appearing across more Facebook clusters than pro-vaccine messages.

• Algorithms amplify this disinformation by rewarding content that gets clicks, reactions, and shares, making it more visible and influential.