Manipulating the Immune Response Flashcards
What is passive immunity?
- Natural?
- Artificial
When is passive immunisation used?
Passive immunity – Develops after you receive antibodies from someone or somewhere else
- Natural – Antibodies received from mother e.g. through breast milk
- Artificial – Antibodies received from medicine e.g. gamma globulin injection/infusion
Used in situations where immediate protection is needed or there is no time for active immunisation e.g. protecting immunocompromised individuals
What is active immunity?
- Natural?
- Artificial
Commonly used vaccines that induce active immunity?
Active Immunity – Develops in response to an infection or vaccination
- Natural – Antibodies developed in response to infection
- Artificial – Antibodies developed in response to a vaccination
Common vaccines that induce active immunity include the MMR vaccine, influenza vaccine, COVID-19 mRNA vaccine
What are some examples of artificial passive immunisation?
- Anti-toxin
- Prophylactic use (prevent disease)
- COVID-19
- Anti-venins
Anti toxin used to treat botulism
Used prophylactically to reduce chance of infection after exposure to rabies
Monoclonal antibodies used to to treat COVID-19
Anti-venins used in snake and insect bites
Advantages and disadvantages pf passive immunisation?
- Speed
- Prevention
- No vaccine
- Survivors
- Long term?
- Memory
Advantages:
- Use of pre-formed antibodies can quickly neutralise toxins and venoms
- Conventional immune response may be too slow
- In case of highly virulent pathogens, pre-formed antibodies can be used to prevent or limit infection
- If no vaccine is available then pre-formed antibodies isolated or engineered from immunised animals may be the only means of treatment e.g. ebola
- In some cases, antibodies from surviving patients can be used; Level or risk with this
Disadvantages:
- Does not activate immunological memory
- No long term protection
- Possibility of reaction to anti-sera (if cross species)
What is active immunisation/vaccine?
Triggers an immune response to safely mimic natural infection and generate a persistent protective response
What is immunological memory in adaptive immunity?
What is this important for?
Allows the body to recognise and respond more effectively to pathogens it has encountered previously
This capability is crucial for long-term immunity and is the basis for the effectiveness of vaccines (active immunisation)
Advantages of immunological memory? (2 advantages)
- Booster vaccines?
Rapid Response - Upon re-exposure to the same pathogen, memory cells can mount a faster and more robust immune response, often neutralising the pathogen before it can cause significant illness
Long-term Protection - Memory cells can persist for years or even decades, providing long-lasting immunity
This is the principle behind booster vaccinations, which re-expose the immune system to the antigen to “refresh” immunological memory
Vaccine definition?
Vaccine – Biological substance that safely stimulates immune response to recognise and defend against specific pathogens, preventing future infection and illness
What are the 3 main types of vaccine?
Attenuated pathogen – Virulence reduced so causes mild infection
Killed pathogen – Unable to replicate; Non-living
Subunit – Molecular component(s) of pathogen; Non-living
What are the key features of an effective vaccine? (6 features) (hint - safety, sustained, induction, practicality)
Safe - Vaccine must not itself cause illness or death
Protective - Vaccine must protect against illness resulting from exposure to live pathogen
Sustained protection against illness - Lasting years
Induces neutralising antibody - Neutralising antibody is essential to prevent infection of cells which can’t be replaced
Induces protective T cells - Some pathogens (e.g. intracellular) are more effectively dealt with by cell-mediated responses
Practical considerations - Lost cost, stability, few side effects
What is an adjuvant? Give example
What is it required for?
Ingredient added to vaccines to enhance immune response by inducing inflammation
e.g. aluminium salts
Only required for non-living vaccines
What is an attenuated live vaccine?
Why are they better than other types?
Vaccine containing weakened living pathogen
More effective as they simulate “real” infection at appropriate site, inducing appropriate response to pathogen
State 4 methods of attenuation
Give examples
Serial passage through cell culture in vitro (viruses) e.g. polio (Sabin oral vaccine)
Serial passage in vitro (bacteria) e.g. BCG against Mycobacterium tuberculosis
Adaptation to low temperatures (viruses)
Genetic manipulation e.g. Vibrio cholerae missing a toxin subunit
What are sub-unit vaccines?
How are they better and worse?
Toxoids are used in this vaccine. What is it?
Vaccine that contains purified parts of the pathogen that are antigenic, or necessary to elicit a protective immune response
Safer and fewer side effects
However they require adjuvants, multiple injections and immunity may be shorter-lived
Toxoid is a chemically inactivated toxin
What is a recombinant vector vaccine?
Pros?
Genetically engineered virus that acts as a vector to express pathogen antigen in host cells
Generates immune responses similar to natural infection
What is a DNA/RNA vaccine?
Pros?
Use DNA or RNA to transiently express pathogen antigen in host cells
Generates immune responses similar to natural infection
What is herd immunity and why is it important?
Why types of disease does it reduce risk of?
Large portion of a community becomes immune to a disease, making the spread of disease from person to person unlikely
Whole community becomes protected; Not just those who are immune
Important as it protects those who cannot be vaccinated such as newborns and those with certain medical conditions
For infections spread by person-to-person contact, risk of disease to an unvaccinated person dramatically reduced if 80-95% population vaccinated
Give some examples of historical uses of vaccination
- Variolation
- Edward Jenner
Variolation – Pus taken from smallpox blister and introduced via a scratch to uninfected person to confer protection
Edward Jenner developed vaccination principles
- Cowpox and smallpox share antigens so by infecting host with cowpox they developed immune response that was effective against smallpox
What milestones has vaccination made in public health?
Control and eradication of many infectious diseases
Eradication of smallpox with smallpox vaccine
Goal of vaccination is to generate long lasting and protective immunity
What are the 2 aims of vaccination?
Aim 1 – Eradicate disease e.g. small pox eliminated in 1979
Aim 2 – Reduce incidence/transmission of disease
1st step in vaccine development is discovery and characterisation of antigens. What does this process involve?
Identifying Potential Antigens
– Research uses genomics, proteomics, and bioinformatics tools to identify proteins or other molecules from pathogens that can serve as targets for the immune system
Characterising antigens
– Once potential antigens are identified, they are characterised using various analytical methods such as PCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), and mass spectrometry
These methods help confirm identity, purity and immunogenic properties of the antigens
After identifying and characterising the antigen, the next step is designing the vaccine. What does this involve?
Choosing the vaccine platform
– Depending on nature of the antigen and the pathogen, different types of vaccines may be developed, including live attenuated, inactivated, subunit, conjugate, DNA, RNA, and vector-based vaccines
In silico modelling strategies (using bioinformatics and immunoinformatic tools) can be useful in facilitating the identification of epitopes and helping to economise some stages of the development of safe vaccines
Advanced techniques such as structure-based vaccine design is increasingly used to optimise surfaces on immunogens that will elicit protective antibody responses against target proliferation
How is amino acid substitution used to improve vaccine efficacy?
e.g. Proline substitution at helix-turn-helix motifs that undergo conformational change
Stabilised prefusion conformation (increase structural rigidity)
Enhance immunogenicity
Improve vaccine efficacy
How is domain insertion, deletion, replacement and combination used to enhance immune response?
OligoD inserted into spike protein for enhancing neutralising antibody responses
What stages help ensure a vaccine is safe and potentially effective?
What is their primary goal?
Preclinical testing and safety evaluation
Primary goal – Assess the safety, immunogenicity, and potential efficacy of a vaccine candidate using laboratory and animal models
This stage helps predict how the vaccine might behave in humans
What are the methods (3 methods) and outcomes (2 outcomes) of preclinical testing and safety evaluation stages?
Methods
- In vitro studies – Initial tests are conducted using lab-grown cells to evaluate the vaccine’s ability to induce an immune response and to identify any cytotoxic effects
- Animal models – Vaccine candidates are tested in animals, such as mice, rats, or non-human primates, to assess safety and immunogenicity; These studies help determine the appropriate dosage and identify potential side effects
- Toxicology Studies – These studies evaluate the potential toxicity of the vaccine, including single and repeat-dose toxicity, reproductive toxicity, and other specific safety concerns
Outcomes:
- Preclinical testing provides data on the vaccine’s ability to elicit an immune response and its safety profile
- Successful preclinical results are necessary to proceed to human clinical trials
What happens in Phases 1-3 of clinical trials
Phase I – Involves small group of 20-100 healthy volunteers; Primary goal is to assess safety of the vaccine and determine appropriate dosage
Phase II – This phase expands to several hundred participants who have characteristics similar to the target population to further evaluate safety and optimise dosage
Phase III – In this phase, the vaccine is tested on thousands of participants to confirm its efficacy and monitor for any rare side effects; This phase provides the critical data needed for regulatory approval
What are the 3 parts of regulatory approval of a vaccine?
Submission of Data – Vaccine manufacturer submits all data from preclinical and clinical studies to regulatory agencies
Regulatory Review – Regulatory experts review the data to ensure the vaccine meets all safety, efficacy, and quality standards; This process includes inspecting the manufacturing facilities to ensure they comply with Good Manufacturing Practices (GMP)
Licensure – If the vaccine meets all requirements, it is granted a licence for public use
- Post-licensure surveillance (Phase IV) continues to monitor the vaccine’s safety and effectiveness in the general population
What are the 5 main steps of large-scale vaccine manufacturing and what happens at each one?
Antigen Production
- Depending on the type of vaccine, antigens are produced using various methods such as cell culture, recombinant DNA technology, or viral vectors
e.g. cell culture methods involve growing cells that produce the necessary components for the vaccine
e.g. recombinant techniques use genetic engineering to produce specific proteins
Formulation
- Antigen is combined with other components, such as adjuvants, stabilisers, and preservatives, to enhance the immune response and ensure the vaccine’s stability and shelf life
Purification
- The vaccine components are purified to remove any contaminants and ensure the final product’s safety and efficacy
Filling and Packaging
- The purified vaccine is filled into vials or syringes under sterile conditions and then packaged for distribution
Quality Control and Assurance
- Throughout the manufacturing process, rigorous quality control measures are implemented to ensure that the vaccine meets all safety, efficacy, and quality standards
This includes testing for potency, purity, sterility, and consistency
Adjuvants are use to strengthen the immune response elicited by inactivated pathogens.
Give examples of 2 adjuvants and what they do
CpG 1018
- Synthetic oligonucleotide that mimics bacterial DNA, used in the Heplisav-B vaccine for hepatitis B to enhance the immune response
Aluminium Salts:
- Widely used in vaccines for diseases like diphtheria, tetanus, and hepatitis B
They have a long history of safe use but are limited in their ability to stimulate a broad immune response
What are the 3 elements of vaccine quality control and assurance?
Good Manufacturing Practices (GMP):
- All vaccine manufacturing processes must adhere to GMP standards, which ensure that products are consistently produced and controlled according to quality standards
This includes maintaining aseptic conditions, proper documentation, and regular inspections
Batch Testing:
- Each batch of the vaccine is tested for quality and consistency before it is released for distribution This includes tests for sterility, potency, and absence of contaminants
Post-Market Surveillance:
- Even after a vaccine is approved and distributed, ongoing monitoring is conducted to detect any adverse effects and ensure continued safety and efficacy
Proper distribution and storage are essential to maintain the vaccine’s effectiveness. How is this ensured?
Cold Chain Management:
- Most vaccines require refrigerated storage at temperatures between 2°C and 8°C
- Some vaccines, like mRNA vaccines, require ultra-cold storage at temperatures as low as -70°C
Specialised equipment and protocols are used to maintain these temperatures during transportation and storage
Distribution Networks:
- Vaccines are distributed through a network of refrigerated trucks, warehouses, and portable iceboxes to ensure they remain within the required temperature range until they reach the point of administration
Development of vaccines for emerging infectious diseases presents several challenges. What are they?
Rapid response:
- Emerging diseases require a swift response to develop and distribute vaccines
- Often involves accelerated research and regulatory processes, as seen with the COVID-19 vaccines
Unknown pathogens:
- New pathogens may have unknown characteristics, making it difficult to identify suitable antigens and develop effective vaccines quickly
What factors are driving anti-vaccine movement?
Misinformation:
- Spread of misinformation about vaccine safety and efficacy can lead to reduced vaccination rates and outbreaks of preventable diseases
Public Trust:
- Building and maintaining public trust in vaccines is crucial
- Transparent communication about the benefits and risks of vaccines, as well as addressing concerns and misconceptions, is essential to combat vaccine hesitancy
- Expense, lack of appropriate medical infrastructure, patient compliance
- Personal/religious objections
- “Fake news”
Discuss vaccine equity
- Issues
- Initiatives providing solutions
Distribution Inequities
- Disparities in vaccine distribution can leave low- and middle-income countries without adequate access to vaccines, exacerbating health inequalities
Global Collaboration
- Initiatives like COVAX aim to ensure fair distribution of vaccines worldwide, but logistical, financial, and political challenges remain
mRNA vaccines represent a significant advancement in vaccine technology, particularly highlighted by their role in combating the COVID-19 pandemic
What are they and how do they work?
- Advantages and examples
mRNA vaccines use messenger RNA to instruct cells to produce a protein that triggers an immune response
Mechanism – mRNA vaccines deliver genetic instructions to cells to produce a viral protein, such as the spike protein of the SARS-CoV-2 virus
Once the protein is made, the immune system recognises it as foreign and mounts an immune response, including the production of antibodies
Advantages – These vaccines can be developed and produced more quickly than traditional vaccines
They are also highly adaptable, allowing for rapid updates to address emerging variants
Examples – Pfizer-BioNTech and Modern vaccines were the first mRNA vaccines authorised for emergency use and have shown high efficacy in preventing COVID-19
What are viral vector viruses?
Give 2 examples
Vector virus is engineered to be harmless and unable to replicate
Carries genetic code for an antigen, such as protein from target pathogen
Once inside body, cells produce the antigen, eliciting immune response
- AstraZeneca/Oxford COVID-19 Vaccine – Uses a chimpanzee adenovirus vector to deliver the spike protein gene of SARS-CoV-2
- Beyond COVID-19, viral vector vaccines are being explored for diseases such as Ebola, HIV, and Zika virus
Nanomaterials are increasingly being used to enhance vaccine delivery and efficacy
What are nanomaterials and what benefits do they provide?
Give an example
Types of Nanomaterials – Lipid nanoparticles, polymeric nanoparticles, and inorganic nanoparticles are commonly used
Functions:
- Stabilisation – Protects the antigen from degradation
- Targeted delivery – Enhances delivery to specific cells or tissues
- Adjuvant Effect – Enhances the immune response by acting as an adjuvant
- Pfizer-BioNTech and Moderna COVID-19 vaccines use lipid nanoparticles to encapsulate and deliver the mRNA into cells
What are personalised vaccines?
How do they work?
Where are they being applied?
Future directions?
Vaccines tailored to the individual characteristics of a patients disease, particularly in the context of cancer
Mechanism – These vaccines are designed based in specific mutations or antigens present in a patients tumour
They aim to elicit a strong immune response against these unique antigens
Applications – BioNTech and Genentech have been conducting clinical trials for mRNA vaccines targeting various cancers, including melanoma, colorectal and lung cancers
These trials involve creating individualised vaccines based on each patients tumour profile
Personalised vaccines are also being explored for infectious diseases (e.g. HIV), where individual genetic differences affect disease susceptibility
What are the factors of an infectious disease that favour its global eradication and why? (5 factors)
Disease limited to human - No reinvasion by microbe from animal
No long term carrier state - No reinvasion by microbe from human carriers
Few unrecognised clinical cases - Good surveillance
One or few serotypes - Single vaccine is enough
Stable, cheap and effective vaccine and programme - Worldwide programme feasible
Give 2 examples of major vaccine-preventable diseases? Think of how vaccines have helped global health
Polio – Caused by the poliovirus, polio can lead to paralysis and even death; Disease has been nearly eradicated globally due to widespread vaccination with the inactivated polio vaccine (IPV) and oral polio vaccine (OPV)
Human Papillomavirus (HPV) – Group of viruses that can cause genital warts and are linked to several cancers, including cervical cancer; HPV vaccine is recommended for adolescents to prevent infection and associated cancers
What are the challenges in vaccine research?
Barriers in developing effective vaccines for existing infectious diseases due to:
- Complex life-cycle of pathogen
- T cell immunity needed
- High mutation rates
- Many types of pathogen
Give an example of an infectious disease we lack an effective vaccine for
- Deaths
- Where?
- Promise?
Malaria – Approximately 249 million cases (2022) and 608,000 deaths (2012)
African Region bears a disproportionate burden, accounting for 94% of malaria cases (233 million) and 95% (580,000) of malaria deaths in 2022
Malaria vaccine, R21/Matrix-MTM licensed for use in Ghana 2023, 77% effective in clinical trials (endorsed by WHO)
Give another example of an infectious disease we lack an effective vaccine for
- Deaths
- Economic
- Treatment
Approximately 1.3 million people became newly infected with HIV in 2022
In 2022, around 630,000 people died from AIDS-related illnesses worldwide, compared to 1.2 million in 2010
Substantial economic impact of HIV/AIDS
No really effective current vaccine
Treatment – not cure
Treatments consume the majority of household budget, especially in low-income settings without adequate healthcare coverage
Why is it important to continue vaccination efforts? (3 reasons)
Preventing Disease Outbreaks
– High vaccination coverage is necessary to maintain herd immunity and prevent the resurgence of vaccine-preventable diseases
Protecting Vulnerable Populations
– Vaccination protects those who cannot be vaccinated, such as infants and immunocompromised individuals, by reducing the spread of infectious diseases
Global Health Security
– Vaccination is a key component of global health security, helping to prevent and control infectious disease outbreaks and pandemics
