L14 - Trends in vaccinology 2 (Dr Alice Halliday) Flashcards
1. Describe and analyse some of the key current challenges in vaccinology 2. Describe the recent and emerging new developments in vaccinology 3. Explore the possible future directions for vaccinology
What are the main current challenges in vaccinology?
🌍 Current challenges in vaccinology include:
- Emerging pathogens like Ebola, SARS, and SARS-CoV
- Evolving viruses like influenza and HIV
- Old pathogens, such as TB, polio, and group A strep
- The aging population and the need for durable immune responses
- The rise in antibiotic resistance
- Growing interest in vaccines for non-communicable diseases like cancer
How do emerging pathogens impact vaccinology?
🦠 Emerging pathogens (e.g., SARS-CoV-2) pose a significant threat due to their pandemic potential, requiring rapid vaccine development and novel approaches for prevention.
What is a key problem with viruses like influenza and HIV in vaccinology?
🦠 Influenza and HIV are moving targets because they rapidly evolve and change their genetic makeup, making it difficult to create long-lasting, effective vaccines against them.
What is a major challenge related to older pathogens like TB and Polio?
🔬 Some older pathogens, like TB and Polio, lack effective vaccines, or the existing vaccines do not provide sufficient protection in all populations, leading to ongoing challenges in public health.
How does an aging population affect vaccinology?
👵 Aging populations require vaccines that generate durable immune responses because they are more susceptible to infections and may have weakened immune systems due to immunosenescence (the aging of the immune system).
Why are antibiotic resistance and vaccines closely related?
💊 With the rise in antibiotic resistance, vaccines become an essential tool in preventing infections, reducing the need for antibiotics and potentially decreasing the emergence of resistant pathogens.
What are some emerging trends in vaccinology?
🌟 Some emerging trends in vaccinology include:
- Rational vaccine design
- Development of therapeutic vaccines (for treatment, not just prevention)
- The use of adjuvants to enhance vaccine effectiveness
- The push towards a global vaccinology industry
- Ensuring pandemic preparedness through new vaccine platforms
What is rational vaccine design in the context of vaccinology?
🧬 Rational vaccine design focuses on targeting specific antigens that can generate effective immune responses, using advanced knowledge of pathogens to guide the development of vaccines more strategically.
What role do therapeutic vaccines play in modern vaccinology?
💉 Therapeutic vaccines are being explored to treat existing diseases (like cancer) rather than just prevent new infections, marking a shift in how vaccines could be used in the future.
How do adjuvants contribute to vaccine development?
🧪 Adjuvants are substances added to vaccines to enhance the immune response, improving the effectiveness and durability of the vaccine without needing to increase the antigen dose.
What challenges does the global vaccination landscape face?
🌍 The goal of making vaccines accessible worldwide requires addressing inequality, ensuring vaccines are available to everyone, regardless of where they live, and expanding global collaboration in vaccine production and distribution.
Why is pandemic preparedness a focus in vaccinology?
🌍 Pandemic preparedness is essential in vaccinology, as rapid vaccine development for emerging diseases (like SARS-CoV-2) is critical to preventing widespread outbreaks and mitigating the impact of future pandemics.
How can new approaches improve vaccine evaluation?
🧑🔬 New approaches to vaccine evaluation aim to speed up the process of determining vaccine efficacy and safety, especially in emergency situations, by using innovative methods like accelerated trials or alternative evaluation models.
Why are live attenuated vaccines still important in vaccinology today?
💉 Despite newer technologies, live attenuated vaccines remain important because they often generate strong and long-lasting immune responses. They continue to be some of the most effective vaccines available for diseases like measles, mumps, and rubella.
How does the history of vaccine development influence current trends in vaccinology?
🧬 The history of vaccine development has laid the foundation for modern approaches. Early methods, such as live attenuated and killed whole organism vaccines, paved the way for advanced strategies like reverse vaccinology and RNA vaccines, while still valuing the effectiveness of older vaccines.
How does the development of RNA vaccines change the future of vaccinology?
💉 RNA vaccines, like those used in the COVID-19 pandemic, represent a game-changing technology. They allow for rapid development, flexibility in responding to emerging pathogens, and the ability to generate strong immune responses without using live virus.
What is the “valley of death” in vaccine development?
🚧 The “valley of death” refers to the difficult phase in vaccine development where candidate vaccines face substantial challenges, and many fail to move forward due to lack of funding, manufacturing capacity, or problems with safety and efficacy.
How do vaccine schedules get determined?
📅 Vaccine schedules are determined by immunological principles, the epidemiology of diseases, and licensing requirements. They can be adjusted to reduce doses as the epidemiology of the disease changes, which helps reduce cost and injections while maintaining effectiveness.
What is reverse vaccinology, and how does it differ from traditional vaccine development?
🔄 Reverse vaccinology is a new approach that moves away from the traditional method of isolating and growing the pathogen to identify its antigens. Instead, it starts with the pathogen’s genome sequence and uses computer-based methods to identify target antigens that could elicit a protective immune response. This approach allows for more efficient and precise vaccine design, using genomic data to select the best targets for vaccine development.
How was vaccine development traditionally carried out before reverse vaccinology?
Traditional vaccine development focused on identifying, purifying, and growing the pathogen of interest in the lab. The pathogen was then used to identify components (whole pathogen or parts of it) that could elicit a protective immune response. This approach was hypothesis-driven and required culturing the actual pathogen.
What methods have enabled advancements in reverse vaccinology for understanding pathogens?
Advances in genomics and proteomics, particularly sequencing technologies, have enabled reverse vaccinology. Researchers can now sequence the pathogen’s genome and use computer-based methods to identify potential vaccine targets, moving away from the need to culture the organism.
*** 🧬 DNA sequencing has been a key method, with the first microbial sequence released in 1995 (Haemophilus influenza). Today, sequences for thousands of microbial species are available, which can be analyzed using subtractive pathogenome analysis to identify unique pathogen sequences. Mass spectrometry has also advanced protein science, enabling identification of surface-expressed proteins and their functions on the pathogen.
What is subtractive pathogenome analysis?
🔬 Subtractive pathogenome analysis is the process of comparing pathogen sequences with those from other species to identify unique pathogen-specific sequences. This helps pinpoint the genes and proteins that are specific to the pathogen and can serve as potential vaccine targets.
What is pathoproteome analysis in reverse vaccinology?
🧪 Pathoproteome analysis is similar to pathogenome analysis but focuses on protein-level information. It identifies which pathogen proteins are involved in virulence and surface expression, helping researchers find suitable vaccine candidates by studying proteins that the immune system can recognize and respond to.
What is the basic process of reverse vaccinology in vaccine development?
Reverse vaccinology begins with obtaining the genome sequence of the pathogen. From this, computer-based approaches identify antigens specific to the pathogen that may be presented on its surface or contain immunogenic epitopes. These antigens are then tested through in vitro and in vivo studies to determine if they can elicit a protective immune response.
How does reverse vaccinology differ from traditional vaccine design in terms of target selection?
In reverse vaccinology, target antigens are selected based on genomic data and computational analysis, not on a hypothesis-driven approach. Researchers can now screen thousands of sequences to find antigens that are likely to elicit a protective immune response, rather than focusing on a few specific proteins like in traditional methods.
What is the significance of reverse vaccinology in modern vaccine science?
Reverse vaccinology represents a major transformation in vaccine development. By utilizing genomic data and immunological insights, this approach makes it possible to design vaccines more efficiently and precisely, offering new avenues for addressing emerging pathogens and diseases that were difficult to tackle with traditional methods.
How has reverse vaccinology helped in the development of the MenB vaccine for Neisseria meningitidis?
🧫 The MenB vaccine, known as Bexsero, was developed using reverse vaccinology, a method that involves identifying surface-expressed proteins from Neisseria meningitidis serogroup B through computational techniques. Initially, 300 proteins were tested in mice, of which 91 were found to be surface-exposed. After further testing, three key proteins were selected and combined with an adjuvant, forming the basis of the Bexsero vaccine.
What challenges did Neisseria meningitidis serogroup B pose in developing a vaccine?
❌ Neisseria meningitidis serogroup B posed challenges due to its high antigenic diversity (over 1000 strains) and the capsular polysaccharide being poorly immunogenic. Additionally, the capsule’s antigenic similarity to host glycoproteins led to tolerance, meaning the immune system didn’t effectively respond to it.
How effective is the Bexsero vaccine against invasive disease and what is its effect on carriage?
💉 Bexsero, the vaccine for MenB, has good efficacy against invasive disease, showing around 62% efficacy in children after 2 doses. However, it has little to no effect on carriage, meaning it doesn’t significantly reduce the spread of the bacteria among carriers.
When was Bexsero adopted in the UK, and who is it given to?
🇬🇧 Bexsero was adopted in the UK in 2015 and is given to infants and at-risk adults as part of the national immunization schedule.
What diseases can Group A Streptococcus (GAS) cause?
🦠 Group A Streptococcus (GAS) can cause both mild and severe diseases.
What are mild infections caused by group A streptococcus
Mild infections include impetigo and pharyngitis.
What are some severe diseases caused by Group A streptococcus?
Severe diseases include scarlet fever, sepsis, necrotizing fasciitis, pneumonia, as well as autoimmune diseases such as rheumatic fever and post-streptococcal glomerular nephritis, which can lead to rheumatic heart disease.
What challenges do researchers face in developing a vaccine for Group A Streptococcus (GAS)?
💉 Challenges in developing a GAS vaccine include the variability of surface proteins (e.g., M protein), the risk of driving bad immune responses (like autoimmune diseases), and the difficulty in identifying which immune responses (antibodies, cells, or mucosal responses) are protective. Additionally, large, expensive trials are required due to the low infection rate and serotype diversity.
How can reverse vaccinology help in addressing the challenges of a GAS vaccine?
🔄 Reverse vaccinology can help by identifying conserved, widely expressed surface proteins that are not highly variable across GAS strains. Using bioinformatics tools, immunoinformatics, and in silico algorithms, researchers can identify proteins that are expressed in natural infection and can elicit protective immune responses without causing harmful immune reactions.
What has recent research found in developing a GAS vaccine?
🧬 Recent research has sequenced over 2000 GAS genomes worldwide and identified 15 highly conserved, widely expressed surface proteins. Three of these proteins (SpyAD, SpyCEP, SLO) were shown to induce protection in mice and are being taken forward in the GSK Combo Vaccine for GAS. This approach uses reverse vaccinology to identify conserved antigens that are likely to provide protection.
What are the challenges with using whole-cell vaccines for Group A Streptococcus?
🚫 The challenges with whole-cell vaccines for Group A Streptococcus include serotype diversity and strain variability. These factors make it difficult to create a universal vaccine that works against all GAS strains. Additionally, whole-cell vaccines might drive unwanted immune responses, which is a concern for safety.
What are the key considerations when designing a GAS vaccine to avoid negative immune responses?
⚖️ Key considerations include identifying antigens that are conserved, expressed in natural infection, and do not drive autoimmune reactions. Research should also focus on understanding which type of immune response (antibodies, T cells, mucosal) is required for protection and ensuring the vaccine does not cause harmful autoimmunity (e.g., rheumatic heart disease).
How are controlled human infection models useful for GAS vaccine development?
🧫 Controlled human infection models help by simulating natural infection in a controlled environment. This allows researchers to test vaccines for safety and efficacy while dealing with the challenge of low infection rates in the population, reducing the need for large, costly trials.
What is the SpyAD protein, and why is it important for GAS vaccine development?
🧬 The SpyAD protein is one of the three proteins identified in reverse vaccinology as a potential vaccine candidate for GAS. It is highly conserved and surface-expressed, making it a good candidate for inducing a protective immune response against Group A Streptococcus.
What is immunoinformatics and how does it contribute to GAS vaccine development?
🖥️ Immunoinformatics involves using bioinformatics tools to analyze immune system data, such as identifying T cell and B cell epitopes through in silico methods. It helps design vaccines by predicting which antigens will elicit a protective immune response, aiding in the development of a GAS vaccine.
What does the future of GAS vaccine development look like?
🔮 The future of GAS vaccine development looks promising as recent advancements in reverse vaccinology, genomic sequencing, and immunoinformatics continue to identify conserved and immunogenic proteins for effective vaccines. GSK’s combo vaccine is one step forward, and future clinical trials will help determine its efficacy and safety in humas.
What is a challenge with the conserved proteins in Group A Streptococcus (GAS) vaccines?
Conserved proteins in GAS are often weakly immunogenic, meaning they don’t generate a strong immune response.
On the other hand, more variable proteins (like the M protein) are immunodominant, meaning they trigger stronger immune responses, but they are associated with immune system issues, such as autoimmune reactions (e.g., rheumatic heart disease).
What does the research in Bristol focus on regarding immune responses across different ages for Group A Streptococcus (GAS)?
🔬 The research examines how immune responses to pharyngitis and invasive disease vary by age. Pharyngitis peaks in childhood, while invasive disease peaks in both the very young and elderly.
Why is it important to study immune responses in different age groups when developing a vaccine for GAS?
🔬 Studying immune responses in younger and older populations helps identify protective immunity, particularly in the older group, to improve vaccine development.
How is mucosal immunity relevant to GAS vaccine research in Bristol?
🦠 Researchers are particularly interested in mucosal immunity because it can help target infection at early stages, which is crucial for an effective vaccine.
What is the focus of gene expression research in GAS vaccine development in Bristol?
🧬 The research looks at which genes are expressed in clinically relevant scenarios, helping to identify potential target antigens for vaccine development.
What are adaptable vaccine platforms, and why are they important?
💉 Adaptable vaccine platforms are manufacturing approaches that can quickly be modified to insert new antigens. These platforms are crucial for responding rapidly to emerging pathogens with pandemic potential.
What are the pros and cons of DNA vaccines?
🧬 Pros: Cheap, used for West Nile Virus (in horses)
❌ Cons: Poorly immunogenic in humans, limiting effectiveness for human use.
What are the advantages and disadvantages of RNA vaccines?
🧬 Pros: Rapid production and effective (e.g., BNT162B2 for COVID-19)
❌ Cons: Expensive to produce, limiting accessibility.
What are the advantages and disadvantages of viral vector vaccines?
💉 Pros: Cheap, storage at 4°C, rapid production (e.g., ChAdOx-S1 for COVID-19)
❌ Cons: Uncertain pre-existing immunity may affect efficacy.
What are the benefits and drawbacks of virus-like particle (VLP) vaccines?
🦠 Pros: Safe, easy to produce, no adjuvant needed (e.g., HBV, HPV vaccines)
❌ Cons: Slower manufacture, which delays availability.
Why are adaptable vaccine platforms particularly important for emerging pathogens?
🔬 These platforms allow for rapid adaptation to new antigens, making them essential for quick responses to pandemics and other emerging diseases.
How have new vaccine platforms allowed for faster development of vaccines?
⏱️ New approaches, like mRNA vaccines, have allowed vaccines to be developed at record speed. For example, after the COVID-19 sequence was released, an mRNA vaccine was developed almost immediately, drastically reducing the time between pathogen identification and vaccine licensure. In contrast, older vaccines, such as for typhoid, took much longer to develop.
How were SARS-CoV-2 vaccines developed so quickly?
⚡ Decades of research in multiple fields allowed for the rapid development of vaccines. This included advancements in sequencing (which led to the virus being sequenced and released quickly), synthetic biology (enabling lab-grown sequences), and mRNA and viral vector platforms developed for other viruses like MERS and influenza.
How does the SARS-CoV-2 work ?
🔬 The mRNA vaccine works by encoding the spike protein in the lab and triggering immune responses. The ChAdOx vaccine, developed at Oxford, used prior knowledge from MERS to rapidly create a COVID-19 vaccine. This academic-driven project was later scaled up with AstraZeneca for mass production.
How long did it take for COVID-19 vaccines to be licensed?
⏳ The timeline for COVID-19 vaccine development was remarkably fast compared to historical vaccines. After the sequence for SARS-CoV-2 was released, vaccines were developed in months. The mRNA vaccine technology allowed for an almost immediate response once the viral sequence was known. This was in stark contrast to older vaccines, like typhoid, which took decades to develop.
How do mRNA vaccines work?
💉 mRNA vaccines are synthesized in the lab to encode a target antigen, like the spike protein in the case of COVID-19. Once injected, the mRNA is taken up by the host cells, prompting them to produce the spike protein. The immune system then recognizes this protein and creates antibodies and T cells to fight the virus. This technology was key in the rapid development of COVID-19 vaccines.
What are viral vector vaccines and how do they work?
🧬 Viral vector vaccines, such as the ChAdOx-S1 developed by Oxford, use a harmless virus to deliver genetic material into cells, prompting them to produce the spike protein of SARS-CoV-2. This generates an immune response, training the body to recognize and fight the virus. This approach has been used successfully for other viruses like MERS, allowing for a quicker response to COVID-19.
What is a Controlled Human Infection Model (CHIM)?
💉 A CHIM is a carefully managed research study where volunteers are purposely exposed to an infection in a safe and controlled environment, with healthcare support
What do Controlled Human Infections help with?
❓It helps understand the immune response and accelerates the development of new drugs and vaccines.
What ethical considerations are involved in CHIM studies?
⚖️ CHIM studies involve weighing the risk of harm to individuals against the potential health benefits for the global population. Ethical principles are similar to those used in Phase 1 clinical trials, and informed consent is essential. Volunteers are also appropriately compensated.
How does CHIM today compare to Edward Jenner’s smallpox experiment?
📜 Jenner’s smallpox experiment involved deliberately infecting a child, which would be unethical today. However, modern CHIMs are controlled and highly regulated, with careful monitoring and ethical oversight, making them a safer approach for studying infections and developing vaccines.
How have CHIM studies evolved over time?
📊 CHIM studies have expanded significantly in recent years. Initially, they were used for cold viruses like influenza and RSV, but now they are applied to a broad range of pathogens, including malaria (Plasmodium falciparum) to aid vaccine development.
What is Systems Immunology
🔬 Systems Immunology is a broad approach to immune profiling using advanced laboratory techniques like high-dimensional flow cytometry, sequencing, and proteomics. It helps analyze immune responses, including T-cell and B-cell activity, to design better vaccines.
How does Systems Immunology improve vaccine development?
🔍 It allows for thorough immune profiling, helping to identify key immune responses (like T-cell and B-cell responses). This is particularly valuable when the correlates of protection are unclear and can help find more effective vaccine targets.
What laboratory techniques are used in systems immunology?
🧬 Techniques include high-dimensional flow cytometry, sequencing, proteomics, and systems serology. These tools allow scientists to analyze immune responses at a deeper, more comprehensive level.
What recent controlled human infection model was established for Group A Streptococcus?
🧑🔬 A controlled human infection model was established where adults without pre-existing antibodies to Group A Streptococcus were exposed to the pathogen at the back of their throat to study immune responses. Around 75% developed pharyngitis, and this model is helping with vaccine development.
Why is Systems Immunology useful for diseases with unclear correlates of protection?
🧬 Systems Immunology provides a comprehensive approach to identifying immune responses beyond antibodies, which are not always the key to protection. It helps uncover alternative correlates of protection, especially when traditional markers like antibodies are insufficient.
How is Systems Immunology applied in vaccine trials?
🔬 In vaccine trials, immune samples are taken to apply systems immunology techniques. These techniques help identify immune signatures that predict the generation of a broad and durable immune response, aiding in vaccine efficacy evaluation.
How are new models like organoid and humanized mice improving vaccine development?
🧬 New models like organoids (human or mouse cells) and humanized mice make infection models more relevant to human biology, providing more accurate insights into infections and vaccine development.
What are adjuvants in vaccines?
🧬 Adjuvants are components added to vaccines to boost the immune response. They are especially important for subunit or toxoid vaccines, which only contain antigens and need help to generate a strong immune response.
How do adjuvants enhance vaccine effectiveness?
💥 Adjuvants work by activating the innate immune system, triggering immune responses through mechanisms like TLR activation and intracellular pathogen-associated molecular patterns. They can also act as a depot to hold the antigen at the injection site for longer exposure.
Why are adjuvants especially important for certain vaccines?
🦠 Subunit or toxoid vaccines that only contain antigens in protein form are not immunogenic on their own. Adjuvants are needed to enhance their ability to stimulate an immune response.
What are some of the new developments in adjuvant technology?
🔬 New adjuvants target TLR4 (Toll-like receptor 4), which is activated by lipopolysaccharides (LPS). These new adjuvants, such as MPL, are modified LPS that trigger a strong immune response without the harmful effects of the toxic form of LPS.
Why are some adjuvants called immunologists’ “dirty little secret”?
💬 In the past, adjuvants were included in vaccines with little understanding of how they worked, leading to the term “dirty little secret” as coined by immunologist Jane Way. Today, we have a better understanding of how they boost the immune system.
What are the challenges with HIV vaccines?
💉 HIV has a high mutation rate with antigenic variability, making it difficult to create a vaccine. It also infects T cells and can hide within the body, creating a latent infection, with no natural example of viral clearance.
How does HIV complicate vaccine development?
🧠 Since HIV can hide and persist in the body, we must do better than nature to clear the virus, which makes creating an effective vaccine very challenging.
Why is influenza vaccine development so challenging?
🔄 Influenza has multiple types (A, B, C) and strains that change annually. Antigenic shift and drift cause the virus to evolve rapidly, so a new vaccine is needed every year with variable efficacy.
What is “original antigenic sin” in relation to flu vaccines?
🧬 Original antigenic sin refers to the immune system’s tendency to remember and respond better to the first strain of flu it encountered, which can impair immune responses to new strains, making vaccines less effective.
Is a universal flu vaccine possible?
🦠 Vaccine developers are working towards a universal flu vaccine that would protect against all flu strains, including future pandemic strains, but no breakthrough has been achieved yet.
What is the current vaccine for tuberculosis (TB)?
💉 The current vaccine is BCG, a live attenuated vaccine that is safe and cheap, but has variable efficacy and does not protect against latent infection.
Why is latent TB infection a global challenge?
🌍 Latent TB affects about 25% of the world’s population. These individuals may develop active TB later in life, making a better vaccine essential to prevent both infection and disease progression.
What kind of immune response is important for TB vaccines?
🧠 The protective immunity for TB is cell-mediated (not antibody-based), which involves T cells to fight off intracellular TB infection.
What recent findings show promise for TB vaccines?
🔬 Recent studies suggest that re-vaccinating with BCG in adolescence can protect against sustained TB infection, and the M72/AS01 subunit vaccine showed 49.7% efficacy against disease progression after 3 years.
How has India contributed to global vaccine supply?
🇮🇳 India is now a major contributor to global vaccine supply, developing vaccines cheaply and performing studies in low and middle-income countries to ensure efficacy for these populations.
Why do vaccine efficacy studies in high-income countries not always translate to target populations?
💡 Vaccine efficacy studies conducted in high-income countries (e.g., UK, US) may not reflect the unique conditions and health disparities of target populations in low and middle-income countries.
What is the significance of the new malaria vaccine?
🌍 The new malaria vaccine improves upon older versions and is a significant step forward in fighting malaria, especially in endemic areas where the disease remains a major health burden.
What is the focus of the meningitis A vaccine developed for Africa?
🌍 The meningitis A vaccine, developed in collaboration with the Serum Institute of India, focuses specifically on meningitis A, which causes significant disease and disability in Africa’s meningitis belt.
How can vaccines be used to treat cancer?
🧬 Cancer vaccines aim to reprogram the immune system to target cancer antigens. This is challenging because tumors have multiple immune evasion mechanisms, but it remains an exciting field of research.
Are vaccines being developed for diseases beyond infectious ones?
💡 Yes, therapeutic vaccines are being developed for diseases like HIV, Alzheimer’s, and cancer, aiming to treat conditions after they are acquired rather than just prevent them.
How are vaccines different from antibiotics in terms of resistance?
💉 Vaccines rarely lead to resistance by pathogens, unlike antibiotics, which frequently face resistance. This makes vaccines a powerful tool for disease eradication.
Why is immunology key in the field of vaccinology?
🧠 Immunology plays a crucial role in vaccinology, as understanding the immune response is essential for developing effective vaccines and improving vaccine design across various diseases.
