Trends in Vaccinology 2

• LO:


  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
• Current challenges


  • Moving targets: influenza, HIV,
  • Emerging pathogens: Ebola, SARS, SARS-CoV-2
  • Old pathogens, new problems: TB, Polio, GAS
  • Aging population
  • Antibiotic resistance
  • Non communicable diseases
• Vaccine developments - timeline

  
• Current trends


  • Rational Vaccine Design

  1. Meningitis B
  2. SARS-CoV-2

  • Therapeutic vaccines
  • Towards a truly global vaccinology industry

  1. Improving LMIC production and capacity
  2. Examples: Men A vaccine, malaria vaccine

  • Ensuring pandemic preparedness

  1. Rapid manufacturing
  2. Adaptive vaccine platforms: mRNA, viral vector, VLP

  • New approaches to vaccine evaluation

  1. Controlled Human Infection Models (CHIMs)
• Reverse vaccinology 1.0 & 2.0

  
• Reverse vaccinology – how now?


  • DNA

  1. Whole genome sequencing
  2. NCBI Microbial Genomes: >7000 species
  3. Subtractive pathogenome analysis

  • Protein

  Mass spectrometry

  Subtractive pathoproteome analysis

  Protein function

  Subcellular localization

  
• The challenge of N. meningitidis serogroup B


  • Neisseria meningitidis
  • Invasive disease – serogroups A, B, C, W135 & Y
  • Serogroup B challenges:

  >1000 strains with high antigenic diversity

  Capsular polysaccharide poorly immunogenic

  Capsule antigenically similar to host glycoproteins

  
• Reverse vaccinology and Men B


  • Vaccine = Bexsero (4CMenB)
  • Given to infants and at risk adults
  • UK adopted Bexsero in 2015
  • Good efficacy vs invasive disease (62% in children after 2 doses)
  • No/little effect on carriage (indirect effects)
• Group A Streptococcus (GAS) Streptococcus pyogenes

  
• Vaccine for Group A Streptococcus challenges

  
• Reverse vaccinology & GAS


  • Can’t use whole cell vaccines
  • Serotype/strain diversity
  • 3 proteins induced protection in mice: SpyAD, SpyCEP, SLO
  • GSK Combo Vaccine
  • The dawn of immunoinformatics

  The human immune repertoire

  Screen T & B cell epitopes using in silico algorithim/database (IEDB)

  
• GAS Research in Bristol


  • Characterise T & B cell responses to GAS infection in different clinical groups
  • Mucosal responses
  • Bacterial gene expression in clinicallyrelevant scenarios
  • ->> Rational approaches to inform vaccine development

  
• Adaptable vaccine platforms


  • Vaccine manufacturing approaches which can be rapidly adapted to ‘insert’ new antigens
  • Ideally suited to allow rapid responses to emerging pathogens with pandemic potential

  
• SARS-CoV-2 Vaccines


  Decades of pre-existing research in multiple areas

  Sequencing

  Manufacturing

  mRNA and vector biology technology

  
• Technology for emerging pathogens

  
• mRNA vaccines

  
• Viral vector vaccines


  • Example: ChAdOx-S1

  1. Oxford Vaccine Group
  2. Pipeline established for other infections including MERS (2018)
  3. Rapidly deployed to develop new COVID-19 vaccine in early 2020 (also included ‘Spike’ protein)

  • Set up by an academic lab with mostly non-commercial funding
  • Partnered with AstraZeneca for mass production and distribution
• What’s next for SARS-CoV-2 vaccines?


  • Existing vaccines

  1. Provide short term protection against severe disease
  2. Not able to prevent transmission
  3. Must be stored at low temp

  • Live attenuated vaccine?
  • Mucosal administration?
  • Seasonal vaccination, like influenza?
  • Combat vaccine hesistancy
• CHIMs: Controlled human infection models


  • A carefully managed research study during which volunteers are purposefully exposed to an infection, in a safe way and with healthcare support.
  • CHIM studies are a valuable tool for understanding the underlying immunological response to infection, and enabling, accelerating and de-risking the development of novel drugs and vaccines
  • There are robust ethical review processes in place to protect the safety of volunteers.
• Challenge models

  
• Ethical considerations around CHIMs


  • Seemingly breach the ‘do no harm’ principle
  • Must weigh risk of individual harm with global population health impact
  • Ethical principles similar to phase 1 clinical trials
  • Informed consent process is critical
  • Appropriate renumeration
• SARS-CoV-2 CHIM


  • Unique findings on viral kinetics, sites of infection, and performance of tests
  • Was not set up fast enough to support evaluation of the first vaccines
  • May have ongoing utility to study vaccine effectiveness vs transmission (sterilising immunity)

  Mucosal vaccines?

  
• Ongoing challenge: moving targets


  • HIV

  1. High mutation rate - antigenic variability
  2. Infects T cells • Infection can be latent (hiding, silent)
  3. No natural example of viral clearance

  • Influenza

  1. Multiple types (A, B, C) and strains
  2. Variability – antigenic shift and drift
  3. Seasonal flu
  4. Seasonal flu vaccine generated annually
  5. Variable efficacy
  6. Pandemic flu

  A universal influenza vaccine?
• Challenge: improving vaccines for old diseases


  Tuberculosis

  • Over 1.4 million deaths/year
  • Current vaccine – BCG (live attenuated)
  • Safe cheap,variable efficacy
  • Large proportion (~25%) latently infected
  • Ideal vaccine would prevent infection and progression
  • Immunity–cell mediated
  • Recent signs for hope:

  
• Making vaccines equitable


  • Requires international collaboration
  • Improving production capacity in LMICs

  1. India now major contributor to global vaccine supply
  2. Cost effective manufacturing
  3. Easier to perform efficacy studies in LMICs

  • Vaccines for diseases of LMICs

  1. Malaria =newvaccines RTS,S & R21/Matrix
  2. Meningitis A = MenAfriVac vaccine

  WHO, PATH, Serum Institut India

  Protein conjugate vaccine

  
• Therapeutic vaccines


  • Vaccines that can help treat an illness, after it’s acquired
  • Cancer

  1. Theoretically possible
  2. New technologies for neoantigens, personalized vaccines
  3. Challenging – tumours have multiple immune evasion mechanisms

  • HIV
  • Alzheimer’s Disease

  Vaccine forthe amyloid beta
• Summary


  • Vaccinology has moved into a new area of rationale vaccine design
  • Vaccinology is a truly multi-disciplinary field
  • Recent progress in multiple areas allowed for SARS-CoV-2 vaccine development in rapid time
  • Understanding natural immunity is important
  • Success of vaccines depends not only on the product, but on multiple other factors