L11 - trends in vaccinology 2

• reverse vaccinology 1

  have technologies that can look at whole genome - take sequence and work out which will be expressed or secreted

  can also predict likely antigens recognised by immune system

  lab studies - cloned and expressed in bacteria

  pre-clinical trials to see if can raise antibodies and see if have response in vitro

  can narrow down to to few proteins that can be effective in vaccine

  look at molecular epidemiology

  once assessed - candidate vaccines can go into human trials

  once approved can be implemented into larger population
• reverse vaccinology 2

  further developments

  can also use information from human response

  take people vaccinated or previously infected and identify B-cells specific to organism

  process the antibody reservoir

  proliferated in vitro and sequence

  look at the functions of individual antibody
• reverse vaccinology how?

  DNA

  • whole genome sequencing
  • NCBI microbial genomes
  • subtractive pathogenome analysis

  protein

  • mass spectrometry
  • subtractive pathoproteome analysis
  • protein function
  • subcellular localisation
• challenge of N. meningitidis serogroup B

  neisseria meningitidis

  invasive disease

  serogroup B challenges:

  • >1000 strains with high antigenic diversity
  • capsular polysaccharide poorly immunogenic - does not induce an effective antibody response
  • capsule antigenically similar to host glycoproteins

  have vaccines to all serogroups apart from B
• reverse vaccinology and Men B

  • vaccine = Bexsero (4CMenB) - multicomponent vaccine composed of four major proteins of Neisseria meningitidis: the fHbp, NHBA, NadA and PorA - potential to protect against invasive MenB strains
  • given to infants and at risk adults
  • UK adopted in 2015
  • good efficacy vs invasive disease
  • no/little effect on carriage - compared to others that target the capsule
• group A streptococcus (GAS) Streptococcus pyogenes

  impetigo - given antibiotics

  scarlet fever - rash and fever

  look over
• vaccine for group A streptococcus challenges

  variable immunodominant surface protein eg M protein

  possibility of driving bad immune responses

  which immune responses are protective?

  large, expensive vaccine trials required
• variable immunodominant surface protein challenge


  identify other possible targets

  • not variable
  • present in all strains
  • expressed in natural infection

  conserved region of M - 1 being looked into

  StreptAnova targets N terminus of the M protein
• possibility of driving bad immune responses

  more research into GAS-induced immune disorders:

  • which antigens?
  • which type of immune response?
  • identify safety signals - look at possibility this is happening
  • response to an infection that then becomes an autoimmune disease
• which immune responses are protective?

  antibodies, cells?

  mucosal responses?

  immune correlate of infection - key thing to identify

  • likely combination of responses, T, B, humoral
• large expensive vaccine trials required

  controlled human infection models

  genuinely low in the population, would be expensive to fund
• reverse vaccinology and GAS

  • 2000 genome sequences
  • 15 high conserved, widely expressed surface expressed proteins

  likely good targets for vaccine:
• reverse vaccinology and GAS

  cant use whole cell vaccines

  serotype/strain diversity

  3 proteins induced protection in mice

  • SpyAD
  • SpyCEP
  • SLO

  GSK combo vaccine - also induces group A carbohydrate - mixed carb and protein and vaccine

  more conserved regions = more immunogen

  more variable = immunodominant

  the dawn of immunoinformatic

  • human immune repertoire
  • screen T and B cell epitopes using in silico algorithm/database (IEDB)
• GAS research in Bristol

  characterise T and B cell responses to GAS infection in different clinical groups

  mucosal responses

  bacterial gene expression in clinically relevant scenarios - look at host response at site of infection

  different epidemiology at different types of infection

  rational approaches to inform vaccine development
• GAS young v old

  invasive in the very young and very old

  pharyngitis in the very young

  increasing in age before old, have protection against milder form of infection

  as get older it protects us
• adaptable vaccine platforms

  vaccine manufacturing approaches which can be rapidly adapted to insert new antigens

  ideally suited to allow rapid responses to emerging pathogens within pandemic potential
• how were SARS-CoV-2 vaccines developed at rapid speed?

  decades of pre-existing research in multiple areas:

  • funding - governments + funding bodies joined forces to remove financial obstacles
  • sequencing
  • manufacturing - produced large batches
  • mRNA and vector biology technology
  • volunteers - no issue recruiting as many volunteered
  • priority and collaboration - scientists, doctors, ethics, approval boards etc came together to work harder and faster
• technology for emerging pathogens - most vaccines take years to develop


  meningitis - ~90 years

  polio - ~50 years

  SARS-CoV-2 produced in days for testing to be taken through clinical trials as pandemic and infection spreading - record time - genome sequence available,
• how do mRNA vaccines work

  genetic sequence of virus spike used to make synthetic mRNA sequence - instructions to make spike protein

  mRNA packaged into lipid naoparticle - vaccine - which can deliver mRNA to immune cells

  immune cells follow mRNA code to produce spike protein, displayed on cell surface, stimulating immune response

  innate immune response in target cells

  taken up by dendritic cells in particular

  produce in large amounts and stimulate response in T-cells and antibody
• viral vector vaccines example = ChAdOx-S1

  • oxford vaccine group
  • pipeline established for other infections including MERS (2018)
  • rapidly deployed to develop new COVID-19 vaccine in early 2020 - also included S protein

  spike protein important in MERS and SARS - quickly look at it

  take adenovirus vector and insert S into it to produce at rapid speed
• problems with current SARS-CoV-2 vaccines?

  problems

  • provide short term protection against severe disease - not long lived, need boosters
  • not able to prevent transmission
  • must be stored at low temperatures
• what's next for SARS-CoV-2 vaccines

  live attenuated vaccine

  mucosal administration? - nasal spray, more mucosal immunity - protection against initial infection and therefore transmission

  seasonal vaccination like influenza?

  combat vaccine hesitancy - problem in high roll out as people were against them
• CHIMs - controlled human infection models


  carefully managed research study during which volunteers exposed to infection in safe way and with healthcare support

  valuable tool for understanding the underlying immunological response to infection and enabling accelerating and de-risking the development of novel drugs and vaccines

  robust ethical review processes in place to protect safety of volunteers
• example of CHIMs


  Edward Jenner

  • CHIM model on gardners son - trialled vaccine for smallpox
  • few weeks later infected him with smallpox after vaccine
  • vaccine from cowpox protected him so didnt get smallpox
• ethical considerations around CHIMs

  seemingly breach the do not harm principle

  weigh risk of individual harm with global population health impact

  ethical principles similar to phase 1 clinical trials - individuals given potentially harmful product

  informed consent process is critical - people understand the risks

  appropriate renumeration - given some compensation - money, however not too much so isn't an incentive
• SARS-CoV-2 CHIM


  in UK with young adults

  shows low risk of infection to SARS-CoV-2
• GAS CHIM


  young adults taken who are not already infection with strain

  challenged by placing pathogens on back of throat

  some didn't get it as naturally protected from infection
• SARS-CoV-2 CHIM Summary


  unique findings on viral kinetics, sites of infection, and performance of tests

  was not set up fast enough to support evaluation of first vaccines

  may have ongoing utility to study vaccine effectiveness vs transmission - sterilising immunity
• ongoing challenges HIV


  HIV

  • high mutation rate - antigenic variability - even within same individual
  • infects T-cells
  • infection and can be latent
  • must do better than nature - some long term, non progressors - don't actually clear the infection
  • no natural example of viral clearance
• ongoing challenge influenza - moving targets

  influenza

  • different strains can combine and have potential to become pandemic
  • multiple types A, B, C and strains
  • Variability - antigenic shift and drift
  • -seasonal flu - vaccine generated annually, variable efficacy
  • -pandemic flu
  • original antigenic sin
  • universal influenza vaccine? - based on antigens not so variable
• challenge - improving vaccines for old diseases - tuberculosis


  tuberculosis

  • >1.4 million deaths/year
  • current vaccine - BCG (live attenuated) - safe cheap, variable efficacy
  • large proportion latently infected (25%)
  • ideal vaccine would prevent infection and progression
  • immunity - cell mediation
  • recent signs for hope:
  • -re-vaccination with BCG in adolescence protects vs sustained infection
  • -new subunit vaccine M72-AS01 provided 49.7% efficacy after 3 years
• vaccines needed for tuberculosis - cell mediated

  this pathogen is different to what is normally illicit in vaccines

  • most vaccines illicit antibody response which can be effective, clear infection, prevent and protect against it
  • for Tb need cell mediated disease - intracellular bacteria that lives within macrophages to kill these bacteria even in latency
  • requires CD4 T-cells to activate infected cells towards killing the bacteria
  • T-cell mediated immunity is important - however hard to illicit in vaccine or for long period of time
• making vaccines equitable


  requires international collaboration

  improving production capacity in LMICs

  • india now major contributor to global vaccine supply
  • cost effective manufacturing - serum institute in India - make lower costed vaccine compared to others, huge player in cheaper and more affordable vaccines in COVID-19
• making vaccines equitable for LMICs

  malaria = new vaccines RTS,S & R21/Matrix

  Meningitis A = MenAfrVac vaccine

  • WHO, PATH, Serum institut India
  • protein conjugate vaccine
• therapeutic vaccines


  vaccines can help treat an illness after it's acquired

  cancer

  • theoretically possible
  • new technologies for neoantigens, personalised vaccines
  • challenging - tumours have multiple immune evasion mechanisms

  HIV

  Alzheimer's disease

  • vaccine for the amyloid beta