L7 Vaccines and vaccine development Flashcards
What is immunisation
- Is an artificial process by which an individual is rendered immune
Types of immunisation
Passive immunisation - no immune response in recipient
Active immunisation (vaccination) - recipient develops a protective adaptive immune response
- One of the cheapest and most effective methods of improving survival and reducing morbidity
- Estimated reduction in mortality worldwide 3 million/yr
What is passive immunisation
- Immunity conferred without an active host response on behalf of recipient
- Passive vaccines are preparations of antibodies taken from hyper-immune donors, either human or animal
- Protection is temporary
Examples of passive immunisation
- Immunoglobulin replacement in antibody deficiency
- VZV prophylaxis eg during exposure during pregnancy
- Anti-toxin therapies eg snake anti-serum
Can VZV affect pregnancy
- VZV during pregnancy can cause fetal complications
- In case of exposure, women should contact their GP
- Urgent VZV serology is available when required
What is active immunisation
- Immunity conferred in recipient following the generation of an adaptive immune response
- General principle is to stimulate an adaptive immune response without causing clinically-apparent infection
Active immunisation - gen principles 1
- To be effective, vaccines need to be administered to targeted cohorts in advance of exposure to the pathogen of interest
- Vaccination of sufficient numbers impacts the transmission dynamic so that even unimmunised individuals are at low risk (called herd immunity)
- As vaccines are given to healthy individuals, the risk-to-benefit ratio requires that vaccines meet high safety standards
Active immunisation - gen principles 2
- Most vaccines work by generating a long-wasting, high-affinity IgG antibody response
- These antibodies are sufficient to prevent primary infection
- A strong CD4 T cell response is a pre-requisite for this
- The most effective vaccines are for diseases where natural exposure results in protective immunity
- ‘Problem’ diseases are generally those where the immune system cannot eliminate infection or generate long-lasting protective immunity during natural infection (eg common cold, MTB, HIV, malaria)
What goes into a vaccine
Antigen - to stimulate an antigen-specific T and B cell response
Adjuvants - Immune potentiators to increase the immunogenicity of the vaccine
‘Excipients’ - various diluents and additives required for vaccine integrity
Classification of active vaccines on the basis of the antigen
Active vaccines – whole organism + subunit
Whole organism – live-attenuated + inactivated (killed)
Examples of subunits
- Toxoids
- Capsular polysaccharides
- Conjugated polysaccharide
- Recombinant subunit
Features of live-attenuated vaccines
- Prolonged culture ex vivo in non-physiological conditions
- This selects variants that are adapted to live in culture
- These variants are viable in vivo but are no longer able to cause disease
Examples of live-attenuated vaccines
- Measles
- Mumps
- Rubella
- Polio (sabin)
- BCG
- Cholera
- Zoster
- VZV (not routinely used for primary prevention in UK at present)
- Live influenza (not routinely used in UK at present)
Pros of live vaccines
- Replication within host, therefore produces highly effective and durable responses
- In case of viral vaccine, intracellular infection leads to good CD8 response
- Repeated boosting not required
- In some diseases, may get secondary protection of unvaccinated individuals, who are infected with the live-attenuated vaccine strain eg polio
Cons of live vaccines
- Storage problems, short shelf-life
- May revert to wild type (eg vaccine associated poliomyelitis: around 1 in 750 000 recipients)
- Immunocompromised recipients may develop clinical disease
Features of varicella-zoster vaccine
- Primary infection - chickenpox
- Cellular and humoral immunity provide lifelong protection, but viruses establishes permanent infection of sensory ganglia
- Viral reactivation = zoster
- Particularly elderly, fairly debilitating and may cause long-term neuropathic pain
How does the varicella-zoster vaccine work
- Live-attenuated VZV, works by induction of anti-VZV antibodies
How effective is the varicella-zoster vaccine
- 95% effective at preventing chickenpox
Is it possible for a subsequent zoster after a varicella-zoster vaccine
- Attenuated virus does establish infection of sensory ganglia, but subsequent zoster is probably rare
- 3-5% mild post-vaccination varicella infection
Why is the varicella-zoster vaccine not on UK schedule at the moment
VZV is a fairly benign childhood infection
Safety concerns based on evidence from other countries
- ‘Disease shift’ to unvaccinated adults, in whom VZV is less well tolerated
- Increase in zoster - probably reduced immune boosting in adults
Link between zoster, immunity and ageing
- The incidence of zoster increases with age, in parallel with declining cell-mediated immune responses to zoster
Preparation of zoster vaccination
- Similar VZV preparation, but much higher dose
- Aims to boost memory T cell responses to VZV
- In over 60s, 50% reduction in zoster incidence after vaccination compared to controls; reduced severity and complications amongst vaccinated cases
What is poliomyelitis
- Enterovirus establishes infection in oropharynx and GI tract (alimentary phase)
- Spreads to peyers patches then disseminated via lymphatics
- Haematogenous spread (viremia phase)
- 1% of patients develop neurological phase: replication in motor neurones in spinal cord, brainstem and motor cortex, leading to denervation and flaccid paralysis
Features of sabin oral polio vaccine (OPV)
OPV - live attenuated
- Viable virus can be recovered from stool after immunisation
- Highly effective, and also establishes some protection in non-immunised population
- 1 in 750 000 vaccine-associated paralytic polio
Features of salk injected polio vaccine (IPV)
IPV - inactivated
- Effective, but herd immunity inferior
- OPV better suited to endemic areas, where benefits of higher efficacy outweigh risks of vaccine-associated paralysis (UK switched to IPV in 2004)
Features of TB
- During primary infection, MTB establishes infection within phago-lysosomes of macrophages
- Macrophages present TB antigen to MTB-specific CD4 T cells, which secrete IFN-g - this activates macrophages to encase TB in granuloma
- May be visible as a calcified lesion on plain CXR (ghon focus)
- Most TB thought to be re-activation of this primary infection
Features of TB vaccination
- Only licensed product is BCG
- Produced by repeat passage of a non-tuberculus mycobacterium: mycobacterium bovis
- Aims to increase Th1 (IFN-g) cell responses to M bovis, thereby conferring protection against MTB
how is a TB vaccination given
- By intradermal injection
How effective is the TB vaccination
- 80% effective in preventing disseminated TB/TB meningitis in children; little or no effect on pulmonary TB
Features of killed (inactivated) vaccines
- Entire organism used, but physical or chemical methods used to destroy viability (eg formaldehyde)
- Stimulates B cells, and taken up by antigen-presenting cells to stimulate antigen-specific CD4 T cells
- Probably elicit minimal CD8 response, as the vaccine cannot undergo intracellular replication
- Responses less robust compared to live-attenuated vaccines
Examples of killed(inactivated) vaccines
- Hepatitis A
- Influenza (standard vaccine - live-attenuated also available but not routinely used)
Pros of killed vaccines
- No potential for reversion
- Safe for immunocompromised
- Stable in storage
Cons of killed vaccines
- Mainly CD4/antibody response
- Responses less durable than live vaccines(generally boosters required)
- Higher uptake generally required to achieve herd immunity
Structure of influenza virus
- The internal antigens (matrix and RNP) are the type-specific proteins and are used to determine whether a particular virus is A, B, or C
- The external antigens (hemagglutinin and neuraminidase) are subtype and strain-specific antigens of influenza A virus (H1N1, H2N2, H3N2)
What are protective antibody responses largely directed against
- Protective antibody responses largely directed against haemagglutinin and neuramidase, and probably mostly work by blocking entry to cells, blocking release of new virions from infected cells and promoting ADCC
Difficulties of influenza vaccination
- Target antigens prone to mutation (antigenic drift) causing seasonal variation (therefore vaccine produced annually based on predictions)
- CDC provide candidate virus strains to manufacturer, injected into fertilised hens eggs and virus then harvested (inactivated for standard vaccine)
- More major changes (antigenic shift) occur when viral strains recombine - eg with animal strain, causing pandemic influenza
Features of subunit vaccines
- Uses only a critical part of the organism
- Components may be:
Purified from the organism or
Generated by recombinant techniques - Protection depends on eliciting CD4 and antibody responses
Examples of toxoids
Many examples relate to toxin-producing bacteria
- Corynebacterium diphtheriae
- Clostridium tetani
- Bordatella pertussis
What are toxoids
- Toxins are chemically detoxified to ‘toxoids’
- Retain immunogenicity
- Work by stimulating antibody response; antibodies then neutralise the toxin
Response to tetanus toxins
- Pre-formed high-affinity IgG antibodies can neutralise the toxin molecules in the circulation; the immune complexes are then removed via the spleen
- Anti-toxin can also be given in established cases(passive immunisation)
Features of subunit vaccines: polysaccharide capsules
- Thick polysaccharide coats of strep. penumoniae and neisseria meningitidis make them resistant to phagocytosis
- Vaccines for these organisms formed of purified polysaccharide coats
Aim of vaccines formed of purified polysaccharide coats
- Aim to induce IgG antibodies that improve opsonisation
- Suboptimal as polysaccharides are weakly immunogenic (no protein/peptide, so no T cell response, stimulate a small population of T-independent B cells)
- Latest vaccines utilise vaccine conjugation to boost responses: protein carrier attached to polysaccharide antigen
What is vaccine conjugation
- Naive B cell expressing surface IgM recognises polysaccharide antigen. Antigen is internalised together with the protein conjugate
- Conjugate is processed in the class II pathway. Naive B cell presents peptides from the conjugate to a helper T cell with the correct receptor
- T cell helps the B cell to perform affinity maturation, but antibody is specific for the polysaccharide and not for the protein conjugate
Features of recombinant protein subunit vaccine
- Knowledge of key immunogenic proteins required
- Proteins expressed in lower organisms
- Purified to produce vaccine(Hep B surface antigen, HPV vaccine)
- This approach is increasingly employed in vaccine development
Major HPV subtypes linked to cervical carcinoma
- HPV subtypes 16 and 18 infection major causal factor in cervical carcinoma
Why is HPV vaccine development difficult
- HPV is difficult to culture
What are subunit vaccines
Empty virus particles that prevent primary infection
What is a quadravalent vaccine
- Covers additional HPV strains (genital warts, penile cancer)
Pros of subunit vaccines
- Extremely safe
- Work well where primary infection may be prevented by an antibody response
- Works when the virus cannot easily be cultured eg HPV and Hep B
Cons of subunit vaccines
- Development requires detailed knowledge of virology, pathogenesis and immunology
- Specialised and expensive production
- Weaker immune responses (boosting often needed and response rate varies)
Function of adjuvants
- Boost immune response to the antigen
- Widely used, but mechanism understood only relatively recently
Examples of adjuvants
- Alum
- Lipopolysaccharide
How do adjuvants work
- Work by binding to pattern-recognition receptors on antigen presenting cells which enhances co-stimulation and cytokine secretion, which ensures a robust T/B cell response
- Important field for development in order to improve responses to subunit vaccines
Examples of novel adjuvants
- Toll-like receptor ligands eg CPG repeats
Novel approaches: DNA vaccines
- Plasmid DNA that encodes vaccine antigen of interest applied; taken up by cells, transcribed and translated
- Elicits host immune response
- Mainly performed in mice models
- Poorly immunogenic to date in human trials
Novel approaches: viral vector
- Benign virus that can be easily grown in culture engineered to carry genes encoding immunogenic antigens
- Altered virus used as a live-attenuated vaccine
- Use restricted to animals to date
