7. Vaccine and vaccine development Flashcards
What is immunisation?
Immunisation is an artificial process by which an individual is rendered immune
Passive and active immunisation
Passive immunisation – no immune response in recipient Active immunisation (vaccination) – recipient develops a protective adaptive immune response
Effects of immunisation
One of the cheapest and most effective methods of improving survival and reducing morbidity
Estimated reduction in mortality worldwide 3 million/ yr
Variolation
Variola =smallpox virus
For variolation, fluid harvested from pustules of recovering individuals and injected under skin of recipient
Crude method of obtaining an ‘inactivated’ vaccine
Documented practice in Far East, Middle East and South Asia from 1000AD
Limited use in UK (1700s)
Jenner
Used fluid from cowpox lesions to protect against smallpox infection in 1796; recipient was James Phipps, aged 8
Subsequently experimented with several other children, including his own infant son; published findings in 1798
The first documented use of a live-attenuated vaccine and the birth of modern immunisation
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
Examples:
Immunoglobulin replacement in antibody deficiency
VZV prophylaxis eg during exposure during pregnancy
Anti-toxin therapies eg snake anti-serum
Protection is temporary
VZV exposure during pregnancy
VZV during pregnancy can cause fetal complications. In case of exposure, women should contact their GP, Midwife or Virology Dept. Urgent VZV serology is available when required
Active immunisation (vaccination)
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
Herd immunity
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
What prevents the primary infection
Most vaccines work by generating a long-lasting, 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
Classifications of active vaccines
Depends on basis of antigen:
Whole organism - live attenuated or inactivated
Subunit - toxoids, capsular polysaccharides, conjugated polysaccharides, recombinant subunit
Live attenuated vaccines
Live but attenuated organisms used
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
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 and cons 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
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
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
Live-attenuated VZV, works by induction of anti-VZV antibodies
95% effective at preventing chickenpox
Attenuated virus does establish infection of sensory ganglia, but subsequent zoster is probably rare
3-5% mild post-vaccination varicella infection
Not on UK schedule at present, because:
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
Zoster, immunity and aging
The incidence of zoster increases with age, in parallel with declining cell-mediated immune responses to zoster
Zoster vaccine
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
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
Sabin polio
Sabin oral polio vaccine (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
Salk polio
Salk injected polio vaccine (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
Tuberculosis
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
TB vaccination
Only licensed product is BCG (bacille Calmette-Guerin)
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
Given by intradermal injection
80% effective in preventing disseminated TB/ TB meningitis in children; little or no effect on pulmonary TB
Killed (inactivated)
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
Hepatitis A
Influenza (standard vaccine – live-attenuated also available but not routinely used)
Pros and cons of killed vaccines
No potential for reversion
Safe for immunocompromised
Stable in storage
Mainly CD4/ antibody response
Responses less durable then live vaccines
Generally boosters required
Higher uptake generally required to achieve herd immunity
What do influenza vaccines target?
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
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
Subunit vaccines: toxoids
Many examples relate to toxin-producing bacteria
Corynebacterium diphtheriae
Clostridium tetani
Bordatella pertussis
Toxins are chemically detoxified to ‘toxoids’
Retain immunogenicity
Work by stimulating antibody response; antibodies then neutralise the toxin
Tetanus vaccine
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)
Subunit vaccines: polysaccharide capsules
Thick polysaccharide coats of Streptococcus pneumoniae and Neisseria meningitidis make them resistant to phagocytosis
Vaccines for these organisms formed of purified polysaccharide coats
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
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
Recombinant protein subunit vaccine
Knowledge of key immunogenic proteins required
Proteins expressed in lower organisms
Purified to produce vaccine
Hepatitis B surface antigen
HPV vaccine
This approach is increasingly employed in vaccine development
HPV vaccine
HPV subtypes 16 and 18 infection major causal factor in cervical carcinoma
Vaccine development problematic as HPV is difficult to culture
Subunit vaccines are ‘empty virus particles’ that prevent primary infection
Quadravalent vaccine covers additional HPV strains (genital warts, penile cancer)
Pros and cons 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
Development requires detailed knowledge of virology, pathogenesis and immunology
Specialised and expensive production
Weaker immune responses – boosting often needed and response rate varies
Adjuvants
Boost immune response to the antigen
Widely used, but mechanism understood only relatively recently
Eg alum, lipopolysaccharide
Work by binding to pattern-recognition receptors on antigen presenting cells
This 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
Novel adjuvants are 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
