T1 L8. Vaccines and vaccine development (MTz)(1).ppt

Module 204 Vaccines Dr Michael D Tarzi Senior Lecturer&Honorary Consultant Immunologist Aims • This lecture will cover: – Definitions and historical aspects of immunisation – Classification of immunisations – Examples of passive, live-attenuated, killed and subunit vaccine strategies – Adjuvants...

Module 204 Vaccines Dr Michael D Tarzi Senior Lecturer&Honorary Consultant Immunologist Aims • This lecture will cover: – Definitions and historical aspects of immunisation – Classification of immunisations – Examples of passive, live-attenuated, killed and subunit vaccine strategies – Adjuvants and vaccine conjugation – Novel approaches to vaccination Learning outcomes • You should be able to: – Define the following terms: immunisation, passive immunisation, vaccination – Give examples of passive immunisation strategies – Provide a classification scheme for vaccinations – Describe the merits and drawbacks of different vaccine types, with examples of each – Explain how adjuvants and vaccine conjugation are used to improve responses to vaccination – Describe novel approaches to vaccination Definitions • Immunisation is an artificial process by which an individual is rendered immune • Term includes: – 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 Historical background 1: 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) Historical background 2: 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 Scenario Bloods Action Definite history of previous chickenpox Not indicated Reassure No history of chickenpox or unsure VZV IgG positive Reassure No history of chickenpox, or unsure VZV IgG negative or equivocal VZV immunoglobulin (IG) 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 clinicallyapparent infection General 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 General principles 2 • 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 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 Live-attenuated Whole organism Active Vaccines Inactivated (killed) Subunit Toxoids Capsular polysaccharide Conjugated polysaccharide Recombinant subunit ?mRNA, VLPs, viral vector 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 main product 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 liveattenuated 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 longterm neuropathic pain Varicella-Zoster Vaccine • 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 – ?Schedule is already crowded and controversial – 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 Levin MJ Cur Opin Immunol 2012 Zoster vaccination • Similar VZV preparation to that used for primary disease, 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 Prevaccine 6 wks 1 yr 2 yr 3 yr RCF=responder cell frequency in peripheral blood after stimulation with VZV antigens CD4 T cell responses to VZV virus in vaccine recipients compared to placebo 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 Salk vs 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 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 CalmetteGuerin) • 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 • Weaker responses compared to live vaccines, and no CD8 response, therefore – Responses less durable then live vaccines • Generally boosters required – Higher uptake generally required to achieve herd immunity Influenza • Seasonal viral illness • Protective antibody responses largely directed against haemagglutinin (H) and neuramidase (N) surface antigens • Natural antigenic ‘drift’ each year means that protective immune response from previous years may not be protective • Major antigenic ‘shift’ when virus recombines with animal influenza strain – eg ‘Spanish’ Influenza (1918), H1N1 (2009) Influenza • As immune responses are not durable, CDC attempts to predict likely dominant viruses for next season • Candidate viruses grown in hens eggs and distributed to manufacturers – Killed vaccine is standard UK approach – Live vaccine also available (nasal spray) • Success varies from year to year 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 • Certain newer types of subunit vaccines also elicit CD8 response (eg mRNA) 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 Adjuvants • Boost immune response to the antigen • 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 and M-Protein Tetanus 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 Polysaccharide Protein conjugate B Naive B cell expressing surface IgM recognises polysaccharide antigen. Antigen is internalised together with the protein conjugate MHC II CD 4 CD 4 B B 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 Human papilloma virus vaccination • 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) ‘Novavax’ SARS-Cov2 vaccine • Engineered spike protein expressed in system with cells transfected by baculovirus • Spike proteins assembled into ‘nanoparticle’ – this increases immunogeniticy • Product adjuvanted with ‘Matrix M’, a saponin-based adjuvant • Efficacy 90.4% (infection) and 100% (severe disease) against alpha variant – in vitro and boosting studies support activity against current variants Malaria R21-Matrix M • Circumsporozoite-based protein (CSP) raises immune response which targets preerythrocytic phase of plasmodium falciparum • Vaccine is a fusion of Hepatitis B surface antigen and CSP to form a virus-like particle • Much more immunogenic with better efficacy compared to existing CSP-based vaccine Infants age 5-17 months 3 doses for primary vaccination course Group 3 = placebo vaccine Groups 1 and 2 both active R21 vaccine, differ only in quantity of adjuvant Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Terms and Conditions (10.1016/S0140-6736(21)00943-0) The Lancet 2021 3971809-1818DOI: 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 New approaches: mRNA vaccines • For mRNA vaccines, sequence generated which codes for critical pathogen antigens – Delivered via vector eg lipid nanoparticles OR ex vivo (harvest circulating monocytes then return to recipient) – Sequence translated by host cells to produce encoded antigens, which then stimulates host immune response • In development since 1990s • Key technical challenges – Preventing degradation of mRNA – solution was lipid nanoparticle delivery – Inflammatory response caused by mRNA – solution was modifying nucleosides • Potentially rapidly available and modifiable; relatively quick and easy to produce and adapt once facility established • Utilised in new SARS-CoV2 vaccines made by Pfizer and Moderna; mRNA codes for viral spike protein 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 or a non-replicating viral vaccine Challenges – – • • • Pre-existing immunity to viral vector Immune responses to viral vector may affect later use Astra-Zenica SARS-CoV2 vaccine utilises replication-deficient Simian adenovirus carrying spike protein gene Russian Sputnik V vaccine uses similar approach, but with two different replication-deficient human adenovirus vectors – one for priming, one for boosting Johnson and Johnson product is another replication-deficient simian adenoviral vector; trialled to demonstrate single-dose protection Example of lenteviral vaccine transduction Learning outcomes • After this lecture, you should be able to: – Define the following terms: immunisation, passive immunisation, vaccination – Give examples of passive immunisation strategies – Provide a classification scheme for active vaccinations – Describe the merits and drawbacks of different vaccine types, with examples of each – Explain how adjuvants and vaccine conjugation are used to improve responses to vaccination – Describe novel approaches to vaccination