Immunological basis of vaccines

1. Immunological basis of vaccines G. Walzl For MBChB II Respiratory block 2013

2. What is a vaccine? • Biological preparation • Improves immunity (protection to a disease) • Contains agents that resemble the disease-causing agent: • Weakened or killed microbe, toxin or protein • Types: • Prophylactic • Therapeutic (against cancer)

3. Figure 1-1 The name ‘vaccine’: from use of cow pox (Variolavaccinia, from Latin for cow= vacca) • Attributed to Edward Jenner, although the Chinese practiced this 800 years earlier already), followed by the Turks and introduced to England by Lady Mary WortlyMontague • 1796, cowpox (vaccinia) vaccination against smallpox • By 1979: smallpox eradicated

4. A patient with smallpox

5. Figure 1-2

6. How do vaccines work? • The immune system selects B cells with a high affinity and specificity for the antigen and these become effector or memory cells. This occurs in the germinal centres of secondary lymphoid follicles and requires interactions with other immune cells, like CD4 T cells. The ability to change the isotype of antibody produced (class switching) by a B cell also occurs in germinal centres. • Antigen-specific CD4+ T cells are selected during a primary immune response and expand to produce clones of T cells with high specificity for the activating antigen. • CD8 T-cell responses lead to the generation of large numbers of antigen-specific cytotoxic cells that are capable of directly killing infected cells

7. The three phases of the adaptive immune response: naive, memory, and effector cells. Lymphocytes of the immune system can exist in one of three phases. All cells initially are naive lymphocytes, until antigenic stimulation changes their fate. Some become effector cells, which die once they have completed their effector functions. Others become memory cells, which can also mature into effector cells on re-exposure to antigen. From: Immunobiology

8. …How do vaccines protect? • Antigen-specific cells can increase 105-fold during an acute infection because of rapid cell division. • The adaptive immune response can develop the right combination of gene segments to deal with the particular pathogen through clonal selection. It can rapidly expand that cell population to mount a primary response with 2 effects: • elimination of the infectious agent • generation of memory cells that can rapidly and specifically respond to any reinfection (secondary response). • Memory cells form the third phase of the immune response, when they encounter their antigen again, undergo rapid proliferation, so that an effective secondary immune response is developed even more rapidly—within a few days.

9. Figure 1-20 Memory is an important feature of the adaptive immune response and vaccines are based on this feature.

10. Effects of vaccine-induced protection CD8+ memory T cells • Memory B cells • differentiate into plasma cells • Circulating antibody protects CD4+ memory T cells Induction of apoptosis

11. Types of vaccines • Killed microbes (killed by heat or antibiotics or formaldehyde), i.e. influenza, cholera, plague, polio, hepatitis A, rabies vaccines) • Attenuated • durable immunological responses and are the preferred type for healthy adults • Mostly viral, cultivated under conditions that disable their virulent properties, • Or use closely related but less dangerous organisms to produce a broad immune response, i.e. BCG, a live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin by passaging M. bovismultiple times on a special agar) • Other examples: yellow fever, measles, rubella, and mumps and the bacterial disease typhoid) • Toxoid: inactivated toxic compounds that cause illness rather than the microorganism, i.e. against tetanus and diphtheria.

12. …types of vaccines • Subunit: fragment of a protein of the microbe, rather than the whole organism, • i.e. Hepatitis B vaccine: composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients, now produced by recombinant yeast into which the viral protein gene has been inserted), • the virus-like particle (VLP) vaccine against human papillomavirus (HPV) containing the viral major capsid protein, • hemagglutininand neuraminidase (HA) subunits of the influenza virus. • Conjugate: some bacteria have polysaccharide outer coats that are poorly immunogenic. Outer coats can be linked to proteins so that the immune system recognizes the polysaccharide as if it were a protein antigen, i.e. Haemophilusinfluenzae type B vaccine.

13. …types of vaccines • Experimental: new approaches that are being studied • Dendritic cell vaccines: combine dendritic cells with antigens to present the antigens to lymphocytes, i.e. anti-cancer vaccines (treatment) • Recombinant Vector – by making use of the properties of of one micro-organism (i.e. non-virulent persistence) and the DNA of the other, immunity can be created against diseases that have complex infection processes, i.e. experimental TB vaccines (modified vaccinia Ankara expressing the TB antigen antigen 85A) • DNA vaccination – the DNA from an infectious agent is inserted into human cells. Due to the continuous expression of the associated protein for a very long time and lead to long-lasting immunity. • Valence of a vaccine • Monovalent/univalent: against a single pathogen • Multivalent/polyvalent: one vaccine against more than one strain of the same or against more than one organism. Sometimes the different vaccines can interfere with each other.

14. Vaccination schedules • Differ depending on setting, i.e. developed versus developing world- see pediatric lectures for SA schedules • Common vaccines offered to children include hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia • To reduce number of injections in first 2 years of life and to improve compliance, combination injections are now often used, i.e. MMRV • Specific vaccinations are recommended for special situations, like older ages and repeat vaccination, • Human papilloma virus before girls become sexually active • Elderly: pneumococcus and influenza • Health care workers: influenza (hepatitis B, although this should be for all)

15. Vaccine production • Antigen needs to be generated: • i.e. viruses grown on primary cells like chicken eggs (flu), or on cell lines (hepatitis A), and more and more on cultured mammalian cells • bacteria are grown in bioreactors (i.e. Hib) (large flasks with bacteria that express the antigens) • Recombinant proteins can be produced by viruses, bacteria or yeast and isolated after production through i.e. ultrafiltration, column chromatography • Adjuvants stabilizers, preservatives are added

16. Other compounds in vaccines • Aluminum salts as adjuvants. Adjuvants improve the immunogenicity/immune response of the vaccine. Allow lower dosing • Antibiotics- prevent bacterial contamination • Egg protein if produced in egg • Formaldehyde in vaccines where bacterial toxins, viruses or live bacteria need to be killed/inactivated • Monosodium glutamate (MSG) and 2-phenoxyethanol as stabilizers against heat, light and humidity • Thimerosal contains mercury and prevent bacterial growth- used in multi-dose vaccine preparations

17. Vaccine delivery systems • Oral (i.e. polio) • Percutaneous, subcutaneous • Intramuscular • Nanopatch(needle-free) • Aerosol • Genetically engineered plants…

18. Opposition to vaccination • Benefits far outweigh the risks on population level. • At individual level this can be more complicated when the overwhelming majority of the population is vaccinated and protected • Safety: disasters have occurred • Luebeck disaster: live MTB was accidentally given to 251 children in 1929, of whom 72 died and 135 got active TB. • Formalin inactivated respiratory syncytial virus trial in US • Polio vaccine that led to polio in 149 children in the US in 1955 • Link to autism: rejected by scientific consensus, scientist who originally reported this link found to have committed fraud • Religious, ethical, individual liberty issues