Foundations in Pharmacology PHRM2005 Vaccines – Part A PDF

Foundations in Pharmacology PHRM2005 Dr Ricky Lareu Vaccines – Part A 1 2 Information See Lecture Outline document for Key Concepts, Learning Outcome and Lecture Summary Reading and reference material: Mim’s Medical Microbiology 5th Ed, Chapter 34 3 Vaccine Principle and Aims Principle To prime the...

Foundations in Pharmacology PHRM2005 Dr Ricky Lareu Vaccines – Part A 1 2 Information See Lecture Outline document for Key Concepts, Learning Outcome and Lecture Summary Reading and reference material: Mim’s Medical Microbiology 5th Ed, Chapter 34 3 Vaccine Principle and Aims Principle To prime the adaptive immune system to the antigens of a particular microbe so that on first contact with the live organism a rapid and effective secondary immune response will be induced by memory T and B cells. Aims: Public health - The most ambitious aim of vaccination is eradication of the disease e.g. smallpox, the eradication of polio is being attempted Individual level - to protect the individual against symptoms or pathology from infectious diseases e.g. diphtheria and tetanus vaccines only induce immunity against the toxins produced by the bacteria 4 Historical Perspective Evidence that as early as 2,500 years ago, people knew immunity worked Greek physicians noticed that people who survived smallpox never got it again The insight: becoming infected by certain diseases gives immunity 5 Immunisation by Variolation In China, developed the technique of variolation, far back as 10th-century Variolation – immunisation for smallpox The deliberate infection with smallpox – from infected patient to recipient ‘Variola’ – from Latin ‘varus’ – mark on the skin Ground dried scabs were blowing into nostrils Dried scabs (from mild cases)were blown into the nose of an individual who then contracted a mild form of the disease Upon recovery, the individual was immune to smallpox Not risk-free but effective: between 1%-2% of those variolated died compared to 30% who died when they contracted the disease naturally 6 Advent of Modern Immunisation Edward Jenner The first to publish scientific results Observed that milk maids infected with cowpox (mild disease) were resistant to smallpox (already folklore) In 1796, Inoculated a poor farm boy with fluid from a blister/pox of a cowpox-infected milk maid Weeks later he challenged the boy with an injection of a lethal dose of smallpox  boy was protected from smallpox Immunised 1000s in his garden shed! During the 20th century, it is estimated that smallpox was responsible for 300–500 million deaths Smallpox eradication – last case in 1977 7 Advent of Modern Immunisation cont. Louis Pasteur, 1822-1895 Recognised as the Father of microbiology. Responsible, with Robert Koch, for demonstrating that spontaneous regeneration did not exist and the microbes originated for existing, contaminating microbes. Developed the process of sterilisation i.e. pasteurisation. Recognized the value of Jenner’s work and believed that vaccines could prevent many infectious diseases. Developed the idea of attenuated microbes (weakened organisms). Pasteur developed vaccines for chickenpox, cholera, rabies, and anthrax by using attenuated pathogens 8 Vaccines Save Lives Vaccines are one of the most effective public health tool  very cost-effective as a public health measure  save many lives - immunization saves an estimated 2.5 million lives each year from diphtheria, tetanus, pertussis and measles  an estimated 1.5 million people still died from a vaccine-preventable disease, as a result of poor vaccine uptake and supply to remote and wartorn areas 9 Global Coverage 10 Major Diseases without Vaccines Currently lack effective vaccines against these organisms Most of the deaths from HIV are in Africa, and most of the deaths from malaria are in African children (Sources: Figures for 2015 from WHO) Disease Estimated annual deaths (millions) AIDS 1.1 Mycobacterium tuberculosis Tuberculosis 1.8 Plasmodium spp. Malaria 0.4 Organism HIV Total 3.3 Although bacille Calmette–Guérin (BCG) vaccination can provide protection against disseminated forms of childhood tuberculosis, and pulmonary tuberculosis in some parts of the world. 11 How Vaccines Work 1) Expose a patient to an antigen(s) from a pathogen: can be whole organism: live (attenuated), inactivated (killed) or components (e.g. protein, polysaccharide) must be capable of producing a specific immune response 2) The patients immune system responds: by mounting a limited response = primary immune response followed by memory cells – years to life-time immunity Adapted from https://prezi.com/yyajzxpb8k_g/vaccinations/ 3) A subsequent exposure to the wild-type pathogen/antigen: the immune system will be challenged and memory cells and long-lived plasma cells producing antibodies will respond quickly to kill/ neutralise pathogen and avoid illness = secondary immune response 12 Vaccines Prime the Immune System http://nrvs.info/faqs/toomanytoosoon/ 13 There are Different Types of Vaccines Vaccines can be based on whole organisms, either live or inactivated, or components of the infectious agent The key principle for vaccine design - The more similar a vaccine is to the disease-causing form of the organism, the better the immune response to the vaccine e.g. polio vaccines Types of vaccine Examples Live attenuated Viral Measles, mumps, rubella, vaccinia, varicella, yellow fever, zoster, oral polio, intranasal influenza, rotavirus Bacterial BCG, oral typhoid Inactivated Whole virus Polio, influenza, hepatitis A, rabies Whole bacteria Pertussis, cholera, typhoid Fractions Toxoids Diphtheria, tetanus Protein subunits Hepatitis B, influenza, acellular pertussis, human papillomavirus Polysaccharides Pneumococcal, meningococcal, Salmonella typhi (Vi),Haemophilus influenzae type b Conjugates Haemophilus influenzae type b, pneumococcal, meningococcal Note that not all types of vaccine are available in all countries. Vaccines are also available for bioterrorism agents such as anthrax and plague, and for vaccinia. 14 Live Attenuated Vaccines Usually created from the naturally occurring pathogen The vaccine pathogen can still infect people but they very rarely cause serious disease – can most closely mimic natural infection Viruses are weakened (or attenuated) by growing them over and over again in a laboratory under nourishing conditions  lessen the disease-causing ability of the virus i.e. virulence factors lost Mostly possible with viruses due to relatively simple genome e.g. measles, mumps, rubella, oral polio Also possible for bacteria e.g. BCG, oral typhoid 15 Pros and Cons Advantages Replicate immune response is closer to the natural infection Usually effective with 1-2 doses Disadvantages Generally not suitable for immunocompromised patients or during early pregnancy Concern about recreating a wild-type pathogen that can cause disease, although very minute possibility e.g. Oral Polio Vaccine (OPV, Sabin) – approx. 1/2.7 million 1st doses vaccine virus can cause paralysis Fragile – must be stored carefully and difficult to get to remote places e.g. MMRV vaccine must be stored between 5 and -15 °C 16 Measles, Mumps, Rubella (MMR) MMR – MMR-II and Priorix Contain live attenuated viruses: measles, mumps, rubella and varicella (for Priorix-tetra) Requires 2 doses: 1 and ~4 yrs (13 months-5 years)  Because 1st dose confers immunity to 95% of recipients, and 2nd dose gives 99-100%  Confers life-long immunity Contraindication:  immunosuppressed: HIV/AIDS, immunosuppressive therapy, chemo and radiation therapy  Pregnancy, need to wait 28 days after vaccine MMRV (MMR + varicella) – Priorix-tetra, given only as second dose 17 Inactivated (killed) Vaccines Inactivated vaccines contained killed, whole microorganisms. They cannot replicate and cause an infection. They still stimulate a protective immune response. Viruses are inactivated with chemicals such as formaldehyde and glutaraldehyde; antigens still present. Advantages: No chance of recreating live pathogen i.e. no reversion to virulent form Safe to use in the immunocompromised individuals Disadvantages: Cannot replicate and thus generally not as effective Limited immune response – usually antibody only Usually require 3-5 doses for significant immunological memory. 18 Polio Vaccines: Attenuated vs Inactivated The inactivated polio vaccine (IPV), Salk vaccine, 1954 The attenuated Oral polio vaccine (OPV), Sabin vaccine, 1960s Inactivated (IPV) Attenuated (OPV) Introduced Salk 1954 Sabin 1957 Route Injection plus alum Oral Advantages Can be given with other childhood vaccines Disadvantages Risk if Reversion to inadequately killed virulence* Boosts IgA immunity^^ Herd immunity ^^ Reproduces natural infection – produces mucous membrane immune mechanism, IgA, which stops transmission i.e. replication in gut - which IPV does not  Still a significant problem in many developing countries * vaccine-associated paralytic polio (VAPP) – 1/1 million doses 19 Attenuated vs Inactivated Immune Response Inactive (Salk) Vaccine 512 Attenuated (Sabin) Vaccine Serum IgG Serum IgG Reciprocal virus antibody titer 128 32 Serum IgM Serum IgM Nasal IgA Serum IgA 8 Limits wildtype virus replicating Serum IgA 2 Duodenal IgA Nasal and duodenal IgA 1 48 Vaccination 96 Days Vaccination 48 96 20 Progress Towards Polio Eradication 1988 2016 From MMM 6th Ed 21 Polio Vaccine in Infanrix Hexa Vaccine Developed countries are only using inactivated polio vaccine as there is limited possibility of spread Infanrix vaccine: a sterile suspension: diphtheria toxoid and tetanus toxoid three purified antigens of Bordetella pertussis (pertussis toxoid (PT), pertussis filamentous haemagglutinin (FHA) and pertactin (PRN)), the purified major surface antigen (HBsAg) of the hepatitis B virus (HBV) purified polyribosyl ribitol phosphate (PRP) capsular polysaccharide of Haemophilus influenzae type b (Hib) covalently bound to tetanus toxoid, adsorbed on aluminium salts three types of inactivated polio viruses (type 1: Mahoney strain; type 2: MEF-1 strain; type 3: Saukett strain) Doses: 6-8 weeks, 4 and 6 months, 4 years 22 Toxoid Vaccines Toxoids are modified bacterial exotoxins. Toxins are treated with iodine, pepsin, ascorbic acid, or formalin to reduce toxicity while retaining the ability to stimulate an immune response. Antibodies directed at the toxoid neutralize exotoxins before they reach the target cell. Examples: Diphtheria and tetanus vaccines contain toxoids which stimulate an immune response Vaccine – Infanrix hexa 23 Protein Subunit Vaccines Only the immunogenic determinant or antigenic molecules critical for protection against pathogen. Originally purified proteins from infected patients but now use recombinant DNA technology to produce specific proteins in yeast. Examples: Hepatitis B virus vaccine – composed of only the surface proteins; HBsAg. Human papillomavirus (HPV) vaccine – composed of the viral major capsid protein. Influenza virus vaccines - composed of the hemagglutinin and neuraminidase subunits. 24 Polysaccharide and Conjugate Vaccines Revolutionised vaccine approach against encapsulated bacterial pathogens. Humoral immunity (antibodies) is critical for protection against encapsulated bacteria but:  Most polysaccharides are T-independent antigens and are usually poor immunogens + no immunological memory  Children up to the age of 2 respond poorly to these antigens, particularly Type 2 T-independent antigens  at high risk e.g. S. pneumoniae and H. influenzae By linking these outer coat polysaccharides to other immunogenic proteins (e.g. toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen  T cell dependent mechanism  strong + memory 25 Polysaccharide and Conjugate Vaccines cont. 26 H. influenzae Type b Conjugate Vaccine – The Gambia Of the 6 capsular sub-types, type b causes 95% infections Conjugated the polysaccharide to Tdependent antigen (e.g. tetanus toxoid) Need 3-4 doses to induce good immunity 27 Summary Evidence show that vaccinations save millions of lives each year and are very safe Vaccines work by priming the immune system:  Provoking a specific primary immune response  When host infected with actual, virulent microbe, a secondary immune response develops  fast and strong There are different types of vaccines consisting of:  Live microbe without virulence components (attenuated)  Killed microbe  Components and product of microbes e.g. purified protein components, polysaccharides from bacterial capsules, inactivated toxins 28 There Will Always Be Debates about Vaccination but the Fact is They Work. http://winkgo.com/vaccines-work-maki-naro/ 29