Classical Vaccines

1. Classical Vaccines Ole Lund

2. Vaccination • Vaccination • Administration of a substance to a person with the purpose of preventing a disease • Traditionally composed of a killed or weakened micro organism • Vaccination works by creating a type of immune response that enables the memory cells to later respond to a similar organism before it can cause disease

3. Early History of Vaccination • Pioneered India and China in the 17th century • The tradition of vaccination may have originated in India in AD 1000 • Powdered scabs from people infected with smallpox was used to protect against the disease • Smallpox was responsible for 8 to 20% of all deaths in several European countries in the 18th century • In 1721 Lady Mary Wortley Montagu brought the knowledge of these techniques from Constantinople (now Istanbul) to England • Two to three percent of the smallpox vaccinees, however, died from the vaccination itself • Benjamin Jesty and, later, Edward Jenner could show that vaccination with the less dangerous cowpox could protect against infection with smallpox • The word vaccination, which is derived from vacca, the Latin word for cow.

4. Edward Jenner. Vaccine trials The arm of Sarah Nelmes, a dairy maid, who had contracted cowpox. Jenner used material from her arm to vaccinate an eight year old boy, James Phipps. (1798).

5. Early History of Vaccination II • In 1879 Louis Pasteur showed that chicken cholera weakened by growing it in the laboratory could protect against infection with more virulent strains • 1881 he showed in a public experiment at Pouilly-Le-Fort that his anthrax vaccine was efficient in protecting sheep, a goat, and cows. • In 1885 Pasteur developed a vaccine against rabies based on a live attenuated virus • A year later Edmund Salmon and Theobald Smith developed a (heat) killed cholera vaccine. • Over the next 20 years killed typhoid and plague vaccines were developed • In 1927 the bacille Calmette-Guérin (BCG vaccine) against tuberculosis was developed

6. Vaccination since WW II • Cell cultures • Ability to grow cells from higher organisms such as vertebrates in the laboratory • Easier to develop new vaccines • The number of pathogens for which vaccines can be made have almost doubled. • Many vaccines were grown in chicken embryo cells (from eggs), and even today many vaccines such as the influenza vaccine, are still produced in eggs • Alternatives are being investigated

7. Effectiveness of vaccines 1958 start of small pox eradication program

8. Vaccines Today • Vaccines have been made for only 34 of the more than 400 known pathogens that are harmful to man (<10%). • Immunization saves the lives of 3 million children each year, but that 2 million more lives could be saved if existing vaccines were applied on a full-scale worldwide • Many vaccine products of today are short lived • Maintained cool and last < 1 year • The cost for developing new vaccine is estimated to be close to 500 million us $, • and the time span from development to the vaccine marked is between 10 and 30 years

9. R&D Productivity is Down Because of Increased Costs and Decreased Success Rates NME: New Molecule entries Industry R&D Expense ($Billions) No. of NME Approvals 1 Source:PhRMA, FDA, Lehman Brothers

10. By 2002, 25 separate influenza strains in over 28,000 people tested as CAIV reassortants Example: Live Influenza VaccineThe First 36 years FDA VRBPAC Review - #2 John Maassab describes cold adapted influenza viruses Aviron formed Four-year efficacy study FDA VRBPAC Review - #1 First human studies Licensure 6/17/03 First FluMisttm trial 1967 1976 1985 1989 1995 2003 Johnson 1963 - 69 Nixon 1969 - 74 Ford 1974 - 77 Carter 1977 - 81 Reagan 1981 - 89 Bush 1989 - 93 Clinton 1993 - 01 Bush, “W” 2001- William C. Gruber, M.D. VP, Global Clinical Research Wyeth Vaccines Research June 17, 2005

11. Live Influenza Vaccine – FluMist® • Development Time 1967-2003 ( 36 years) • Development Costs >> $1 Billion (3 companies) • Price $45/dose • Launched 2003/04 season • Projected sales >50M doses • Manufactured in ‘03 5M doses in 1st season • Sold in ’03/04 <1M doses • Impact on public health yet to be determined William C. Gruber, M.D. VP, Global Clinical Research Wyeth Vaccines Research June 17, 2005

12. Human Vaccines against pathogens Immunological Bioinformatics, The MIT press.

13. Categories of Vaccines • Live vaccines • Are able to replicate in the host • Attenuated (weakened) so they do not cause disease • Subunit vaccines • Part of organism • Genetic Vaccines • Part of genes from organism

14. Live Vaccines • Characteristics • Able to replicate in the host • Attenuated (weakened) so they do not cause disease • Advantages • Induce a broad immune response (cellular and humoral) • Low doses of vaccine are normally sufficient • Long-lasting protection are often induced • Disadvantages • May cause adverse reactions • May be transmitted from person to person • Cannot repeat vaccination (boost)

15. Subunit Vaccines • Definition: Vaccine composed of a purified antigenic determinant that is separated from the virulent organism. • Advantages • Relatively easy to produce (not live) • Create a better-tolerated vaccine that is free from whole microorganism cells • The vaccine may be purified • Selecting one or a few proteins which confer protection • Disadvantages • Induce little CTL • Viral and bacterial proteins are not produced within cells

16. Subunit Vaccines: Polysaccharides • Definition: A vaccine containing purified capsular polysaccharide antigen from the most common infectious types of Streptococcus pneumoniae, used to immunize against pneumonococcal disease. • Many bacteria have polysaccharides in their outer membrane • Polysaccharide based vaccines • Neisseria meningitidis • Streptococcus pneumoniae • Generate a T cell-independent response • Inefficient in children younger than 2 years old • Overcome by conjugating the polysaccharides to peptides • Used in vaccines against Streptococcus pneumoniae and Haemophilus influenzae.

17. Subunit Vaccines: Toxoids • Definition: A substance that has been treated to destroy its toxic properties but that retains the capacity to stimulate production of antitoxins, used in immunization. • Toxins • Responsible for the pathogenesis of many bacteria • Toxoids • Inactivated toxins • Toxoid based vaccines • Bordetella pertussis • Clostridium tetani • Corynebacterium diphtheriae • Inactivation • Traditionally done by chemical means • Altering the DNA sequences important to toxicity

18. Subunit Vaccines: Recombinant • The hepatitis B virus (HBV) vaccine • Originally based on the surface antigen purified from the blood of chronically infected individuals. • Due to safety concerns, the HBV vaccine became the first to be produced using recombinant DNA technology (1986) • Produced in bakers’ yeast (Saccharomyces cerevisiae) • Virus-like particles (VLPs) • Viral proteins that self-assemble to particles with the same size as the native virus. • VLP is the basis of a promising new vaccine against human papilloma virus (HPV) • Merck, In phase III For more information se: http://www.nci.nih.gov/ncicancerbulletin/NCI_Cancer_Bulletin_041205/page5

19. Genetic Vaccines • Introduce DNA or RNA into the host • Injected (Naked) • Coated on gold particles • Carried by viruses • Vaccinia, adenovirus, or alphaviruses • bacteria such as • Salmonella typhi, Mycobacterium tuberculosis • Advantages • Easy to produce • Induce cellular response • Disadvantages • Low response in 1st generation • That is “Does not work in primates”

20. Epitope based vaccines • Advantages (Ishioka et al. [1999]): • More potent • Better control • Induce subdominant epitopes (e.g. against tumor antigens where there is tolerance against dominant epitopes) • Target multiple conserved epitopes in rapidly mutating pathogens like HIV and Hepatitis C virus (HCV) • Designed to break tolerance • Overcome safety concerns associated with entire organisms or proteins • Epitope-based vaccines have been shown to confer protection in animal models ([Snyder et al., 2004], Rodriguez et al. [1998] and Sette and Sidney [1999])

21. Passive Immunization • Immunity acquired by the transfer of antibodies from another individual, as through injection or placental transfer to a fetus (The outbreak, Dustin Hoffman) • Used in special cases against many pathogens: • Cytomegalovirus • Hepatitis A and B viruses • Measles • Varicella • Rubella • Respiratory syncytial virus • Rabies • Clostridium tetani • Varicella-zoster virus • Vaccinia • Clostridium botulinum • Corynebacterium diphtheriae • Hanta virus

22. Therapeutic vaccines • Vaccines to treat the patients that already have a disease • Targets • Tumors • AIDS • Allergies • Autoimmune diseases • Hepatitis B • Tuberculosis • Malaria • Helicobacter pylori • Concept • suppress/boost existing immunity or induce immune responses.

23. Cancer vaccines • Break the tolerance of the immune system against tumors • 3 types • Whole tumor cells, peptides derived from tumor cells in vitro, or heat shock proteins prepared from autologous tumor cells • Tumor-specific antigen–defined vaccines • Vaccines aiming to increase the amount of dendritic cells (DCs) that can initiate a long-lasting T cell response against tumors. • Therapeutic cancer vaccines can induce antitumor immune responses in humans with cancer • Antigenic variation is a major problem that therapeutic vaccines against cancer face • Tools from genomics and bioinformatics may circumvent these problems Se also: http://cis.nci.nih.gov/fact/7_2.htm

24. Allergy vaccines • Increasing occurrence of allergies in industrialized countries • The traditional approach is to vaccinate with small doses of purified allergen • Second-generation vaccines are under development based on recombinant technology • Genetically engineered Bet v 1 vaccine can reduce pollen-specific IgE memory response significantly • Example of switching a “wrong” immune response to a less harmful one. Figure by Thomas Blicher.

25. Therapeutic Vaccines against Persistent Infections • For example for preventing HIV-related disease progression • Most of the first candidate HIV-1 vaccines were based entirely or partially on envelope proteins to boost neutralizing antibodies • Envelope proteins are the most variable parts of the HIV genome. Vaccines composed of monomeric gp120 molecules induce antibodies that do not bind to trimeric gp120 on the surface of virions • A number of recent vaccines are also designed to induce strong cell-mediated responses. • Escapes from CTL responses are associated with disease progression and high viral loads • Some CTL epitopes escape recognition quickly because they are not functionally constrained, others might need several compensatory mutations because they are in functionally or structurally constrained regions of HIV-1

26. Vaccines Against Autoimmune Diseases • Multiple sclerosis • T cells specific for mylein basic protein (MBP) can cause inflammation of the central nervous system. • The vaccine uses copolymer 1 (cop 1), a protein that highly resembles MBP. Cop 1 competes with MBP in binding to MHC class II molecules, but it is not effective in inducing a T cell response • On the contrary, cop 1 can induce a suppressor T cell response specific for MBP, and this response helps diminish the symptoms of multiple sclerosis • A vaccine based on the same mechanisms is developed for myasthenia gravis More information: http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12667659&query_hl=4

27. Vaccines Market • The vaccine market has increased fivefold from 1990 to 2000 • Annual sales of 6 billion euros • Less than 2% of the total pharma market. • Major producers (85% of the market) • GlaxoSmithKline (GSK), Merck, Aventis Pasteur, Wyeth, Chiron • Main products (>50% of the market) • Hepatitis B, flu, MMR (measles, mumps, and rubella) and DTP (diphtheria, tetanus, pertussis) • 40% are produced in the United States and the rest is evenly split between Europe and the rest of the world [Gréco, 2002] • It currently costs between 200 and 500 million US dollars to bring a new vaccine from the concept stage to market [André, 2002] More information:Gréco, 2002André, 2002

28. Trends • From • Whole live and killed organisms • Problems • Adverse effects • Production • To • Subunit vaccines • Genetic vaccines • Challenges • Enhance immunogenecity