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  1. Newer VaccinesforClinical Use Dr.T.V.Rao MD

  2. What is a “Vaccine” • The term vaccine derives from Edward Jenner's 1796 use of the term cow pox(Latin)variola vaccinæ, adapted from the Latin vaccīn-us, from vacca cow), which, when administered to humans, provided them protection against smallpox

  3. Vaccine- Definition • A vaccine is any preparation intended to produce immunity to a disease by stimulating the production of antibodies. Vaccines include, for example, suspensions of killed or attenuated microorganisms, or products or derivatives of microorganisms. The most common method of administering vaccines is by injection, but some are given by mouth or nasal spray.

  4. Dr Jenner and Cow Pox • THE MODERN SCIENCE OF IMMUNOLOGY HAD ITS BEGINNINGS IN 1798 , WHEN THE ENGLISH PHYSICIAN EDWARD JENNER PUBLISHED A PAPER IN WHICH HE MAINTAINED THAT PEOPLE COULD BE PROTECTED FROM THE DEADLY DISEASE SMALLPOX BY THE PRICK OF A NEEDLE DIPPED IN THE PUS FROM A COWPOX BOIL .

  5. Historical Picture of Vaccination

  6. Vaccine stimulates Immune System • A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters

  7. Preparation of Vaccines a. Live attenuated organisms which have been passed repeatedly in tissue culture or chick embryos so that they have lost their capacity to cause disease, but retained an ability to induce antibody response, such as polio (Sabin), measles, rubella, mumps, yellow fever, BCG, typhoid and plague. b. Inactivated or killed organisms which have been killed by heat or chemicals but retain and ability to induce antibody response. They are generally safe but less efficacious than live vaccines and require multiple doses; e.g. polio (Salk), influenza, rabies and Japanese encephalitis.

  8. Preparation of Vaccines c. Cellular fractions: usually polysaccharide fraction of the cell wall of a disease causing organism, such as pneumococcal pneumonia or meningococcal meningitis d. Recombinant vaccines: produced by methods in which specific DNA sequences are inserted by molecular engineering techniques, e.g. DNA sequences spliced to vaccinia virus grown in cell culture to produces an effective influenza vaccine, and Hepatitis B vaccine by similar methods.

  9. Passive Immunity “Vaccination” Toxoids or antisera: are modified toxins made non-toxic to stimulate formation of an antitoxin, such as those produced to protect against toxins of tetanus, diphtheria, botulism, gas gangrene, snake and scorpion venom. Immune globulin: An antibody containing solution derived from human blood in the form of pooled plasma, used primarily for immunity for passive immunization such as for immuno-compromised persons e.g. smallpox response groups. Antitoxin: is an antibody derived from serum of animals after stimulation with specific antigens and used to provide passive immunity in humans.

  10. Life cycle of Vaccination

  11. Timeline of Vaccines • 18th century • 1796 First vaccine for smallpox, first vaccine for any disease • 19th century • 1882 First vaccine for rabies

  12. Timeline of Vaccines • 20th century • 1932 First vaccine for yellow fever • 1945 First vaccine for influenza • 1952 First vaccine for polio • 1954 First vaccine for Japanese encephalitis • 1957 First vaccine for adenovirus-4 and 7 • 1962 First oral polio vaccine • 1964 First vaccine for measles • 1967 First vaccine for mumps

  13. Timeline of Vaccines • 1970 First vaccine for rubella • 1974 First vaccine for chicken pox • 1977 First vaccine for pneumonia • 1978 First vaccine for meningitis • 1981 First vaccine for hepatitis B • 1992 First vaccine for hepatitis A • 1998 First vaccine for rotavirus

  14. World Health OrganisationReports • "Nearly nine million children under 14 years of age die every year from infectious disease. And at least a third of them could be saved if existing vaccines were more widely used, but the rest only if suitable new vaccines were developed..."

  15. Vaccines use in the world • For the past two decades, in most developing countries, vaccination restricted only to the initial EPI vaccines • Where-as in most developed countries, several new vaccines such as Hep B, Hib, meningococcal, pneumococcal, were gradually added to the initial EPI vaccines, • Thus widening the gap in protection against infectious diseases between the rich and the poor

  16. Number of Childhood Vaccines Routinely Used in Developing and Established Market Countries Acell pertussis Pneumococcal * meningoccoal C* Varicella Haemophilus Influenzae Hepatitis B Measles Mumps Rubella DPT Poliomyelitis Hepatitis B** Measles DPT Poliomyelitis BCG *Estimated future use **Used in ~ 50% of global birth cohort

  17. Newer Vaccines

  18. Stages of Review and Regulation for Devloping Vaccines • Phase 1 - Safety, immunogenicity (prelim) • Phase 2 – Immunogenicity, Safety, Dose Ranging • Phase 3 – Efficacy, Safety, Immunogenicity • BLA – Pre-clinical and clinical data to support approval, inspection • Phase 4 – Inspection, Safety, Efficacy, Lot Release • BLA-Supplement (post-approval changes)

  19. Stages of Vaccine Development • Vaccine development proceeds through discovery, process engineering, toxicology and animal studies to human Phase I, II, and III trials. The process can take more than 10 years, depending on the disease.

  20. Stage I Development • The human trials focus initially on safety, involving small groups of people

  21. Stage II of Development • Progress to moderate-sized "target" populations (persons close to the age and other characteristics for whom the vaccine is intended) to determine both safety and the stimulation of immune response.

  22. Stage III of Development • Finally to large target populations to establish whether a vaccine actually prevents a disease as intended (efficacy)

  23. An ideal Vaccine should be …. • Good immune response • Both Cell Mediated Immunity and antibody responses. • Immunity is long lived • Single dose • Safety • Danger of reversion to virulence, or Severe disease in immunocomprised • Stability • Organisms in the vaccine must remain viable in order to infect and replicate in the host • Vaccine preparations are therefore very sensitive to adverse storage conditions • Maintenance of the cold chain is very important. • Expense • Cheap to prepare

  24. Causes of death in children less than 5 years old 20% 20% 19% 13% The Global Burden of Disease Murray and Lopez, editors Total - 12.8 million

  25. New approved vaccines • A number of new vaccines with major potential for controlling infectious diseases have just been licensed or are at advanced stages of development. Among the illnesses targeted are rotavirus diarrhoea, pneumococcal disease, and cervical cancer (as caused by human papillomavirus), which together kill more than a million people each year, most of them in developing countries.

  26. Bacterial Meningitis kills several in Developing world • Haemophilus influenzae type b (Hib) • 30% -50% of bacterial meningitis • Pneumococcus • 25- 35% of bacterial meningitis • Meningococcus • 25 - 35% of bacterial meningitis (except during epidemics)

  27. Meningococcal Meningtis Threat to AFRICA • The African "meningitis belt" - which includes all or part of 21 countries stretching south of the Sahara desert from Senegal to Ethiopia - is the site of frequent epidemics, usually caused by serogroup A meningitis. Over the past decade more than 700 000 cases have been reported. Roughly 10-20 % of persons infected die, and one out of five survivors is likely to suffer from a permanent disability such as hearing loss, mental retardation, or paralysis.

  28. Status of vaccine development Polysaccharide vaccines (vaccines made from complex sugars taken from the outer coats of the Men bacterium) are currently in use, but are not very effective at protecting young children, do not create long-lasting immunity, and do not confer a "herd effect". Because of these shortcomings, immunization with polysaccharide vaccines is usually undertaken only after the onset of an epidemic.

  29. Rotavirus Diarrhoeas Acute diarrhoea is responsible for nearly 1.9 million deaths per year in children under age five. Rotavirus is responsible for as much as one fourth of these casualties, almost all of which occur in developing countries.

  30. Global Density of Rota viral Infections

  31. Status of vaccine development: • RotaRix, a vaccine developed by GlaxoSmithKline (GSK), against rotavirus diarrhoea is now licensed in many countries. In addition to being available on the private market in these countries, it has now been introduced in the public sector immunization programmes of Brazil, El Salvador, Mexico, Panama and Venezuela. . A Phase III trial is also under way in South Africa and Malawi.

  32. Merck & Co.’s RotaTeq • RotaTeq, introduced in 2006 for kids aged 2 months, 4 months, and 6 months, is a highly promising protection against the highly contagious disease –Rotavirus, says CDC. • The Centers for Disease Control and Prevention (CDC) believes that the level of protection provided by the vaccine is much stronger than they originally anticipate

  33. Pneumococcal diseaseand Vaccination • Acute lower respiratory infections are responsible for close to two million deaths per year and a large proportion of these are caused by Streptococcus pneumoniae (pneumococcus).

  34. Prevenarcontain seven serotypes • A seven-valent conjugate vaccine called Prevnar (or Prevenar) is designed to act against seven strains of pneumococcal disease. It has been developed by Wyeth Vaccines and is licensed in the United States and over 70 other countries, but does not include two serotypes (types 1 and 5) that cause a high percentage of pneumococcal illness in developing countries. (

  35. Nine-valent conjugate vaccine a Succesul trial in Gambia • Wyeth Vaccines has also completed evaluation of a nine-valent conjugate vaccine, including serotypes 1 and 5. A Phase III trial of the vaccine involving 40 000 people was completed in South Africa in 2002, and a Phase III trial with 17 437 subjects was concluded in the Gambia in 2004.

  36. Challenges to identify Pneumococcal infections • It can be difficult to establish the extent of pneumococcal disease as developing countries often lack the laboratory facilities, expertise, and resources to do so. As a result, public health decision-makers are often unaware of the prevalence of the disease and of the toll it exacts in death and disability. Because of the scarcity of data from developing countries, there is concern over the appropriate serotype valence for developing countries

  37. Human papillomavirus (HPV) • Sexually transmitted HPV is the major cause of cervical cancer, the most common cause of cancer deaths among women in developing countries. About 5,00 000 cases occur each year, 80% of them in developing countries. Cervical cancer kills some 240 000 women annually.

  38. HPV 16 and 18 major types causing Carcinoma cervix • HPV types 16 and 18 cause around 70% of HPV cervical cancers globally, but the vaccines in development will not cover the 30% of cancers attributed to other HPV types. Because these other types are numerous and individually only contribute a small percentage, significantly expanding vaccine coverage against them may present technical challenges for manufacturers.

  39. Two types of vaccines for Human Papilloma virus prevention • Bivalent human papillomavirus vaccine (HPV2) licensed for use in females • Either HPV2 or quadrivalent HPV vaccine (HPV4) used for females ages 19-26 years • Quadrivalent human papillomavirus vaccine (HPV4) licensed for use in males • HPV4 may be administered to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts.

  40. GARDASIL • Gardasil, an HPV vaccine recently licensed by Merck, covers four types of HPV, including the cancer-causing types 16 and 18 and types 6 and 11 for non-cancerous genital warts. A second vaccine, developed by GSK, covers HPV types 16 and 18 alone

  41. GARDASIL • GARDASIL is the only human papillomavirus (HPV) vaccine that helps protect against 4 types of HPV. In girls and young women ages 9 to 26, GARDASIL helps protect against 2 types of HPV that cause about 75% of cervical cancer cases, and 2 more types that cause 90% of genital warts cases. In boys and young men ages 9 to 26, GARDASIL helps protect against 90% of genital warts cases.

  42. How long vaccination is effectiveandIdeal age for Vaccination • The duration of the immunity conferred by the vaccines is not yet known, and only time and follow up studies will provide this critical information... Because HPV is spread by sexual contact, and the high-risk years for infection are roughly from ages 18 to 25, the best subjects for vaccination will likely be pre-adolescents or adolescents, unlike for traditional vaccination programmes, which are aimed mostly at infants and pregnant women.

  43. FDA approves Gardasil • In October 2009, the FDA approved the use of GARDASIL in boys and young men ages 9 to 26 to protect against 90% of genital warts cases.

  44. Meningococcal meningitis A Vaccine (Men A) • Polysaccharide vaccines (vaccines made from complex sugars taken from the outer coats of the Men bacterium) are currently in use, but are not very effective at protecting young children, do not create long-lasting immunity, and do not confer a "herd effect" - that is, do not prevent spread of the disease in non-vaccinated people through reduction of the carriage of the infectious agent by vaccinated people during epidemics • Because of these shortcomings, immunization with polysaccharide vaccines is usually undertaken only after the onset of an epidemic.

  45. Better Vaccine for Meningococcal Infection • To provide greater and more efficient protection, a public-private effort called the Meningitis Vaccine Project (MVP) is developing a Men A conjugate vaccine. This vaccine is intended to have long-lasting effect, to create immunity in infants, and to allow protection to be conferred in advance through mass immunization programmes

  46. Meningococcal vaccine • Meningococcal conjugate vaccine (MCV4) if preferred for adults aged 55 years or younger; meningococcal polysaccharide vaccine (MPSV4) is preferred for adults aged 56 years or older. • Revaccination with MCV4 after 5 years is recommended for adults previously vaccinated with MCV4 or MPSV4 who remain at increased risk for infection.

  47. Other Vaccines in Meningococcal Infection • Other conjugate vaccines, including a heptavalent vaccine (DTP Hep B Hib) covering Sero groups A, and C, are being developed by the private sector; and a tetravalent vaccine has recently been licensed by Sanofi-Pasteur in the United States and Canada.