Session 27: Vaccines. Patricia Fitzgerald-Bocarsly May 18, 2009

Transcription

1 Session 27: Vaccines Patricia Fitzgerald-Bocarsly May 18, 2009

2 A brief history of vaccination Immunity: comes from the Latin immunis meaning exempt Concept dates to 430 B.C. when Thucydides, the historian of the Peloponnesian War, wrote that those who had recovered from Plague could care for those with disease Variolation - used in ancient Asia; brought to Europe in 1721 by Lady Mary Wortley and subsequently used in the Revolutionary War 1796: Jenner used cow pox to protect from smallpox. The term vaccination ( vacca is Latin for cow ) derives from this.

3

4 History, cont s: Koch proved that infectious diseases are caused by microorganisms- anthrax 1860 s-1880 s: Louis Pasteur developed vaccines against cholera quite by accident - attenuation. Coined vaccine in honor of Jenner. Also made first anthrax and rabies vaccines.

5 Vaccines do not prevent infection But They can prevent disease

6 THE GOAL OF IMMUNIZATION: MEMORY

7

8

9 Polio: another success story 1952: 58,000 Americans contract polio Salk: inactivated polio vaccine - 50th anniversary last year Sabin: live vaccine 1994: Western world free of polio Success leads to modification of recommendation

10

11

12

13

14

15

16 Passive Cellular Immunity Transfer of NK cells or activated NK cells - LAK therapy Transfer of immune T cells - Tumor infiltrating lymphcytes

17

18 Traditional Vaccine Approaches LIVE VACCINES Smallpox 1800 Rabies 1880 Tuberculosis 1927 Yellow Fever 1938 Measles 1963 Polio 1963 Mumps 1967 Rubella 1969 Adenovirus 1980 Typhoid fever 1985 Cholera 1995 Varicella 1996 Rotavirus 1998 INACTIVATED VACCINES Typhoid Fever 1896 Cholera 1896 Plague 1897 Pertussis 1914 Influenza 1936 Polio 1956 Rabies 1980 Tick-borne encephalitis 1990 Japanese encephalitis 1992 Hepatitis A 1995 PROTEIN VACCINES Diphtheria 1923 Tetanus 1927 Pertussis 1981 Hepatitis B 1981 Hepatitis B 1986 Cholera toxin 1992 Lyme Disease 1998 POLYSACCHARIDE VACCINES Pneumococcus 1977 Meningococcus 1982 Haemophilus influenzae b 1985 Typhoid fever 1998 Haemophilus influenzae b 1987 Pneumococcus 2000

19 Live, Attenuated Mimic natural infection without disease Can be delivered at appropriate site Classically done by passaging virus in foreign host cells or by temperature Often work with one administration - develop good immunological memory and long-term protection. Major advantage in developing world Now can be done by deletion of virulence factors from the organism

20 Inactivated Vaccines Typically chemicaly inactivated - formaldehyde treated Advantages: Stable; safer than live vaccines; refrigeration not reqd. Disadvantages: Weaker immune response; boosters reqd. Salk vs. Sabin polio vaccines Why the switch? Reversion 1:2.4 million; may spread through water system

21 Toxoid Vaccines Disease is caused by a toxin released by the organism Give chemically modified toxin - toxoid E.g. tetanus, diptheria

22 Conjugate Vaccines - H. Flu Haemophilus influenzae Infection problematic in young children Antibody to capsular polysaccharides is protective Young children respond poorly to polysaccharide vaccines (T independent response weak; poor memory) Creation of polysaccharide-toxin conjugate enables child to respond H flu polysaccharides conjugated with tetanus toxoid, known to induce strong immune responses in children

23

24 Figure 6-37

25

26 Multi-valent subunit vaccine

27 LIPOSOME or ISCOMS: DELIVER ANTIGEN TO THE CYTOPLASM

28

29 VACCINIA VIRUS VECTORS

30

31 Dangers of Vaccination Current recommendation: Salk Flu also Acellular

32 How do we know if someone is immune? Check for antibody - just knowing the individual is immunized isn t enough IgG vs. IgM - titer Measure T cell proliferation to antigen Measure CTL responses Skin test - e.g. PPD Boosters: stimulate memory cells, raise affinity, raise Ab titer

33 Does Immune Response = Not Necessarily! Immunity? E.g. HIV-1 initially induces a good antibody response, but it is not protective HIV-1 vaccines that induce antibody haven t been protective

34 Why do I need a flu vaccine every year? Antigenic shift and antigenic drift: virus escapes immune response Short incubation time (2 days) No time to activate memory cells No time to boost antibody levels Existing antibody might not be protective anyway

35 What about the Novel flu? Novel flu (AKA H1N1, swine flu) Nearing pandemic levels - what does this mean? Has genes from two swine flu viruses, common human flu and bird flu Arising by.. (fill in the blank) Last seen at pandemic levels in seems less deadly than expected in older individuals, suggesting memory is helpful Young individuals more affected? Unclear if this is holding up Cytokine storm resulting in too robusts an immune response? Some immunity in older individuals Sensitive to antivirals (e.g. Tamiflu) Vaccine?

36 Synopsis (from During week 18 (May 3-9, 2009), influenza activity remained at approximately the same level as last week in the United States, indicating that there are higher levels of influenza-like illness than is normal for this time of year. One thousand four hundred fifty-four (11.9%) specimens tested by U.S. World Health Organization (WHO) and National Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories and reported to CDC/Influenza Division were positive for influenza. The proportion of deaths attributed to pneumonia and influenza (P&I) was below the epidemic threshold. Three influenza-associated pediatric deaths were reported. The proportion of outpatient visits for influenza-like illness (ILI) was above the national baseline. Three of the ten surveillance regions reported ILI above their region-specific baselines. Eight states reported geographically widespread influenza activity, 14 states reported regional activity, the District of Columbia and 15 states reported local influenza activity; and 13 states reported sporadic influenza activity. Overall: 4,714 confirmed cases in US, 4 deaths. 14 in New Jersey During a normal flu season, up to 20% of Americans are infected and up to 36,000 die.

37 What s New.. Flumist - live influenza vaccine, cold attenuated Papilloma virus vaccine - cervical cancer Viral vectors - e.g. canarypox DNA vaccines - stable at room temp. DC vaccines - let the DC choose the epitopes tumors (melanoma, others), infectious disease

38 What s Needed? Effective vaccines for HIV, HSV, EBV, malaria etc. Better compliance - e.g. measles - Can it be eradicated? Better adjuvants for human use Adjuvants increase magnitude and duration of response - stimulate expression of co-stimulatory molecules Most current vaccines induce Th2 responses Asthma connection Need adjuvants that will favor Th1, costimulation Inclusion of cytokine, plasmid DNA (CpG)

39 What s needed (cont.) Safer vaccines More effective vaccines Cheaper vaccines - fewer whole organisms? Stable vaccines - no refrigeration DNA vaccines

40 Can we eradicate more diseases by vaccination? Smallpox vs. measles Smallpox eradicated; goal to eradicate measles by 2010, but it s still a major killer in 3rd world Relatively low infectivity vs. higher infectivity. Herd immunity: the number of people needed to give immunity to population depends on the infectivity of the virus and the rate of vaccine takes ; for measles, this required rate is much higher than for smallpox Man is only host for both (no animal reservoir); no latency Immunity lifelong to both but measles requires two doses Compliance: Timing and dosing; Should vaccination be a choice?

41 Other Vaccine Strategies Therapeutic vaccination- enhance host immune response against existing cells Tumor vaccines: enhance immunity to existing tumors. Therapeutic vaccination in infectious disease - turn on or switch to more protective immunity HIV?

42 Challenges to Developing an HIV Vaccine Surface Glycosylation Confirmational epitopes Latency/Integration Reservoir sites

43 Why we need a vaccine against HIV Percentage of population in need receiving antiretroviral therapy Source: World Health Organization and Joint United Nations Programme on HIV/AIDS (UNAIDS) 2006 Report

44 Worldwide variation of HIV

45 gp120 Subunit Vaccination Ineffective February 24, 2003 LARGE TRIAL FINDS AIDS VACCINE FAILS TO STOP INFECTION By ANDREW POLLACK WITH LAWRENCE K. ALTMAN The first AIDS vaccine ever to be tested in a large number of people has failed, over all, to protect them from infection with the virus that causes the disease, the company that makes it, VaxGen, said today.

46 Viral Vectors Poxviridae: Canarypox Fowlpox Modified Vaccinia Ankara Adenovirus In development Semliki Forest Virus, VEE, alphavirus, AAV Pre-exisiting anti-vector immunity is a limitation Priming with DNA vaccines improves immunogenicity

47 Merck STEP Trial Overview 3000 HIV negative participants at high risk for HIV infection Vaccinated with Ad5gag/ Ad5pol/ Ad5nef at months 0, 2, 6

48 Primary STEP Data Analysis n (HIV neg) n (HIV pos) Incidence Vaccine Placebo n (HIV pos) VL mean log Vaccine 24 40, Placebo 21 25,

49 Immunosuppressive/immunoregulatory Therapies Steroids NSAIDS - ibuprofen, aspirin etc. - antiinflammatory Cyclosporin, FK506 - inhibit signaling Anti-histamines

50 Other immunotherapies IFN-alpha/beta: MS, cancer, HCV Direct antiviral effects Augment immune responses to viral, tumor Ags Shift response in MS? Anti-TNF or TNF-R antibodies - rheumatoid arthritis, Crohn s Risk: severe infection Anti-IgE therapy for severe asthma, peanut allergy Allergy shots : shift from Th2 to Treg - desensitize Ascaris egg therapy: Crohn s - shift from a Th1 to a Th2 response Gene therapy: e.g. ADA SCID