1. IMMUNE RESPONSES TO MICROBES AND VACCINES DEVELOPMENT

2. Infectious diseases are among the leading causes of death worldwide

3. Innate Immunity to Extracellular Bacteria
Complement activation
Activation of phagocytes and inflammation

4. Adaptive Immunity to Extracellular Bacteria

5. Bacteria Can Evade Host Defense Mechanisms at Several Different Stages

6. multiple mechanisms used by Neisseria to evade humoral immunity

7. IMMUNITY TO INTRACELLULAR BACTERIA

9. Mechanisms of Immune Evasion by intercellular Bacteria

10. Innate and adaptive immune responses against viruses

11. Many Viruses Are Neutralized by Antibodies
influenza virus binds to sialic acid residues in cell membrane glycoproteins and glycolipids
rhinovirus binds to inter cellular adhesion molecules (ICAMs)
Epstein-Barr virus (EBV) binds to type 2 complement receptors on B cells. So
antibodies may block viral penetration
Fc-receptore –mediated phagocytosis
complement-activating antibody
lysis or C3b-receptore mediated phagocytosis

12. Cell-Mediated Immunity Is Important for Viral Control and Clearance
Antibodies can not eliminate established infection!!!
NOW, cell-mediated immune mechanisms are most important in host defense.
CD8+ TC cells and CD4 TH1 cells
cytokines, including IL-2, IFN-γ, and tumor necrosis factor- α (TNF-α)

13. Viruses Employ Several Different Strategies to Evade Host Defense Mechanisms
Hepatitis C virus (HCV)
human immunodeficiency Virus (HIV)
Herpes simple virus (HSV)
Polio virus

15. Cytosolic receptors for PAMPs and DAMPs
HIV
Vaccinia
RIG-1-like receptors

16. HIV HIV and human CMV C3bBb3b C3 Factor B C3bB C3bBb C3 C3b Factor H
C3a
C3b
C3bBb3b
Alternative C5 convertase C3 Ba Bb
Factor B
C3bB
C3bBb
Alternative C3 convertase C3
C3b
Factor H
Factor D C5
Bacterium
Properdin
HIV
Lysis
MEMBRANE ATTACK COMPLEX
C5-C9 MAC
C5b
C5a C6 C7 C8 C9
(CD59)
HIV and human CMV

17. Negative feedback regulator
IL-10
An anti-inflammatory cytokine.
An inhibitor of activated MQs and DCs.
Negative feedback regulator.
Inhibits production of IL-12 and ultimately IFN-γ.
Inhibits the expression of class II MHC and costimulators on MQs and DCs.
Epstein-Barr virus (EBV) produce IL-10 like cytokine
Negative feedback regulator

18. Innate and Adaptive Immunity to Fungi
The principal mediators of innate immunity against fungi are neutrophils and macrophages.
TLRs and lectin-like receptors (dectins)
Dendritic cells activated via this lectin receptor produce TH17-inducing cytokines, such as IL-6 and IL-23.
The Th17 cells stimulate inflammation, and the recruited neutrophils and monocytes destroy the fungi
Cell-mediated immunity is the major mechanism of adaptive immunity against fungal infections.
CD4+ and CD8+ T cells cooperate to eliminate the yeast

19. Mechanisms of Immune Evasion by fungal
Virulent strains of Cryptococcus neoformans inhibit the production of cytokines such as TNF and IL-12 by macrophages and stimulate production of IL-10, thus inhibiting macrophage activation.

20. Immune Responses to Disease-Causing Parasites

21. Mechanisms of Immune Evasion by Parasites

22. STRATEGIES FOR VACCINE DEVELOPMENT

23. What are different types of
immunization?
Passive Immunization
-- direct transfer of protective antibodies
-- no immunological memory
Active Immunization
-- activation of immune response
-- immunological memory

24. Active Vaccination: What are some important considerations in the design of vaccines?
Characteristics of pathogen & disease
Intra- vs extra-cellular
short or long incubation
acute or chronic disease
Antigenic stability
route of infection
Characteristics of vaccine
efficacy
appropriate response
booster
safety
stability, cost

25. Why are boosters needed?

26. How effective are vaccines?
Vaccine “efficacy”
incidence among those administered
and
incidence among those not administered
-- e.g., 60% efficacy
-- depends upon population, age, etc
Is 100% efficacy necessary?
-- “herd immunity”
Cases per Year Decrease
before in in Cases
(average) per Year
Diphtheria 175, %
Hib (<5 yrs old) 20,000 (est.) %
Measles 503, %
Mumps 152, %
Pertussis 147, , %
Polio (paralytic) 16, %
Rubella 47, %
Smallpox 48, %
Tetanus 1, %
Sources
CDC. Impact of vaccines universally recommended for children — United States,
MMWR 8(12):243-8
CDC. Notice to Readers: Final 2003 Reports of Notifiable Diseases. MMWR 2004;53(30):687
Example efficacies
Diphtheria: 87%-96%
Tetanus: >90%
Oral polio: 90%-100%
Mumps/Measles/Rubella:
90%-95%
HIV vaccine trials
150 vaccines developed
6 have made it to efficacy testing
2009: 1st with efficacy (31%)
[2007 had negative efficacy]
Malaria vaccine trial
2011: 45 – 56%

27. How are vaccines made? Remember Adjuvants?
Dead (inactivated) pathogens
IPV – Inactivated polio vaccine – ‘Salk’ vaccine
[old pertussis of DPT -- Bordetella pertussis]
Live attenuated pathogens
MMR – measles, mumps, rubella viruses
OVP -- oral polio vaccine – ‘Sabin’ vaccine
Subunit / Peptide components
HBsAG -- Hepititis B surface antigen
Flu – purified HA & NA antigens
Conjugates (polysaccharides coupled to protein carrier)
HiB – Haemophilus influenzae type B
PCV – pneumococcal conjugate vaccine
Toxoids
DTaP -- diphtheria, tetanus toxoids
[ + “acellular pertussis” molecular component]
Cell cultured virus
Remember Adjuvants?
-- increase immune response
e.g., aluminum hydroxide

28. What are pros and cons of different types of vaccines?
Dead (inactivated) pathogens
pros
may be safer; more stable than attenuated
cons
weaker cell mediated response; boosters
contaminants – pertussis endotoxin in old DPT
Live attenuated pathogens
better cell-mediated response
reversion -- Sabin polio
infection in immuno-deficient patients
(malignancies, Receiving corticosteroids,
Radiation, pregnancy)
less stable
Molecular components
No living pathogen present
very stable
fewer epitopes
weaker cell mediated response
Vaccine type
Example reactions
Vaccines from Chicken eggs and cell cultures
Allergic reactions
Contaminating pathogens
Vaccines with Preservatives
Live attenuated
Susceptibility during preganncy and among immunodepressed
Dead whole cell
Contamination with toxins

29. Types of vaccines Live vaccines Attenuated vaccines Killed
Inactivated vaccines
Toxoids
Cellular fraction vaccines
Recombinant vaccines
Small pox variola vaccine
BCG
Typhoid oral
Plague
Oral polio
Yellow fever
Measles
Mumps
Rubella
Intranasal
Influenza
Typhus
Typhoid
Cholera
Pertussis
Rabies
Salk polio
Intra-muscular influenza
Japanise encephalitis
Diphtheria
Tetanus
Meningococcal polysaccharide vaccine
Pneumococcal polysaccharide vaccine
Hepatitis B polypeptide vaccine
Hepatitis B vaccine

30. New Vaccination Strategies
DNA vaccines
DNA for an AG injected
-- expressed in cells
Pros
Both arms respond
DNA is very stable
No pathogen involved
Cons
Still experimental
Limited epitopes

31. The mechanism of action of DNA vaccines

32. New Vaccination Strategies
Recombinant vectors
e.g., HIV genes in an Adenovirus vector
Pors
Easily manufactured and often relatively stable
Cannot “revert” to recreate pathogen
Cons
Poorly immunogenic
Post-translational modifications
Poor CTL response

33. برنامه واکسیناسیون جدید در ایران (اجرا از آبان 93)
واكسن
برنامه
ب ث ژ ، هپاتيت ب، فلج اطفال خوراكي
بدو تولد
پنج گانه (سه گانه + هپاتيت ب + هموفيلوس انفلوانزای B) ، فلج اطفال خوراكي، فلج اطفال تزریقی
۲، ۴ و ۶ ماهگي
MMR
۱۲ ماهگي
يادآور اول سه گانه ، يادآور فلج اطفال خوراكي ، MMR
۱۸ ماهگي
يادآور دوم سه گانه، يادآور فلج اطفال خوراكي
۶ سالگي