IMMUNE RESPONSES TO MICROBES AND VACCINES DEVELOPMENT

Infectious diseases are among the leading causes of death worldwide

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

Adaptive Immunity to Extracellular Bacteria

Bacteria Can Evade Host Defense Mechanisms at Several Different Stages

multiple mechanisms used by Neisseria to evade humoral immunity

IMMUNITY TO INTRACELLULAR BACTERIA

Mechanisms of Immune Evasion by intercellular Bacteria

Innate and adaptive immune responses against viruses

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

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)

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

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

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

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

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

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.

Immune Responses to Disease-Causing Parasites

Mechanisms of Immune Evasion by Parasites

STRATEGIES FOR VACCINE DEVELOPMENT

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

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

Why are boosters needed?

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) 2003 per Year Diphtheria 175,885 1 99.9% Hib (<5 yrs old) 20,000 (est.) 259 98.8% Measles 503,282 56 99.9% Mumps 152,209 231 99.9% Pertussis 147,271 11,647 92.1% Polio (paralytic) 16,316 0 100.0% Rubella 47,745 7 99.9% Smallpox 48,164 0 100.0% Tetanus 1,314 20 98.5% Sources CDC. Impact of vaccines universally recommended for children — United States, 1900-1998. 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%

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

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

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

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

The mechanism of action of DNA vaccines

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

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