Immunotherapy for Infection (2)

8/7/2019 Immunotherapy for Infection (2)

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IMMUNOTHERAPY FOR

INFECTION

Dr. Ashutosh Srivastava

Moderator- Prof. Janak kishore

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Introduction

History

Agents Mode of action

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INTRODUCTION & HISTORY

alteration in immune system in order to combat

diseases,

enhance the immunity e.g. in Cancer immunotheray

degrade it for control of self injuries. E.g. For

infectious diseases.

Emil Behring and Shibasaburo Kitasato in

1890 showed passive transfer of immunity withtetanus1.

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In 1930, Maxwell Finland reported the clinical

experience from 1919 through 1929 at Boston

City Hospital, using equine serum to treat

pneumococcal pneumonia.

During the 1930s and 1940s, passive

immunotherapy, transfer of the agent of immunity

from an immunized donor to an unimmunized

recipient, was used to prevent or modify thecourse of measles and hepatitis A1.

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MECHANISMS OF ACTION OF AGENTS

Preventing entry Ab mediated ( polyvalent /monoclonal)

APC potentiation

Prevention of replication- drugs

Immune response regulation & inflammation I

mmunosuppressant Cytokine antagonist

Receptor antagonism (binding protein & antagonistic peptides)

Tolerance induction

Lymphocyte destruction

Hematopoietic stem cell transplantation

Killing the pathogen/ infected cell ADCC

CMI enhancement

Cytokine induction

Transfer of Tc / NK cells

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MODE OF ACTION

The ability to deliver massive amounts of antibodyrapidly and repeatedly has promptedinvestigations of new clinical uses ofIgpreparations, including new uses as anti-infectiveagents1 .

Polyvalent IVIg Activation of complement & cytokine

Fc receptor modulation

Idiotype antibody production

T & B cell activation

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IMMUNOTHERAPIES

Vaccines

Adjuvants (nonspecific immune stimulant)

Passive Antibody

(IVIG, humanized Mabs/ immunotoxins)

Cytokines or cytokine antagonists

(anti-TNF, soluble cytokine receptors)

Co-stimulator or suppressor signaling

molecules (CTLA-4)

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AGENTS contd.

Adoptive transfer of immune cells

Immune Tc cells

Lymphokine activated NK cells

Antagonist peptides

(inhibit specific T cells by blocking TcR)

Oral tolerance(ingestion of antigen induces suppressive

factors[TGF-]

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AGENTS contd. immunosupressive

Corticosteroids

(block cellular infiltration, cytokine release, T cellmaturation, etc.)

Azathioprine

(inhibit lymphocyte proliferation)

Cyclosporine

(inhibit IL-2 gene expression) Anti-lymphocyte serum

(causes lymphocyte destruction and removal)

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AGENTS contd.

Anti-CD3 & Anti CD4

(T cell destruction)

Cytotoxic drugs and ionizing radiation

(block cell proliferation, lymphopoiesis)

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AGENTSAgents Rationale Status

Monoclonal Antibodies or Toxins Against T or B Cells

Anti-CD3 and T cell murine

monoclonal antibody (OKT3)

Inhibit T cell function;

induce T cell lymphopenia

FDA approved - ofcar iac an renal allograft

rejection

Diphtheria toxin-IL2 fusion protein Kills activated T cells FDA approved for GVHD an transplant

repertoire; understudy to kill T regulatory cell

to embrace tumor vaccine efficacy

Humanized anti-CD3 monoclonal

antibody (hOKT3 gamma-1)

Eliminates auto-reactive T

cells

Human study underway in ype I ia etes,

psoriasis

Humanized anti-CD25 (IL-2R)

monoclonal antibody (daclizumab)

Eliminates activated T cells FDA approved for GVHD; studies underway in

ulcerative colitis

Anti-CD40 ligand (CD154)

monoclonal antibody

Inhibit CD40-CD40 ligand ;

induces T cell tolerance

In primate trials for prevention of renal

allograft rejection

Humanized anti-CD20 (anti-B cell)

monoclonal antibody (rituximab)

Eliminates autoreactive B

cells

Human study underway for treatment of

AN A+ vasculitis

Humanized anti-IgE monoclonal

antibody (omalizumab)

Block allergy causing IgE Human study underway for allergy (Hay

fever, allergic rhinitis)

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Agents Rationale Status

Cytokines and Cytokine Inhibitors to Inhibit Immune Responses and Inflammation

Anti-TNF- monoclonal antibody;humanized mouse chimeric

MAb, infliximab, fully humanized

MAb, adalimumab

Inhibit TNF- FDA approved for RA, Crohn's colitis(infliximab); rheumatoid arthritis

(adalimumab)

Recombinant TNF-receptor-Ig

fusion protein (etanercept)

Inhibit TNF- FDA approved for RA, juvenile

rheumatoid arthritis, psoriasis

Recombinant IL-1 receptor

antagonist (IL-1Ra) (anakinra)

Inhibit IL-1

and -

FDA approved for rheumatoid arthritis

Soluble T Cell Molecule

Soluble CTLA-

4 protein

Inhibit CD28-B7-1 and B7-2

interactions; induces tolerance to

organ grafts; inhibit autoimmune T

cell reactivity in autoimmune

diseases

In trials for preventingGVHD in

BMT and for treatment of

psoriasis and systemic lupus

erythematosus

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Agents Rationale Status

Intravenous Immunoglo in

IVIg Reticuloendothelial cell blockage;

complement inhibition; regulation ofidiotype/anti-idiotype antibodies;

modulation of cytokine production;

modulation of lymphocyte production

FDA approved for Kawasaki's isease an I P;

treatment of GVHD, multiple sclerosis,myasthenia gravis, G S, an chronic

inflammatory emyelinating polyneuropathy

supported by clinical trials

ytokines for Immune Reconstitution

IL-2 Induce proliferation of peripheral

memory CD4+ and CD8+ T cells

In trial for treatment of HIV infection

IL-7 Induce renewed thymopoiesis Under consideration for treatment of disease

associated with cell eficiency

Hematopoietic Stem ell ransplantation

Hematopoietic stem

transplantation for immune

reconstitution

Remove pathologic

autoreactive immune system

and replace with less

autoreactive immunity

In clinical trials for systemic lupus

erythematosus, multiple sclerosis,

an sclero erma

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CONSIDERATIONS

Need of therapy- mode? When?

Route of administration

Safety, dose Trials & diseases covered

Marketing & cost estimation

Future trend

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NEED OF THERAPY

Prophylactic

Vaccination

Immunomodulation e.g. probiotics

Therapeutic

Rational of therapy

Population involved

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USE OF POLYVALENT IVIG

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RATIONAL OF THERAPY

conditions limitations

sis, m lidiosis,

s domonas / n mococcal

inf ction, T tc.

ndotoxins l ading to IC, T , m ltir sistant

HCV Poor tol ranc , costly, Genoty e dependent, no vaccine

H V Rec rrence of latent, high viral load, no vaccine, co infection

with HIV

CMV Rec rrence of latent, high viral load, no vaccine

EBV Rec rrence, high viral load, no vaccine or therapy

HIV Virologic response b t not imm nologic, no vaccine

RSV No vaccine, significant infection

H5N1 Navepopulation, no vaccine

Fungal invasion Poor T cell immunity & PMN function, drug toxicity & poor

bioavailability of drugs at site

Parasitic infections Limited drug options, drug resistance, no vaccines, drug

toxicity,

General Immune incompetencee.g. BMT 21


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POPULATION INVOLVED

Immunocompromised patients e.g. CGD. 10 disorder

Chronically infected persons e.g. HCV, HIV

Failure of available drug options e.g. TB, RSV, EBV

Multiple & complex ongoing therapy e.g. HAART

Poor immunologic response e.g. HIV

Research purposes.

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PREREQUISITE BEFORE THERAPY

Exact diagnosis & co morbid conditions.

Full natural disease course

pathogenesis & molecular cross talk Immunological response of human to agent

Suitable animal model & experiments

Clinical trials outcome

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BACTERIAL IMMUNOTHERAPY

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INTRAVENOS HYPERIMMUNE GLOBULIN

USED IN CLINICAL TRIALS FOR

INFECTIOUS DISEASES1

Pseudomonas aeruginosa

Cytomegalovirus

Grup B streptococus , J-5 Antiendotoxin*

Pneumococcal/ Haemophilus influenzae

Re Antiendotoxin*

* failed

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GN SEPSIS

several anti-J-5 monoclonal antibodies are

evaluated in clinical trials1.

Role of polyvalent IVIG requires multicentre

RCT as contradicting results of various

studies2.

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FOR TREATMENT OF BURKHOLDERIA

PSEUDOMALLEI1

gamma interferon (IFN-) very low doses ofIFN-

and ceftazidime elicited strong synergistic

inhibition1.

G-CSF was not effective when it was combined

with ceftazidime for the treatment ofB.

pseudomalleiinfection2.

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S. AUREUS TSS.

ClassificationEffect on exotoxin at subgrowth inhibitory

concentrations

-lactam

Glycoprotein

Lipopepetide NA

Macrolide

Lincosamide

Oxazolidinone

Streptogramin NA

Aminoglycoside

Tetracycline

Sulfonamide NA

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S. AUREUS

Reagent Mechanisms of action Supporting evidence

GML Inhibit growth of S.aureus

Delay the production of

exoproteins

Immunomodulation effects on

mammalian cells via membrane

stabilization

In vitro: GML reduces the production of

proinflammatory cytokines and chemokines by

epithelial cells in response to S. aureus and purified

TSST-1

In vivo: GML, as 5% vaginal gel, prevents lethality in

rabbits challenged vaginally with purified TSST-1

Tampon coated with GML reduces S. aureus growth,

exotoxin production and vaginal IL-8 secretion

Hemoglobin

subunit inhibitors

Target two-component and

quorum sensing systems to inhibit

exoprotein production [87]

In vitro: mixtures of and hemoglobin (1 g/ml)

inhibit S. aureus exoproteins[87]

In vivo: TSST-1 and -toxin were only detected in

tampon sections containing little or no menstrual

blood, despite the high bacterial counts [86]

V peptides (SEB

antagonists)

A synthesized immunoglobulin-

like peptide competes with the

particular TCR binding site to

prevent SEB-mediated T-cell

activation and lethality in rabbits

intravenously administered with

SEB [88]

In vivo: rabbits injected with V protein (dose 32.5

g/kg) survived through endotoxin enhancement

model of TSS[88]

The protective capacity of the V agent was 2000-

times greater than that ofIVIG

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BacterialtargetPutativerolein

virulence

Proposedstrategy

(product/company)Trialconclusion

Capsule

polysaccharide

(CP5 and CP8)

Avoidance of

phagocytosis

Active immunization

(StaphVAX/Nabi)

Vaccine efficacy (57%) only last up to 40 weeks after immunization in end-stage

renal disease (ESRD) hemodialysis patients (n = 1804). However, no significant

protection was detected against bacteria in a confirmatory follow-up trial (n = 3600)

Human polyclonal

antiserum(Altastaph/Nabi)

No reduction in preventing Staphylococcus aureus bacteremia in very low-birth

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MDR TUBERCULOSIS

low-dose Recombinant Human Interleukin-2 in

combination with multidrug chemotherapy1.

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HCV INFECTION

a new albumin-conjugated IFN- (albIFN-). ableto extend its half-life up to 6 days allowing it to beadministered once every 2-4 weeks.

consensus interferon (CIFN). an un-naturallyoccurring recombinant type I interferon derivedfrom the alignment of a variety of differentnaturally occurringIFN- subtypes. Initial studies

have shown that CIFN is able to exert a ten- to100-fold antiviral, antiproliferative and gene-inductive activities

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HCV INFECTION

Toll-like Receptor Agonists- CPG 10101 and

isatoribine

CPG 10101 is a synthetic oligodeoxynucleotide

TLR9 agonist 2- Th1 induction- more emphasis on

cancer therapy.

Isatoribine, a TLR7 agonist3 stopped due to safety

concern

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NEWER APPROACHES

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CMV

limiting the load of latent viral genome should alsoreduce the risk of virus recurrence & Antiviral CD8T cells prevented CMV disease and accelerated

the resolution of productive infection3

. a preemptive CD8 T-cell immunotherapy of CMV

disease is in clinical trials1.

Generation of specific T cells by CMV peptide-

pulsed dendritic cells or genetically modifiedAPCs2, 4, 5

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CMV CONTD.

treated eight patients with antiviral-resistantCMV reactivation, and who had a CMV-

seropositive donor2 using Tc cells.

vaccine3 description Status

Towne Live attenuated Used in prim. Boost with DNA vaccine

gB Recombinant,

soluble

Phase II complete in healthy, Phase I in

Tx pt.

Canarypoxpp65

Live single cycleexpression

Phase I

Pp65, gB DNA plasmid Phase I

AlphaVax Alphavirus vector

with gB pp65

Phase I

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FOR HSV

Agonist to TLR 3 & 7, have been used transientlyeffective.

imiquimod (Aldara), an imidazoquinoline amine

analog to guanosine and a TLR7 agonist the cocirculation of HIV has provided a great

challenge for researchers and healthcareproviders to develop HSV-2 therapies that either

do not increase HIV-1 susceptibility or replication,or simultaneously protect against both infections1.

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HSV contd..

In recent Phase III clinical trials of a recombinantglycoprotein D vaccine, approximately 74%prevention of genital HSV disease was observed

but only in women seronegative for both serotypesof HSV1.

TLR-mediated immunomodulation and vaccinesconjugated to TLR agonists enhance resistance to

genital HSV-2 infections but additional work isrequired to dissect their impact on HIV-1infections.

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EBV

Adoptive transfer of T cells in trials.

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FOR HIV

how should we treat patients who respond

virologically but not immunologically?

A study by Katlama and colleagues, in France

suggests that interleukin-2 (IL-2) may be an

option1. still do not know whether an IL-2-

induced CD4+ cell increase will prove clinically

beneficial.

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Interleukin-7 is currently in clinical trials to treat

cancer and infection with hepatitis C virus and

HIV.

immunotherapy will probably be tailored to the

individual patient on the basis of specific

laboratory or clinical findings.

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RSV

Mortality 50% if treated with ribavirin in

posttransplant pt. & pt. on chemotherapy.

Lack of effective vaccine

RSV immunoglobulin (RSVIG) asimmunoprophylaxis in high risk1.

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FOR H5N1

specific equine anti-H5N1 IgGs from horses

vaccinated with inactivated H5N1 virus, and

then obtained the F(ab')2 fragments by

pepsin digestion ofIgGs1.

On mice model. Fit to human trial.

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FUNGAL IMMUNOTHERAPY

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INTERFERON Gamma IMMUNOTHERAPY FOR INVASIVE


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INTERFERON-Gamma IMMUNOTHERAPY FOR INVASIVE

FUNGAL INFECTIONS IN KIDNEY TRANSPLANT PATIENTS1

in nonneutropenic solid organ transplant patients

T cell-mediated immune defects are becoming anincreasingly important risk factor for IFIs.

compared to standard approaches, the accelerated cureof life threatening, disseminated IFIs with 6 weeks of

combination antifungal drug therapy andIFN-immunotherapy saved lives, retained allograft function

and led to substantial cost savings in this small patientgroup.

In 2005,published the case report of a renal transplantpatient in whom disseminated cryptococcal disease wascured only after the addition of recombinant IFN-therapy.

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Notably, a patient with disseminated (includingcerebral) aspergillosis (mortality 90%) and apatient with disseminated (including cerebral)

O. gallopavum infection (mortality previously100%) were cured.

Intranasal Granulocyte-Macrophage Colony-Stimulating Factor Reduces the Aspergillus

Burdeninan Immunosuppressed MurineModel of Pulmonary Aspergillosis1.

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FOR P. JEROVACII1

Anti-P. carinii hyperimmune serum was highly

effective at reducing the number of P. Jerovacii

organisms in early, intermediate, and advanced

stages of PCP and was capable of increasing

the mean life expectancy.

On SCID mice.

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PARASI I RAPY

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FOR VISCERAL LEISHMANIASIS

Modulation of T-Cell Costimulation

injection of agonist anti-CD40 monoclonal

antibody (MAb) induced killing of60% of

parasites within liver macrophages, stimulated

gamma interferon (IFN-) secretion, and

enhanced mononuclear cell recruitment and

tissue granuloma formation. anti-CD40 and anti-CTLA-41.

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LEISAHMANIA .

immunotherapy with cytokines (interleukin-12

and interferon-).

The frequency of asymptomatic

infections needs to identify the deficiencies in

the host or the parasite-induced responses that

predispose phenotypically normal persons to

progressive disease.

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CRYPTOSPORIDIOSIS

Anti-CSL MAb 3E2 had the highest protective

activity of all Mabs, reducing infection levels by

62 to 92%. 3E2 combined with anti-GP25-200

MAb 3H2 and anti-P23 MAb 1E10 conferred

significant additive protection over that

provided by the individual MAbs and reduced

infection levels by 86 to 93%

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TRYPANOSOMA CRUZI

DNA Vaccines in Mice

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BONE MARROW TRANSPLANTATION

IGIV, 500 mg per kilogram weekly1, from 7 to90 days after transplantation, the incidence ofgram negative septicemia and viral infections

was reduced substantially in the globulinprophylaxis group.

the incidence of interstitial pneumonitis wasconsiderably reduced by the globulin

prophylaxis, as was that of graftversus- hostdisease for patients older than 20 years.

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SAFETY

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SAFETY

Drawbacks of polyclonal immunoglobulin therapy1

1. High dosage required

2. Safety of plasma-derived product

3. Product standardization

4. Product availability

monoclonal antibodies contain foreign protein and cansensitize human recipients.

dilemma pertaining to monoclonal antibodies of any

source is the potential for anti-idiotypic antibodyformation. Anti-id antibodies may neutralize the activityof the monoclonal if used in a prolonged fashion.

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Isolated y-globulin preparations tend to form small aggregates

spontaneously and these can lead to severe anaphylactic

reactions when administered intravenously, on account of theirability to aggregate platelets and to activate complement and

generate C3a and C5a anaphylatoxins. For this reason, the

material were injected intramuscularly1.

Preparations free of aggregates are available, and separatepools with raised antibody titers to selected organisms such as

vaccinia, herpes zoster, tetanus and perhaps rubella would be

available soon.

Four Cases of Disseminated Mycobacterium bovis Infection

FollowingIntravesical BCGInstillation for Treatment of Bladder

Carcinoma2 .

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HUMANIZED MONOCLONAL ANTIBODIES

Use of mouse monoclonal antibodies for immunotherapyin humans is limited by immune responses in humans

against the foreign mouse antibody proteins.

Complementarity determining regions (CDR) of mouse

monoclonal antibodies can be grafted onto theframework of a human immunoglobulin. Recombinant

antibodies are less immunogenic and induce less allergic

reactions.

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IL- 12 AS AGENT

has adjuvant activity when it is co delivered withDNA vaccines. systemic IL-12 therapy has beenlimited by high levels of toxicity.

The activity was greater with the single polypeptidescIL-12. An antigen-specific cellular response (i.e.,secretion of Th1 cytokines, IL-2, and IFN-) elicitedby a recombinant L. lactis straindisplaying a cellwall-anchored human papillomavirus type 16 E7

antigen was dramatically increased bycoadministration with an L. lactis strain secretingIL-12 protein.

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EFFICACY

efficacy of immunotherapy was dependent

upon two conditions.

First, an accurate microbiologic diagnosis,

including serotyping, was necessary. And

second, therapy had to be administered early in

the course of infection.

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FUTURE TRENDS

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SUMMARY OF CHIMPANZEE IMMUNIZATION AND


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SUMMARY OF CHIMPANZEE IMMUNIZATION AND

CHALLENGE STUDIES FOR HCV1

Vaccine Immune response Challenge results

Recombinant gpE1/gpE2 in

oil/water adjuvants

Humoral immune response

induced in chimpanzees

Five out of seven chimpanzees showed

sterilizing immunity againsthomologous HCV challenge

DNA prime followed by protein

boost (E1, E2, core and NS3)

Humoral and cellular

immune responses induced

in chimpanzees

One out of two cleared infection

following heterologous challenge

Recombinant gpE1/gpE2 Humoral and cellular

immune responses inchimpanzees

The only chimpanzee studied became

persistently infected

DNA prime-adenoviral boost (core,

E1, E2, NS3-NS5)


immune responses in

chimpanzees

Two out of six did not proceed to

chronic infection upon slightly

heterologous HCV challenge, one had

sterilizing immunity; one resolved

infection

Adenoviral prime-DNA boost (NS3-NS5)

Induced cellular immuneresponses in chimpanzees

Four out of five resolved infection uponheterologous challenge

DNA prime-MVA boost (core, E1,

E2 andNS3)


immune responses in

chimpanzees

Three out of four became chronically

infected upon homologous challenge

Recombinant HCV virus-like

particles (core, E1 and E2)

Cellular immune responses

and weak humoralresponses in chimpanzees

Two out of four HCV RNA negative 2

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THERAPEUTIC HCV VACCINES

InnoVac- (recom inant gpE1)-Humoral and cellular immune responses induced in both healthy and chronically

infected individuals; no significant reduction in HCV RNA levels in chronically infected

individuals

I -41 (pepti e- ase vaccine containing eight ifferent epitopes erive from NS3,

core an NS4)-Cellular immune responses in both healthy and chronically infected

individuals; small but significant reduction in viral load in chronically infected

individuals

hron ac- ( N vaccine enco ing NS3; electroporation elivery)-

Cellular immune responses induced in one chronically infected individual

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BloodMonocytes

IL-4 + GM-CSF

ImmatureDendritic cells

Peptide +

MatureDendritic cells

Inject i.v.

Freeze forboosts

LPS

Poly I:C

CpG oligoTNFE

CD40L

TLR

ligands

Making dendritic cell vaccines

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INFECTIOUS AGENTS & OTHERS AS

IMMUNOTHERAPEUTICS

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USE OF LISTERIA MONOCYTOGENES

an irreversibly attenuated and highly

immunogenic L. monocytogenes platform,the

L. monocytogenes dal-,dat-,andactA-deleted

strainthatexpresses the human prostate-specific antigen (PSA) using an antibiotic

resistance marker-free plasmid1.

Oral Immunotherapy With H. InfluenzaeReduces Severity of COPD Flares2 .

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MACROLIDES AS IMMUNOMODULATORY

MEDICATIONS1-

their long-term use in treating neutrophil-dominated inflammation in diffusepanbronchiolitis, bronchiectasis,

rhinosinusitis, and cystic fibrosis. due to inhibition of extracellular signal-

regulated kinase 1/2 (ERK1/2)phosphorylation and nuclear factor kappa B

(NF- B) activation. A concern is that long-termuse of macrolides increases the emergence ofantimicrobial resistance.

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TO SEARCH

9. Doherty, T. M., and A. Sher. 1998. IL-12 promotes drug-inducedclearance ofMycobacteriumavium infectioninmice. J. Immunol.160:54285435.

Onyeji, C. O., K. Q. Bui, D. P. Nicolau, C. H. Nightingale, L. Bow, and R.Quintiliani. 1999. Influence of adjunctive interferon-gamma on

treatment of gentamicin- and vancomycin-resistantE

nterococcusfaecalis infectioninmice. Int. J. Antimicrob. Agents 12:301309.

Pammit, M. A., V. N. Budhavarapu, E. K. Raulie, K. E. Klose, J. M.Teale, and B. P. Arulanandam. 2004. Intranasal interleukin-12treatment promotes antimicrobial clearance and survival inpulmonary Francisella tularensis subsp. novicida infection.A

ntimicrob.Agents Chemother.

48:4513

4519

.

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OTHERS

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S l bl MHC tid t t i l b d t d t t ifi T ll


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Soluble MHC-peptide tetrameric complexes can be used to detect specific T cells

E1E2

E3 F2M

E1E2

E3 F2M

Membrane

DomainBiotin

Natural Class I1HC Soluble Class I1HCPeptide

Avidin

PE

Fluorescent MHC-peptide

Tetrameric complex

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Human normal immunoglobulin (HNIG) is derivedfrom the pooled plasma of donors and containsantibodies to infectious agents that are currentlyprevalent in the general population. HNIG is usedfor the protection of immunocompromised childrenexposed to measles and of individuals afterexposure to hepatitis A.

Specific immunoglobulins are available fortetanus, hepatitis B, rabies and varicella zoster

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successful use ofIFN- in the treatment of thephagocytic cell defect in chronic granulomatousdisease.

Intermittent infusions ofIL-2 in HIV-infectedindividuals in the early or intermediate stages ofdisease have resulted in substantial and sustainedincreases in CD4+ T cells.

CTLA-4 protein into clinical trials- block T cellactivation via TCR/CD28 ligation during organ orbone marrow transplantation .

Documents

Immunotherapy for Infection (2)