Immunity Specific defenses - PowerPoint Presentation

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Immunity

Specific defensesImmunity

Passive immunity

Active immunity

Following clinical infection

Following subclinical infection

Following vaccination

Following administration ofImmunoglobulin or antiserum

Transfer of maternal Antibodies Through milk

Transfer of maternal Antibodies Through placenta

natural

acquired

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Viral Vaccines

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Immunizing agents

Immunizing agents

antisera

immunuglobulins

vaccines

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Vaccination

Vaccination is a method of giving antigen to stimulate the immune response through active immunization.

A vaccine is an immuno-biological substance designed to produce specific protection against a given disease.

A vaccine is “antigenic” but not “pathogenic”.

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Let’s go back in time to seehow this strategy works

The time: 500 B.C.

The place: Greece

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Even 2,500 Years Ago, People Knew Immunity Worked.

Greek physicians noticed that people who survived smallpox never got it again.The insight: Becoming infected by certain diseases gives immunity.

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Fast forward 2300 years

pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

I had a brilliant idea

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Vaccination

Charles Jenner 1796 : Cowpox/Swinepox 1800’s Compulsory childhood vaccination

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Smallpox

1% v. 25% mortality

Life-long immunity UK: 1700’s China 1950 Pakistan/Afghanistan/ Ethiopia 1970

pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

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No animal reservoir Lifelong immunity Subclinical cases rare Infectivity does not precede overt symptoms One serotype

pathmicro.med.sc.edu/

ppt-vir/vaccine.ppt

Smallpox presented many advantages that made this possible

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As a result, after a world-wide effortSmallpox was eliminated as a human disease in 1978

pathmicro.med.sc.edu/

ppt

-vir/

vaccine

.

ppt

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Types of vaccines

Live vaccines

Attenuated live vaccines

Inactivated (killed vaccines)

Toxoids

Polysaccharide and polypeptide (cellular fraction) vaccines

Surface antigen (recombinant) vaccines.

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Live vaccines

Live vaccines are made from live infectious agents without any amendment.

The only live vaccine is “Variola” small pox vaccine, made of live vaccinia cow-pox virus (not variola virus) which is not pathogenic but antigenic, giving cross immunity for variola.

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Live attenuated (avirulent) vaccines

Virulent pathogenic organisms are treated to become attenuated and avirulent but antigenic. They have lost their capacity to induce full-blown disease but retain their immunogenicity.

Live attenuated vaccines should not be administered to persons with suppressed immune response due to:

Leukemia and lymphoma

Other malignancies

Receiving corticosteroids and anti-metabolic agents

Radiation

pregnancy

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Live Attenuated Vaccineshave several advantages

Attenuated (weakened) form of the "wild" virus or bacteriumCan replicate themselves so the immune response is more similar to natural infectionUsually effective with one dose

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Live Attenuated Vaccinesalso have several disadvantages

Severe reactions possible especially in immune compromised patientsWorry about recreating a wild-type pathogen that can cause diseaseFragile – must be stored carefully

MMWR, CDC

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A number of the vaccines you received

were live Attenuated Vaccines

Viral measles, mumps, rubella, vaccinia, varicella/zoster, yellow fever, rotavirus, intranasal influenza, oral polioBacterial BCG (TB), oral typhoid

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Inactivated (killed) vaccines

Organisms are killed or inactivated by heat or chemicals but remain antigenic.

They

are usually safe but less effective than live attenuated vaccines.

The

only absolute contraindication to their administration is a severe local or general reaction to a previous dose.

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Inactivated Vaccines

Cannot replicate and thus generally not as effective as live vaccinesUsually require 3-5 dosesImmune response mostly antibody based

Minuses

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Inactivated Vaccines

No chance of recreating live pathogenLess interference from circulating antibody than live vaccines

Pluses

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Inactivated Vaccines are alsoa common approach today

Viral polio, hepatitis A, rabies, influenza*Bacterial pertussis*, typhoid* cholera*, plague*

Whole-cell vaccines

*not used in the United States

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Other Inactivated Vaccinesnow contain purified proteinsrather than whole bacteria/viruses

Proteins hepatitis B, influenza, acellular pertussis, human papillomavirus, anthrax, LymeToxins diphtheria, tetanus

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Sabin Polio Vaccine

Attenuated by passage in foreign host (monkey kidney cells)Selection to grow in new host makes virusless suited to original host

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Sabin Polio Vaccine

Attenuated by

passage in foreign host

(monkey kidney cells)

Selection to grow in new host makes virus

less suited to original host

Grows in epithelial cells

Does not grow in nerves

No paralysis

Local gut immunity (IgA)

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Salk Polio Vaccine

Formaldehyde-fixed No reversion

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US: Sabin attenuated vaccine ~ 10 cases vaccine-associated polio per year =1 in 4,000,000 vaccine infections Scandinavia: Salk dead vaccine No gut immunity Cannot wipe out wt virus

Polio Vaccine illustrates the pluses and minuses of live vaccines

pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

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Reciprocal virus antibody titer

512

128

32

8

2

1

Serum

IgG

Serum

IgG

Serum

IgM

Serum

IgM

Nasal and duodenal

IgA

Nasal

IgA

Serum

IgA

Serum

IgA

Duodenal

IgA

Days

Vaccination

Vaccination

48

48

96

96

Killed (Salk) Vaccine

Live (Sabin) Vaccine

Live virus generates a more complete immune response

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Modern molecular biologyhas offered new approaches to make vaccines

Clone gene from virus or bacteriaand express this protein antigenin yeast, bacteria or mammalian cells in culture

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Modern molecular biologyhas offered new approaches to make vaccines

2. Clone gene from virus or bacteriaInto genome of another virus (adenovirus, canary pox, vaccinia)And use this live virus as vaccine

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Cloned protein antigenshave pluses and minuses

Pluses

Easily manufactured and often relatively stable

Cannot “revert” to recreate pathogen

Minuses

Poorly immunogenic

Post-translational modifications

Poor CTL response

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Viral vectors have pluses and minuses

Pluses

Infects human cells but some do not replicate

Better presentation of antigen

Generate T cell response

Minuses

Can cause bad reactions

Can be problems with pre-

exisiting

immunity to virus

Often can only accommodate one or two antigens

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Toxoids

They are prepared by detoxifying the exotoxins of some bacteria rendering them antigenic but not pathogenic. Adjuvant (e.g. alum precipitation) is used to increase the potency of vaccine.

The antibodies produces in the body as a consequence of toxoid administration neutralize the toxic moiety produced during infection rather than act upon the organism itself. In general toxoids are highly efficacious and safe immunizing agents.

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Polysaccharide and polypeptide (cellular fraction) vaccines

They are prepared from extracted cellular fractions e.g. meningococcal vaccine from the polysaccharide antigen of the cell wall, the pneumococcal vaccine from the polysaccharide contained in the capsule of the organism, and hepatitis B polypeptide vaccine.

Their efficacy and safety appear to be high.

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Surface antigen (recombinant) vaccines.

It is prepared by cloning HBsAg gene in yeast cells where it is expressed. HBsAg produced is then used for vaccine preparations.

Their efficacy and safety also appear to be high.

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Types of vaccines

Live

vaccines

Live

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

Plague

Rabies

Salk polio

Intra-muscular influenza

Japanise encephalitis

Diphtheria

Tetanus

Meningococcal polysaccharide vaccine

Pneumococcal polysaccharide vaccine

Hepatitis B polypeptide vaccine

Hepatitis B vaccine

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Routes of administration

Deep subcutaneous or intramuscular route (most vaccines)

Oral route (sabine vaccine, oral BCG vaccine)

Intradermal route (BCG vaccine)

Scarification (small pox vaccine)

Intranasal route (live attenuated influenza vaccine)

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Scheme of immunization

Primary vaccination

One dose vaccines (BCG, variola, measles, mumps, rubella, yellow fever)

Multiple dose vaccines (polio, DPT, hepatitis B)

Booster vaccination

To maintain immunity level after it declines after some time has elapsed (DT, MMR).

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Periods of maintained immunity due to vaccines

Short period (months): cholera vaccine

Two years: TAB vaccine

Three to five years: DPT vaccine

Five or more years: BCG vaccine

Ten years: yellow fever vaccine

Solid immunity: measles, mumps, and rubella vaccines.

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Levels of effectiveness

Absolutely protective(100%): yellow fever vaccine

Almost absolutely protective (99%): Variola, measles, mumps, rubella vaccines, and diphtheria and tetanus toxoids.

Highly protective (80-95%): polio, BCG, Hepatitis B, and pertussis vaccines.

Moderately protective (40-60%) TAB, cholera vaccine, and influenza killed vaccine.

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HIV Vaccine

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Given that introduction, should we search for a vaccine against HIV and how would we do so?

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This formidable array of defense mechanismsAllows HIV to avoid being suppressed by our immune system

Antigenic escape

Inaccessible epitopes

Downregulating MHC

Destruction of CD4+ T cells

Integration and latency

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An effective vaccine could have a MAJOR

Impact on the future prognosis

iavi.org

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An effective vaccine must get around

the strategies HIV uses to evade the immune system

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The vaccine must be able to target conservedand essential parts of the viruses machinery

Antigenic escape

Inaccessible epitopes

+ existence of many viral strains

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Molecular Biology of the Cell Alberts et al

The vaccine must act early in the processBefore the virus becomes firmly establishedAnd destroys the immune system

Destruction of CD4+ T cells

Integration and latency

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There are many possible HIV Vaccine Approaches

Protein subunit

Synthetic peptide

Naked DNA

Inactivated Virus

Live-attenuated

Virus

Live-vectored Vaccine

Ramil

Sapinoro

, University of Rochester Medical Center

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To begin we need to ask some key questions

What should vaccine elicit?

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To begin we need to ask some key questions

What should vaccine elicit?

Neutralizing antibodiesto kill free virus

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To begin we need to ask some key questions

What should vaccine elicit?

Neutralizing antibodiesto kill free virus

T cell response tokill infected cells

OR

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To begin we need to ask some key questions

What should vaccine elicit?

Neutralizing antibodiesto kill free virus

T cell response tokill infected cells

OR

OR BOTH?

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The biology of HIV provides some clues

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Long term progressorsInfected with a Nef mutant virus?

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This would generate both an antibody and a T cell responseCould this be used to generate a vaccine?

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This prompted an experimentthat demonstrated the feasibility of a vaccine

December 1992: Live attenuated SIV vaccine

Lacking the gene

Nef

protected all monkeys for 2 years against massive dose of virus

All controls died

cell mediated immunity was key

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However, this approach is still viewed as too risky to try on human subjects

December 1992: Live attenuated SIV vaccine

Lacking the gene

Nef

protected all monkeys for 2 years against massive dose of virus

All controls died

cell mediated immunity was key

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The next efforts attempted touse recombinant viral proteins as antigensin an effort to generate neutralizing antibodies

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VaxGen made two different formsof gp120 from different HIV strainsand began human trials after chimp testing

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Human vaccine trials are large and very expensive

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The trial was a failure, with only minor effects seen that were viewed as statistically insignificant

NY Times

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The next approach involved usingviral vectors to try to also boost the T cell response

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Many different viral vectors are being investigated but this trial used the human cold virus called adenovirus

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They actually used three adenoviruses carrying three different viral proteins

Gag

Pol

Nef

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Early results suggested the immune system was being stimulated

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The hotly awaited results were released at the 2007 AIDS Meeting

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You be the judge—what happened?

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This stunning failure led to a re-thinkingof the approach

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The field has decided in part togo back to the basics: how does HIV workand how can we assess vaccine success?

Questions: For a vaccine what are the measures of protection? Can we overcome polymorphism? What are the key antigens? Attenuated or killed or neither? Is Mucosal immunity critical? Should it Prevent infection or prevent disease? What are the best Animal modelsHow does HIV kill cells anyway?

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However trials continue, but with more focus on the details of how they affect immunity