Immunity Specific defenses Immunity Active immunity Following clinical

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Immunity Specific defenses Immunity Active immunity Following clinical infection Passive immunity natural Following subclinical

Immunity Specific defenses Immunity Active immunity Following clinical infection Passive immunity natural Following subclinical infection acquired Following vaccination Transfer of maternal Antibodies Through placenta Transfer of maternal Antibodies Through milk Following administration of Immunoglobulin or antiserum

Viral Vaccines

Viral Vaccines

Immunizing agents vaccines immunuglobulins antisera

Immunizing agents vaccines immunuglobulins antisera

Vaccination • Vaccination is a method of giving antigen to stimulate the immune response

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”.

Let’s go back in time to see how this strategy works The time: 500

Let’s go back in time to see how this strategy works The time: 500 B. C. The place: Greece

Even 2, 500 Years Ago, People Knew Immunity Worked. • Greek physicians noticed that

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.

Fast forward 2300 years I had a brilliant idea pathmicro. med. sc. edu/ppt-vir/vaccine. ppt

Fast forward 2300 years I had a brilliant idea pathmicro. med. sc. edu/ppt-vir/vaccine. ppt

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

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

Smallpox • 1% v. 25% mortality • Life-long immunity • UK: 1700’s • China

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

Smallpox presented many advantages that made this possible • No animal reservoir • Lifelong

Smallpox presented many advantages that made this possible • No animal reservoir • Lifelong immunity • Subclinical cases rare • Infectivity does not precede overt symptoms • One serotype • pathmicro. med. sc. edu/ppt-vir/vaccine. ppt

As a result, after a world-wide effort Smallpox was eliminated as a human disease

As a result, after a world-wide effort Smallpox was eliminated as a human disease in 1978 pathmicro. med. sc. edu/ppt-vir/vaccine. ppt

Types of vaccines Live vaccines Attenuated live vaccines Inactivated (killed vaccines) Toxoids Polysaccharide and

Types of vaccines Live vaccines Attenuated live vaccines Inactivated (killed vaccines) Toxoids Polysaccharide and polypeptide (cellular fraction) vaccines • Surface antigen (recombinant) vaccines. • • •

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

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.

Live attenuated (avirulent) vaccines • Virulent pathogenic organisms are treated to become attenuated and

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

Live Attenuated Vaccines have several advantages • Attenuated (weakened) form of the "wild" virus

Live Attenuated Vaccines have several advantages • Attenuated (weakened) form of the "wild" virus or bacterium • Can replicate themselves so the immune response is more similar to natural infection • Usually effective with one dose

Live Attenuated Vaccines also have several disadvantages • Severe reactions possible especially in immune

Live Attenuated Vaccines also have several disadvantages • Severe reactions possible especially in immune compromised patients • Worry about recreating a wild-type pathogen that can cause disease • Fragile – must be stored carefully MMWR, CDC

A number of the vaccines you received were live Attenuated Vaccines • Viral measles,

A number of the vaccines you received were live Attenuated Vaccines • Viral measles, mumps, rubella, vaccinia, varicella/zoster, yellow fever, rotavirus, intranasal influenza, oral polio • Bacterial BCG (TB), oral typhoid

Inactivated (killed) vaccines • Organisms are killed or inactivated by heat or chemicals but

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.

Inactivated Vaccines Minuses • Cannot replicate and thus generally not as effective as live

Inactivated Vaccines Minuses • Cannot replicate and thus generally not as effective as live vaccines • Usually require 3 -5 doses • Immune response mostly antibody based

Inactivated Vaccines Pluses • No chance of recreating live pathogen • Less interference from

Inactivated Vaccines Pluses • No chance of recreating live pathogen • Less interference from circulating antibody than live vaccines

Inactivated Vaccines are also a common approach today Whole-cell vaccines • Viral polio, hepatitis

Inactivated Vaccines are also a common approach today Whole-cell vaccines • Viral polio, hepatitis A, rabies, influenza* • Bacterial pertussis*, typhoid* cholera*, plague* *not used in the United States

Other Inactivated Vaccines now contain purified proteins rather than whole bacteria/viruses • Proteins hepatitis

Other Inactivated Vaccines now contain purified proteins rather than whole bacteria/viruses • Proteins hepatitis B, influenza, acellular pertussis, human papillomavirus, anthrax, Lyme • Toxins diphtheria, tetanus

Sabin Polio Vaccine Attenuated by passage in foreign host (monkey kidney cells) Selection to

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

Sabin Polio Vaccine Attenuated by passage in foreign host (monkey kidney cells) Selection to

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 (Ig. A)

Salk Polio Vaccine • Formaldehyde-fixed • No reversion

Salk Polio Vaccine • Formaldehyde-fixed • No reversion

Polio Vaccine illustrates the pluses and minuses of live vaccines US: Sabin attenuated vaccine

Polio Vaccine illustrates the pluses and minuses of live vaccines US: Sabin attenuated vaccine ~ 10 cases vaccine-associated polio per year = 1 in 4, 000 vaccine infections Scandinavia: Salk dead vaccine • No gut immunity • Cannot wipe out wt virus pathmicro. med. sc. edu/ppt-vir/vaccine. ppt

Live virus generates a more complete immune response 512 Killed (Salk) Vaccine Live (Sabin)

Live virus generates a more complete immune response 512 Killed (Salk) Vaccine Live (Sabin) Vaccine Serum Ig. G Reciprocal virus antibody titer 128 32 Serum Ig. M Nasal Ig. A Serum Ig. A 8 Serum Ig. A 2 1 Duodenal Ig. A Nasal and duodenal Ig. A Vaccination 4 8 96 Days Vaccination 48 9 6

Modern molecular biology has offered new approaches to make vaccines 1. Clone gene from

Modern molecular biology has offered new approaches to make vaccines 1. Clone gene from virus or bacteria and express this protein antigen in yeast, bacteria or mammalian cells in culture

Modern molecular biology has offered new approaches to make vaccines 2. Clone gene from

Modern molecular biology has offered new approaches to make vaccines 2. Clone gene from virus or bacteria Into genome of another virus (adenovirus, canary pox, vaccinia) And use this live virus as vaccine

Cloned protein antigens have pluses and minuses Pluses • Easily manufactured and often relatively

Cloned protein antigens have pluses and minuses Pluses • Easily manufactured and often relatively stable • Cannot “revert” to recreate pathogen Minuses • Poorly immunogenic • Post-translational modifications • Poor CTL response

Viral vectors have pluses and minuses Pluses • Infects human cells but some do

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

Toxoids • They are prepared by detoxifying the exotoxins of some bacteria rendering them

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.

Polysaccharide and polypeptide (cellular fraction) vaccines • They are prepared from extracted cellular fractions

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.

Surface antigen (recombinant) vaccines. • It is prepared by cloning HBs. Ag gene in

Surface antigen (recombinant) vaccines. • It is prepared by cloning HBs. Ag gene in yeast cells where it is expressed. HBs. Ag produced is then used for vaccine preparations. • Their efficacy and safety also appear to be high.

Types of vaccines Live Killed Attenuate Inactivated d vaccines • Small pox variola vaccine

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

Routes of administration • Deep subcutaneous or intramuscular route (most vaccines) • Oral route

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)

Scheme of immunization • Primary vaccination – One dose vaccines (BCG, variola, measles, mumps,

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).

Periods of maintained immunity due to vaccines • • • Short period (months): cholera

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.

Levels of effectiveness • Absolutely protective(100%): yellow fever vaccine • Almost absolutely protective (99%):

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.

HIV Vaccine

HIV Vaccine

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

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

This formidable array of defense mechanisms Allows HIV to avoid being suppressed by our

This formidable array of defense mechanisms Allows HIV to avoid being suppressed by our immune system Integration and latency Destruction of CD 4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC

An effective vaccine could have a MAJOR Impact on the future prognosis iavi. org

An effective vaccine could have a MAJOR Impact on the future prognosis iavi. org

An effective vaccine must get around the strategies HIV uses to evade the immune

An effective vaccine must get around the strategies HIV uses to evade the immune system

The vaccine must be able to target conserved and essential parts of the viruses

The vaccine must be able to target conserved and essential parts of the viruses machinery Inaccessible epitopes Antigenic escape + existence of many viral strains

The vaccine must act early in the process Before the virus becomes firmly established

The vaccine must act early in the process Before the virus becomes firmly established And destroys the immune system Integration and latency Destruction of CD 4+ T cells Molecular Biology of the Cell Alberts et al

There are many possible Vaccine Approaches HIV Protein subunit Synthetic peptide Naked DNA Inactivated

There are many possible Vaccine Approaches HIV Protein subunit Synthetic peptide Naked DNA Inactivated Virus Live-attenuated Virus Live-vectored Vaccine Ramil Sapinoro, University of Rochester Medical Center

To begin we need to ask some key questions What should vaccine elicit?

To begin we need to ask some key questions What should vaccine elicit?

To begin we need to ask some key questions What should vaccine elicit? Neutralizing

To begin we need to ask some key questions What should vaccine elicit? Neutralizing antibodies to kill free virus

To begin we need to ask some key questions What should vaccine elicit? Neutralizing

To begin we need to ask some key questions What should vaccine elicit? Neutralizing antibodies to kill free virus OR T cell response to kill infected cells

To begin we need to ask some key questions What should vaccine elicit? Neutralizing

To begin we need to ask some key questions What should vaccine elicit? Neutralizing antibodies to kill free virus OR T cell response to kill infected cells OR BOTH?

The biology of HIV provides some clues

The biology of HIV provides some clues

Long term progressors Infected with a Nef mutant virus?

Long term progressors Infected with a Nef mutant virus?

This would generate both an antibody and a T cell response Could this be

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

This prompted an experiment that demonstrated the feasibility of a vaccine December 1992: Live

This prompted an experiment that 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

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

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

The next efforts attempted to use recombinant viral proteins as antigens in an effort

The next efforts attempted to use recombinant viral proteins as antigens in an effort to generate neutralizing antibodies

Vax. Gen made two different forms of gp 120 from different HIV strains and

Vax. Gen made two different forms of gp 120 from different HIV strains and began human trials after chimp testing

Human vaccine trials are large and very expensive

Human vaccine trials are large and very expensive

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

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

The next approach involved using viral vectors to try to also boost the T

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

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

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

They actually used three adenoviruses carrying three different viral proteins Gag Pol Nef

They actually used three adenoviruses carrying three different viral proteins Gag Pol Nef

Early results suggested the immune system was being stimulated

Early results suggested the immune system was being stimulated

The hotly awaited results were released at the 2007 AIDS Meeting

The hotly awaited results were released at the 2007 AIDS Meeting

You be the judge—what happened?

You be the judge—what happened?

This stunning failure led to a re-thinking of the approach

This stunning failure led to a re-thinking of the approach

The field has decided in part to go back to the basics: how does

The field has decided in part to go back to the basics: how does HIV work and 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 models How does HIV kill cells anyway?

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

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