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Immunity
Specific defensesImmunity
Passive immunityActive 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
Viral Vaccines
Immunizing agents
Immunizing agents
antiseraimmunuglobulinsvaccines
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 seehow this strategy works
The time: 500 B.C.The place: Greece
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
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt
I had a brilliant idea
Vaccination• Charles Jenner 1796 : Cowpox/Swinepox
• 1800’s Compulsory childhood vaccination
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
• 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
As a result, after a world-wide effortSmallpox 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 polypeptide (cellular
fraction) vaccines• Surface antigen (recombinant) vaccines.
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 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 Vaccineshave 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 Vaccinesalso 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 receivedwere 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 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
• Cannot replicate and thus generally not as effective as live vaccines
• Usually require 3-5 doses• Immune response mostly antibody based
Minuses
Inactivated Vaccines
• No chance of recreating live pathogen• Less interference from circulating antibody than
live vaccines
Pluses
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
Other Inactivated Vaccinesnow contain purified proteins
rather than whole bacteria/viruses
• Proteins hepatitis B, influenza,acellular pertussis,human papillomavirus, anthrax, Lyme
• Toxins diphtheria, tetanus
Sabin Polio VaccineAttenuated by passage in foreign host (monkey kidney cells)
Selection to grow in new host makes virus
less suited to original host
Sabin Polio VaccineAttenuated 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)
Salk Polio Vaccine
• Formaldehyde-fixed
• No reversion
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
Reci
proc
al v
irus
antib
ody
titer
512
128
32
8
2
1
Serum IgGSerum IgG
Serum IgM Serum IgM
Nasal and duodenal IgA
Nasal IgASerum IgA
Serum IgA
Duodenal IgA
DaysVaccination Vaccination
48
4896 96
Killed (Salk) Vaccine
Live (Sabin) Vaccine
Live virus generates a more complete immune response
Modern molecular biologyhas offered new approaches to make vaccines
1. Clone gene from virus or bacteriaand express this protein antigenin yeast, bacteria or mammalian cells in culture
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
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
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 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 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 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.
Types of vaccinesLivevaccines
LiveAttenuated vaccines
KilledInactivated vaccines
Toxoids Cellular fraction vaccines
Recombinant vaccines
•Small pox variola vaccine
•BCG•Typhoid oral•Plague•Oral polio•Yellow fever•Measles•Mumps•Rubella•IntranasalInfluenza•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
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,
rubella, yellow fever)– Multiple dose vaccines (polio, DPT, hepatitis B)
• Booster vaccinationTo maintain immunity level after it declines after
some time has elapsed (DT, MMR).
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%): 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
Given that introduction, should we search for a vaccine against HIV and how would we do so?
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
An effective vaccine could have a MAJORImpact on the future prognosis
iavi.org
An effective vaccine must get around the strategies HIV uses to evade the immune system
The vaccine must be able to target conservedand essential parts of the viruses machinery
Antigenic escape
Inaccessible epitopes
+ existence of many viral strains
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
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
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 antibodies
to kill free virus
To begin we need to ask some key questions
What should vaccine elicit?
Neutralizing antibodies
to kill free virusT cell response to
kill infected cellsOR
To begin we need to ask some key questions
What should vaccine elicit?
Neutralizing antibodies
to kill free virusT cell response to
kill infected cellsOR
OR BOTH?
The biology of HIV provides some clues
Long term progressorsInfected with a Nef mutant virus?
This would generate both an antibody and a T cell responseCould this be used to generate a vaccine?
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
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 touse recombinant viral proteins as antigens
in an effort to generate neutralizing antibodies
VaxGen made two different formsof gp120 from different HIV strains
and began human trials after chimp testing
Human vaccine trials are large and very expensive
The trial was a failure, with only minor effects seen
that were viewed as statistically insignificant
NY Times
The next approach involved usingviral vectors to try to
also boost the T cell response
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
Early results suggested the immune system was being stimulated
The hotly awaited results were released at the 2007 AIDS Meeting
You be the judge—what happened?
This stunning failure led to a re-thinking
of the approach
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 models
How does HIV kill cells anyway?
However trials continue, but with more focus
on the details of how they affect immunity