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104 Cards in this Set

  • Front
  • Back
What are the top 3 disease killers in the world? Why?
1. HIV
2. TB
3. Malaria
-Because there is no effective vaccine against any of them
How many deaths are caused by HIV every year?
3 million
I thought there was a vaccine for TB?
It is just the BCG vaccine and doesn't elicit long lasting immunity.
So what are the 3 main goals of vaccination programs?
-To protect from symptoms
-To control disease spread
-To eradicate diseases
What is an example of a disease for which a vaccine is used to protect populations from symptoms?
Rabies
What are some examples of diseases for which a vaccine is used to control disease spread?
-MMR, VZV, Hep A/B, Influenza
What disease has been eradicated, and what has ALMOST been eradicated?
Smallpox - eradicated
Polio - almost
What are 4 things that make a virus an important and feasible target for vaccine development?
1. Severity warrants vaccine
2. Limited # of serotypes
3. No rapid mutation
4. Natural infection is acute and self-limiting, and elicits long lasting immunity.
Why is it difficult to create vaccines against CHRONIC infections?
Bc the immune system is not good at clearing the virus - we don't want to purposely put a chronic infection in a host.
2 Chronic infections that vaccines are being attempted to be made for:
-Hepatitis C virus
-HIV
What are the 2 main goals of vaccines in regard to disease?
-To prevent infection
-To prevent symptoms if the infection does occur
What are the 3 things that we have to keep in mind in developing vaccines?
1. Safety issues
2. Efficacy issues
3. Practical considerations
What are 2 safety issues re vaccines?
-Don't cause significant illness
-Not harmfully transmissible
What are 3 features that make a vaccine most effective?
-Elicits long-lived immunity
-Elicits humoral immunity
-Elicits cell-mediated immunity
What is humoral immunity?
What is cell-mediated immunity?
Humoral = Neutralizing antibody
Cellmediated = CTLs
What are some practical considerations in vaccine development?
-Cost
-Shelflife
-Ease of distribution
-Ease of administration
-Side effects/contraindications
What immunological event has to occur in order to drive an efficient immune response to a vaccine?
Presentation of immunogens on professional APCs
What happens as the dose of vaccine antigen increases?
The number of responding naive lymphocytes increases
What has to happen when responding naive lymphocytes have undergone 10-15 cell divisions?
They must rest as committed cells
What can happen to these committed cells then?
Re-stimulation to proliferate again after a period of weeks/months
What is this restimulation called?
Boosters
What determines how much humoral vs cell-mediated immunity will contribute to the immune response elicited by a vaccine?
The virus type
What are 3 ways to balance the cellular vs humoral response?
-Antigen formulation
-Immunization route
-Adjuvant
What exactly is affected by these 3 methods of balancing cellular vs humoral responses?
Th1 cells vs Th2
What has to happen for mucosal immunity to be induced?
Antigen presentation to MALT
What is the first goal of vaccination?
To generate neutralizing antibody
What are 3 things that can happen when neutralizing antibody recognizes and binds free virus?
1. Direct viral neutralization
2. Complement-mediated virolysis
3. Complement-mediated phagocytosis and inactivation
What is required for the complement mechanisms?
Binding of complement to antibody-virus complexes.
If you were to passively immunize a person with HIV antibody, what would be most important for preventing HIV replication and release?
-Fc receptor mediated functions

-NOT complement mediated functions
What are 2 things that can happen as a result of Ab binding to viral antigen on infected cell surfaces?
-Killing of the infected cells
-Inhibition of viral replication, release, and spread
So what are 3 important things that Antibodies block?
-Binding of a virus to epithelial cell surfaces
-Viral Infection of tissue cells
-Cell-cell spread of virus released from infected dead cells
What is faster; free viral invasion of an epithelial cell, or cell-cell spread of virus?
Cell-cell spread
So what is really the more important mechanism achieved by antibody blocking?
Blockage of cell-cell spread of the virus
Can protection be afforded by passive transfer of antibodies?
Yes
What are 2 ways that passive antibody affords protection against viral infection? which way si more common?
-Sterile protection - prevention of viral replication (rare)
-Blunting protection - allow other immune responses to take over (more common)
Why is sterile prevention of viral replication rare?
Because it requires very high titers of antibody to be passively given, and it is transient.
In an HIV infection, what is Virus-specific Ab effective against?
What is it NOT effective in?
-Effective against free virus
-NOT effective against latently infected cells
-Poorly effective against virus-infected cells
In HIV infections how are CTLs -effective?
-NOT effective?
Effective against Virus-infected cells
NOT effective against Latently infected cells
NOT effective against free virus
What are 2 things that need to be adequete for it to be worthwhile for a vaccine to stimulate Antibody production?
-Induce long lived plasma cells
-Induce memory Bcells that can be activated upon re-exposure
How do viral vaccines elicit production of neutralizing antibody?
Very effectively - their repetitive surface antigens are good at eliciting antibody.
What would PREVENT a virus from eliciting strong neutralizing Ab production?
Very rapid transmission between hosts so that there is not TIME to develop an immune response
What is NOT a good way to elicit strong neutralizing antibody?
Relying on re-infections of the same individual; the repetition of surface antigen must be in the same infection.
What is a distinguishing feature of how influenza elicits neutralizing antibody?
Its epitopes (HA) against which Ab is generated are loops that undergo extensive variation
What is the result of Influenza's undergoing frequent epitope changes?
Different SEROTYPES arise
What are the 2 main types of vaccines that we currently use?
1. Live attenuated
2. Dead inactivated
What is the goal of a live attenuated vaccine?
To mimic the natural infection without causing disease
What is the best example of this?
Vaccinia virus for smallpox
How can vaccinia elicit immune memory that is specific for smallpox?
The two viruses are related; vaccinia just doesn't cause the same virulent disease
For what other disease is a live attenuated vaccine
-very good
-very bad
Good = polio
Bad = HIV
What are 3 ways of "attenuating" viruses for vaccines?
1. Pass through cells of different species to yield host range variants
2. Select for altered temperature optimum
3. Select for altered tissue tropism
What is an example of a virus vaccine that has an altered temperature optimum?
Cold adapted influenza virus
What is an example of a virus vaccine that has altered tissue tropism?
Reduced neurotropism poliovirus
What is achieved by passing a virus through cells of heterogenous species?
It diminishes the ability of the virus to grow in HUMAN cells, thus it is attenuated.
What is an example of an attenuated vaccine that was made by this method?
The SABIN polio vaccine
What is BAD about the Sabin poliovirus vaccine?
-It is only different at 10 of 7429 nucleotides from the WT
-It can revert back to the WT and cause disease in vaccinated individuals!
How can genetic engineering be used to attenuate a virus?
By taking out the virulence gene either by mutating or deleting it.
What is the critical virulence factor in HIV and SIV that can be taken out to create a vaccine?
NEF
What are 5 advantages of live attenuated vaccines?
-Mimics natural infection
-Expresses full range of gene products
-Elicits Ab and Cellmediated responses to both surface and intracellular Ags
What are 2 things that live attenuated vaccines elicit that inactivated vaccines cannot?
-Mucosal immunity
-Herd immunity
What is the drawback of herd immunity?
If it spreads to the wrong individual - immunocompromised - it can result in disease
What are 5 other problems with live attenuated viruses?
-Residual pathogenicity
-Possible reversion to virulent strains
-Growth in culture may contain other agents
-Interference from related viruses
-May need special storage conditions and administration
How can live attenuated viruses evade the immune system?
By downregulating MHC1
What are the 3 ways that attenuated vaccines are administered?
1. Oral
2. Subcutaneous
3. Intradermal
What are the 3 ways that inactivated vaccines are administered?
1. Intramuscular
2. Subcutaneous
3. Intradermal
Which type of vaccine is more safe?
Inactivated
What are 3 examples of inactivated vaccines?
-Polio
-Rabies
-Influenza
What are the 2 advantages of inactivated vaccines?
-Avoids the risks of attenuated viruses
-No interference from related infections
What are the 4 problems of inactivated vaccines?
1. May not be completely inactivated
2. No mucosal immunity
3. May elicit imbalance immunity
4. Longevity is controversial
What is an alternative approach to avoid the problems of live attenuated vaccines and inactived?
Recombinant vaccines
What is a recombinant virus?
A virus that is generated by treating a cell that contains WT virus, with a viral vector containing a foreign gene.
What is the goal in using recombinant viruses?
To generate a viral vector that carries genes from one or more additional viruses
What is the best example of a recombinant virus?
Recombinant pox virus
(vaccinia, yellowpox, etc)
Why is the pox virus such a great vector for recombination?
It has a huge DNA genome and can accomodate as many as 10 foreign genes!
What does a recombinant virus elicit?
-Good B and T-cell immunity
What is currently in trial using a recombinant vaccine?
HIV in both Adenovirus and Vaccinia virus
How do recombinant virus vaccines avoid viral persistence or latency?
The gene only encodes for an immunogenic PART of the virus, not the whole thing.
What are 2 viruses for which 2nd generation subunit or recombinant vaccines have been very effective?
-Hep B
-HPV (papillomavirus)
What part of HBV is good at eliciting fully protective and neutralizing antibody?
HepBsAg
What did the hepB vaccine USED to be?
Just isolated HBsAg - not so safe
what HPV types cause 70% of cervical cancer?
Types 16 and 18
What are the 2 recombinant vaccines against HPV 16 and 18?
-Gardasil
-Cervarix
What has been developed since?
Quadrivalent HPV against 6, 11, 16, and 18
What HPV gene is used in the recombinant vaccine?
L1
What is a totally different alternative approach to developing vaccines?
PEPTIDE based vaccines
What can immunodominant epitopes isolated from viruses elicit?
-Neutralizing antibody
What can be done with the epitopes?
Presentation on MHC1 and 2
What do you have to give WITH peptides to induce a strong enough immune response?
Adjuvants
How can peptides be improved for better presentation on MHC and better TCR recognition?
By engineering their amino acids so that they have enhanced affinity.
What is the 3rd generation of vaccines?
DNA inoculation
What is DNA inoculation most promising for?
HIV vaccine development
How is DNA inoculation done?
By physically injecting DNA encoding viral antigens into appropriate tissues
What happens to the DNA once injected into the tissue?
It is expressed, and the proteins elicit an immune response that is specific.
What is the result of intradermal DNA delivery?
The DNA is taken up by
-Epithelial cells
-Dendritic cells
What is the result of intramuscular DNA delivery?
The DNA will traffic to lymph nodes to be taken up by APC
-Also taken up by muscle cells
What is the advantage of a DNA vaccine?
It's much easier to prepare
How can the efficacy of DNA vaccines be improved?
By including genes encoding cytokines and co-stimulatory molecules
What is an immunological adjuvant for DNA vaccines?
CpG sequences WITHIN the plasmids
What type of regimen works well with DNA vaccination?
Prime-Boost
What is the Prime step?
DNA vaccination
What is the boost step?
Using recombinant adenovirus, vaccinia virus, or recombinant proteins to boost the initial prime.
What do you really have to do for a vaccine to be able to generate mucosal immunity?
Mimic the infection - apply the immunogen to the actual mucosal area.
For what diseases is mucosal immunity very important?
STDs
So how do you start off a mucosal type of infection for HIV or HPV for instance?
Use a gel to introduce antigen to the mucosal epithelium.
What needs to happen then after antigen gets applied to the mucosal epithelium?
Uptake by APCs and trafficking to lymphoid tissue.