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104 Cards in this Set
- Front
- Back
What are the top 3 disease killers in the world? Why?
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1. HIV
2. TB 3. Malaria -Because there is no effective vaccine against any of them |
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How many deaths are caused by HIV every year?
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3 million
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I thought there was a vaccine for TB?
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It is just the BCG vaccine and doesn't elicit long lasting immunity.
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So what are the 3 main goals of vaccination programs?
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-To protect from symptoms
-To control disease spread -To eradicate diseases |
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What is an example of a disease for which a vaccine is used to protect populations from symptoms?
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Rabies
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What are some examples of diseases for which a vaccine is used to control disease spread?
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-MMR, VZV, Hep A/B, Influenza
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What disease has been eradicated, and what has ALMOST been eradicated?
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Smallpox - eradicated
Polio - almost |
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What are 4 things that make a virus an important and feasible target for vaccine development?
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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. |
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Why is it difficult to create vaccines against CHRONIC infections?
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Bc the immune system is not good at clearing the virus - we don't want to purposely put a chronic infection in a host.
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2 Chronic infections that vaccines are being attempted to be made for:
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-Hepatitis C virus
-HIV |
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What are the 2 main goals of vaccines in regard to disease?
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-To prevent infection
-To prevent symptoms if the infection does occur |
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What are the 3 things that we have to keep in mind in developing vaccines?
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1. Safety issues
2. Efficacy issues 3. Practical considerations |
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What are 2 safety issues re vaccines?
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-Don't cause significant illness
-Not harmfully transmissible |
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What are 3 features that make a vaccine most effective?
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-Elicits long-lived immunity
-Elicits humoral immunity -Elicits cell-mediated immunity |
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What is humoral immunity?
What is cell-mediated immunity? |
Humoral = Neutralizing antibody
Cellmediated = CTLs |
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What are some practical considerations in vaccine development?
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-Cost
-Shelflife -Ease of distribution -Ease of administration -Side effects/contraindications |
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What immunological event has to occur in order to drive an efficient immune response to a vaccine?
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Presentation of immunogens on professional APCs
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What happens as the dose of vaccine antigen increases?
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The number of responding naive lymphocytes increases
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What has to happen when responding naive lymphocytes have undergone 10-15 cell divisions?
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They must rest as committed cells
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What can happen to these committed cells then?
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Re-stimulation to proliferate again after a period of weeks/months
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What is this restimulation called?
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Boosters
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What determines how much humoral vs cell-mediated immunity will contribute to the immune response elicited by a vaccine?
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The virus type
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What are 3 ways to balance the cellular vs humoral response?
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-Antigen formulation
-Immunization route -Adjuvant |
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What exactly is affected by these 3 methods of balancing cellular vs humoral responses?
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Th1 cells vs Th2
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What has to happen for mucosal immunity to be induced?
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Antigen presentation to MALT
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What is the first goal of vaccination?
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To generate neutralizing antibody
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What are 3 things that can happen when neutralizing antibody recognizes and binds free virus?
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1. Direct viral neutralization
2. Complement-mediated virolysis 3. Complement-mediated phagocytosis and inactivation |
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What is required for the complement mechanisms?
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Binding of complement to antibody-virus complexes.
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If you were to passively immunize a person with HIV antibody, what would be most important for preventing HIV replication and release?
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-Fc receptor mediated functions
-NOT complement mediated functions |
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What are 2 things that can happen as a result of Ab binding to viral antigen on infected cell surfaces?
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-Killing of the infected cells
-Inhibition of viral replication, release, and spread |
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So what are 3 important things that Antibodies block?
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-Binding of a virus to epithelial cell surfaces
-Viral Infection of tissue cells -Cell-cell spread of virus released from infected dead cells |
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What is faster; free viral invasion of an epithelial cell, or cell-cell spread of virus?
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Cell-cell spread
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So what is really the more important mechanism achieved by antibody blocking?
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Blockage of cell-cell spread of the virus
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Can protection be afforded by passive transfer of antibodies?
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Yes
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What are 2 ways that passive antibody affords protection against viral infection? which way si more common?
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-Sterile protection - prevention of viral replication (rare)
-Blunting protection - allow other immune responses to take over (more common) |
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Why is sterile prevention of viral replication rare?
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Because it requires very high titers of antibody to be passively given, and it is transient.
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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 |
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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 |
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What are 2 things that need to be adequete for it to be worthwhile for a vaccine to stimulate Antibody production?
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-Induce long lived plasma cells
-Induce memory Bcells that can be activated upon re-exposure |
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How do viral vaccines elicit production of neutralizing antibody?
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Very effectively - their repetitive surface antigens are good at eliciting antibody.
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What would PREVENT a virus from eliciting strong neutralizing Ab production?
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Very rapid transmission between hosts so that there is not TIME to develop an immune response
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What is NOT a good way to elicit strong neutralizing antibody?
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Relying on re-infections of the same individual; the repetition of surface antigen must be in the same infection.
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What is a distinguishing feature of how influenza elicits neutralizing antibody?
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Its epitopes (HA) against which Ab is generated are loops that undergo extensive variation
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What is the result of Influenza's undergoing frequent epitope changes?
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Different SEROTYPES arise
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What are the 2 main types of vaccines that we currently use?
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1. Live attenuated
2. Dead inactivated |
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What is the goal of a live attenuated vaccine?
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To mimic the natural infection without causing disease
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What is the best example of this?
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Vaccinia virus for smallpox
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How can vaccinia elicit immune memory that is specific for smallpox?
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The two viruses are related; vaccinia just doesn't cause the same virulent disease
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For what other disease is a live attenuated vaccine
-very good -very bad |
Good = polio
Bad = HIV |
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What are 3 ways of "attenuating" viruses for vaccines?
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1. Pass through cells of different species to yield host range variants
2. Select for altered temperature optimum 3. Select for altered tissue tropism |
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What is an example of a virus vaccine that has an altered temperature optimum?
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Cold adapted influenza virus
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What is an example of a virus vaccine that has altered tissue tropism?
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Reduced neurotropism poliovirus
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What is achieved by passing a virus through cells of heterogenous species?
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It diminishes the ability of the virus to grow in HUMAN cells, thus it is attenuated.
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What is an example of an attenuated vaccine that was made by this method?
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The SABIN polio vaccine
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What is BAD about the Sabin poliovirus vaccine?
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-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! |
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How can genetic engineering be used to attenuate a virus?
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By taking out the virulence gene either by mutating or deleting it.
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What is the critical virulence factor in HIV and SIV that can be taken out to create a vaccine?
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NEF
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What are 5 advantages of live attenuated vaccines?
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-Mimics natural infection
-Expresses full range of gene products -Elicits Ab and Cellmediated responses to both surface and intracellular Ags |
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What are 2 things that live attenuated vaccines elicit that inactivated vaccines cannot?
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-Mucosal immunity
-Herd immunity |
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What is the drawback of herd immunity?
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If it spreads to the wrong individual - immunocompromised - it can result in disease
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What are 5 other problems with live attenuated viruses?
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-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 |
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How can live attenuated viruses evade the immune system?
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By downregulating MHC1
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What are the 3 ways that attenuated vaccines are administered?
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1. Oral
2. Subcutaneous 3. Intradermal |
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What are the 3 ways that inactivated vaccines are administered?
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1. Intramuscular
2. Subcutaneous 3. Intradermal |
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Which type of vaccine is more safe?
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Inactivated
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What are 3 examples of inactivated vaccines?
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-Polio
-Rabies -Influenza |
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What are the 2 advantages of inactivated vaccines?
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-Avoids the risks of attenuated viruses
-No interference from related infections |
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What are the 4 problems of inactivated vaccines?
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1. May not be completely inactivated
2. No mucosal immunity 3. May elicit imbalance immunity 4. Longevity is controversial |
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What is an alternative approach to avoid the problems of live attenuated vaccines and inactived?
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Recombinant vaccines
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What is a recombinant virus?
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A virus that is generated by treating a cell that contains WT virus, with a viral vector containing a foreign gene.
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What is the goal in using recombinant viruses?
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To generate a viral vector that carries genes from one or more additional viruses
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What is the best example of a recombinant virus?
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Recombinant pox virus
(vaccinia, yellowpox, etc) |
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Why is the pox virus such a great vector for recombination?
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It has a huge DNA genome and can accomodate as many as 10 foreign genes!
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What does a recombinant virus elicit?
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-Good B and T-cell immunity
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What is currently in trial using a recombinant vaccine?
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HIV in both Adenovirus and Vaccinia virus
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How do recombinant virus vaccines avoid viral persistence or latency?
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The gene only encodes for an immunogenic PART of the virus, not the whole thing.
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What are 2 viruses for which 2nd generation subunit or recombinant vaccines have been very effective?
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-Hep B
-HPV (papillomavirus) |
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What part of HBV is good at eliciting fully protective and neutralizing antibody?
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HepBsAg
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What did the hepB vaccine USED to be?
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Just isolated HBsAg - not so safe
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what HPV types cause 70% of cervical cancer?
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Types 16 and 18
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What are the 2 recombinant vaccines against HPV 16 and 18?
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-Gardasil
-Cervarix |
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What has been developed since?
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Quadrivalent HPV against 6, 11, 16, and 18
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What HPV gene is used in the recombinant vaccine?
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L1
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What is a totally different alternative approach to developing vaccines?
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PEPTIDE based vaccines
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What can immunodominant epitopes isolated from viruses elicit?
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-Neutralizing antibody
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What can be done with the epitopes?
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Presentation on MHC1 and 2
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What do you have to give WITH peptides to induce a strong enough immune response?
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Adjuvants
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How can peptides be improved for better presentation on MHC and better TCR recognition?
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By engineering their amino acids so that they have enhanced affinity.
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What is the 3rd generation of vaccines?
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DNA inoculation
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What is DNA inoculation most promising for?
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HIV vaccine development
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How is DNA inoculation done?
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By physically injecting DNA encoding viral antigens into appropriate tissues
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What happens to the DNA once injected into the tissue?
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It is expressed, and the proteins elicit an immune response that is specific.
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What is the result of intradermal DNA delivery?
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The DNA is taken up by
-Epithelial cells -Dendritic cells |
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What is the result of intramuscular DNA delivery?
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The DNA will traffic to lymph nodes to be taken up by APC
-Also taken up by muscle cells |
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What is the advantage of a DNA vaccine?
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It's much easier to prepare
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How can the efficacy of DNA vaccines be improved?
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By including genes encoding cytokines and co-stimulatory molecules
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What is an immunological adjuvant for DNA vaccines?
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CpG sequences WITHIN the plasmids
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What type of regimen works well with DNA vaccination?
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Prime-Boost
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What is the Prime step?
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DNA vaccination
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What is the boost step?
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Using recombinant adenovirus, vaccinia virus, or recombinant proteins to boost the initial prime.
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What do you really have to do for a vaccine to be able to generate mucosal immunity?
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Mimic the infection - apply the immunogen to the actual mucosal area.
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For what diseases is mucosal immunity very important?
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STDs
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So how do you start off a mucosal type of infection for HIV or HPV for instance?
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Use a gel to introduce antigen to the mucosal epithelium.
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What needs to happen then after antigen gets applied to the mucosal epithelium?
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Uptake by APCs and trafficking to lymphoid tissue.
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