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MBB311 - Molecular Immunology > Watson - vaccination > Flashcards

Watson - vaccination Flashcards

1
Q

In what ways are vaccines better than pharmaceuticals?

A
  • comparatively successful and cost effective
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2
Q

Why is a HIV-1 vaccine needed?

A
  • 16,000 new infections per day
  • substantial economic impact (triple therapy v expensive)
  • now a pandemic
  • destruction of economies and human capital
  • only treatment (no cure) w/ antiretrovirals, eg. AZT
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3
Q

When and how was immunity 1st observed?

A
  • in ancient times when infection w/ particular disease makes indiv resistant to infection w/ same disease again
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4
Q

How was variolation used to treat smallpox?

A
  • infection w/ mild case of smallpox protected from subsequent serious infection
  • scratched on arm were inoculated w/ pus from pustule
  • Jenner observed milkmaids often suffered from cowpox and were resistant to smallpox –> so deliberately infected people w/ pus from cowpox lesion
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5
Q

What is the principle of active immunisation?

A
  • manipulating IS to gen persistent protective response against pathogens
  • triggers immune response and safely mimics natural infection
  • mobilising approp arms of IS and gen immunological memory (ideally life long)
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6
Q

What is passive immunisation?

A
  • transfer of preformed antibodies (antisera)
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7
Q

What is natural passive immunity?

A
  • occurs naturally by transfer of maternal antibodies across placenta to dev fetus
  • provides protection against diphtheria, tetanus, streptococcus, rubella, mumps, poliovirus
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8
Q

What are indications for the use of artificial passive immunity?

A
  • indivs w/ agammaglobulinemia (lack of IgG in plasma) –> treated w/ pooled human IgG
  • exposure to disease that could cause complications –> eg. immunocompromised patient (HIV/chemo) exposed to measles or other pathogen
  • when no time for active immunisation to give protection –> ie. pathogen w/ short incubation time
  • when acute exposure, so danger of infection –> eg. to ebola
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9
Q

Where are anti-toxins and antivenins usually from?

A
  • horse serum –> inject horse w/ enough to mount response but not to kill
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10
Q

For some pathogens what is the main hazard, when not 1° infection which can be eliminated by IS?

A
  • effects of v potent toxins released by bacteria, eg. tetanus and botulinum
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11
Q

Why is difficult to achieve immunity to toxins/venoms?

A
  • exposure to sufficient amount to stim IS would be lethal
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12
Q

What can be used as vaccines against toxins?

A
  • deactivated toxin derivatives (toxoids)

- most commonly used is tetanus toxoid

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13
Q

What is the problem w/ using horse serum for anti-toxins/antivenins?

A
  • can only use once

- as recognised as foreign 2nd time, causing anaphylactic shock

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14
Q

What are the adv of passive immunity?

A
  • can quickly neutralise toxins and venoms
  • conventional immune response may be too slow
  • for highly virulent pathogen can prevent or limit infection
  • if no vaccine, may be only treatment
  • in some cases can use antibodies from surviving patients (certain level of risk)
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15
Q

What are the disadv of passive immunity?

A
  • doesn’t activate immunological memory
  • no LT protection
  • poss of reaction to antisera if cross species
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16
Q

What are the aims of a perfect vaccine (active immunisation)?

A
  • LT protection
  • stim B and T cells and induce memory B and T cells
  • stim protective high affinity IgG prod (and poss IgA)
  • induce approp immune response
  • safe
  • stable and easy to transport
  • should not rew repeated boosting (to reduce problems w/ patient compliance)
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17
Q

What is the aim of perfect vaccine dep on?

A
  • nature of targeted pathogen (not history of disease)

- and importance of memory B cell response dep on nature of pathogen

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18
Q

What do B cells and antibodies generally recognise?

A
  • shapes and structures

- not enough to determine if pot target is non self

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19
Q

What are the advs of live attenuated vaccines?

A
  • sets up transient infection
  • activation of full natural immune response
  • prolonged contact w/ IS
  • stim of memory response in B and T cells –> prolonged and comprehensive protection
  • often only singe immunisation req (+ve in 3rd world)
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20
Q

Why do live attenuated vaccines often only req a single immunisation?

A
  • vaccine able to replicate, so antigens released over time

- in contrast to single vaccination w/ antigenic extracts or inactivated organisms

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21
Q

What are the disadvs of live attenuated vaccines?

A
  • immunocompromised patients (or other rare indivs) may become infected as result of immunisation
  • complications –> eg. for live measles vaccine 1 per 1 mil post infection encephalomyelitis and occasionally can revert to virulent form (can cause serious outbreak in areas w/ poor sanitation)
  • refrigeration and transport –> typically live organisms need to be refrigerated for stable storage, issue in remote areas
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22
Q

What are the advs of whole inactivated pathogen vaccines?

A
  • no risk of infection
  • storage less critical
  • wide range of diff antigenic components present so good immune response poss
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23
Q

What are the disadvs of whole inactivated pathogen vaccines?

A
  • tends to just activate humoral responses
  • lack of T cell involvement
  • w/o transient infection immune response can be quiet weak
  • repeated booster vaccinations req
  • adjuvants may be needed to increase immune response
  • patient compliance can be issue (esp for multiple vaccinations)
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24
Q

What is the importance of the correct inactivation procedure?

A
  • so that vaccine is safe

- also doesn’t decrease immunogenicity of pathogen

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25
Q

How are pathogens inactivated for vaccines?

A
  • heat treatment not preferred as can alt conformation of target antigens
  • modern approaches can exploit DNA tech to remove genes that control virulence, but leave genes for infection intact
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26
Q

What are the 3 major types of subunit vaccines currently in use?

A
  • inactivated exotoxins (toxoids)
  • capsular polysaccharides
  • recomb microbial antigens
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27
Q

What are bacterial exotoxins responsible for, and how can they be used as a vaccine?

A
  • symptoms of disease caused by no. important pathogens
  • eg. diphtheria toxin inhibits translation by inactivating EF2
  • eg. tetanus toxin causes uncontrolled contraction of voluntary muscles
  • use toxoid = heat treated or chem modified to eliminate toxicity
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28
Q

What are capsular polysaccharides and what is their role?

A
  • highly polar, hydrophilic cell surface polymers consisting of oligosaccharide repeating units
  • main antigens involved in protective immunity to encapsulated bacteria
  • may interfere w/ bacterial interactions w/ phagocytes by blocking opsonisation
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29
Q

How can purified proteins be used as subunit vaccines?

A
  • cultivation of pathogen and subsequent processing to purify single component (eg. toxoids)
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30
Q

How can recomb proteins be used as subunit vaccines?

A
  • cloning and expression of single gene in recomb host –> eg. subunit vaccine comprised of hep B surface proteins
  • virus coat proteins expressed in yeast and spontaneously assemble in virus like patches
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31
Q

What is a conjugate vaccine and what issue do they solve (type of subunit vaccine)?

A
  • in some cases target antigen (eg. CPS) may only stim weak T cell response
  • would decrease induction of immunological memory, so CPS can be chem conjugated to 2nd antigen (freq, but not necessarily from same organism)
  • immunisation w/ this conjugate vaccine can then stim B and T cell responses
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32
Q

What are the advs of subunit vaccines?

A
  • safer as only portions of pathogen used
  • no risk of infection
  • easier to store and preserve
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33
Q

What are the disadvs of subunit vaccines?

A
  • immune response less powerful than live attenuated
  • repeat vaccines needed
  • adjuvants have to choose subunit that elicit response in widest range of subjects (MHC difference?)
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34
Q

What is the aim of DNA vaccines?

A
  • transiently express genes from pathogens in host cells and gen immune response similar to natural infection, leading to B and T cell memory responses
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35
Q

Do only B and T cells take up DNA from a DNA vaccine?

A
  • other cell types may too, eg. antigen presenting cells (follicular dendritic cells)
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36
Q

What proof of the principle of DNA vaccines is there, and is this enough?

A
  • immune responses in animals obtained using genes from variety of infectious agents, inc influenza, hep B, HIV, rabies
  • in some cases protective response resulted
  • but too little known about how they lead to immune response –> poss side effects? what adjuvants could be useful?
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37
Q

What are the advs of DNA vaccines?

A
  • don’t req complex storage and transportation

- delivery can be simple and adaptable to widespread vaccination programmes –> DNA gun

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38
Q

What are the disadvs of DNA vaccines?

A
  • as w/ “killed” vaccines and subunit vaccines, no transient infection
  • only likely to prod mild immune response and req subsequent boosting
39
Q

What is the aim of recomb vector vaccines, and how do they work?

A
  • imitate effects of transient infection w/ pathogen, but using non-pathogenic organism
  • genes for major pathogen antigens introd into non-pathogenic or attenuated MO and introd into host
  • viral or bacterial
40
Q

What are the advs of recomb vector vaccines?

A
  • create ideal stimulus to IS
  • prod immunological memory
  • flexible –> diff components can be engineered in
  • safe (relative to live attenuated pathogen)
41
Q

What are the disadvs of recomb vector vaccines?

A
  • req refrigeration for transport
  • can cause illness in compromised indivs
  • immune response can negate effectiveness
42
Q

What is the aim of using synthetic peptides as vaccines?

A
  • prod peptides that inc immunodominant B cell epitopes and can stime memory T cell dev
43
Q

What are the difficulties w/ using synthetic peptides as vaccines?

A
  • knowledge of MHC presentation of peptides essential
  • peptides can be stimulatory or suppressive
  • most B cell epitopes are conformational
44
Q

What are adjuvants?

A
  • essentially any substance added to vaccine to stim IS

- can inc whole killed orgs, toxoids, proteins (as in conjugate vaccines), chemicals (aluminium salts, oil emulsions)

45
Q

How do aluminium salts act as adjuvants, and is this the same as other adjuvants?

A
  • may extend half life of immunogen in site of injection (depot effect)
  • mechanisms can vary
46
Q

What is the issue w/ using chemicals as adjuvants?

A
  • can cause irritation and inflam
47
Q

How do toxoids and whole killed orgs act as adjuvants?

A
  • trigger IS and send out “danger signals”
48
Q

What is the role of adjuvants?

A
  • act as delivery system and immune stimulators

- essentially trigger innate IS

49
Q

What are some eg.s of adjuvants used in humans?

A
  • alum
  • oil/water emulsions
  • detoxified bacterial lipopolysaccharide
  • more recently, toll-like receptor agonists
50
Q

What is often the downside of high efficiency adjuvants?

A
  • can be accompanied by safety hazards –> risk of inapprop immune responses and chronic inflam
51
Q

What did evo of the cell membrane lead to?

A
  • definition of self and non-self

- and war w/ viruses

52
Q

How is AIDS transmitted?

A
  • through blood and bodily fluids

- or perinatal

53
Q

What is the origin of HIV-1?

A
  • evolved from related lentivirus in monkeys (SIV)
54
Q

When do viruses usually cause the most problems?

A
  • when they cross species
55
Q

What is the role of the TM glycoprotein on cell surface of HIV-1?

A
  • req attachment point to get into cell
56
Q

Why would passive immunisation not help against HIV?

A
  • integrates into host genome and can be dormant when integrated for long periods
57
Q

Why is HIV not recognised as foreign?

A
  • packaged and secreted out of infected host cells, so has human membrane
58
Q

What happens when HIV is activated?

A
  • prod many copies by reverse transcriptase

- billions per day

59
Q

What are the characteristics of the HIV genome?

A
  • ds RNA
  • dense and efficient
  • accessory proteins all enhance ability to rep
60
Q

What part of the HIV genome is the target for vaccines, why?

A
  • envelope protein

- stop it getting into cells in the 1st place

61
Q

What does expression of envelope protein of HIV involve, and what can be used to combat this?

A
  • expressed and cleaved by protease into 2 subunits (gp41 and gp120)
  • form structure that is key to life cycle
  • protease inhibitors used to break life cycle
62
Q

What happens during the HIV infection process?

A
  • fusion w/ membrane via gp120/gp41 “spike”
  • interacts w/ CD4 and accessory proteins CCR5 (chemokine receptor)
  • target cells are CD4 T cells, macrophages, dendritic cells
  • reverse transcrip of genome from RNA to cDNA
  • migration to nucleus and integration into host genome
  • expression of viral proteins
  • gen of viral RNA genome and encapsulation
  • expression of envelope protein and cleavage
  • secretion of mature virions from cell surface
63
Q

Why cant HIV infect some people, and why could these people be useful?

A
  • mutant CCR5

- could be good source of antibodies against HIV

64
Q

What are the effects of HIV infection for cells?

A
  • increased apoptosis of infected cells

- targeting of infected cells by CD8 killer cells

65
Q

What is the pathology of HIV/AIDS?

A
  • acute phase = CD4 T cells depleted by cytotoxic T cells
  • initially CD4 cells recover as evades IS
  • chronic slow depletion of CD4 T cells, due to generalised immune activation and loss of ability to prod new CD4 T cells
  • when CD4 cell levels fall below critical level, IS is compromised
  • get opportunistic infections w/ rare pathogens and cancers
66
Q

Are antibodies for HIV/AIDS present in patients, and what do they show?

A
  • yes, but don’t prevent infection or progression

- but show level of infection

67
Q

What makes HIV so adapted to evading IS?

A
  • accessory mols –> nef, vif, vpu, vpr
68
Q

What is the role of nef in HIV?

A
  • stabilises interaction between CD4 and AP2
  • AP2 is another adaptor for clathrin
  • by similar mechanism surface CD4 misdirected to endolysomal compartment and degraded
  • assists viral release as CD4 would tether nascent viral to surface via gp41/gp120 interaction
69
Q

What are the roles of vif/vpu/vpr in HIV?

A
  • subvert cellular ubiquitination system to neutralise anti-viral responses –> act as adaptors to cause E3 to target viral defense proteins
70
Q

Why is HIV so difficult to eradicate?

A
  • attacks cells of IS
  • accessory proteins downreg immune response
  • can be dormant for long periods –> evading IS and creating ‘reservoir’ of virus that can later re-establish infection
71
Q

Why is there such a need for a HIV vaccine?

A
  • big impact on communities
  • > 1% of worlds pop now infected
  • 1 of handful of devastating world pandemics
72
Q

What does triple therapy involve using?

A
  • inhibitors of membrane fusion/infection
  • inhibitors if reverse transcriptase
  • inhibitors of integration
  • protease inhibitors
73
Q

What evidence is there for the possibility of a HIV vaccine?

A
  • “long term non-progressors” and natural immunity exist
  • experiments w/ pre-formed antibody (passive immunisation) showed infection could be prevented
  • pre-infection w/ less virulent HIV-2 confers some protection against HIV
  • possess antibodies w/ broad neutralising activity against many strains
  • target gp120 stalk and block infection
74
Q

What are “LT natural progressors”?

A
  • people who carried HIV for long periods (30+ yrs) w/o dev AIDS
75
Q

How could broad neutralising antibodies be used against HIV?

A
  • can be cleaved from LT supporessor patients and expressed in recomb form (a kind of passive immunisation)
76
Q

In theory is a HIV vaccine poss?

A
  • not infectious (on av takes over 200 exposures to cause infections)
  • infection often by 1 virion or v small no.
  • so theoretically vaccination could present infection and/or progression
77
Q

What are the aims of a HIV vaccine?

A
  • cause humoral responses –> B cell vaccines

- route is purified recomb subunits and repeated doses

78
Q

What were early vaccine trials for HIV, and were they effective?

A
  • inactivated virus and attenuated virus –> not really pursued
  • subunits –> purified recomb proteins (gp120, gp41, gp160)
  • subunits expressed in recomb viral vectors
  • all proved ineffective –> patient gen antibodies but infection and progression not prevented
79
Q

What are the features of HIV that hinder immune responses?

A
  • high genetic variability
  • immunodominance and cryptic epitopes
  • immunosuppressive factors
80
Q

How does HIV exhibit genetic variability?

A
  • exists in series of related variants or clades
  • high genetic variability, even w/in indivs
  • new variants constantly emerging as virus rep –> due to error prone rep by reverse transcriptase
  • allows evo selection w/in infected indiv –> observed as resistance to antiviral drugs freq arises w/ AZT and other therapies
81
Q

Does infection w/ HIV prevent subsequent infections, and what are the implications of this?

A
  • no, still get subsequent superinfections w/ other variants
  • so patients either fail to dev neutralising antibody or cellular immune response
  • or HIV mutated and evades IS
  • after initial small scale infection remains in IS and begins prolif (≈ 1 bil virions/day)
  • created conditions for natural selection to gen novel variants
82
Q

What is a key target for preventing infection w/ HIV?

A
  • env “spike” –> trimer of membrane spanning gp41 in complex w/ gp120
  • gp120 has recognition sites for CD4 and CCR5
  • blocking these sites w/ antibody can sterically inhibit binding of CD4 and infection
  • non-progressors target this site
83
Q

What is the main problem w/ targeting CD4 and CCR5 binding sites?

A
  • not exposed to IS
  • transiently exposed as result of CD4 binding and conformational changes
  • these epitopes masked, so not easily targeted by IS
  • Ig too large to access these sites
84
Q

What are further problems with targeting CD4 and CCR5 binding sites?

A
  • gp120 features no. solvent exposed peptide loops that are highly variable
  • these are preferred immunodominant targets for B cell responses = decoys
  • adaptive IS is not “intelligent”
85
Q

What is sterilising immunity?

A
  • stopping infection from occurring in 1st place
86
Q

Should a HIV vaccine cause sterilising or non-sterilising immunity?

A
  • rate of infection must be decreased
  • decreased viral load could decrease rate of transmission
  • strategy must shift to decrease spread
  • elimination may be impossible
87
Q

What is the potential of non-progressors?

A
  • discovery of neutralising B cell epitopes by screening these people?
  • isolate patient sera who have broad neutralising activity and determine corresponding epitopes
88
Q

What is the challenge, now we know natural neutralising antibodies for HIV do exist?

A
  • to make immunogen that would elicit same antibody response in subjects receiving vaccine
  • titer of neutralising antibody correlates w/ protection so req high levels
  • likely that protection will req both neutralising antibody and cytotoxic T cell responses
89
Q

What are the future trends for dev a HIV vaccine?

A
  • exploit natural non-progressors
  • clone their antibodies
  • broadly neutralising
  • use in passive immunisation approach to decrease viral load
  • decrease viremia and halt transmission
90
Q

What features of HIV make dev vaccine problematic?

A
  • vaccines mimic natural immunity against reinfection → but don’t see recovery
  • most vaccines protect from disease, not infection, but if infects too late, due to latency
  • can’t use whole killed or live attenuated which are most effective
  • most vaccines protect from pathogens encountered infreq, but daily for those at high risk
  • most vaccines protect from infection through mucosal surfaces of resp/GI tract, but through UG
91
Q

Why can’t we use live attenuated or killed vaccines for HIV?

A
  • attenuated too dangerous

- killed lose immuno-characteristics so doesn’t gen approp Ab

92
Q

What are the issues with T cell vaccines for HI?

A
  • difficult in immunocompromised patients as can establish widespread lethal infection
  • unlikely to target latent reservoir
93
Q

What are the options in terms of what a HIV vaccine could do, and how could these be studied?

A
  • prevent infection (stim B cell and gen Ab) → look at no. new infections in vaccinated group comp to control
  • delaying progression (stop immune depletion/prog to AIDS) → viral load tests, comp those infected after receiving vaccine to those infected w/o vaccine
  • blocking transmission (decrease viral load) → look at if rates of infection decrease after vaccine and comp pops where vaccine available, to those where its not
94
Q

What recent dev has there been for a target for HIV vaccine?

A
  • density spikes on env quite sparse (14/virion)
  • hard for Ab to bind 2 spikes sim
  • found in some infected appear to be polyreactive Abs –> bind glycoprot w/ 1 arm and unknown surface Ag w/ other
  • aim = artificially make these

MBB311 - Molecular Immunology (2 decks)

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