MBIO module 4

vaccines

vaccine:

a material that can artificially induce immunity to an infectious disease

* usually administered via injection but also through ingested material
* person exposed to harmlessand /or dead pathogen, or destroyed bits of a pathogen

what happens to a vaccine after it is ingected?

macrophages and dendritic cells phagocytize the vaccine and display antigens on their MH2 molecules, activating TH! and TH2 as well as B and cytotoxic T cells

* also forms memory T helper, B and cytotoxic T cells which is protective for 15-20 years depending on the patients immune system

live attenuated vaccines:

composed of strains of a microbe which has been bred to be weakened or progress at a much slower rate

* before given the chance to cause widespread disease, the humoral and cell-mediated response has already been activated, and antibodies/cytotoxic T cells have been produced.

a live attenuated vaccine works the same way as:

the wild type , pathogenic microbe, thus the patient can mount a similar, highly effective defense if the pathogen is encountered in daily life

* considered the most effective

drawback for live attenuated vaccines:

the most effective, but it can be hard to find strains that stimulate the immune response without causing disease

can you give a live attenuated vaccine to someone who is pregnant or immunocompromised?

NO; you are relying on the immune system to be able to outcompete the weakened strain, which occurs with a normal immunocompetent system.

inactivated pathogen vaccine:

pathogenic microbe is gorwn in a lab, isolated and killed using heat, chemical or radiological sterilization

* dead material injected into patient, where enough inflammation is usually generated to recruit macrophages or dendritic cells, who phagocytize and present antigens on MH2, and acitvate T helper cells, B cells and cytotoxic T cells

advantages to a inactivated pathogen vaccine:

* microbe entirely dead
* no infection occurs thus very few side effects
* can be given to those who are pregnant or immunocompromised with little to no risk

disadvantages to inactivated pathogen vaccines:

* since they do not cause a local infection, they generally dont mimic a natural infection as well as a live attenuated strain= do not generate a strong immune response

subunit/toxoid/conjugate vaccines:

vaccines made up of components of a microbe rather than the entire organism, such as just the adhesins or just the outer membrane

* even fewer side effects; can be givedn to almost anyone, including neonates
* least effective- rarely cause enough inflammation to generate macrophage/dendritic cell presentation on their own

adenovirus vector vaccines:

used a modified adenovirus, which have had their replication and integration genes removed and replaced with the NDA of SARS-CoV-2 spike protein

* the vfiral capsid can bind to your muscle cells upon injection
* spike protein DNA inserted into those cells
* spike proteins made and expressed by your own cells, which triggers immune response, the same way it would if your were injfected with covid

what does the adenovirus vaccine ensure?

the spike protein looks identical to the one generated by the viral infection itself, increasing the likelihood of generating a strong andibody binding and strong cytotoxic T cell recognition whne an infection with SARS-CoV-2

* reduces possibility of an autoimmune disease being accidentally generated

why did astra-zeneca use chimpanzee adeovirus when J&J used a human version?

to reduce the chance that a person might have pre-existing antibodies which might bind to and reduce the effectiveness of the vaccine

which brand make adenovirus vaccines for covid?

* astrazeneca and J&J Jansen vaccines

mRNA vaccines:

mRNA sequence of the viral spike protein (adhesion) is lipid coated, injected and fuses with local cells membranes

* generates identical viral spike proteins to act as antigens

what are mRNA vaccines grown in? why is this a problem?

chicken eggs or Yeast; if the person is allergic to the growth medium, this can trigger anaphylaxis

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drawbacks of heat/formaline killed mRNA vaccines:

* if they are heat/formalin killed versions, some of the pathogen proteins might misfold and not work as well for generating immunity, or antibodies can form against other similar proteins in your own cells= autoimmune response

how do mRNA vaccines work?

* rather than using bits of the pathogen, filtered or not, the viral adhesin mRNA is injected and the patients own cells take it up and make the viral adhesin only
* immune system recongized foreign viral adhesins and makes antibodies and cytotoxic t cells against it

three important factors of the mRNA vaccine:

1. the viral adhesin comes out looking exactly like it would during infection because it is using the same mRNA-→ protein machinery as the virus would use= same post-translational process, and far fewer risks of an autoimmune disease
2. its just the mRNA of the adhesin, meaning it cant reactivate, and cannot self-replicate like the weakened pathogen vaccines= no risk to immuncompromised
3. not being grown in yeast or chicken eggs= almost no allergic reactions, and being mRNA, it degrades within 24 hours, so no long term risks of anything

which brand made an mRNA covid vaccine?

* pfizer
* moderna

what determines the amount and type or antibodies produced by a vaccine?

1. nature of the antigen
2. the site of the antigen stimuli
3. the amount of antigen
4. the number of times the person is exposed to the antigen

why cant vaccines protect everyone?

what is their only option?

1. some are too young to recieve the vaccine
2. some are allergic to their ingredients
3. some dont have the B-cell and cytotoxic T-cell receptors to recognize that particular pathogen, which is needed to create antibodies
* only option for these individuals= herd immunity

herd immunity:

the immunization of a large enough population that a pathogenic microbe has a low a chance as possible to spread from one unprotected individual to another

what does R0 stand for?

the number representing the average number of people in an unprotected population that one person could pass the disease along to

DTaP-IPV-Hib:

diptheria, tetanus, acellular pertsussis, inactivated polio and haemophilia influenzae type B combination vaccine; with or without hepatitis B

* “5 in 1”

dTaP:

diptheria, tetanus, acellular pertussis (booster later in life)

Rot:

rotavirus

Pneu-C-13:

pneumococcal vaccine

Men-C-C:

meningococcal cojugate vaccine (monovalent or quadrivalent)

MMR:

Measle, mumps, rubella

MMRV:

measles, mumps, rubella + varicella

HB:

hepatitis B

HPV:

human papillomavirus

Inf:

influenza

what are the risks to vaccines?

* risk for Guillan-barre syndrome (1/50,000-1/100000 a year for all cases)
* risk of air emboli
* risk of bruising/bleeding around injection site
* risk of needle damaging local nerve
* risk of bacterial infection at puncture site

are there risks for DTaP?

* no evidence of significant risk
* did not increase type 1 diabetes

risks for Haemophilus influenzae type B vaccine:

* risk of redness and swelling but not hospitalization
* not associated with high fever, convulsions, diarrhea, fungal infections or acid reflux

risks for Hepatitis A vaccine:

* purpura was no associated with any of the vaccines in children aged 2-6
* purpura was associated with Hep A vaccine in children aged 7-17 years

risks for Heptatitis B vaccine:

* relationship between the vaccine and anaphylaxis in yeast-sensitive individuals
* does not cause multiple sclerosis

risks for polio vaccine:

* newborns immunized against polio had higher odds of sensitivity to food allergens
* this doesnt hold for those immunized for polio after 2 months or later

are there risks witht eh influenza vaccine?

* no association between flue vaccines and febrile seizures/fever fits in 2011 study
* recent study shows association of flu vaccine with febrile seizures, which increased with concominant administration of pneumococcal vaccine

why should tylenol be used as a last resort to prevent/treat febrile seizures?

may decrease the vaccines effectiveness by reducing amount of inflammati9on generated

risks of meningococcal vaccine:

may cause anaphylaxis in children who are allergic to ingredients

measles/mumps/rubella vaccine risks:

* relationships between MMR and measles inclusion body encephalitis in immunocompromised children and anaphylaxis in allergic patients
* risk for febrile seizures is 1/3000-1/4000
* NOT associated with increased rate of autism

drawback of administering vaccines to younger children:

* harder to identify autimmune disorders, as breastmilk Ab’s can provide coverage for quite some time
* if an unknown immunocompromised child recieves a live attenuated vaccine, this can cause serious systemic infection
* MMR vaccine would not be effective as patient wouldnt have T-cells anyways

risks of the pneumonia vaccine:

associated with febrile seizures when given in combo with influenza vaccine

risks for rotavirus vaccine:

moderate evidence that vaccination is associated with intussusception, but the occurence is relatively rare (3.7 cases/100,000)

* likely caused by increased inflammation generated by the vaccine enables detection of the intussusception

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intussusception: inversion of one portion of the intestine within another

risks for varicella vaccine:

moderate association between varicella vaccine and purpura in children aged 11-17 years (however can indicate that vaccine is working effectively)

risks for HPV vaccine:

* no significant associated risks
* does not casue children to become sexually active

known issues with the astra-zeneca vaccine:

* typical risk of anaphylaxis
* risk of fever/bruising/dizziness/fainting
* 1/100,000 risk of thrombotic event- clots lodge in fine cappilaries and often seen in brain, lungs, kidneys and GI tract.
* thought to occur due to body mistakenly making an antibody against the adenovirus capsid proteins, which cross reacts with platelet factor 4 (type 2 hypersensitivity)

risks of the Pfizer/moderna vaccines:

* typical risk of anaphylaxis
* typical risk of fever/bruising/dizziness/fainting
* very small risk of thrombotic event, likely due to type 2 hypersensitivity to platelet factor 4 within 4 weeks of vaccination
* 4.5/100,000 risk in young males of mild myocarditis or pericarditis
* no incidence of MI and no long term detectable cardiac damage or death

adjuvants:

given with a vaccine to enhance the stimulation of an immune response

* enhances recruitment of macrophages/dendritic cells to increase antigen presentation to our B cells and T cells

examples of adjucants:

* freunds adjuvant- contains M.tuberculosis antigens in mineral oil
* aluminum- alum triggers macrophages to increase MHC presentation
* mercury- added as a preservative as thioethylmercury
* amount added to vaccins is insignificant, rarely casues type 1 or type 4 hypersensitivity in allergic patients
* was removed because of public distrust
* lead- no lead in human vaccines

antimicrobial agents:

* antibiotics/antibacteirals are used to treat bacterial pathogens
* antivirals used to treat viral infections
* antiparasitics used to treat protazoa
* antifungals used to treat fungal diseases

what are many antimicrobials made of?

derived from substances produced by a specific microbe in order to inhibit or kill other microbes that might otherwise compete for the same resources

how do antibiotics work?

* inhibition of cell wall synthesis
* damage to cel membranes
* inhibition of protein synthesis
* inhibition of enzyme activity

*targets an aspect of prokaryotic bacteria cell which differs from that of eukaryotic cells such as your own*

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what are the differences between eukaryotic and prokaryotic cells that antibiotics target?

* peptidoglycan- containing cell wall of gram + or - bacteria
* inner cell membrane, with different composition and charge as our own
* substrates and specific enzymes used in bacterial DNA or RNA synthesis
* the substrates and specific enzymes used in bacterial protein synthesis (specifically the ribosome and transfer RNA’s)
* various other enzymes used by bacteria only

bacteriostatic antibiotics:

inhibit the growth of bacteria, usually bind reversibly

* will bind to and interfere with the production or function of the particular mechanism its targeting
* bacterial growth restarts after antibiotic is eliminated
* allows immune system to catch up and kill it off

bactericidal antibiotics:

killing of bacteria, usually bind irreversibly

narrow spectrum antibiotics:

kill either gram + or gram -

broad spectrum antibiotics:

kill both gram + and gram -

why use a bacteriostatic antibiotic versus a bacteriocidal antibiotic?

* depends on the immune status of the patient and what youre trying to treat
* strong immune system-both equally effective
* when a patient is immunocompromised, a bactericidal drug is essential for treatment of infections

when is it suitable to use narrow spectrum antibiotics?

when the pathogen has been identified

when are broad spectrum antibiotics used?

* waiting for lab results to ID the pathogen
* used for mixed infections during surgery/invasive procedures
* treat and infection whena narrow spectrum drug failts due to drug resistance

several different classes of antibiotics block steps in:

synthesis of peptidoglycan

* makes cells more susceptible to osmotic lysis
* most commonly known is penicillin
* characterized by B-lactam ring found within central structure of the molecule

how does the beta lactam ring work as an antibiotic?

blocks the cross linking of the peptide chains during the biosynthesis of new peptidoglyican in the bacterial cell wall

= bacteria unable to synthesize more peptidoglycan, when cell grows and divides it ends up causing bacteria to burst

vancomycin:

* bacteriocidal
* inhibits gram positive peptidoglycan synthesis
* doesnt work on gram negative bacteria
* poor GI absorption
* only works well against invasive gram positive bacteria when given by IV
* also works well against gram-positive intestinal bacteria since absorption not required

how does vancomycin work?

inhibitis peptidoglycan incorporation into the cell wall

when is vancomycin useful?

because it is poorly absorbed, it makes treating VRE and C.diff, where its tendency to stay in the intestine and not pass into the blood is beneficial

vancomycin has an important role in:

antibiotic resistance- many antibiotic-resistant bacteria have no yet evolved to acquire resistanced to vancomycin

potential side effects to vancomycin:

1. blood clots
2. capillary damage
3. potential kidney failure

why are ribosomes a good target for antibiotics?

because they are structurally distinct from eukaryotes, so protein synthesis can be interrupted in the bacteria and not the human cells

protein synthesis inhibitors:

* antibiotics that target or alter the way proteins are formed
* can be bacteriocidal or bacteriostatic

which antibiotics bind to the 50s ribosomal subunits? what else to they do?

chloramphenicol, macrocodes and lincosamides

* prevent peptide bond formation
* stop protein synthesis

which antibiotics bind to the 30s ribosomal subunit? what else do they do?

amingoglycosides

* impair proofreading, resulting in production of faulty proteins

tetracyclines
* -block the binding of tRNA’s= inhibiting protein synthesis

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aminoglyclosides:

* bactericidal and narrow spectrum
* cause mismatch in the way proteins are formed, disrupting the cytoplasmic membrane
* affective against gram-negative aerobic or facultative anaerobic bacteria (P. aeruginosa or E. coli)

limitations to aminoglyclosides:

* not against anaerobes
* significant side effects including nephrotoxicity, neurotoxicity and ototoxicity

tetracyclines:

* bacteriostatic and broad spectrum
* bind reversibly to 30s subunits and prevent mRNA translation entirely
* significant side effects= phytotoxicity, discolouration of developing teeth, hepatotoxicity with high doses or kidney impairment

macrolides:

* bacteriostatic and broad spectrum
* reversibly bind to 50s subunit and inhibit protein synthesis by blocking elongation of proteins
* used in penicillin allergy

lincosamides and chloramphenicol:

* bind to the 50s subunit and prevent protein elongation

oxazolidinone:

* broad spectrum
* bind to 50s subunit
* interfere with formation of the initiation complex for translation rather than interfering with amino acid chain elongation

membrane function inhibitors:

antibiotics that target the cal membrane integrity

* bacteriocidal or bacteriostatic

polymyxin B:

* binds to gram negative LPS and destroys membrane integrity (like detergent)
* narrow spectrum and bacteriocidal
* cause cell death via non-specific immune system

drawbacks to membrane-targeting antibiotics:

* not selective
* damage membranes of kidney and neuronal cells when given systemically
* poor absorption from GI
* used in OTC topical creams

daptomycin:

* lipopeptide
* targets gram-positive bacteria
* penetrates thick peptidoglycan layer and enters gram-positive inner membrane where it clumps and forms pores
* bacterias ions leak out of the cell causing eventual cell death
* given IV and well tolerated, with reversible toxicity in skeletal muscles

nucelic acid synthesis inhibitors:

antibiotics that interfere with nucleic acid synthesis to inhibit DNA or RNAformation and stop cell growth

why are nucelic acid synthesis inhibitors good targets for antibiotics?

the RNA polymerase enzymes in bacteria are structually different from those in eukaryotes- little to no harm to human cells

rifamycin/rifampin

* blocks RNA polymerase activity
* bacteriostatic


* linked to liver dysfunction as a side effect, especialy when given with other liver-metabolized medications

fluroquinolones:

* bacteriocidal
* inhibit DNA synthesis by binding to DNA gyros or topoisomerase IV
* braod spectrum against gram negative and gram positive
* most commonly prescribed antibiotics
* treat UTIs, respiratory infections, abdominal infections and skin infections

drawbacks to fluroquinolones:

wide range of side effects

* phototoxicity, neurotoxicity, cardiotoxicity, glucose metabolism dysfunction and increased risk for tendon rupture

metabolic inhibitors:

antibiotics that interfere with the produciton of acids required for metabolic functions

sulfonamides

* bacteriostatic and broad spectrum
* inhibit folate synthesis, which is required for DNA and RNA production
* prevents DNA synthesis and causes bacteria to be unable to divide

drawbacks to sulfonamides:

* allergic reactions common
* may displace bilirubin from albumin, so brain damage d/t excess billirubin can occur

trimethoprim:

structural analoge of dihydrofolic acid- inhibits a later step in the same pathway that sulfonamides target

* when used in combo with sulphonamides, it decreases folic acid synthesis to a level that is lethal to the bacteria
* should be avoided in pregnancy

isoniazid:

* used in combo with rifampin or streptomycin in the treatment of M. tuberculosis
* when metabolized by the bacteria, prevents synthesis of mycolic acid which is essential for mycobacterial cell walls

drawbacks to isonaizid:

side effects

* hepatotoxicity, neurotoxicity and anemia

why are antivirals difficult to develop?

need to target a virus within the host cell, without affecting the host cell

* usually administered as cocktails in combination and simultaneously= expensive

why are antivirals given in combination with each other?

by targeting the virus in multiple areas, it is far less likely to develop resistance in a single one of those areas

ex: why HIV medications usually contain at least 3 antiviral medications

nucleotide inhibitors:

antivirals that interfere with the replication of viral DNA

acyclovir:

prevents replication of virus by acting as an analoge to dGTP, which gets inserted into newly synthesized viral DNA of any virus whose DNA polymerase is without error checking= inhibition of viral DNA polymerase from synthesizing new DNA and replication