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Flashcards in 4: Treatment of viral disease Deck (13):
1

Prophylaxis:

vaccines
7
smallpox
6

Therapy:
antiviral drugs 4

Prophylaxis: preventing disease before the etiologic agent acquired, thru vaccines or drugs before infected

• Vaccines:
o prophylactic
o live / inactive
o Can involve herd immunity or a target a specific group
o Safety is considered more important than efficacy
o Governments and WHO regulation
o All UK vaccines are given to children
o e.g. polio vaccine

• To eradicate smallpox, the following occurred:
o No animal reservoirs
o No latent or persistent infections
o Smallpox was an easily recognized disease
o The vaccine was effective against all strains of virus
o Vaccine properties must include potency, low cost, abundance, heat stability and easy administration
o WHO determination of the cost was around $250 million


Therapy: treating the disease after the host infected
• Antiviral Drugs:
o Therapeutic
o Random screen (if current drug works for a new virus) or rational design (design new drug)
o Define the target group – only for the very sick, or available for everyone
o Will impact individuals

2

Types of Viral Vaccines

a
b
c
d
i-iii

o Live natural vaccines – cannot cause disease in humans but can be used to vaccinate against other diseases e.g. smallpox/cowpox
o Inactivated virus vaccine – virulent parental virus' genetic material removed
o Fractionation – non-recombinant purified subunit vaccines formed by breaking down the virulent parental virus into subunits, which are each individually harmless
o Cloning of the virus in bacterial cells (recombination) led to the following advances in the types of vaccines:
i - Live virus vector vaccine – having another harmless vaccines genetic material around the DNA of the harmful virus, thus forming the surface proteins, but nothing else of that virus is expressed
ii - Inserting part of the virus DNA straight into human DNA, causing it to be transcribed and translated, forming a protein, which is foreign
iii - Clone the important genes out and express them in other organisms, and thus form proteins, which could either take the shape of virus like particles, or the proteins themselves acting as the antigen

3

types of vaccines e.g.

live attenuated: adenovirus, influenza, measles, mumps, polio, rotavirus, rubella, smallpox, varicella, yellow fever

inactivated virus: hep A, Japanese encephalitis, polio, rabies, tick-borne encephalitis

purified subunit: influenza

cloned subunit: hep B, human papilomavirus

4

Attenuation of Virus to make a live virus vaccine
1-4

1. Pathogenic virus is isolated from a patient and grown in human cultured cells
2. The cultured virus is used to infect monkey cells, or another similar organism
3. The virus acquires many mutations that allow it to grow well in monkey cells
4. The virus no longer grows well in human cells and may be a candidate for a vaccine

5

polio virus and vaccine
-virus is
-pharmaceutical company 1
-other, but associated with, -->, end

-type vaccine
-taken from
-did not
-then
-to learn,

-virus on the verge of eradication
-Salk invented the inactivated virus
-Sabin developed the live virus:
o 1 in 7 M vaccinations are associated with poliomyelitis
o --> persistence of the virus in immunosuppressed individuals, making it hard to eradicate
o when the end of the polio virus is very near, the end game would be to use the Salk vaccine, as would not cause the poliomyelitis


-live attenuation
-virus taken from child with polio
-did not know the diff between virus and vaccine
-subsequently sequenced, and saw a variety of mutations
-reverse genetics to map polio virus to incorporate individual mutation to see sig

6

inactivated vaccine adv 2 & disadv 2

adv: safe, can be made from wild type virus

disadv: frequent boosting required, high dose needed to be effective

7

Influenza Virus Vaccine
both

a) 2

b) 4

both a live and inactivated virus

inactive virus:
o Needs to be updated regularly
o Does not give the recipient the flu

live virus:
o called LAIV, cold adapted
o Also known as FluMist, as is developed intra-nasally
o It needs to be updated regularly
o Introduced for children in the UK in 2013

8

Recombination Attenuated Virus Vaccines:

rotavirus
-rotatix
-in world
-in UK
-must be used

subunit
-hep B
-pap

shingles
-is
-occurs
-even after
-UK

-taking out one piece of a virus and putting it into another virus

• Rotavirus vaccine:
o Rotatix: live attenuated rotavirus reassortant virus
o In the developing world, it can massively reduce deaths; rotavirus infection --> dehydration from vomiting & diarrhea
o In the UK, 1 in every 50 babies will be admitted to hospital because of rotavirus infection in the first 5 years of life
o vaccine has to be used in a specific timeframe, or it may cause inutussusception/bowel blockage in babies over 3 months

• Subunit vaccines:
o Hepatitis B virus – surface antigens cloned and expressed on yeast
o Papillomavirus – Virus like Particles from recombinant coat proteins

• Shingles Vaccine:
o Shingles is a painful rash resulting from the reactivation of latent VZV/chicken pox virus
o Shingles occurs in people after stress, and is more common and more serious in the elderly as their immune system wanes
o Even after the rash has gone, pain can still persist as Post Herpetic Neuralgia
o Shingles vaccine introduced in September 2013 for people who are 70 or 79 due to limited supply

9

Antiviral Treatment:
-discovered
-side effects
-was

antivrial treatment: Interferons to induce the hosts natural antiviral response:
o Discovered by Isaacs and Lindemann in 1957, with recombinant interferons being made in 1981-1982
o side effects from induction of cytokines and other ISGd
o Was only option for some viruses few years ago but situation improved

10

Directly Acting Antiviral Drugs
-target
-design
-e.g. , only, affinity, resistance

Directly Acting Antiviral Drugs:
o target viral enzymes; act as substrate analogues
o rational drug design: increase understanding of structure of viral components and enzymes
o e.g. acyclovir to treat HSV: similar structure to guanosine, but has no 3’-OH --> acts as a chain terminator; prevents phosphodiester bonds formation
-only activated inside the viral infected cells, as requires enzyme viral thymidine kinase --phosphorylated twice more -- sugar region is added --> active version of acyclovir
-higher affinity for viral DNA polymerase > host cell polymerase
-resistance rare but maps to changes in thymidine kinase

11

Antivirals targeting influenza virus replication
e.g.

2 particular
-virus release to
-when drug acts,

Antivirals targeting influenza virus replication:
e.g. amantacine, amantadine and zanamivir and oseltamivir (each acting in different places)

o zanamivir (marketed as Relenza) and oseltamivir (marketed as Tamiflu) are particularly effective
-The virus releases a neuraminidase enzyme which destroys the cell surface receptor to attach to recognised cell surface receptors on host cell membrane
-drugs act: inhibit enzyme --> prevent spread of virus

12

HIV targeting mechanism
-treated with

-N e.g. 2***
-N e.g. 2
-Ie.g. 1
-C e.g. 1
-H e.g. 1

HIV targeting mechanism:
o drug cocktail acting at different areas:
 NRTI such as Zidovudine and Stavudine, similar structure to nucleotides but don’t polymerise, and thus stop the chain from growing, ***equal effect on host and viral DNA; kill host cells
 NNRTI such as efavirenz and Viramune: allosteric inhibitors
 Integraste Inhibitors such as Raltegravir: block virus-host DNA transfer
 CCR5 and CXCR4 inhibitors, such as Maraviroc, prevent the entry of the virus
 HIV proteases, such as Atazanavir, act as competitive inhibitors for the protease enzyme

13

Antiviral therapy for hepatitis C
-HCV
-treatment ****
-therefore

Antiviral therapy for hepatitis C
o HCV: hepatotropic flavivirus, spread widely in the 70’s in blood products from lack of screening
o treatments for HCV – e.g. NS3-4A, virally encoded protease that processes the polyprotein --> inhibited ***only using an inhibitory drug would lead to rapid selection of mutated species
o treatments used successfully with IFN and RBVN