Nina Ian John “G” Rachel Mark Jocelle Edo Gienah Jho Kath Aynz Je Glad Nickay Ricobear

Teacher Dadang Niňa Arlene Vivs Paulfie Rico Ren Mai Revs Mavis Jepay Yana Mayi Serge Hung Tope Ag Bien

S3 L20: Viral Vaccines and Chemotherapy PPrree oorrPPoosstt TTrraannssw

whhaatteevveerr!!
o RNA-dependent RNA polymerase for RNA viruses
ANTI-VIRAL AGENTS o RNA dependent DNA polymerase (RT) for Retroviruses
o Protease
Little use therapeutically since the VIRUS USES HOST-CELL Integrase
METABOLIC REACTIONS (thus, anti-virus will become anti-cell Neuraminidase
agents)
There are some activities that are virus-encoded and therefore offer 2. Interfere with a cellular function so that the virus cannot replicate
potential VIRUS-SPECIFIC TARGETS
3. It interferes with cellular function that either:
Viral Chemotherapy
It must be crucial to virus but not the cell
IDEAL SHOULD NOT BE only the virus-infected cell must be killed
Water soluble Toxic activation of drug in the infected cell only
Chemically and Carcinogenic
metabolically stable Allergenic Viral Life Cycle: where to attack
Easily absorbed (apolar) Mutagenic attachment to cell surface, perhaps competition with a specific viral
Teratogenic receptor
uptake into intracellular vesicles (endosomes)
A good drug must show more toxicity to the virus than the host cell uncoating of virus (loss of protein coat, fusion of lipid membrane
with endosome/lysosome)
Therapeutic index (T.I.)= Minimum dose toxic to cell the endosome/lysosome compartment is acidic and inhibition of
Minimum dose toxic to virus acidification of this compartment might be a good target
transcription of genome to new RNA or DNA ( polymerases are the
Effective drug: T.I. = 100-1000 target)
mRNA transcription
Problems associated with the use of anti-virals mRNA processing
translation to protein
Development of resistance post-translational
o Herpes virus to acyclovir modification of proteins
o HIV to zidovudine (glycosylation,
o CMV to gancyclovir phosphorylation, fatty
o Influenza A to rimantadine acylation, proteolysis).
Some of these are
Timing of intake of antivirals essential for functional,
o Incubation infective viral progeny
o Time of diagnosis assembly of the
components into the
Latent infections whole virus
o Cell are not actively replicating
Binding to Surface Receptors
Reasons for continuing search for anti-virals versus vaccines:
No effective drug in this class
For many established disease there is still no effective vaccine
ANTIVIRALS AGAINST THIS STEP:
o Rapid mutation (retroviruses)
o Drugs that mimics the receptors.
o Reassortment (influenza)
o Viruses binds to the mimics:
New and emerging diseases - no vaccine available
 CD4 (for HIV)
Vaccine development takes many years  CD4 – Ig2 (reduces virus levels)
Disease that involve immunosuppression (AIDS, cancer,  AMD3100
transplantation) are not good candidates for certain types of  RFI-641 (biphenyl triazine) (active against
vaccines RSV fusion)
Uncoating
NOTE: At present no drug completely suppresses viral replication
(with possible exception of anti-HIV protease inhibitors)
Loss of envelope (+)/ (-) capsid to release the nucleic acid
A successful anti-viral will: often occurs in low ph-endosome or lysosomes
ANTIVIRALS IN THIS STEP:
o Arlidone or WIN compounds (picrona virus)
1. Interfere with a virus-specific function
o Pleconaril (stops the nucleocapsid shedding of the virus)
either because the function is unique to the virus or the similar host
o Amantadine, Rimantadine (Influenze A virus – oral
function is much less susceptible to the drug, e.g. Enzyme
prophylaxis)
o Viral enzymes : find an enzyme unique to the virus
Nucleic acid polymerases
o DNA-dependent DNA polymerase for DNA viruses

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Nucleic Acid Synthesis Acyclovir (ACV): best example
Antivirals against this step is considered the best antiviral since the o It is phosphorylated specifically by herpes simplex virus
effects are specific. thymidine kinase  active form  then it blocks DNA
o the virus may use its own enzyme to activate drug, synthesis by inhibiting the polymerase competitively (
and/or binds to the active site of the enzyme)
o viral polymerases may be much more sensitive to the o Competes with GTP
drug than the corresponding host enzymes o Chain terminator
Antivirals against this step: o Good anti-herpes drug
o Thymidine Kinase o HSV 1, HSV2, VZV
 Viral polymerase of herpes virus o Also inhibits: EBV and CMV
 enzyme encoded by some viruses ( herpes) o very effective against:
and used in the synthesis of their DNA o Herpes simplex keratitis (topical)
 Can activate certain drugs so that there is o Latent HSV (iv)
selectivity o Fever blisters – Herpes labialis/ cold sores (topical)
o Most are NUCLEOSIDE ANALOGS with altered sugar, o Zoster (topical)
base or both o Primary genital herpes (topical, oral, iv)
o DNA Polymerase Inhibitors o HSV dendritic ulcers
Sugar Modifications o Systemic Acyclovir for HSV encephalitis and those
o Acyclovir immunocompromised with HSV or VZ infection
o Gancyclovir
o Azidothymidine (AZT, Zidovudine) Gancyclovir
o Adenosine arabinoside
o Others: AZT, DDI, DDC o Similar to acyclovir (phosphorylated)
Base Modification o Has an extra –OH
o Trifluorouridine o More active against cytomegalovirus
Viroptic o Use mostly in CMV retinitis in AIDS patients
o Idoxuridine
o Fluoroiodoaracytosine Azidothymidine (AZT, Zidovudine)
Non-nucleoside inhibitors of reverse transcriptase
o Nevirapine o Also a chain terminator
Other non-nucleoside polymerase inhibitors o It is phosphorylated by a cell kinase so that it can be
o Foscarnet used against viruses with their own kinase.
RNA POLYMERASE INHIBITORS o Reverse transcriptase of HIV is more sensitive to the
o Ribavirin drug
o Used as an anti-HIV drug
Thymidine Kinase o Rapidly leads to emergence or resistant viral mutants
Thymidine kinase from virus activates the antiviral drug (becomes
phsophorylated). Adenine arabinoside
Activated antiviral drug either:
o Inhibit the DNA polymerase o HSV encephalitis
o Is incorporated into the viral DNA resulting in chain o Neonatal herpes
termination o Disseminated herpes zoster
o Thymidine kinase will phosphorylate any o Hepatitis B
deoxynucleoside including drugs – as a result of its
necessary non-specificity
o Nucleoside analog may be given in non-phosphorylated Base Modification
form
 Gets drugs across membrane
 Allows selectivity as only infected cell has
enzyme to phosphorylate the drug

Need for activation restricts drug to:

Viruses such as HSV that code for own thymidine kinase

Virus such as cytomegalovirus and Epstein-Barr virus that induce
cells to overproduce their own thymidine kinase Idoxuridine: Phosphorylated form is incorporated into the viral DNA
In either case it is the VIRUS-INFECTED cell that activates the drug and into the cellular DNA

DNA Polymerase Inhibitors

Sugar Modifications

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 Prodrugs Usually carried out by a host protease in the secretory pathway in
e.g. Famciclovir surface glycoproteins

Protease inhibitors

Sequinavir
Ritonavir
Indinavir
Nelfinavir
Non-nucleoside inhibitors of reverse transcriptase
Non-competitive reverse transcriptors inhibitors Protein Modification inhibitors (Glycosylation, Phosphorylation,
Developed due to the high resistance in AZT and other Sialidation)
nuceloside analogs
ZANAMIVIR
NEVIRAPINE Neuraminidase inhibitor
Active against Influenza A and Influenza B
Approved for AIDS patients as combination therapy Nasal spray
Good blocker of mother to child transmission Shortens symptoms by a few days
Found in breastmilk
Single dose at delivery reduced HIV transmission by 50% OSELTAMIVIR (TAMIFLU):
Single dose to baby by 72 hours Oral neuraminidase inhibitor; a carbocylicsialic acid analogue

Other non-nucleoside polymerase inhibitors VIRAL VACCINES

FOSCARNET Aims of Vaccination

competitive inhibitor of DNA polymerase To block the transmission of the disease (vector-borne disease)
binds to the pyrophosphate site To protect the individual from the symptoms and pathology of the
o Used in gancyclovir- resistant CMV disease
o Used in the treatment of CMV retinitis in AIDS To eradicate a disease

Requirements of a good vaccine

RNA Polymerase Inhibitor Effective
Safe
RIBAVIRIN Stable – for live attentuated vaccine
Low cost
Not a pyrimidine or a purine
Types of Vaccine
Inhibits influenza RNA polymerase non-competitively in vitro but
Live attenuated vaccine
poorly in vivo.
Killed organisms
May introduce mutations into viral RNA rendering it incapable of a
new round of cell infection Subcellular fragments
Aerosol form used against RSV
ATTENUATED VACCINES
RNA Clevage Enzyme
Advantages Disadvantages
Activates all phases of immune Mutation; reversion to virulence
Ribozymes system. (often frequent)
o RNA molecules that have catalytic properties among
which are the specific cleavage of nucleic acids Can get humoralIgG and local IgA Spread to contacts of vaccine who
Heptazyme have not consented to be
o Ribozyme that cleaves Raises immune response to all vaccinated (could also be an
protective antigens. Inactivation advantage in communities where
o hepatitis C RNA at highly conserved regions may alter antigenicity. vaccination is not 100%)
 Recognizes and cuts all known types of the
hepatitis C virus, thereby stopping viral More durable immunity; more Spread vaccine not standardized--
replication cross-reactive may be back-mutated
o Poor in clinic Problem in immunodeficiency
Low cost disease (may spread to these
Viral Protein Synthesis (woooo malulula kayo sa dam neto!) Quick immunity in majority of patients)
vaccinees
o No inhibitors (PERFECT!!! ) In case of polio and adeno
vaccines, easy administration

Viral Protein Processing Inhibitors Easy transport in field

Can lead to elimination of wild type

Protease inhibitors virus from the community
Premise: many viruses must cleave the proteins that they make

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INACTIVATED VACCINES Antigens on the virus-infected cell
In most cases response to internal proteins has little effect on
Advantages Disadvantages humoral immunity to infection
Gives sufficient humoral immunity if Many vaccinees do not raise In order to develop a successful vaccine, certain characteristics of
boosters given immunity
the viral infection must be known.
No mutation or reversion Boosters needed One of these is the site of viral at which the virus enters the body

Can be used with immuno-deficient No local immunity (important) 3 Major Sites for Viral Replication
patients
Higher cost SITE VIRUS

Shortage of monkeys (polio) Mucosal surfaces of respiratory tract and GI Rhino; myxo; corona; parainfluenza;
tract respiratory syncytial; rota
Failure in inactivation and
immunization with virulent virus
Infection at mucosal surfaces followed by picorna; measles; mumps; HSV;
spread systemically via blood and/or varicella; hepatitis A and B
VACCINE ADVANTAGES DISADVANTAGES neurons to target organs
Live Reproduces many of the features Insufficient attenuation Direct infection of blood stream via needle hepatitis B; alpha; flavi; bunya; rhabdo
attenuated of the infection itself reversion to wild type or bites and then spread to target organs
Will spread to the population by Administration to
normal transmission routes immunodeficient patients
protecting those not yet vaccintated (may cause severe disease)
(herd immunity) Vaccines – Problems
Persistent infection

Contamination of other Different viruses may cause similar disease--e.g. common cold
viruses Antigenic drift and shift -- especially true of RNA viruses and those
with segmented genomes (e.g. influenza)
Fetal damage o Shift: reassortment of segmented genomes (‘flu A but
Killed Contamination of living not rota or ‘flu B)
(inactivated) organisms
o Drift: rapid mutation – retroviruses
Allergic reactions Large animal reservoirs - Reinfection may occur
Integration of viral DNA. Vaccines will not work on latent virions
autoimmunity
Genetically Inclusion of oncogenes unless they express antigens on cell surface. In addition, if vaccine
engineered virus integrates it may cause problems
Transmission from cell to cell via syncytia
Recombination of the virulent strain or of the vaccine virus
Living vs. Non-Living Vaccine
Smallpox vaccination
CRITERIA LIVING NON-LIVING
Preparation Attenuation (not always inactivation
feasible) JENNERIAN APPROACH
Administration May be natural route,May be Injection,Usually multiple dose Jenner 1796 : Cowpox/Swinepox
single dose 1800’s Compulsory childhood vaccination
Adjuvant Not required Usually required
1930’s Last natural UK case
Safety May revert to virulence Pain from injection 1940’s last natural US case
1958 WHO program
Heat lability Requires cold chain satisfactory October 1977: Last case (Somalia)
(for tropical use)
Classification of Viral Vaccines
Cost Low High

Duration of Usually years May be long or short Polio (Salk) Inactivated

immunity Polio (Sabin) Attenuated

Immune IgG, IgA Cell-mediated Mainly IgG, little or no cell-

response mediated Rabies Original rabies vaccine developed by Pasteur. It was the first
attenuated viral vaccine. Passed through nerve cords of
rabbits. Current vaccine is inactivated
Adjuvants Mumps Attenuated
Measles Attenuated
Rubella Attenuated
Substances that will enhance the immune response when
Influenza Inactivated
administered simultaneously with the antigen Hepatitis A Inactivated
Alum and calcium salts Hepatitis B Subunit
Varicella Attenuated
Immunity to viral infections usually depends on the development of an Rotavirus Attenuated
immune response to Yellow Fever Attenuated
Antigens on the virus surface

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Measles Vaccine Hepatitis B considered a candidate for eventual eradication

Candidate for worldwide eradication Hepatitis A Vaccine

Debates on when to give it (maternal antibodies)
If uncommon, given at one year Vaccine derived from human diploid cells
In developing countries, may be given at 6 or 9 months followed by
a booster after 6 months Rabies Vaccine
Protection is long lasting because of boosters during natural
epidemics Rabies is the only disease where post-exposure vaccination is
If measles disappears from the population, adults may become successful due to its long incubation period.
susceptible again Neurotissue vaccine, vaccine from virus grown in human diploid
cells
Mumps Vaccine Looking into introducing the attenuated vaccine to wildlife via
infected food bait
Conveniently given with measles and rubella vaccine
Need for the vaccine? Vaccines for Arbovirus
Mumps meningitis
Deafness Available for yellow fever, Japanese encephalitis, and Rift valley
fever but not for dengue
Rubella Vaccine Problem of the existence of 4 serotypes
One manifestation of the disease is immunopathologic
Controversy on giving the vaccine to boys Hemorrhagic Shock Syndrome – infection with second serotyp after
Need for vaccination vs. risk of vaccine complications exposrue to a first.
Circulation of the wild virus in the population is considered helpful in
boosting immunity against girls Vaccine for Influenza
Danger of vaccination: level of infection in the community falls ---
cases may occur at a later stage Partially effective
Does not induce good long lasting immunity even after recovery
Polio Vaccine from inection in healthy people
Due to the abiltiy to undergo antigenic shift and drift
2 types of vaccine available:
o The killed virus (Salk 1954) – IPV Varicella Zoster Virus (VZV) Vaccine
o The live attenuated virus (Sabin 1957) – OPV
CONCERNS:
CRITERIA Inactivated (IPV) Attenuated (OPV) o Some early cases when severe chicken pox followed
Introduced Salk 1954 Sabin 1957 vaccination
In use Sweden, France, Holland, Most other countries o Does the risk of zoster increase or decrease?
Iceland o Availability of alternative methods of treating chickenpox
Dosage schedule Injection plus alum Oral at 2,4,6 months in children with leukemia (Zoster immunoglobulin plus
Risks Inadequately killed (very rare) In immunodeficiency; acyclovir)
otherwise safe Reversion to virulence
?inteference by other viruses
Cold chain failure Human Papillomavirus Vaccine

o New kid on the block (Got a bunch of hits, chinese food

Advantages Can be added to other IgA boosted
childhood vaccines Herd immunity
makes me sick.. naaalala mo ba ang kantang to? dagdag
Cheaper than Salk vaccine ko lang to. Hahaha )

Under development: ----------------------------------------END OF TRANS-----------------------------------------

Production of better and cheaper vaccines
Use of combined regimens (IPV followed by OPV)

Hepatitis B Vaccine

Cannot be grown in cell cultures

Non-living antigenic preparation can be derived from the blood of Ang trans na ito ay pamaskong
carriers because the surface coat antigen (HBsAg) is overproduced
handog ng:
by the virus (circulates as free non-infectious particles)
Concerns for Plasma-Derived Vaccine:
MICROBIOMAN
o Risk of transmitting live HBV or other viruses (derived
from human blood)
Ayna. Katuray. Edo. Nickie.
o Even after 3 doses antibody levels start to fall after 1-2 Teacher. Niña. Paulfie
years so boosting may be necessary
o Expensive
Development of Vaccine via Recombinant DNA technology
The same antigen is involved
The gene being cloned to a yeast vector which produces large
amounts of the antigenic protein

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