MLS 312: VIROLOGY

Viral Immunotherapy

 Immunotherapy .
 Chemotherapy in Viral Infection
 Viral Vaccines
 Immunoprophylaxis (Passive Immunity)

BY
Dr. Omosigho, Omoruyi Pius

DEPARTMENT OF MEDICAL LABORATORY SCIENCE

 Immunotherapy

• Immunotherapy also called biologic therapy, is a type of cancer treatment

that boosts the body's natural defenses to fight cancer.

• It uses substances made by the body or in a laboratory to improve or

restore immune system function.

• Immunotherapy may work by:

 Stopping or slowing the growth of cancer cells

Stopping cancer from spreading to other parts of the body

Helping the immune system work better at destroying cancer cells

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 Types of Immunotherapy
• There are several types of immunotherapy, including:

Monoclonal antibodies and tumor-agnostic therapies

Non-specific immunotherapy's

Oncolytic virus therapy

T-cell therapy

Cancer vaccines

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 Monoclonal Antibodies and Tumor-Agnostic Therapies

• When the body’s immune system detects something harmful, it

produces antibodies. Antibodies are proteins that fight infection.

• Monoclonal antibodies are a specific type of therapy made in a

laboratory. They may be used in a variety of ways.

 Monoclonal antibodies can be used as a targeted therapy to

block an abnormal protein in a cancer cell.
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Monoclonal antibodies can also be used as an
immunotherapy. For example, some monoclonal antibodies
attach to specific proteins on cancer cells.

This flags the cells so the immune system can find and
destroy those cells.

 Other types of antibodies work by releasing the brakes on

the immune system so it can destroy cancer cells.
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• The immune system responds to the cancer by blocking
these pathways with specific antibodies called immune
checkpoint inhibitors.

• Once the immune system is able to find and respond to

the cancer, it can stop or slow cancer growth.

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• Other types of antibodies work by releasing the brakes on the
immune system so it can destroy cancer cells.

• Programmed cell death 1 (PD-1) or Cytotoxic T-lymphocyte-

associated antigen 4 (CTLA-4)

• PD-1/PD-L1 and CTLA-4 pathways are critical to the immune

system’s ability to control cancer growth.

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• These pathways are often called immune checkpoints.

• Many cancers use these pathways to escape the immune system.

• The immune system responds to the cancer by blocking these

pathways with specific antibodies called immune checkpoint
inhibitors.

• Once the immune system is able to find and respond to the cancer, it
can stop or slow cancer growth.
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• Clinical trials of monoclonal antibodies are ongoing for several types
of cancers.

• While many immune checkpoint inhibitors are approved for specific

cancers, some are used to treat tumors anywhere in the body by
focusing on a specific genetic change.

• These are called "tumor-agnostic treatments."

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• For example, Pembrolizumab has been approved by the FDA
to treat metastatic tumors or tumors that cannot be treated
with surgery.

• These tumors must also have specific genetic changes called

microsatellite instability-high (MSI-H) or DNA mismatch
repair deficiency (dMMR).

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• Tumors that have MSI-H or dMMR do not repair damage to
their DNA very well.

• This means that they often develop many DNA mutations, or

changes, in their DNA.

• These changes make it easier for immune cells to find and

attack the tumor.
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• MSI-H or dMMR when chemotherapy does not work. It led to Learning more
about tumor-agnostic treatments.

• The side effects of monoclonal antibody treatment depends on the purpose

of the drug.

• For example, the side effects of monoclonal antibodies used for targeted
therapy are different than those used for immunotherapy.

• The side effects of immune checkpoint inhibitors may include side effects
similar to an allergic reaction.
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 Non-specific immunotherapy's
Like monoclonal antibodies, non-specific immunotherapy's also help
the immune system destroy cancer cells.

• Most non-specific immunotherapy's are given after or at the same

time as other cancer treatments, such as chemotherapy or radiation
therapy.

• However, some non-specific immunotherapy's are given as the main

cancer treatment.

• Two common non-specific immunotherapy's are: Interferon and

Interleukin
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 Interferon's

• Interferons help the immune system fight cancer and may slow the
growth of cancer cells.

• A type of interferon made in a laboratory is called interferon alpha

(Roferon-A [2a], Intron A [2b], Alferon [2a]).

• This is the most common type of interferon used in cancer treatment.

Side effects of interferon treatment may include flu-like symptoms,
an increased risk of infection, rashes, and thinning hair.
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 Interleukins.

• Interleukins help the immune system produce cells that destroy cancer.

• An interleukin made in a laboratory is called interleukin-2, IL-2, or

aldesleukin (Proleukin).

• It is used to treat kidney cancer and skin cancer, including melanoma.

• Common side effects of IL-2 treatment include weight gain and low
blood pressure. Some people may also experience flu-like symptoms.
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 Oncolytic Virus Therapy
• Oncolytic virus therapy uses genetically modified viruses to kill
cancer cells. First, the doctor injects a virus into the tumor.

• The virus then enters the cancer cells and makes copies of itself. As a
result, the cells burst and die. As the cells die, they release specific
substances called antigens.

• This triggers the patient’s immune system to target all the cancer
cells in the body that have those same antigens. The virus does not
enter healthy cells.
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 Cancer Immunotherapy
• Cancer immunotherapy aims to increase the amount and function of
tumor-infiltrating immune cells such as dendritic cells (DCs) and
tumor-infiltrating lymphocytes (TILs) in order to elicit therapeutic
efficacy.

• This may be achieved via multiple different strategies.

 For example, DC vaccinations that aim to increase tumor antigen
presentation, TIL and chimeric antigen receptor (CAR) T cell therapies
that aim to increase cancer killing T cells, and immune checkpoint
inhibitor (ICI) therapies that aim to enhance endogenous anti-tumor
immune responses
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• In particular, ICIs such as antibodies targeted against programmed cell
death 1 (PD-1) or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-
4) have drastically changed the treatment paradigm for many
cancers.

• However, objective responses to ICI therapies have predominantly

been seen in patients with prior anti-tumor immune response (10–
30% of patients are responding to ICIs) .

• OV therapies have been shown to modulate the tumor

microenvironment (TME) towards a less immunosuppressive
phenotype and to enhance anti-tumor immune responses.
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• Combining ICI therapies with OVs may help patients overcome
resistance to ICI therapies. OVs are currently in clinical evaluation in
combination with multiple cancer immunotherapeutic platforms.

• The current engineering strategies to enhance OVs and their

application as cancer immunotherapeutic.

• In addition, the most recent synergistic combinations of OVs with

other immunotherapeutic platforms.
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• In 2015, the U.S. Food and Drug Administration approved the first oncolytic virus therapy to
treat melanoma.
• The virus used in the treatment is called talimogene laherparepvec (Imlygic), or T-VEC.

• The virus is a genetically modified version of the herpes simplex virus that causes cold
sores.

• The doctor can inject T-VEC directly into areas of melanoma that a surgeon cannot remove.

• People receive a series of injections until there are no areas of melanoma left.

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 Side Effects can include:
• Fatigue

• Fever

• Chills

• Nausea

• Flu-like symptoms
• Pain at the injection site
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 Chemotherapy in Viral
Infection
Basic Mechanisms.
• Antiviral drugs specifically inhibits one or more steps of virus replication without
causing unacceptable side effects. Specificity against virus replication is the key
issue in chemotherapy .

• Because of close interaction between virus replication and normal cellular

metabolism , it was originally thought too difficult to interrupt the virus
replicative cycle without adversely affecting the host cell mechanism .

• It is now clear however, that several events in the virus replicative cycle either do
not occur in normal uninfected cells or are controlled by virus specified enzymes
that differs structurally and functionally from the corresponding host22 cell
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enzymes.
Virus replicative cycle can be divided into ten steps

• 1. Adsorption (Attachment) 2. Penetration 3. Uncoating 4. Early transcription

5.Early translation 6.Replication 7. Late transcription 8.Late translation
9.Assembly 10 .Release of new virus particles.

• Adsorption ,penetration and Uncoating are typical examples of replicative

events that are specific for virus infection and do not occur in uninfected cells.

• Example of virus- specified enzymes are the transcription of positive –sense

RNA-to DNA (catalyzed by the reverse transcriptase associated with retroviruses)
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• The replication of DNA to DNA (catalyzed by DNA polymerases of
hepersviruses) and the proteolytic cleavage of viral precursor
proteins (catalyzed by the protease of HIV).

• The various steps in the replicative cycle at which the virus deviates
from normal host processes are potential targets for
chemotherapeutic intervention.

• It is not yet possible to tailor new antiviral agents to virus specific

target molecules
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 Main Targets for Antiviral Drugs
For rational drug design, the molecular targets (proteins or enzymes) should be
identified first and then the drugs should tailored on the basis of the molecular
configuration and action of the target proteins.

Antiviral compounds can be divided into two categories,

Those that can interact directly with their targets such as

 Amantadine
 Rimantadine
 foscarnet
 viral protease inhibitors.

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Those that must first be intracellularly by by phosphorelation to it
active (generally triphosphate) form.

 E,g all nucleosides analogs, whether active as anti herpersvirus

agents such as Acyclovir ,Ganciclovir and Penciclovir

 Or anti- retrovirus agents such as Zidovidine and other

didexynucleoside analogs must be activated through three
consecutive phosphorylation steps before they can interact with
their target enzymestriphosphate, DNA polymerase or reverse
transcriptase
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 Antiviral Chemotherapy (Fundamental Concepts)

• Possible antiviral compounds are screened for activity by automated

screening using infected cells or viral proteins as assays.

• Another approach is to design drugs based on knowledge of the

active sites of the enzymes to be targeted.

• Once a promising candidate is discovered, chemist synthesize

analogues that may have higher antiviral activity.

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An anti HIV drug ,Maraviroe , blocks attachment of virus by binding
to a cellular receptor .

Another anti-HIV drug, Enfuvirtide, blocks a conformational change

in viral envelope protein gP41 that is required for fusion and viral
entry.

Amantadine inhibits uncoating of influenza virus by blocking an ion-

channel protein that allows H+ to enter virions within endosomes.
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Acyclovir is a nucleoside analogue that is preferentially
phosphorylated by herpes simplex virus thymine kinase and is
incorporated into DNA by the viral DNA polymerase, blocking further
DNA replication.

Gancciclovir is phosplorylated by a cytomegalovirus protein kinase

and preferably inhibits activity of the viral DNA polymerase.

A number of nucleoside analogues, beginning with azidothymidine,

inhibit HIV reverse transcriptase by premature termination of
growing DNA chains.
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Other inhibitors of HIV reverse transcriptase are not nucleoside
analogues, but bind near the active site of the enzyme.

A recent anti-HIV drug, raltegravir, inhibits viral integrase.

Protease inhibitors active against HIV inhibits maturation of virus

particles.

Neuraiminidase inhibitors suppress release of influenza virions from

acid residues on the surface of infected cells
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 Discovery of Antiviral Drugs

• Serendipity – trying out compounds used for other purposes.

Amantadine (Inhibits influenza virus uncoating)
Acyclovir (inhibits hepersvirus DNA replication)

• Chemical modification of known active compounds

Ganciclovir(Inhibits herpers virus DNA replication)

Azidothymidine (inhibits HIV-1 reverse transcription).

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High thoughiant screening assays of many compounds

Nevirapine (inhibits HIV-1 reverse transcription)

Raltegravit (inhibits HIV-I integese Rational design, often with and

of three- dimensional structures of viral proteins.

Ritonavir (HIV-protease)

Zanamivir (inhibits influenza neuraminidase)

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 Targets of Antiviral Drugs

Inhibitors of Virus Attachment and Entry

Picornavirus capsid protein
HIV –I envelope proteins and host chemokine receptors
Inhibitors of Uncoating of Viral Genome
Influenza M2 ion channel
Inhibitors of Viral Genome Replication
Herpesvirus nucleoside/nucleotide kinases
Virus DNA and RNA polymerases
HIV-I integrase
Hibibitor of Virion Maturation
HIV-1 protease
Inhibitors of Virus Release from the cell
Influenza
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The Discovery and Widespread Use of Antiviral
Compounds Began Relatively Recently.
 Both bacteria and viruses were first shown to cause disease in the late
nineteenth century.

• Antibiotics active against bacteria disease began to be used in the 1940s.

• However, the clinical use of drugs to treat viral diseases in human lagged behind,
and the first antiviral drugs were introduced only in the 1960s.

• A major factors accounting for this delay is that viruses replicate within host
cells, using many elements of the host cell machinery. Therefore there were
fewer obvious target for chemotherapy against viruses than against bacteria's.
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• For example, may antibiotics are directed against bacterial cell with synthesis
or bacterial protein synthesis, which are clearly distinct from their human
counterparts.

• The development of compounds active against a broad spectrum of viruses is

unlikely, because different viruses do not share common features that
distinguish them from their hosts cells.

• Each virus has its own array of specific proteins required for its replication and
therefore different antiviral drugs may have to be developed for each virus.

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• Because of these difficulties, pharmaceutical companies
have not always been enthusiastic about investing resources
in the development of antiviral drugs.

• Individual virus disease often represent smaller potential

markets then the wide variety of disease caused by bacteria.

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• Moreover, vaccination has been a very successful approach to
controlling viral diseases, for the dampening the interest of
pharmaceutical companies to develop drugs against these diseases.

• Efforts to develop antiviral drugs have focused mainly on those

viruses for which effective vaccines or public health measures are
not available and that cause widespread and easily diagnosed
disease whose treatment would earn substantial profects.

• However, since 1980 may effective antiviral agents have been

developed. This began with the success of gcyclovir a drug directed
against certain herpes-viruses.
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• The AIDS epidemic led to a pressing new for drugs active against Human immune
deficiency virus (HIV) and opportunistic pathogens and coincided with the development
of expand knowledge about virus genetics, molecular biology, enzymology and protein
structure.

• These factors have led to a rapid increase in the number and kinds of anti-viral drugs
available to treat human diseases. Indeed, many advances in rational drug discovery
have come from efforts to develop antiviral drugs.

Although protein drugs such as interferon and nucleic acid-based drugs such as
oligonucleotides are of considerable interest for medicine and virology.

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 Immuno-prophylaxis
• Immunoprophylaxis against viral illnesses includes the use of vaccines or antibody containing
preparations to provide immune protection against a specific disease.

Active Prophylaxis (vaccine)

• Active immunization involves administering a virus preparation that stimulates the body’s
immune system to produce its own specific immunity. Viral vaccines now available for use
include; attenuated live viruses, killed viruses and recombinant produced antigen.

Immune response to Vaccines

• Vaccination evokes an antibody response and stimulates T lymphocytes .Vaccine effectiveness
is assessed in terms of percentage of recipients protected and the duration of protection.
Most effective viral vaccines protects more than 90% of recipients and produce fairly durable
immunity.
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 Passive Prophylaxis
• Passive immunity is conferred by administering antibodies formed in another host .
Human immunoglobulin’s remain a mainstay of passive prophylaxis (and
occasionally therapy) for viral illnesses, they are usually used to protect individuals
who have been exposed to a disease and cannot be protected by vaccination.

• Passive Immunoprophylaxis is most often recommended in one of these situations

When exposure has occurred or if expected to occur very soon and time does not
allow for vaccination and the development of an adequate post- vaccination
immune response.
When no effective vaccine exists
When an underlying illness precludes a satisfactory response to vaccination.

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• Most immunoglobulin’s are now manufactured from human sources Some
examples of immunoglobulin’s .products and uses are as follows;

Immunoglobin (Ig) for modification or prevention of measles, Hepatitis A

 Human Rabies Immunoglobulin (HRIg) for post-exposure prophylaxis (and
administered with vaccine)
 Hepatitis B immunoglobin (HBIg) for post-exposure prophylaxis after an accidental
needle stick, high- risk neonatal immunization ( and administered with vaccine)
Vaccines Immunoglobin (VIg) for therapy of progressive vaccine, eczema and ocular
vaccines
 Varicella-zoster Immunoglobin (VZIg) post exposure prophylaxes of high –risk
individual
CMV Immunoglobulin (CMVIg) for passive immunization of renal transplant
recipients.
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 Standard immunoglobin is produced by pooling plasma
obtained from thousands of donors and contains antibodies
to a numbers of common viruses, while Specific
immunoglobulins are produced from donors with high titres
of antibodies to specific viruses ,often selected following
immunization with the relevant vaccines.
 Antiviral Vaccine
• Vaccine: From Latin Vacca (Cow), because vaccinia virus was thought to be
cowpox virus.

• Vaccination is the most effective means available for prevention of viral infections.

• Small pox and rabies vaccines were ground breaking developments in medical
history. Serious adverse effects following immunization are rare but sometimes
important.
• Requiring vaccination when no vaccine is 100% safe raise ethical issues.

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 A Brief History of Antiviral Vaccines

• Viral pathogens have been serious threat to health and society

throughout the evolution of Homo -sapiens.

• The horror of watching an individual die from rabies virus

encephalitis or Ebola virus hemorrhagic fever is surely the same
today as it was for our ancestors.

• However, these deadly zoonotic (animal-borne) virus infections

have had relatively little impact on human civilization due to their
local distribution and their low capacity to spread from person to
person.
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• Vaccine science has evolved over time with advances in
understanding of the immune response and developments in
technology such as egg culture, tissue culture and recombinant DNA
technologies.

• Cellular immunity is critical for recovery from most viral infections

• Antibodies can protect against many virus infections and prevent re-
infection, but in most cases the humornal response does not play an
important role in recovery from virus infections.

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• In contrast, widespread virus epidemics that are spread directly from
person and are highly contagious such as small pox, influenza and
measles have been limited only by population size and the spread of
transportation.

• The incubation periods of these pathogen are all relatively short (7-
10days) and the disease run their course to recovery or death quite
rapidly.

• Edward Jenner and his European counterparts are widely credited

with discovery vaccination in the late 1700s.
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• However, attempts to confer active immunity using microbial
products have been documented in many culture extending back at
least one or two centering before Jenner’s birth.

• Jenner and his contemporaries were nevertheless the first to

recognize the full potential of active immunization and to
systematically study vaccines and vaccination.

• The fruits of their labour have fundamentally changed human

history. Some milestones in vaccine development are:
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• Early vaccine technology was crude but effective

• Embrocated chicken eggs and cell cutter played major roles in

vaccine development in the twenty via serial passage of human
viruses in animals, the adaptation of viruses form growth in
embrayonated chicken eggs and the growth of viruses in vertebrate
cells cultured in vitro.

• Production of vaccines against avian influenza strain has been

problematic.
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 Fundamental Concepts in Viral Vaccine

• No vaccine can ever be 100% safe, but vaccines are among the
safest medical interventions ever introduced.

• Vaccines are generally held to a very high safety standard because

they are administered to healthy subjects to prevent disease.

• Antiviral vaccines have had enormous positive impacts on global

health, for example eradication of smallpox control of measles and
polio.

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• Vaccine science has evolved over time with advances in
understanding of the immune response and developments in
technology such as egg culture, tissue culture and recombinant DNA
technologies.

• Cellular immunity is critical for recovery from most viral infections

• Antibodies can protect against many virus infections and prevent re-
infection, but in most cases the humornal response does not play an
important role in recovery from virus infections.
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• Live attenuated virus vaccines, inactivated virus vaccines and subunit vaccines
have all been successful. All but live attenuated vaccines are administered with
an adjuvant to augment the immune response.

• To date, only live attenuated vaccines reliably elicit both humoral and cellular
immune responses.

• Among the most promising new vaccine technologies include DNA vaccine,
chemeric vaccines, nanoparticle vaccine and virus like particles.

• Loss of public confidence in vaccines can have devastating effects both for
individuals who refuse vaccination and for population.
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 Modern vaccine production.

• Virus production in cultured cells or embrayonated eggs.

Sophisticated virus purification and detection methods.

• Genetic engineering to modulate virus pathogenicity, infectivity or

immunogenicity production of viral proteins in bacteria yeast or
eukaryotic cell expression systems.

• Production of virus, virus-like particles or viral proteins in plants

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 Types of Antiviral Vaccines

• Live wild –type viruses that infect other animals but are attenuated
in humans
• Live attenuated human viruses with mutations that reduce
virulence.
• Inactivated viruses: retain immunogenicity but are no longer
infective.
• Subunit vaccines: Contain one or more viral proteins but no viral
genome.
• DNA vaccines express immunogenic viral proteins but cannot
generate virus
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• Recombinant viruses engineered to incorporate one or more immunogenic
proteins.

• Chimeric vaccines- benign attenuated microbes (viruses or bacteria) that

express specific immunogenic viral proteins.

• Virus-like particle vaccines (nano particle vaccines) delivery one or more viral
proteins in virus-like particles, virosomes, proteosome e.t.c.

• Multivalent peptide vaccines

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 Live Wild-Type Viruses
Vaccines
These are the simplest vaccines to make and are among the most effective. A
virus that infects one animal species can sometimes be used to infect another
species can sometimes be used to infect another species to protect against a
closely related pathogen.

• Virus are often adapted to replicate well only in their natural host, they can infect
other species, but replicate poorly and have limited or no pathogenic effects.

• However, these viruses may share immunogenic determinants with the target
virus, resulting in an effective immune response against that virus.

• At this point, vaccinia virus is the only such viral vaccine licensed for use in
humans and in its present form it is no longer being used became smallpox has
been eradicated.
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 Live Attenuated Viruses Vaccines

• Serial passage of pathogenic viruses in animals eggs, or cells grown in

vitro often results in the acquisition of variety of mutations that
reduce the pathogenic properties of the virus in its natural host.

• Although there is often little knowledge of the mechanisms of

attenuated in these “black box” viruses, these among the most
successful vaccines currently used.

• These attenuated virus replicates in human and therefore can often

induce protective immune responses as effectively as the parent
viruses, while causing little or no disease.
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. The recently introduced cold-adapted influenza A virus
vaccine is a “second-generation line attenuated virus that
was designed with specific Characteristics.

 Cold-adapted influenza vaccines are produced by combing

the H and N genes of the targeted virus strain with six other
gene segments from mutant viruses known to have
restricted growth at 370c.

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The H and N genes code for the envelope glycoproteins, hemagglutinin and
neuraminidase, which are the most immunogenic influenza virus proteins.

The reassortant viruses produced cannot replicate in the lung at core body
temperature but grow well in the cooler nasal mucosa, who they elicit and
excellent immune response without endangering the vaccinated individual.

 Adenovirus, Yellow fever, measles, mumps, polio (sabin ) Rotavirus,

Reubella .
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 Inactivated Viruses
• This is a common route for production of vaccines when a live virus Vaccine is
not available. Pathogenic viruses are grown in eggs or in cultured cells and
purified.

• The purified virus is then subjected to inactivation by treatment with

formaldehyde, Organic solvents, detergents or high temperature. When
carefully controlled, these treatment preferentially inactivated the virus
genome and therefore virus infectively, proteins.

• Such inactivated viruses can retain their ability to induce an immune response
but are incapable of replication and therefore do not cause disease. Hepatitis
A, influenza A influenza B, Polio (salk), Rabies and Tick-borne encephalitis.
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 Subunit Vaccines

• These consist of purified viral proteins that are known to be

immunogenic. Theses vaccines do not contain other components of
the virus, in particular the nucleic acid gene.

• There major advantage is that they present no danger of

inadvertent infection with live pathogenic virus, which can be a
problem with the other vaccine categories.

• They may also be significantly cheaper to manufacture, because

they do not require expensive virus growth in cell culture systems
and testing of the virus produced.
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• Presently, subunit vaccines are available for only two human viruses, hepatitis
B and human papillomavirus.
These vaccines exploit the capacity of purified viral proteins to self assemble
into virus-like particles (VLP). VLP tends to be more effective immunogens than
proteins that are not assembled into such a structure.

• The hepatitis B virus surface antigen (HbSAg) was originally purified from
infected human serum, but is now produced as a recombinant protein by
expressing the cloned surface antigen gene in yeast or mammalian cells, where
it can form virus like particles.

 While the human papillomavirus (HPV) LI protein is produced using

recombinant technologies and is expressed in either yeast or tras infected
insect cells, where it also spontaneously forms virus-like particles.
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 New Categories of Antiviral Vaccines

• Several new types of vaccines are newly licensed or under late-stage

development.

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 Chimeric Vaccines

• Are based on live organisms that are either non pathogenic in humans
(e.g. strains of the bacterium lactobacillus, and a variety of attenuated
viruses) or know and “trustworthy” (e.g. attenuate salmonella Ty21a, and
vaccine-strain measles virus).

• These organisms can be genetically manipulated to express ore or more

viral proteins and their intrinsic characteristics can be used to deliver
vaccine antigens to be desired locations (e.g. gut mucosa, dendritic cells).

• The newly introduced rotavirus vaccines based on recombinant human

and bovine chimeric viruses are good examples.
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 DNA Vaccine
• Are based on DNA plasmids that encode one or more viral
proteins in a form that can be expressed in host cells.
Injection of these plasmids into a human or animal results in
transient expression of the viral proteins in host cells (e.g
myocytes, immune cells).

• Such plasmids can be effective mimics of viral infection and

can elicit broader immune responses that soluble proteins,
because the viral proteins are synthesized in cells within the
host and thus are more effectively recognized by the immune
system.
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 Virus-like Particle (VLP) Vaccines
•

• They include “nanoparticles” bearing viral antigens that can

be produced using a wide range of technologies.

• Although relatively few viral proteins can self-assemble like

the hepatitis B viruses Ag and the human papillomavirus LI
protein, recombinant proteins that combine a
multimerization domine from one proteins with an
antigenic viral protein can create a family of novel VLPs.
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• Other nanoparticle viruses can be generated by mixing viral
antigens with either lipids (e.g. liposomes, nano-emulsions)
or proteins that tend to aggregate (eg proteosomes).

• Finally, VLPs that mimics that enveloped viruses can be

generated in a number of prokaryotic and eukaryotic
expression system including plants.

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 Multivalent Peptide Vaccines

• With hundreds and even thousands of peptide epitopes are being

developed to address the problems associated with highly mutable
RNA viruses such as HIV and hepatitis C Virus.

• Among these newer approaches, chimeric live vaccines share the

strengths and weakness of the live attenuated vaccines.

• Nanoparticle vaccines such as virus-like particles can elicit very

powerful immune responses, particularly when viral antigens are
combined with immunostimulating molecules such as ligard for
pathogen-recognition receptors.
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• Among these newer approaches, chimeric live vaccines share the strengths and weakness
of the live attenuated vaccines.

• Nanoparticle vaccines such as virus-like particles can elicit very powerful immune
responses, particularly when viral antigens are combined with immune- stimulating
molecules such as ligard for pathogen-recognition receptors.

• More than a decade of frustrating efforts with DNA vaccines that work beautifully in
animal models but less well in human led to the concept of sequential, multiple
formulation vaccination strategies referred to as “prime-boost”(beginning with a DNA
vaccine “prime’ followed by a live attenuated vaccine “boost”).

• These strategies take advantage of the characteristics of each component vaccine to

generate specific patterns of response (more antibody, more cell-mediated response, or
balanced
07/17/2025 humeral and cellular responses). 68
 Advantages and Drawbacks of
Vaccine Types
• The immune response elicited by live wild type or an attenuated vaccine
comes closest to that observed in natural infection, because these viruses
multiply within the vaccinated individual. Immunity after even a single does
of these vaccines is typically long-lived (at least 10 years in most cases).

• Some live virus vaccines can be taken orally or nasally, which simplifies their
delivery.

• However, these vaccines are expenses to manufacture and are relatively

unstable, requring careful attention to refrigeration via the cold chain, a
problem in developing countries.

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• Live vaccines may also be subject to inactivation by
preformed maternal antibodies when administered in early
childhood.

• For example, maternal antibodies can inactivate measles

vaccines strain virus in some children younger than
12months of age. Lives virus strains can occasionally case
serious illness and even death in subjects with abnormal
immune systems.
• In activated whole virus vaccines, like live virus, can generate immune
response to a wide range of viral antigens. These vaccines are generally less
sensitive to storage condition and are safer, for immunocompromised
individuals.

• However, their production is relatively expensive and requires the

manipulation of virulent pathogens.

• Furthermore, because in activated viruses cannot multiply within the host,

they tend to be less successful in inducing a robust immune response.

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• Therefore, multiple does are usually required to achieve protection
and immunity often fades with time requiring booster doses

• Unlike some live virus vaccines, inactivated virus vaccines must be

injected, which makes their administration somewhat more
complex.

• These vaccines typically require the addition of an adjuvant, (a non-

antigenic additive that enhances immunogenicity) to elicit a strong
immune response.
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 If recombinant DNA technology can be used in their preparation subunit vaccines are
potentially the simplex and least expensive vaccines to make.

• These vaccines can be remarkably stable and their use avoids the delivery of irrelevant
and potentially immune pathologic viral antigens responsible for vaccine associated
adverse events.

• These vaccines can also be used without risk in immunocompromised subjects.

However, like inactivated virus vaccines, multiple does of subunit vaccines are normally
required for protection and periodic boosting may be necessary to ensure long-term
immunity.

• Like in activated vaccines, submit vaccines also typically include an adjuvants to

enhance
07/17/2025
immunogenicity. 73
 How do Antiviral Vaccines Work?
• In the current environment of molecular sophistication, it is sometimes hard to
believe that products developed half a century ago are still in use.

• Until very recently, the process of attenuation was essentially “black-box” science.

• Pathogenic viruses were repeatedly passaged though egg or tissue culture cells under
varying conditions until they acquired an attenuated phenotype.

• Astonishingly by today’s ethical standards, the appearance of the attenuated

phenotype was typically demonstrated by inoculation of children.

• Several of our most successful vaccines, including yellow fever, measles, mumps,
rubella and Sabin polio were generated in this way.
07/17/2025 74
• A great deal about molecular characteristics of some of these products had been
learned in recent years.

• The three Sabin attenuated poliovirus vaccine strains very occasionally revert to
neurovirulence, and we now know the sites on the viral genome of many of the
mutations that affect virulence.

• These data help to explain the observation that vaccine-associated paralytic polio is
most often ascribed to pathogenic revertants of type 2 and 3 Sabin vaccine strains
viruses.

• Most of these vaccines continue to be used effectively even though we remain

ignorant of the precise mechanisms of attenuation and protection against infection.
Polio vaccines-In activated (Salk), live attenuated (Sabin).
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 New Developments in Antiviral Vaccines

 New approaches to vaccine development slow great promise

New adjuvant are being developed. Apart from the traditional aluminum (salt)
based adjuncts, oil in water based adjutants, Toll-like receptor (TLRs) e.t.c.
New delivery systems for viral antigens
Vaccination with defined proteins.
Use of live viruses with defined attenuation characteristics
Use of live vectors and chimeric viruses
Vaccines that can break tolerance
The changing vaccine paradigm
07/17/2025 76
 Adverse Effects and Ethical Issues Vaccine-
Associated Adverse Events.

• Although, the currently available antiviral vaccines are among the

safest pharmaceutical products ever introduced, none is 100% safe.

• The history of vaccine, development is troubled by several

unfortunate incidents in which vaccinated individuals have suffered
severe “adverse events”.

• In some cases, these incidents can be explained by the biological

properties of the product.
07/17/2025 77
• For example, vaccine-associated paralytic polio due to reversion of sabin
polio vaccine strain virus to neurovirulence is understood, in terms of the
mutations required to maintain attenuation.

• However, due to incomplete knowledge about many immunologically

mediated reactions, most adverse events following immunization are poorly
understood and therefore are difficult tone see.

• A great deal of enemy is being expanded internationally to refine the tools

available for the surveillance of problem associated with vaccination.

07/17/2025 78
 Ethical issues in the use of Antiviral
vaccines.
• Many of the viruses targeted by vaccines programs are among the
most highly transmissible infections agents known.

• As a result, public health authorities have great interest in

maintaining high levels of vaccine coverage to protect the small
number of individuals who are missed by the program.

• Who have failed to respond to vaccination who respond initially to

vaccination but subsequently lose protection, who have a valid
contradiction to vaccination, or who simply refuse vaccination.
07/17/2025 79
• The protection afforded these individual by high levels of vaccine courage in
the community is termed Herd immunity.

• The desire to establish herd immunity has led public health authorities either
to enforce vaccination difficult in the past, compulsory or heavy-handed
vaccination programs for small pox occasionally resulted in street riots.

• The debates surrounding some childhood vaccination programs are only

slightly less vigorous today. Some individuals at each end of the spectrum are
quite prepared to label those at the opposite extremes as “abuser” of
children.
07/17/2025 80
• Ironically, the great successes of the quasi compulsory vaccination programs that have
eliminated small pox and nearby eliminated polio and measles have also contributed
to growing wave of anti-vaccination sentiments because people currently feel
themselves to be less at risk.

• Another ethical problem arises from the concept of “attruistic” vaccination.

• For example, annual vaccination of health care provides against seasonal influenza
virus strains can reduce the impact of influenza on hospitalizing and institutionalized
individuals.

• Although the danger of influenza to the vaccinated individuals is not as great as when
compared
07/17/2025 to (younger and healthier). 81
• Although, may such institutions has programs to promote immunization, there has
been not attempt to legislate or mandate annual influenza vaccination for health
care worker.

• Since no vaccination can ever be 100% safe, it is seems appropriate that there
should be little or no “cost” or penalty associated with a personal choice not to
receive any particular vaccine. However, it is also reasonable that may jurisdiction
required those who refuse measles vaccine to keep their children out of school in
the event of a measles outbreak.

• A similar argument can be made to exclude from the work place (without pay)
health care personnel reluctant to be vaccinated in the event of a major influenza
07/17/2025 82
pandemic.
•
• Taking this argument further, it is also logical to ask if society should be asked to pay
for the lifelong care of an individual who suffers a vaccine-preventable complication
such as paralytic polio after refusing vaccination. Such issues are obviously
controversial and highly charged.

• This discussion would not be complete without mentioning the balancing

responsibilities of the vaccine industry, governments, healthcare system and the
health care providers to develop and administer the safest possible vaccines and to
take the issue of vaccine safety very seriously.

• This commitment requires the support of adequate surveillance systems and a

program to fairly compensate the rare individual who suffers a serious adverse events
as a07/17/2025
result of vaccination 83
 Severe adverse Effects Associated with Antiviral
Vaccine Administration

Vaccine implicated Event

Smallpox (lymph” vaccine Sepsis due to bacterial contamination

Yellow fever (1942) Vaccine lot contaminated with Hepatitis B

virus leading to 28,000 cases of death

Inactivated polio (1955) Incomplete inactivation of virus, leading to

204 cases of paralytic disease.

Attenuated polo (Sabin) Vaccine associated paralysis (I2.4 million

person vaccinated due to reversion to mo
pathogenic strain.

Inacturated measles (196)

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