VACCINES FOR DISEASES

WITH PANDEMIC POTENTIAL

 Factors that can Lead to a Pandemic Event

No Vaccine

No
Emergence
immunity
of new
towards
virus
disease

Pandemics

Sweeps Spreads
around the easily
world in a person-to-
short time person
 Measures Taken to Manage/ Control a Pandemic

Initial Control Measures

• Impose travel restrictions
• Border Closure
• Quarantine/Social distancing

Preventive/Intervention Future Infections

• Vaccination program
Development of Prophylactic and Therapeutic Vaccines against
HIV/AIDs

VACCINES FOR DISEASES

WITH PANDEMIC POTENTIAL
 Current Focus of HIV Vaccine Research

Prophylactic vaccines Therapeutic vaccines

• Designed for people • Designed for people

who are not infected
with HIV
• If effective, would
reduce risk of infection
or viral load set point
after infection
who are living with HIV
• If effective, would use
the body’s immune
system to help control
or clear HIV in the body
Human Immunodeficiency Virus (HIV)
• RNA virus, spherical in shape
• Each virus has two single chains of RNA.
• For replication, the virus needs a host cell, and the RNA is transcribed into DNA by reverse
transcriptase.
• Infects mainly the CD4+ lymphocytes (T cells), and to a lesser degree, monocytes,
macrophages, and dendritic cells (also CD4+ cells).
• Once infected, the cell turns into an HIV-replicating cell and loses its function in the human
immune system.
• The viral envelope consists two layers of lipids; different proteins are embedded in the viral
envelope, forming "spikes" consisting of the outer glycoprotein (gp) 120 and the
transmembrane gp41.
• The lipid membrane is borrowed from the host cell during the budding process (formation of
new particles). gp120 is needed to attach to the host cell, and gp41 is critical for the cell
fusion process.
Developing an AIDS vaccine is a difficult task

 Numerous modes of transmission

 HIV kills the immune cells used in defending the
body against HIV.
 HIV makes many copies of itself and mutates,
making itself unrecognizable to the immune
system
 Mutation leads to different subtypes of the virus
throughout the world
 HIV
Spikes

To acquire protection against HIV:

Antibodies must bind the viral surface envelope
glycoprotein, gp120 (surface, recognises CD4
receptors of T lymphocytes) and the gp41 (trans-
membrane domain, assists fusion of viral membrane
with cell membrane).
Examples of vaccine candidates, include recombinant
enveloped proteins, gp120 & gp160; recombinant
viral vectors & nucleic acids.
 Common Strategies for AIDS Vaccines

DNA Vaccine
Use copies of single or multiple genes from the HIV pathogen.
Genes from pathogen integrate with human gene resulting in the
formation of a protein, which is seen as a foreign antigen by the immune
system and results in the production of an immune response.
To improve the immunogenicity of DNA vaccines, ‘molecular adjuvants’
included in the DNA vaccine.
“Molecular adjuvant”: recombinant DNA plasmid carrying gene/s coding
for cytokines that can stimulate the host immune system.
Will not cause HIV infection, because the vaccines do not contain all the
genes of the live pathogen.
 Common Strategies for AIDS Vaccines

Recombinant Vector Vaccine

• Same strategy as DNA vaccines, except that the genes
are carried by a vector .
• Will not cause HIV infection because they contain copies
of only one or several HIV genes.
• Choice of vector would be harmless bacteria or virus eg.
canary pox, adenovirus.
• One promising candidate is cytomegalovirus engineered to
express Simian immunodeficiency virus (SIV) protein.
AIDS vaccine candidate appears to completely clear virus
from the body in monkeys
Date:
September 11, 2013
Source:
Oregon Health & Science University
Summary:
An HIV/AIDS vaccine candidate appears to have the ability to completely
clear an AIDS-causing virus from the body. It is being tested through the
use of a non-human primate form of HIV, called simian immunodeficiency
virus, or SIV, which causes AIDS in monkeys. Following further
development, it is hoped an HIV-form of the vaccine candidate can soon
be tested in humans.

Potential Candidate Vaccine: cytomegalovirus engineered to express

SIV protein, generates and indefinitely maintains so-called "effector
memory" T-cells that are capable of searching out and destroying SIV-
infected cells.

http://www.sciencedaily.com/releases/2013/09/130911141746.htm
 Common Strategies for AIDS Vaccines

Subunit Vaccine
• Contain a small protein or piece of the pathogen; the protein acts as a foreign
antigen and elicits B cells of the immune system to produce antibodies against
the antigen.
• This approach was used to develop first AIDS vaccine, eg. AIDSVAX gp120
vaccine.
• Unfortunately this subunit vaccine failed the clinical trial – implying that the
application of monomeric or monovalent vqccine might not be effective enough
in eliciting protective immune response.
• A combination of recombinant vector vaccine (ALVAC-HIV) and AIDVAX
vaccination trial in Thailand gave a modest outcome; it lowered the HIV
infection rate by 31%, compared to placebo group.
Thai Prime Boost Vaccine Trial - RV144 Trial
 Broadly Neutralizing Antibodies (BrNAbs) - Promising New
Approach to Vaccine Design

HIV-positive Patients

• Observed the evolution of a potent immune molecule that

recognizes many different HIV viruses in a patient.
• A minority of HIV-positive people produce antibodies that can
neutralize a broad spectrum of HIV variants.
• The broadly neutralizing antibodies (BrNAbs) developed only after
the population of viruses in the patient had diversified.
• Studying BrNAbs will help to understand what gives these molecules their
ability to bind to and recognize many different HIV viruses.
• Potential candidate as therapeutic HIV vaccine.
 Broadly Neutralizing Antibodies

• Advanced screening techniques have identified 100s of broadly

neutralizing antibodies (BrNAbs).
• Examples of BrNAbs: VRC01, CH103, PG9, PG16
• Aim of HIV researchers is to induce the production of BrNAbs
with an immunogen/ vaccine:
• In order to do come up with an immunogen/vaccine that can
induce BrNabs,
• Scientists must understand shape and identify the region
where BrNabs bind with HIV
• Binding of antibody with virus will block infection
• BrNAbs binds to the vulnerable site of HIV-1 (conserved
enveloped (Env) regions of functional importance; the initial site
of attachment for the CD4 receptor).
 Neutralizing Antibodies: Research pathways in 2013 and beyond

HIV-infected individual

Broadly neutralizing
antibodies
Reverse Engineering Vaccines Passive Immunization Trials
A protein from HIV Development of clinical grade purified form of BNAbs
surface (envelope)
interacting with an
antibody.
Phase I: Safety and pharmacokinetic evaluation
Molecular characterization of the interaction
between HIV envelope and BNAbs

* Modified env Phase II/III: Efficacy trials

Development of immunogens to mimic the
portion of HIV envelope that connects with
BNAbs

?
*

Combination of several immunogens = vaccine

Source: Adapted from: Burton, “Antibodies, viruses and vaccines,” Nature Reviews Immunology (2002) 2: 706-713.
 Passive Administration of BrNabs for HIV
Treatment or Prevention
• Some HIV BrNabs are now being tested in humans for their ability to
promote immune control of HIV in infected individuals and potentially to
eliminate HIV-infected cells.
• These include VRC01, VRC07-523, 3BNC117, and N6 (CD4 binding site–
targeting antibodies); 10-1074 and PGT121 (V3-glycan–targeting antibodies)
• In animal models: humanized mice, macaques chronically infected with
simian human immunodeficiency virus (SHIV), or in HIV-infected humans,
single BrNabs can lower the viral load by ~10- to 100-fold, but unfortunately,
antibody-resistant viruses rapidly emerge.
• A combinations of BrNabs are more effective in preventing the emergence of
antibody-resistant virus.
• Eg.: Administration of BrNabs early after SHIV infection can lead to persistent
viral clearance in some animals.