HIV

VACCINES

PRESENTER: NATASHA SAWHNEY

MODERATOR: P.S GROVER

HISTORY
1981.

New York and Los Angeles

Unexplained outbreak of two very rare
diseases, Kaposis sarcoma & Pneumocystis
carinii pneumonia.. AIDS
1983.Luc Montagnier (Pasteur Institute, Paris)
isolated a retrovirus..LAV
1984.Robert Gallo (National instt of
health,USA)HTLV-III
1986.International committee on virus
nomenclatureHIV
2

ACCORDING TO WHO
40

Million HIV infected persons currently

worldwide.
5 Million.newly infected annually
14 000.daily
INDIA.1986.first case reported Chennai among sex worker
5.1 million infected with HIV in India by
end of 2009
3

HUMAN IMMUNODEFIDIENCY VIRUS

Family Retroviridae
Subgroup Lentivirus
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STRUCTURAL GENES

Gag
Env
Pol
6

Gag gene
Determines

the core and shell of the virus

Expressed as precursor protein, p55
p55 cleaved into 3 protiens p15, p18 and
p24 which makes up the viral CORE and
SHELL.
CORE ANTIGEN - p24, p15
SHELL ANTIGEN - p18 (nucleocapsid
protein)
7

Env gene
Determines

the synthesis of envelope

glycoprotein gp 160.
gp 160 cleaved into gp 120 (surface
spikes) and gp 40 (transmembrane
anchoring protein) which makes up
the viral ENVELOPE
ENVELOPE ANTIGEN - gp 120,
gp 40
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Pol

gene

Determines

the enzyme polymerase

reverse transcriptase, protease and
endonuclease.
Expressed as a precursor protein
which is cleaved into protein p31,
p51, p66.
POLYMERASE ANTIGENS - p31,
p51, p66
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MAJOR ANTIGENS OF
HIV
ENVELOPE
ANTIGENS
gp 120
gp40
POLYMERASE
ANTIGENS
p31 p51
p66

SHELL
ANTIGENS
p 18

CORE ANTIGENS
p24
p15
p55

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tat

NON STRUCTURAL
GENES

nef
rev
vif
vpu
vpx

(trans activating gene)

(negative factor gene)
(reulator of virus gene)
(viral infectivity factor gene)
gene
gene

11

AIDS VACCINE
An

AIDS vaccine is an experimental

strategy that aims to teach the bodys
immune system how to fight HIV to
reduce the risk of infection or to
reduce viral load in those who get the
vaccine and go on to become infected.
All of the candidate vaccines being
studied are experimental; there are no
effective AIDS vaccines available
today..
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OBSTACLES
Antigenic

diversity and hypervariability of the virus

Transmission of disease by mucosal route
Transmission of the virus by infected cell
Resistance of wild type virus to seroneutralization
Integration of the virus genome into the host cell
chromosomes
Latency of the virus in resting memory T-cells
Rapid emergence of viral escape mutants in the host
Downregulation of major histocompatibility class I
antigens
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PRINCIPLE OF HIV
VACCINE
The goal for a preventive HIV vaccine is to generate
1. Humoral immunity which involves antibodies that
neutralize HIV in vitro directed against various
epitopes
. a 35- amino acid linear portion of the V3 region of
gp120(V3 loop)
. CD4 binding domain of envelope protein.
. V2 region of gp120
. Various sequences on gp41
. Gag and pol proteins (minor role)
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PRINCIPLE

Contt.

Cell mediated responses . The CTL

response is triggered by HIV specific THLs
and generation of various cytokines thereby
removing HIV infected cells from the host.
Thus identifying epitopes of HIV and knowing
which epitope should be targeted for the
development of cell mediated and humoral
immune responses forms the basis of HIV
vaccine development.

2.

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ANTIGEN

DOMAIN

NEUTRALISZAT
ION

CTL

Env

V3 LOOP
CD4 BINDING

+
+

+
_

Gag

P18
p24

Unconfirmed
_

+
+

Pol

nef

vif

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AIDS

VACCINE
APPROACHES

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WHOLE VACCINE
Entire virus particle is used but it cannot infect or replicate

1.WHOLE KILLED
VACCINE
Inactivated chemically
or physically.
Eg. REMUNE
VACCINE

2. LIVE
ATTENUATED
Attenuated genetically.
decreased antigenicity
by deletion of nef or
vpf gene.
Disadv- chance of
reverting is a serious
concern.
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SUBUNIT VACCINES
part of microorganism is used to prepare the
vaccine

3. RECOMBINANT
ENVELOPE
SUBUNIT VACCINE
4.LIVE
RECOMBINANT
VACCINES
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RECOMBINANT ENVELOPE
SUBUNITS

1. Recombinant soluble HIV env glycoproteins have been

used as subunit vaccines.
gp120
gp140
gp160
DISADVANTAGES
Induced only a transient response even with strong
adjuvant or special delivery formulations
Elicited antibodies against lab adapted viruses grown in
T- cell lines only
Antibodies produced neutralized only CXCR4 strain &
incapable of neutralizing CCR5 isolates.
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2. HIV tat protein optimal target for vaccine

more conserved than envelope protein, is
essential in virus life cycle and is expressed very
early upon virus entry.
Both HI & CMI to tat have been reported to
correlate with delayed progression of disease.
Subunit vaccines based on tat protein
developed & tested in humans
3. gp120 nef/tat fusion adjuvanted subunit protein
vaccine.induces mediocre response in
humans.
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LIVE RECOMBINANT VECTORS

Either

a live attenuated viral or bacterial

strain used as a vector to carry HIV genes
encoding the antigens
Stimulate both HI & CMI.

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LIVE RECOMBINANT VECTORS USED AS HIV VACCINES

VIRUSES
Pox viruses: vaccinia, canarypox (ALVAC), fowlpox,

BACTERIAS
Bacillus Calmette &

Modified Vaccinia Ankara (MVA), NYVAC

Salmonella
Adenoviruses
Shigella
Adeno-associated viruses (AAV)
Lactobacillus
Alphaviruses: Venezuelan equine encephalitis,
Streptococcus
Semliki Forest (SFV) viruses
Listeria
Flaviviruses: Yellow fever virus
Rhabdoviruses: vesicular stomatitis and rabies viruses
Myxovirus: Influenza virus
Paramyxoviruses: Senda virus, measles virus
Picornavirus:

poliovirus

NYVAC, Attenuated

vaccinia by genetic engineering

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5.SYNTHETIC
PEPTIDES

Chemically

sythesized HIV protein fragments are

used.
Most vaccines based on peptide sequence of V3
loop
LIPOPEPTIDES
Target specific epitopes that lie within the
conserved area of the virus.
Tested in Francegave impressing immune
responses with upto 83% of HIV specific CD8
responders
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6.NAKED DNA
One

of the newest technology

Particles of HIV DNA are incorporated
into harmless plasmid DNA from bacteria.
These bacterial plasmids that have been
genetically engineered are injected into
muscle or skin.
Developed using HIV antigen from env
and core region of the virus
25

USA.Vaccination using electroporated

DNA
along with the adjuvanting cytokine
interleukin 12 is among the most exciting
breakthroughs in vaccine development
recently.

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7.PSEUDOVIRIONS
Non

infectious particles resembling HIV that

has one or more HIV proteins.
Replication incompetent viruses produced in
mammalian cell cultures that contain all the
viral proteins for viral assembly but dont
contain RNA genome that makes it non
infectious.
Eg., core particles of hepatitis B virus
engineered & evaluated preclinically to
present HIV antigens.
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8.PRIME BOOST
CONCEPT
Is

a combination regime to elicit broad

spectrum immunity.
Involves primary vaccination with one
vaccine generating CMI response followed
by boost with another vaccine, often a
subunit protein to elicit humoral response.
Eg.. DNA vaccine for priming &
recombinant MVA or fowlpox vaccines for
boosting elicited the best CTL response.
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PRIME BOOST
STRATEGIES
Vaccinia
+ recombinant envelope subunit
Canarypox

+ recombinant envelope subunit or

synthetic lipopeptide
Salmonella + recombinant envelope subunit
Recombinant envelope subunit + synthetic
peptide
DNA + recombinant envelope subunit
DNA + pox virus (canarypox, fowlpox, MVA,
NYVAC)
DNA + adenovirus
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Vector

+ vector
homo- or heterologous adenovirus
adenovirus + canarypox
AAV + homo- or heterologous AAV or MVA
MVA + fowlpox
SFV + MVA

MVA, Modified vaccinia Ankara,

AAV, Adeno-associated virus,
SFV, semliki forest virus
NYVAC, Attenuated vaccinia by
genetic engineering
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What is happening
now?
There

is one large scale vaccine efficacy trial

going onHVTN 505 in USA
Vaccine being tested is DNA-Ad5
Participants are the high risk people
The trial will determine whether the regimen
will reduce viral load in people who receive the
vaccine & later become infected.
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Where are AIDS VACCINE

TRIALS TAKING PLACE?
There

are 30 clinical trials of experimantal

vaccines currently underway in 25 countries,
enrolling thousands of participants.
INDIA. National AIDS Research Institute,
Pune.clinical trials with AAV based
vaccine is going on.
Tuberculosis Research Centre, Chennai
.clinical trials with MVA vaccine going
on.
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Who is participating in AIDS

vaCCINE RESEARCH?
Among differert populations.
Homosexuals
Injecting drug users
Sex workers
Heterosexual men & women in subsaharan Africa.

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When are results expected?

Data

from HVTN 505 is expected in 2013

.
The trials being coordinated by P5 launch
are planned to launch in 2014.

34

Recent
developments/SUCCESS in
AIDS vaccine field
2009RV144,

a thai prime-boost AIDS

vaccine trial resultsregimen reduced the
risk of HIV infection by 31%.
It is a HIV vaccine clinical trial combining 2
vaccines
ALVAC HIV- viral vector with genetically
eng. versions of 3 HIV genes & ALVAC is
an inert form of CANARYPOX
AIDSVAX- genetically eng. Gp 120 protein.
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Strong & renewed political

leadership
Flexibility of processes
Medical & scientific
dedication
Community
participation
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THANKING YOU..

AIDS

VACCINE

A
RAY
OF
HOPE.
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