The Federal Medical-Biological Agency
National Research Center Institute of Immunology
Moscow, Russia
Novel approaches
to vaccine development
at the Institute of Immunology
- Development
- Production
- Introduction
Managua, Nicaragua, November 26-28, 2014
Challenges
• Newly emerged infections (HIV, Ebola)
• Increasing of the old infections (tuberculosis,
malaria, hepatitis)
Effective vaccine and vaccination
represent the best way to control
socially significant diseases
Requirements
• Safety
• Efficiency
• Specificity
Evolution of vaccines
• Traditional vaccines (whole virus/bacteria,
live or attenuated)
• Split vaccines
• Subunit vaccines
• Vaccines based on recombinant products
(recombinant viruses, DNA vaccines,
recombinant antigens)
Effective vaccine and vaccination:
traditional vaccines
attenuated or killed
viruses/bacteria
Effective vaccine and vaccination:
traditional vaccines
• side effects
• the cases we cannot use attenuated or killed
virus due to safety reasons (HIV);
• we cannot cultivate virus or the titers are too
low;
• the production (manufacturing) requires high
safety standards.
Evolution of vaccines
Split vaccines: parts of
destroyed virus/bacteria
Subunit vaccines:
purified antigens
Effective vaccine and vaccination:
new approach
• Novel antigens:
(recombinant viruses,
DNA vaccines,
recombinant antigens)
• New adjuvants
• New design to achieve
improved efficiency and
safety
Ideal vaccine:
safety, efficiency, specificity
• Low dose, standard antigen
• Imrovement of immune memory – less or no
revaccination
• Phenotypic correction of the immune
response
• Effective vaccination of persons with
immunodeficiency
Ideal vaccine:
safety, efficiency, specificity (cont-d)
•
•
•
•
Management of the immune response
Therapeutic vaccination
Overcoming of the biological barriers
Antigen address delivery
New antigens (subunit, recombinant):
advantages and challenges
Advantages
Challenges
• Production of
sufficient amounts
of highly purified
standard antigens
• Safety
• The level of the
immune response
• Immunogenecity
Phenotypic correction of genetic control
of immune response
(immunization with T,G-A-L polyelectrolyte
conjugate)
120
Ab titer
100
(Т,Г)-A-Л
80
60
40
20
CBA
no PE
C57BL
+ PE
Т-independence of immune response
to Ag-PE conjugate
140
BSA
BGT
120
BSA-PE
BGT-PE
Ab titer
100
80
60
40
20
4
3
2
1
nu/+
nu/nu
nu/+
nu/nu
New technology: polymer-subunit vaccines
The use of synthetic water soluble adjuvantimmunomodulator POLYOXIDONIUM
_
Br
N
О
N СН
2
СН
+
2
N
CН2СООН
ММ 60000 - 100000D
N СН 2 СН
2
n
Mechanisms of polyoxidonium action to human
immune system
Polyoxidonium
Neutrophil
Monocytes/
macrophages
Active O2 forms
NK-cells
Cytotoxicity
Dendritic cells
Th1-cell
activation
Co-stimulators
Killing of
extracellular
microbes
IL-12
HLA-DR
expression
Interferon 
synthesis
Antigen
presentation
Antiviral
defence
Colonystimulating
factor
Anti-inflammatory cytokines
TNF, IL-6, IL-1
Active
nitrogen forms
Leukopoiesis
Anti-bacterial
defence
Т- and В-cells
Killing of
extracellular
microbes
The first polymer-subunit vaccine we
developed: Flu vaccine Grippol®
Flu virus
hemagglutinin
and neuraminidase
+
Immune adjuvant
А (Н1 N1)
А (Н3 N2)
В
Ag 5 µg
+
POLYOXIDONIUM®
PO 500 µg
3-fold dose decrease
Flu vaccine evolution
WHOLE VIRUS
VACCINES
SUBUNIT
VACCINES
POLYMER-SUBUNIT
NANOVACCINE
killed or alive
VACCIGRIP
GRIPPOL
LOW EFFECTIVE
REACTOGENIC
EFFECTIVE
LOW TOXIC
HIGH EFFECTIVE
NONTOXIC
EFFECTIVE DOSE
100 MKG
EFFECTIVE DOSE
15 MKG
EFFECTIVE DOSE
5 MKG
The use of Polyoxidonium® improves
vaccine safety and efficiency
• PO interacts with HA subunits y multipoint binding,
thus producing the stable 117-220 nm structures
• These structures imitate 80-120 nm flu virions
• The way of presentation PO-HA strustures to
immune system is similar to the way of
presentation native flu virus
Result: induction of the adequate immune response
The use of the Flu vaccine
Grippol®
Number of vaccinated with GRIPPOL:
• 2007 – 8 mln p
• 2008 – 14 mln
• 2009 – 22 mln
• 2010 – 26 mln
• Total > 100 millions of people
HIV candidate vaccine Vichrepol
Immunomodulator
Polyoxdonium
Recombinant protein
rec(24-41)
Poly
-His
р24
Vichrepol
structure
gр41
N
N
CH2
Br - +
…
N
CH2
N
CH2
CH2
CH2
O
CO
n
NH
rec (24-41)
C
N
O
H
m
HIV vaccine Vichrepol Phase I clinical
trials results: safety
Tolerability
- well tolerated
Adverse
reactions
-no incidence adverse events for any
local or systemic toxicity, autoimmunity,
vaccine allergy,
-no immediate or delayed
hypersensitivity
Safety
-no changes in clinical or biochemical
parameters due to vaccination
Immune response to Vichrepol correlates with dose
mcg/injection 2.5 mcg
responders/
subjects
AB detected by EIA
12
1/3
2,5 mcg
5 mcg
1/3
5 mcg
10 mcg
2/3
10 mcg
25 mcg
3/3
25 mcg
50 mcg
3/3
50 mcg
10
8
6
4
2
1
0
2.1.1.
3.1.1. 5.1.1.
6.2.1. 9.2.1. 14.2.1
13.3.1 15.3.1 21.3.2
patient ID
18.4.1 20.4.1 30.4.1 24.5.1 26.5.1 29.5.1
HIV vaccine Vichrepol Phase I clinical
trials results: immunogenecity
• Vichrepol induces anti HIV Ab in immunized
volunteers
• The higher dose the higher the immune
response in individual and the higher the
number of responders per group
Summary: Vichrepol is the safe
and immunogenic product
Vichrepol included in rating lists of IAVI
Our vaccines:
vaccines against allergy
Allergoid + Polioxidonium
Main steps of allergotropine creation
purification of native allergen
creation of its allergoid form by chemical
modification
- conjugation of allergoid with immunomodulator
Polyoxidonium
Аllergoid
Polyoxidonium
_
Br
N
О
N СН2 СН2
+
N
CН2 С
N СН2 СН2
О
NН
аllergoid
n
Stimulation of Th1-cells
by Polyoxidonium (PО)
Antigen (allergen)
presentation
IFN-γ
Th0
CD80/86
PО
MHC-II
DC
MP
МN
DC - dendrite cell
MP - macrophage
MN - mononuclear cell
CD28
Th1
TNF-α
TCR
IL-2
Recognition
of MHC-II-peptide
and co-stimulation
The results of ASIT with allergen
and allergotropines
1200
1000
PNU
800
600
400
200
0
1
5
9
13
17
No of immunisations
21
25
29
33
- ALLERGOTROPINES
37
41
45
- ALLERGEN
Our allergotropins
Our vaccines:
vaccines against enteric infections
Constructing of lipopolysacharide
vaccines
Enzyme
LPS(O-antigen)
O- LIPOSACHARIDE (LPS)
capsule
Vianvac®: vaccine against typhoid
fever, VI polisacharide, liquid
ENZYME
Vi-antigen
Кd=0,25
Nucleus
Sip ABCD
LPS(O-antigen)
capsule
Salmonella enterica sv typhi
Gel chromatography of Vi-antigen
Sephacryl S-1000, 0,2М NaCl
Vianvac®: vaccine against typhoid
fever, VI polisacharide, liquid
 chromatographically
pure
 the high safety level
 single injection scheme
 the fast (2-3 weeks) start
of adaptive immune
response
Registered in 14th countries,
including 6 countries
of the Asian region
 effective vaccination of
children from 3 years
Shigellvac®:
vaccine against Sonnei disenntery
 chromatograpically pure
 the high safety level
 single injection scheme
 the fast (2-3 weeks) start of
adaptive immune response
 effective vaccination of children
from 3 years
Also developed: vaccine against
Flexner`s dysentery
(Sh. flexneri 2a,1b)
 high seroconvention,
independent from background
antibody level
Anti shock vaccine for endoseptic
shock prophilaxis and correction
120
100
80
Vaccine
Control
60
40
20
0
12
Vaccination
Immune
response
24
36
48
64
72
86
Correction
Pathogenic strains
toxins competition
for binding site
72 hours
Vaccination
Endotoxin
3 mg per mouse
NT-LPS antishock candidate
vaccine
Experimental technology of low
toxic lipopolysaccharide (NT-LPS) and
its derivatives production dreveloped
The pilot series of NT-LPS and its
derivatives issued
Scientific and technical
documentation has been prepared: a
project of experimental and industrial
regulations for NT-LPS production
NT-LPS preclinical studies performed
Low toxic lipopolysaccharide
(NT-LPS)
from Shigella sonnei
Our vaccines
Conjugated polymer-subunit
recombinant vaccine against
tuberculosis
Combined vaccine against
A and B hepatitis
“Hepol-А+В ”
The new adjuvants-immunimodulators
muramilpeptide constructions
synthetic polyelectrolytes immunomodulators
(-СH2-CH-)n
(-СН2-CH-)n
СН3
(-CH2-CH-)n
+
-
Х
С2H 5
+
-CH2 CH2
+
- CH2 CH2
X
C2H 5
X
C2H 5
n
n-m
- CH2 CH2
X
CH2C6H5
+
m
Vaccines developed at the
Institute of Immunology:
large scale production
• Grippol® - vaccine against flu
• Vianvac® - vaccine against typhoid fever
• Shigellvac® - vaccine against shigellosis
Sonnei
Vaccines developed at the
Institute of Immunology (cont-d)
• HIV/AIDS candidate vaccine VICHREPOL:
clinical trials Phase I completed
• Vaccines against allergic diseases: ongoing
clinical research
• Vaccine against hepatitis (A&B combined):
preclinical studies completed
• Vaccine against tuberculosis: laboratory studies
• Anti cancer vaccine: laboratory studies
We are open to cooperation
• Registration, marketing, distribution
• Manufacturing production
• Development of the new vaccines and
adjuvants
• Research in the field of the search the new
technologies for vaccine preparation and
construction
Thank you for your attention!
Gracias!