Novel approaches to vaccine development at the Institute of Immunology Novel approaches to vaccine...
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Novel approaches to vaccine development at the Institute of Immunology - Development - Production - Introduction The Federal Medical-Biological Agency National Research Center Institute of Immunology Moscow, Russia Managua, Nicaragua, November 26-28, 2014
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Transcript of Novel approaches to vaccine development at the Institute of Immunology Novel approaches to vaccine...
Novel approaches to vaccine development
at the Institute of Immunology
Novel approaches to vaccine development
at the Institute of Immunology
- Development- Production
- Introduction
The Federal Medical-Biological Agency
National Research Center Institute of Immunology
Moscow, Russia
The Federal Medical-Biological Agency
National Research Center Institute of Immunology
Moscow, Russia
Managua, Nicaragua, November 26-28, 2014Managua, Nicaragua, November 26-28, 2014
ChallengesChallenges
• Newly emerged infections (HIV, Ebola)• Increasing of the old infections
(tuberculosis, malaria, hepatitis)
• 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
Effective vaccine and vaccination represent the best way to control
socially significant diseases
RequirementsRequirements
• Safety• Efficiency• Specificity
• 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
Effective vaccine and vaccination:
traditional vaccines
attenuated or killed viruses/bacteria
Effective vaccine and vaccination:
traditional vaccines
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.
• 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
Effective vaccine and vaccination:
new approach• Novel antigens: (recombinant viruses, DNA vaccines, recombinant antigens) Novel antigens: (recombinant viruses, DNA vaccines, recombinant antigens) • New adjuvantsNew adjuvants• New design to achieve improved efficiency and safety 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 challengesAdvantages
• Production of sufficient amounts of highly purified standard antigens
• Safety
Challenges
• The level of the immune response
• Immunogenecity
Phenotypic correction of genetic controlof immune response
(immunization with T,G-A-L polyelectrolyte conjugate)
Phenotypic correction of genetic controlof immune response
(immunization with T,G-A-L polyelectrolyte conjugate)
NHNH CCOO
ппооллииааннииоонн
......
......
......
......
(Т,Г)-A-Л(Т,Г)-A-Л
120120
100100
8080
6060
4040
2020
CBACBA C57BLC57BLA
b t
iter
Ab
tit
er
no PEno PE + PE+ PE
Т-independence of immune responseto Ag-PE conjugate
Т-independence of immune responseto Ag-PE conjugate
120120
100100
8080
6060
4040
2020
44
33
22
11
nu/+nu/+ nu/+nu/+nu/nunu/nu nu/nunu/nu
BSA
BSA-PE
BGT
BGT-PE
140140
Ab
tit
er
New technology: polymer-subunit vaccines The use of synthetic water soluble adjuvant-
immunomodulator POLYOXIDONIUM
New technology: polymer-subunit vaccines The use of synthetic water soluble adjuvant-
immunomodulator POLYOXIDONIUM
ММ 60000 - 100000D
N N СН СН 2 2
О
N N СН СН 2 2
CН СООН2
Br+
_
n
Killing of extracellular
microbes
Mechanisms of polyoxidonium action to human immune system
Mechanisms of polyoxidonium action to human immune system
Neutrophil Monocytes/macrophages Dendritic cellsNK-cells
Antigen presentation
Antiviraldefence Leukopoiesis
Anti-bacterial defence
Т- and В-cells
HLA-DRexpression
Colony-stimulating
factor
Anti-inflam-matory cytokinesTNF, IL-6, IL-1
Active nitrogen forms
Interferon synthesis
Active O2 forms
Killing of extracellular
microbes
CytotoxicityCo-stimulators Th1-cell
activation
IL-12
Polyoxidonium
The first polymer-subunit vaccine we developed: Flu vaccine
Grippol®
А (Н3 N2)А (Н3 N2)
А (Н1 N1)А (Н1 N1)
ВВ
POLYOXIDONIUM®POLYOXIDONIUM®++
Flu virus hemagglutinin
and neuraminidase
Flu virus hemagglutinin
and neuraminidase
Immune adjuvantImmune adjuvant++
Ag 5 µg PO 500 µg
3-fold dose decrease
Flu vaccine evolutionFlu vaccine evolution
killed or alive
WHOLE VIRUS VACCINES
SUBUNIT VACCINES
VACCIGRIP
POLYMER-SUBUNIT NANOVACCINE
GRIPPOL
LOW EFFECTIVE REACTOGENIC
EFFECTIVE DOSE
100 MKG
EFFECTIVELOW TOXIC
EFFECTIVE DOSE 15 MKG
HIGH EFFECTIVENONTOXIC
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
Recombinant protein rec(24-41)
Recombinant protein rec(24-41)
Immunomodulator Polyoxdonium
Immunomodulator Polyoxdonium
Poly-His
р24 gр41
HIV candidate vaccine VichrepolHIV candidate vaccine Vichrepol
Vichrepol structureVichrepol structure
NN NN CH2CH2 CH2CH2
OO
…… NN NN CH2CH2 CH2CH2
CH2CH2
COCO
NHNH
NNCC
OO HH
mm
Br -Br -
nn
++
rec (24-41) rec (24-41)
HIV vaccine Vichrepol Phase I clinical trials results: safety
Tolerability
Adverse reactions
Safety
- well tolerated
-no incidence adverse events for any local or systemic toxicity, autoimmunity, vaccine allergy,-no immediate or delayed hypersensitivity
-no changes in clinical or biochemical parameters due to vaccination
Immune response to Vichrepol correlates with dose
5 mcg 10 mcg 25 mcg 50 mcg
0
2
4
6
8
10
12
2.1.1. 3.1.1. 5.1.1. 6.2.1. 14.2.1 13.3.1 15.3.1 21.3.2 18.4.1 20.4.1 30.4.1 24.5.1 26.5.1 29.5.1
1
50 mcg25 mcg10 mcg5 mcg2,5 mcg
AB
de
tec
ted
by
EIA
patient ID9.2.1.
2.5 mcg 5 mcg 10 mcg 50 mcg
1/3 1/3 2/3 3/3 3/3responders/
subjects
mcg/injection
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
ab
HIV
ab
HIV
ab
Vichrepol included in rating lists of IAVI
Our vaccines: vaccines against allergy
Allergoid + Polioxidonium
Main steps of allergotropine creationMain steps of allergotropine creation
PolyoxidoniumPolyoxidonium
АllergoidАllergoid
purification of native allergen creation of its allergoid form by chemical modification - conjugation of allergoid with immunomodulator Polyoxidonium
purification of native allergen creation of its allergoid form by chemical modification - conjugation of allergoid with immunomodulator Polyoxidonium
N N СН2
О CН2
Br_
nСNН аllergoid
О
СН2
+N N СН2
СН2
Stimulation of Th1-cellsby Polyoxidonium (PО)Stimulation of Th1-cellsby Polyoxidonium (PО)
CD80/86 CD28
MHC-IIMHC-II TCRTCR
DCMPМN
DCMPМN
Th0Th0
PОPО
IL-2IL-2
IL-12IL-12
Th1
IFN-γIFN-γ
TNF-αTNF-α
DC - dendrite cellMP - macrophageMN - mononuclear cell
Recognitionof MHC-II-peptideand co-stimulation
Antigen (allergen)presentation
0
200
400
600
800
1000
1200
1 5 9 13 17 21 25 29 33 37 41 45
PN
U
- - ALLERGENALLERGEN- - ALLERGOTROPINESALLERGOTROPINES
The results of ASIT with allergen and allergotropines
No of immunisations
Our allergotropins
Our vaccines:vaccines against enteric
infections
O- LIPOSACHARIDE (LPS)
LPS(O-antigen) capsulecapsule
Enzyme
Constructing of lipopolysacharide vaccines
Gel chromatography of Vi-antigenSephacryl S-1000, 0,2М NaCl
Gel chromatography of Vi-antigenSephacryl S-1000, 0,2М NaCl
Кd=0,25
Salmonella enterica sv typhiSalmonella enterica sv typhi
capsulecapsulecapsulecapsule
Vi-antigenVi-antigen
LPS(O-antigen)LPS(O-antigen)
NucleusNucleus
Sip ABCD
ENZYMEENZYME
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
effective vaccination of children from 3 years
chromatographically 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
Registered in 14th countries, including 6 countries
of the Asian region
Registered in 14th countries, including 6 countries
of the Asian region
Vianvac®: vaccine against typhoid fever, VI
polisacharide, liquid
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 high seroconvention, independent from background antibody level
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 high seroconvention, independent from background antibody level Also developed: vaccine against
Flexner`s dysentery (Sh. flexneri 2a,1b)
Also developed: vaccine against Flexner`s dysentery (Sh. flexneri 2a,1b)
Shigellvac®: vaccine against Sonnei
disenntery
Vaccination
Immune response
Correction
Pathogenic strains toxins competition
for binding site
0
20
40
60
80
100
120
12 24 36 48 64 72 86
VaccineControl
Vaccination
72 hours
Endotoxin3 mg per mouse
Anti shock vaccine for endoseptic shock prophilaxis
and correction
Low toxic lipopolysaccharide (NT-
LPS) from Shigella sonnei
Low toxic lipopolysaccharide (NT-
LPS) from Shigella sonnei
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
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
NT-LPS antishock candidate vaccine
Conjugated polymer-subunit recombinant
vaccine against tuberculosis
Conjugated polymer-subunit recombinant
vaccine against tuberculosis
Combined vaccine against
A and B hepatitis “Hepol-А+В ”
Combined vaccine against
A and B hepatitis “Hepol-А+В ”
Our vaccines
The new adjuvants-immunimodulators
muramilpeptide constructionsmuramilpeptide constructions
n-m mCH2 CH2
C2H5
+X- CH2 CH2
CH2C6H5
X-
nCH2 CH2
C2H5
+X-
+
(-CH2-CH-)n
С2H5
+ Х-
(-СН2-CH-)n
СН3
(-СH2-CH-)n
synthetic polyelectrolytes -immunomodulators
synthetic polyelectrolytes -immunomodulators
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!
