VENTRI BIOLOGICALS · Concepts in IBD Vaccination Half life: Upto first 4 days of life the MAb remains about the same and from 4 days onwards the titre decreases 1Log. 2. step per

:: DEVELOPMENT OF INDIANIZED IMMUNE COMPLEX VACCINE-VIPx ::EFFECTIVE APPROACH FOR INTERVENTION OF NOVEL vvIBDV INFECTION

VENTRI BIOLOGICALSVaccine Division of Venkateshwara Hatcheries Pvt. Ltd.

Dr Sanjay GavkareGeneral Manager (Technical)

Ventri Biologicals, Vaccine Division of Venkateshwara Hatcheries Pvt. Ltd.

RNA Viruses

Top 10 Poultry Diseases of the World

3

Bunting Farm, 1957


Lasher & Cosgrove Gumboro, Delaware

Introduction



✓Avian Nephritis/Nephrosis

✓Infectious bronchitis variant?

✓Gumboro Disease caused by Avibrinavirus; Birnaviridae

Infectious Bursal Disease

Non enveloped, single-shelled capsid of about 70

nm in diameter, composed 2 segments of linear dsRNA

genome

Target B-cells of Bursa of Fabricius leading to

destruction of lymphocytes, immunosuppression, and

disease


Chronological events regarding IBD

1950 1960 1970 1980 1990 2000 2010 2020

Classical IBDV outbreaks in US

First licensed live vaccine of a mild

field strain

Incidences and spread of

vvIBDV in West Africa

OIE designated IBDV as important

socio economic disease

Ventri IM Live Vaccine

Seven majorgenogroupsidentified

Spread of vvIBDVEurope

and Middle East

Spread of vvIBDV to

Israel, South Africa, India,

Thailand

Severe Immunosupression cases in US caused by IBD

Variant


IBDV: Two Serotypes & Four Pathotypes

➢Classical strains

➢Attenuated strains

➢Variant strains

➢Very virulent strains

✓ The vvIBDV strains were reported to break through high levels of maternal antibodies

✓ High morbidity and mortality than the classical viruses. (60-100%)

✓ In India, emerged in 1992 resulting in severe economic losses to the poultry industry.

✓ Demands a Very Effective Vaccine


Distribution of Infectious Bursal Disease World Wide

Gomez et al 2018

https://www.google.com/url?sa=i&url=https://link.springer.com/chapter/10.1007/978-3-319-90137-4_7&psig=AOvVaw1VkxGVLb_zo9_lNhgr-rNq&ust=1582205769948000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCPCGg_3d3ecCFQAAAAAdAAAAABAt


Classification of Available Traditional IBD Vaccines/ vaccine strains

Bursine-2

B Blen M

2512

V877

Bursine Plus

228E

BurcellD78

Bursavac

S706

Univax

Bursimune

Vi Bursa L

Mild Intermediate Invasive

Ventri’s Plus

Ventri’s Int. Std.

Lukert

MB Abic

VENTRI INTERMEDIATE PLUS VACCINE BETTER SUITED FOR CONTROLLING vvIBDV IN INDIA

Nu

mb

er

of

Ou

tbre

aks

*

Ve

ntr

i

IM P

lus

A Decade Before A Decade Later


https://www.oie.int/wahis_2/public/wahid.php/Diseaseinformation/statusdetail


Distribution of Infectious Bursal Disease World Wide 2020

CABI, 2020

Control strategy : What type of virus prevalent ?

A well designed control strategy needs to know The type of virus prevalent in the region or premices

➢Evolving virus

✓ Very virulent IBDV

✓ Variant IBDV

13Ventri Biologicals, Vaccine Division of Venkateshwara Hatcheries Pvt. Ltd.

FACTORS

Vaccinevirus Selection,

Immunization Schedule

Downtime between

Flocks

Drinking Water

Vaccination and its

Drawbacks

Poultry House Cleaning and Disinfection

Vaccine Delivery System,

Vaccination Uniformity

Factors Influencing Control Strategy

Husbandry Practices

Maternal Antibody

Drinking Water Vaccinations

Multi-age Farms


CAUSES FOR SPORADIC OUTBREAKS DESPITE BETTER SUITED VACCINE STRAIN

"Just good Vaccines are not

enough"

Concepts in IBD Vaccination

✓ Half life: Upto first 4 days of life the MAb remains about the same and from 4 days onwards the titre decreases 1Log2 step per half life time

✓ MAB Half Life = No. Days to first negative titer

Log2 Beginning titer - Log2 End titer (first negative titer)

✓ Breakthrough titer: End to neutralizing effect of MAb and initiation of Vaccine take

✓ Optimum Vaccination day

If the antibody titre of a chick at hatch is known, then the time of maximum flock susceptibility to the wild or vaccinal virus can be determined. This information is very important when establishing the timing of vaccination programme

15Ventri Biologicals, Vaccine Division of Venkateshwara Hatcheries Pvt. Ltd.

“Breakthrough titre”


Criteria for Ideal Vaccine in current scenario


Early protection in presence of Maternal Antibodies

Stimulate active immunity in presence of MAb

Safe for chickens with low levels of MAb

Safe for chickens with low levels of MAb

Broadly antigenic stimulation of antibodies

Convenient and precise administration

Uniform delivery to every chick

Single administration to provide protection

Easy to administer & Cost effective

The ICx Concept

Inhibition of Field virus replication by Occupancy of target organs by Vaccine virus

Inhibition of Field virus replication by Abs raised by Vaccine virus


" First IBD Virus to Reach the Bursa

Wins ...! "

Y Y

Ab

Tit

er

Age

MECHANISM OF IMMUNE-COMPLEX VACCINE


Xuan-yi Wang et al 2019


Indian vvIBDV: In Conext to the Rest of the World


Classification of IBD virus Genogroup

Geno group Previous

ClassificationLineage Reference Strain

G1 Classic G1a, G1b,

G1c

STC (D00499)

D78 (Y14960)

Lukert (AY918948)

G2 Variant G2a, G2b,

G2c

Del-E (AF133904)

T1 (AF281238)

3Ohio (MF142539)

G3 vvIBD G3a,G3b,G3c

UK661 (NC004178)

Washington St (MF142539)

Russia 716 (MF142563)

G4 dIBD NAdIBDV/UY/2014/2202 (KT336459)

G5Variant/Classic recombinant

NA Mexico04M101 (DQ916210)

G6 ITA NA ITA-02 (JN852986)

G7 Australia G7a, G7b002-73 (AJ878908)

08/95 (AF148081)

Michel and Jackwood.,2017

Phylogenetic analysis of the nucleotide sequences of hvVP2 of IBDV

PD

RC

-2013-W

Z-6

78

PD

RC

-2014-W

Z-1

003

PD

RC

-2013-W

Z845

PD

RC

-2015-V

RB

820

PD

RC

-2013-W

Z-1

895

PD

RC

-2014-S

Z-1

895

KJ547673.1

| V

RD

C-I

BD

V-W

Z

VR

DC

-2015- A

5

PD

RC

-2014-S

ZI-57

PD

RC

-2015-V

RB

821

VR

DC

-2015- A

3

PD

RC

-2016-W

Z-7

11

VR

DC

-2015- A

4

KJ5

4767

4.1|

VR

DC

-IBD

V-N

Z

VRDC-201

4- A

6

VRDC-2

015-

A1

PDRC-2

016-

NZ-

85

VRDC-2

015-

A2

PDRC/201

9/IB

D/WZ-1

340

PDRC-2014-W

Z-995

PDRC-2014-SZ-1833

PDRC-2016-WZ-793

PDRC-2016-WZ-794

PDRC-2016-WZ-792

PDRC-2016-WZ-795

PDRC-2014-NZ-31

PDRC-2013-WZ-832

PDRC-2014-WZ-832

PDRC-2013-WZ-1750

PDRC-2013-WZ-1889

PDRC-2013-WZ-1827PDRC-2013-WZ-708KJ547672.1| VRDC-IBDV-EZPDRC-2013-EZ-11PDRC-2014-WZ-213

PDRC-2015-SZI- Mekaguda

PDRC/2019/IBD/NZ-247

PDRC/19/SZI/127

PDRC-2013-WZ-1746

PDRC-2011-WZ-48

PDRC-2014-WZ-214

PDRC-2013-WZ-695

PDRC-2014-WZ-156

PDRC-2011-W

Z-39

PDRC-2015-W

Z- 897

EF066500 IB

DI+-vaccine

PDRC/2019/IB

D/SZII-1640

PD

RC

-2011-WZ-47

JX424077 IB

DV

78/A

BIC

vaccin

e

KT884486.1

Henan G

en 3

AF092943.1

HK

46 G

en 3

NC

004178.1

UK

661 G

en 3

AY

065634 T

am

ilNadu In

dia

PD

RC

-2011-S

Z-0

5

PD

RC

-2011-S

Z-0

3

PD

RC

-2011-S

Z-0

9

PD

RC

-2011-N

Z-6

7P

DR

C-2

011-N

Z-7

0P

DR

C-2

011-W

Z-3

7

PD

RC

-2016-N

Z-9

2

PD

RC

-2010-S

Z-2

7

EU

788042 V

MB

/Karn

ata

ka/India

/2005

AF

362776.1

| str

ain

BD

3/9

9 s

egm

ent A

PD

RC

/2019/IB

D/W

Z-1

343

PD

RC

/2019/IB

D/W

Z-1

342

PD

RC

-2015-S

Z II-

1838

PD

RC

-2014-S

ZII-1

378

PD

RC

-2015-S

Z II-1891

PD

RC

-2015-S

Z II-1895

PD

RC

-2015-S

Z II-1890

PD

RC

-2014-S

ZII-1

415

PD

RC

-2016-S

ZII-1

455

PD

RC

-2015-S

Z II-1822

PD

RC

/19/

SZII/

2027

PDRC/201

9/IB

D/S

ZII-17

39

PDRC/19/SZI

/131

PDRC/2

019/

IBD/S

ZII-16

82

PDRC/201

9/IB

D/SZII-

1751

PDRC-201

6-SZII-

1449

PDRC-2016-S

ZII-1473

PDRC-2015-SZ II-

1896

PDRC-2015-SZ II-1897

PDRC-2015-SZ II-1899

PDRC-2013-WZ-1726

PDRC-2011-WZ-29PDRC-2011-WZ-32PDRC-2011-SZ-01PDRC-2010-WZ-04PDRC-2010-SZ-30

PDRC-2010-WZ-O5

PDRC-2013-WZ-768

AJ001941 Very Virulant

AY321953.1 F52-70 Gen 1

AJ878886 Classic FRANCE

AY918948.1 Lukert Gen 1

AJ586960 Ventri vaccine

AF457104.1 Int/228E Gen 1

PDRC-2013-WZ-1816

AJ249517 Intermediate type Georgia

AF499929.1 D78 Gen 1

PDRC-2013-WZ-1821

AJ249523 Tri-bio Intermediate type

KF573194 IBD Georgia vaccine

PDRC-2013-W

Z-1765

PDRC-2013-W

Z-1817

JN852986.1 ITA

-02 Gen 6

JF736011.1 A

L-2 Gen 2

AF133904.1 D

elE G

en 2

AF281238.1

T1 G

en 2

DQ

916210.1

Mexico

04M

101 G

en 5

JN

982252.1

MG

4 G

en 4

KT336459.1

dIB

DV

/UY

/2014/2

202 G

en 4

LC

136880.1

TY

2 G

en 4

HM

071991.1

V877-W

Gen 7

vvIBD

2013-2019

vvIBD

Intermediate

plus Like

Strains

Attenuated

vvIBD

strains

Genogroup

1,2,4,5,6 & 7

Field Isolates around India

vvIBD

2010-2016Genogroup 3

INDIAN

FIELD

ISOLATES

vvIBDV ISOLATES

WORLD WIDE


Novel Indian Field Viruses over the years

vvIBDV NOVEL INDIAN

ISOLATES

AM

INO

AC

ID M

UTA

TIO

NS

IN V

P2

G

ENE

OV

ER 2

DEC

AD

ES

2010-2019

2005-2006

2000-2003



Ventri IM Plus: The choice for VIPx

-Genotypic similarity-Antigenic Similarity

- Invasiveness which is time tested

Vaccine belonging to Genogroup similar to field Isolates; Genogroup 3

More Identical to Field viruses than Vaccine virus used by Competitors


Ventri IM Plus: Genetically Similar to India Field Isolates

VENTRI INTERMEDIATE PLUS VACCINE BETTER SUITED FOR CONTROLLING vvIBDV IN INDIA

Nu

mb

er

of

Ou

tbre

aks

*

Ve

ntr

i

IM P

lus

A Decade Before A Decade Later


How Invasive Vaccines Work?


INVASIVE VACCINES

Work in presence of higher MABs

Stronger vaccines immunize quicker

Increased spreadability

“blanketing effect”

✓ More efficacious when given early✓ More birds respond to vaccination

✓ Wider window between onset of protection and onset field of infection

✓ Ensures more uniform and complete flock coverage


About VIPx

➢ Two component vaccine:✓ IBDV (IBD Intermediate Plus)

✓ Homologous Antisera to IBDV

➢ Vaccine virus and antiserum are combined during vaccine assembly and lyophilised

➢ Strong IBD vaccine virus made safe for hatchery administration

Seg B

Seg A

Seg B

Seg A

MECHANISM OF IMMUNE-COMPLEX

Ventri Biologicals, Vaccine Division of Venkateshwara Hatcheries Pvt. Ltd.29

Nat Rev Immunol. Author manuscript; available in PMC 2019 February 11.


In SPF Chicken

VIPx EvaluationIn Broiler Chicken


EXPERIMENTAL DESIGN : IN SPF CHICKEN

:: Group A :: VIPx vaccine

:: Group B :: Control

Vaccination: @ 1 day of age by sub-cutaneous route

Observations and recommendations:

✓ Virus detection by RT-PCR in bursa: Daily from 1 DPV (n = 5)✓ Serum ELISA: Pre-vaccination, 5, 7, 10, 14, 21 and 28 DPV (n = 20)✓ Collection of birds for Challenge on 21st day of age (n = 20)

Virus detection RT-PCR in various organs of SPF chickens inoculated with VIPx

100%

Start


SPF expt contd...

Serological response in SPF chickens (ELISA titer)


SPF expt contd...

After Challenge Results

Groups Mortality % Protection HP score/ results

A / VIPx 0 / 20 100 (1 to 2 Score) Atrophy of follicles with mild cell depletion

B / Control 20 / 20 0(4 to 5 Score) Necrosis in the Medulla and peripheral inflamation in the cortex and hyperemia

Average B:B Ratio

GroupChallenged at 21 days of age

14 dpc 18 dpc 21 dpc 25 dpc

A / VIPx 2.27 2.30 1.50 1.10

Control Un -Challenged 2.01 1.89 1.57 1.35

Average Bursal Ratio of birds challenged and not challenged with the IBD virus in SPF


SPF expt contd...

:: Group A :: VIPx vaccine

:: Group B :: Comp1vaccine

:: Group C :: Comp2vaccine

:: Group D :: Control

Vaccination: @ 1 day of age by sub-cutaneous route

Observations and recommendations:

✓ Virus detection by RT-PCR in various organs: 7, 14, 21, 28, 35, 42 DPV (n = 5)✓ Serum ELISA: Pre-vaccination, 5, 7, 14, 17, 21, 28, 35 and 42 DPV (n = 20)✓ Routine study : Body weight, FCR, clinical observations, etc✓ Collection of birds for Challenge on 21st day of age (n = 20)

EXPERIMENTAL DESIGN : IN BROILER CHICKEN


Virus detection RT-PCR in various organs of broiler chickens inoculated with VIPx

100%

Start


Broiler expt contd...

Serological response in broiler chickens (ELISA titer)



After Challenge Results

Groups Mortality % Protection HP score/ results

A / VIPx 0 / 20 100 (1 to 2 Score) Atrophy of follicles with mild cell depletion

B / Comp 1 0 / 20 100 (1 to 2 Score) Atrophy of follicles, fibrosis with cell depletion

C / Comp 2 0 / 20 100 (1to 2 Score) Atrophy of follicles, with some cell depletion.

D / Control 4 / 20 -(4 to 5 Score) Atrophy of follicles, cystic spaces, fibrosis with cell depletion, infiltration of inflammatory cells



Average Bursa:Body Index of birds challenged and not challenged with IBD Virus in broiler chickens




Bird Performance


CONCLUSIONS✓ vvIBDV has been a endemic in India for last few decades

✓ The Ventri IBD Intermediate Plus Vaccine virus that is most related:

➢ Genotypically, based on sequence similarity

➢ Ability to neutralize Indian field virus based on virus neutralization assay

➢ Better suited in Indian scenarion in terms of invasivness and offer better protection

➢ VIPx Immune-complex vaccine containing Ventri Intermediate Plus vaccine strain provides better protection to control IBD in Indian sub-continent

✓ VIPx is effective in protecting against Mortality and histopathological lesions in SPF and Broiler chickens

✓ The advantage of using more related virus is reflected in our Bird study results in terms of better histopathology scores post challenge

Thank you ...


Documents

VENTRI BIOLOGICALS · Concepts in IBD Vaccination Half life: Upto first 4 days of life the MAb remains about the same and from 4 days onwards the titre decreases 1Log. 2. step per