Zyvac TCV - The Indian Typhoid Conjugate Vaccine

The new generation ‘Indian’ TCV
Zyvac-TCV
Dr. Gaurav Gupta,
for Ambala, 29th Jan 2020

Conflict of Interest
• Received grants from various vaccine
manufacturers including

Scope
• Need for Typhoid Vaccine
• TCV v/s ViPS
• Choosing ‘right’ TCV
• Recommendations
• Zydus Vaccines

GLOBAL BURDEN OF ENTERIC FEVER
Most common etiological
sources of bacteremia in
many developing
countries, with most of
the cases originating in
the Indian subcontinent
of South Asia.
Source: Ajay Kalra, Vipin M. Vashishtha. 3.11 TYPHOID VACCINES. IAP Guidebook on Immunization 2013–14. page no 257-270

BURDEN OF TYPHOID: INDIA
Age group Typhoid Incidence (per 100 000/year)
Typhoid prevalence (per 1000 febrile
episodes with blood cultures taken)
0–1 years 89.2 6.9
2–4 years 340.1 29.1
5–15 years 493.5 52.5
≥ 16 years 119.7 18.1
5
Source: Ochiai RL et al. A study of typhoid fever in five Asian countries: disease burden and implications for controls. Bull World Health Organ. 2008 Apr;86(4):260-8.
High burden of typhoid in children with significantly high rates in age group from
0 to 1 yr & 2 to 4 yrs

SEASONALITY
• Incidence of typhoid fever in India varied seasonally
• Maximum incidence
– 18.8 cases/1,000 person yrs (during the monsoon,
July to October)
• Lower rates
– 5.4 and 4.7 per 1,000 person years (Summer and
winter)

• Typhoid causes _________ cases and
________ deaths every year

• Typhoid causes 20 million cases and 1.9 lakh
deaths every year
• Global mortality increased by 39 % (1990 -
2010)

• How does Typhoid vaccines affect the Widal
Test?

Widal test
o Uses O and H antigens of S. typhi, S. paratyphi A,B,C to
detect antibodies in blood
o O antibodies appear on days 6-8 and H antibodies on days
10-12 after disease onset
o Sensitivity of 47-77% and specificity of 50-92%.
o May be a false-positive- other Enterobacteriace infection,
malaria, typhus, bacteraemia caused by other organisms
and cirrhosis.
o A single Widal has no value, demonstration of a rising titer
of antibodies in paired samples 10 to 14 days apart.

ANTIBIOTIC THERAPY
Chloramphenicol-
drug of choice
• 1948
Trimethoprim-
sulfamethoxazola
nd ampicillin
• 1970s
Ceftriaxone and
ciprofloxacin effective
against MDR strains of
S. typhi,
• 1980’s
Azithromycin-
promising alternative
to FQ and O-
cephalosporins.
1990’s

ANTIBIOTIC RESISTENCE
• Two categories of drug resistance:
1. MDR strains- resistance to antibiotics such as
chloramphenicol, ampicillin and trimethoprim-
sulfamethoxazole.
2. Nalidixic-acid-resistant S. typhi (NARST)- resistance to
nalidixic acid & reduced susceptibility to fluoroquinolones (
FQ resistance may be total or partial).
3. XDR ST

MDR typhoid fever (MDRTF) in the last
15 yrs: India
14
• Incidence of MDRTF: Increased from 34% in 1999 to 66% in 2005
• Mortality during MDRTF epidemics: 7% to 16% (much higher than seen in susceptible typhoid
fever, 2%)
• Increased incidence of complications
Source: Zaki SA, Karande S. Multidrug-resistant typhoid fever: a review. J Infect Dev Ctries. 2011 May 28;5(5):324-37.

• Third-generation cephalosporins (oral or parentral)- first line treatment
– Oral- Cefixime & cefpodoxime proxetil (higher dose than usual in
typhoid)
– Parenterally- ceftriaxone, cefotaxime, and cefoperazone
• Azithromycin is a preferred alternative agent in uncomplicated enteric
fever
• Aztreonam and imepenem are potential second-line drugs

Cost of illness
1. Sharma P et al. Typhoid vaccine: A case for inclusion in national program. Indian J Public
Health 2011;55:267-71.
16
A prospective surveillance carried out in an urban slum in
Delhi, India, estimates the mean cost (both direct and
indirect) per episode of blood culture confirmed typhoid
fever as INR 3,597 (US$ 1 = INR 35.5 in 1996 prices) in an
outdoor setting1
In case of hospitalization, the cost of illness increased by
several folds (INR 22,000)

PREVENTION IS BETTER
• WASH is the KEY
• However, the development of an adequate
infrastructure for improved water and
sanitation requires large investments, and is
therefore a distant goal in the developing
world
• Hence vaccination will play an important role
17

What is the Incubation Period of Typhoid?
What % of Typhoid cases become carriers?
What is the recommended age range for TCV?

Generation: Inactivated Whole Cell Vaccine
1st
Generation: Cell Vaccine (Live Oral)
2nd
Generation: Vi Polysaccharide Vaccine
2nd
Generation: Vi Polysaccharide Conjugate Vaccine
3rd
NTS & Paratyphi Conjugate Vaccine
4th
Different types of Typhoid vaccines

New generation typhoid vaccines
Typhoid
vaccine
Parenteral
Vi-polysaccharide (Vi-
PS)
Vi-Polysaccharide
Conjugate vaccines
Conjugated with
Pseudomonas
aeruginosa exotoxin A
(not available in India)
Conjugated with
Tetanus Toxoid
Oral
(Not available in India)
Conjugated with
Tetanus Toxoid
(25mcg)
Conjugated with
Tetanus Toxoid
(5 mcg)

CONJUGATE VACCINE VERSUS POLYSACCHARIDE
Sr
no
Parameters Polysaccharide Conjugate vaccine
1
T-Cell dependent
immune response
No Yes
2 Immune memory No Yes
3 Effectiveness < 2 years Not effective Effective
4 Efficacy Moderate High
5
Post booster immune
response
Hyporesponsiveness Robust
6 IgG class switch Limited Efficient
Source: 1. V Krishna Mohan, Vineeth Varanasi, Anit Singh, Marcela F Pasetti, Myron M Levine, R Venkatesan, and Krishna M Ella. Safety and immunogenicity of a Vi
polysaccharide-Tetanus Toxoid conjugate vaccine in healthy infants, children and adults in typhoid endemic areas: a multi-center, two-cohort (open-label/double-blind,
randomized, controlled), phase III study. Clin Infect Dis. 2015; 61(3):393-402.
2. Klouwen berg and Bont Neonatal and infantile immune responses to encapsulated bacteria and conjugate vaccines. Clin Dev Immunol.2008; 2008:628963.

Polysaccharide Vaccines Concern 3
Limited efficacy (Evidence 2)
• Single dose of Vi
polysaccharide
vaccine prevents
– Year 1: Efficacy 69%
– Year 2: Efficacy 59%
– Year 3: Cumulative
efficacy of the vaccine is
around 55%
Source: Anwar E, Goldberg E, Fraser A, Acosta CJ, Paul M, Leibovici L. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2014 Jan 2;1:CD001261
This data clearly suggests moderate
efficacy of typhoid polysaccharide
vaccines

Proprietary and confidential — do not distribute
Efficacy and immunogenicity of a Vi-tetanus toxoid
conjugate vaccine in the prevention of typhoid fever using a
controlled human infection model of Salmonella Typhi: a
randomised controlled, phase 2b trial
JIN C ET AL. LANCET. 2017 SEP 28.

RESULTS (3)
• Post-hoc analyses of alternative diagnostic criteria – Fever of 38°C or higher
preceding S Typhi bacteraemia, showed significant differences between the
Vi-vaccinated and control groups
• Vaccine efficacy estimates*
for Vi-TT of 87.1%
for Vi-PS of 52.3%
January 30, 2020 26
Source: Jin C et al. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection
model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet. 2017; 390(10111):2472-2480.

RESULTS (4)
Vi-TT Vi-PS
Seroconversion (≥four-fold
rise in antibody titre 28 days
after vaccination)
100% 88.6%
Geometric mean titre (GMT)
adjusted for baseline
562.9
EU/mL
140.5
EU/mL
Titers of measured IgG
subclasses 1, 2, and 3
Higher Lower
January 30, 2020 27
Source: Jin C et al. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection
model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet. 2017; 390(10111):2472-2480.

ZYVAC-TCV
CLINICAL TRIAL
PHASE II / III CLINICAL TRIAL
RESULTS: IMMUNOGENICITY &
SAFETY
28

Typhoid Vi Conjugate Vaccine I.P.
CT Details
• DCGI permission date: 18/05/2016
• CTRI registration No.: CTRI/2016/05/006975
(registered on 31/05/2016)
• Start date of subject enrollment: 03/06/2016
• End date of subject enrollment: 22/09/2016
• End date of subject follow-up: 07/11/2016
• Study vaccines:
– Test: Typhoid Vi conjugate vaccine of M/s. Cadila Healthcare Ltd.
– Reference: Typhoid Vi conjugate vaccine of M/s. Bharat Biotech
International Ltd.
30-Jan-20

Details of CT sites
3-May-18
Sr.
No.
Name of
Investigator
Institute
Ped /
Adult
Govt /
Private
1 Dr. Uma Nayak
GMERS Medical College &
General Hospital, Vadodara
Ped Govt
2 Dr. Ritabrata Kudnu Institute of Child Health, Kolkata Ped Govt
3 Dr. T. Ramesh Babu
Gandhi Medical College & Hospital,
Secunderabad
Ped Govt
4 Dr. Vimal Kant Goyal Panchsheel Hospital, Delhi Ped Private
5
Dr. Sanjay
Kumar Jangid
Hi-Tech Medical College &
Hospital, Bhubaneswar
Adult Private
6 Dr. Shrikant Sharma SMS Medical College & Hospital,
Jaipur
Adult Govt
7
Dr. Ambrose
Kumar Kandulna
GCS Medical College &
Hospital, Ahmedabad
Adult Govt
8 Dr. Rajesh Vukkala Indo-US Hospital, Hyderabad Adult Private
9

Immunogenicity Results
31
Primary Immunogenicity Endpoint
% subjects with seroconversion at the end of study
Parameter
Test group
(N = 116)
Reference group
(N = 119)
Test – Reference*
Seroconversion Rate 110 (94.8%) 109 (91.6%)
3.2%
(-3.2% to 9.7%)
Data presented as n (%)
* Difference between proportions (95% CI)
P=0.44 (Fisher’s exact test; test group vs. reference group)
Seroconversion denotes ≥ 4-fold rise in antibody titre post-vaccination
The seroconversion after vaccination with the test vaccine was non-inferior
to the reference vaccine in the PP population

32
Secondary Immunogenicity Endpoint
% subjects in the adult cohort with seroconversion
at the end of study
Parameter
Test group
(N = 58)
Reference group
(N = 60)
Test – Reference*
Seroconversion
Rate
56 (96.6%) 55 (91.7%)
4.9%
(-3.5% to 13.3 %)

30-Jan-20 33
Secondary Immunogenicity Endpoint
% subjects in the pediatric cohort with seroconversion
at the end of study
Parameter
Test group
(N = 58)
Reference group
(N = 59)
Test – Reference*
Seroconversion
Rate
54 (93.1%) 54 (91.5%)
1.6%
(-8.1% to 11.2%)

Safety Results
All the AEs resolved completely during the study period
No SAE was reported during the study period
30-Jan-20
Parameter
Test group
(N = 119)
Reference group
(N = 121)
No. (%) of subjects with AEs* 40 (33.6%) 53 (43.8%)
No. of AEs reported 59 93
*P=0.11 (Fisher’s Exact Test; Test group vs. Reference group)
34

Safety Results
35
Test group
(N = 119)
Reference group
(N = 121)
P value#
No. of AEs reported* 59 93 ---
Local AEs 39 49 ---
Pain 30 (25.2%) 39 (32.2%) 0.26
Swelling 5 (4.2%) 6 (5.0%) 1.0
Redness 4 (3.4%) 3 (2.5%) 0.72
Irritation 0 (0.0%) 1 (0.8%) 0.32
Systemic AEs 20 44 ---
Fever 7 (5.9%) 17 (14.1%) 0.05
Diarrhoea 3 (2.5%) 1 (0.8%) 0.37
Cold 2 (1.7%) 4 (3.3%) 0.68
Myalgia 2 (1.7%) 6 (5.0%) 0.28
Malaise 1 (0.8%) 4 (3.3%) 0.37
Headache 1 (0.8%) 2 (1.7%) 1.0
Arthralgia 1 (0.8%) 2 (1.7%) 1.0
Vomiting 1 (0.8%) 2 (1.7%) 1.0
Nausea 1 (0.8%) 0 (0.0%) 0.50
URTI 1 (0.8%) 0 (0.0%) 0.50
Cough 0 (0.0%) 2 (1.7%) 0.50
Running nose 0 (0.0%) 2 (1.7%) 0.50
Urticaria 0 (0.0%) 2 (1.7%) 0.50
Data presented as n(%) unless specified; % calculated from No. of events
*Data presented as No. of events
# Chi Square test/Fisher’s Exact test (test group vs. reference group)

Conclusion
• The results of this randomized, single-blind, multicentre clinical
trial suggest that Typhoid Vi conjugate vaccine of M/s. Cadila
Healthcare Ltd. is non-inferior to Typhoid Vi conjugate vaccine
of M/s. Bharat Biotech International Ltd.
• The test vaccine is immunogenic, well tolerated and its
adverse event profile is similar to the reference vaccine in the
healthy subjects studied in this clinical trial
30-Jan-20

High Rate of
Seroconversion
&
Seroprotection
Protection
Against
Typhoid with
single shot for
long duration
Meat Free
Media
Thiomersal free
ZyVAC-TCV : Salient Features
94.8%

Meat Media Culture
38
new variant
Creutzfeldt–
Jakob disease
Gerstmann–
Sträussler–Scheinker
syndrome
KURU
Classic
Creutzfeldt–Jakob
disease
Using Meat media carries a risk of Transmissible
Spongiform Encephalopathy
Characterized by degeneration of brain tissues
giving a sponge like appearance leading to death

RECOMMENDATIONS
Indian Academy of Pediatrics
(IAP)
• Recommends the new Vi-PS conjugate vaccine < 1 year
of age, preferably between 9-12 mths (min age 6 mths)
• Recommends for routine use
Source: http://www.indianpediatrics.net/dec2013/1095.pdf as accessed on 18 Feb 2015, 9:58 pm; https://www.cdc.gov/typhoid-fever/typhoid-
vaccination.html accessed on 17 May 2017 @ 2:30 PM; http://www.who.int/rpc/TFGuideWHO.pdf accessed on 17 May 2017 @ 3:00 PM

WHO Typhoid Position paper - 2018
Primary vaccination
• Higher and more sustained levels of immunogenicity from one dose
of TCV v/s ViPS.
• WHO recommends TCV as a single dose from 6 mo to 45 yr in
Endemic countries.
• WHO encourages routine programmatic administration of TCV at
the same time as other vaccine visits at 9 months of age or in the
second year of life
Catch-up vaccination
• With TCV up to 15 years of age is recommended as burden of
disease and programmatic feasibility are greater in this age range
than in adults
World Health Organization . Typhoid vaccines: WHO position paper, March 2018 – Recommendations. Vaccine (2018),

Vaccine Manufacturing Capabilities
Confidential 48
▪ Spread over a
area of 2005 m2 a
dedicated facility
for production of
Mumps, Measles,
Rubella and
Varicella vaccines.
Live viral
Vaccine
▪ Spread over a
area of 1000 m2 a
dedicated facility
for Recombinant
vaccines like
Hepatitis B and
HPV.
Recombinant
Vaccines
Influenza Vaccines
▪ Dedicated facility
for Influenza
vaccine (Split).
▪ Fully automated
egg inoculation
and harvesting.
• Fill & Finish
(Ampoule , Vial &
PFS Filling line)
Capacity :
▪ 30.0 Mi. Doses per
annum for vial
filling line (multi
dose).
Bacterial Vaccines

Vaccine Pipeline: Early Stages
49
Vaccine Pipeline: Advance
Typhoid Conjugate

As per WHO guidelines, dosage of
Cefixime in the treatment of typhoid is
10-15kg/body weight
8-20mg/kg body weight
15-20mg/kg body weight
12-16kg/kg body weight

A call to action
• We MUST use Typhoid Vaccination routinely
• TCV is the preferred Typhoid vaccination
offering due to better & higher quality
protection that is longer lasting as well.
• 25 micg containing TCV vaccinations are
recommended by WHO

FAQs
• How effective is the TCV vaccine?
• With a single dose how long would TCV
remain effective?
• With 2 doses appropriately spaced, how long
would TCV remain effective?
• If ViPS given at 2 years, when can we give
TCV?
• How long after Typhoid disease should TCV be
given?

Acknowledgements:
Dr Miti, Zydus Vaccines
Missed something ?
Check www.slideshare.com/gauravg
docgaurav@gmail.com
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Zyvac TCV - The Indian Typhoid Conjugate Vaccine

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Zyvac TCV - The Indian Typhoid Conjugate Vaccine