Zyvac tcv noida aug 2018 - Completely indigenous Typhoid Vaccine - with a Quiz

The new generation ‘Indian’ TCV
Zyvac-TCV
Dr. Gaurav Gupta,
for NOIDA, 9th Aug 2018

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

Global burden of typhoid fever

MDR typhoid fever (MDRTF) in the last
15 yrs: India
6
• 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.

• How does Typhoid vaccines affect the Widal
Test?

• Typhoid causes _________ cases and
________ deaths every year

• Typhoid causes 20 million cases and 1.5 lakh
deaths every year

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

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)
Source: Ajay Kalra, Vipin M. Vashishtha. 3.11 TYPHOID VACCINES. IAP Guidebook on Immunization 2013–14. page no 257-270
Conjugated with
Tetanus Toxoid
(25mcg)
Conjugated with
Tetanus Toxoid
(5 mcg)

Proprietary and confidential — do not distribute
Typhoid Conjugate Vaccine Dose Comparison

STUDY 1
The effect of dosage on immunogenicity of a Vi conjugate vaccine in 2-5 years
old Asian children: (5, 12.5 and 25 µg )
Result:
At 1 year,
• 17 (23%) of the (n=75) 5 µg dose recipients,
• 4 (5%) of the (n=79) 12.5 µg dose recipients,
• and 4 (5%) of the (n=77) 25 µg dose recipients
had <3.52 EU of IgG anti-Vi/ml, the estimated minimal protective level.
• Dose-related response, with the highest IgG anti-Vi levels elicited by the 25 µg
dosage and the lowest elicited by the 5µg dosage at 1 year.
August 14, 2018 14
Source: Canh DG, Lin FY, Thiem VD et al. Effect of dosage on immunogenicity of a Vi conjugate vaccine injected twice into 2- to 5-year-old
Vietnamese children. Infect Immun. 2004 Nov;72(11):6586-8

STUDY 2
• In healthy Asian adults, assessing the safety & immunogenicity, there was a
clear dose response relationship observed with different dosages of the
Typhoid Vi conjugate vaccine.
• At day 28, the highest Vi dose (25 µg) elicited the highest antibody level and
the lowest level was observed for the Vi 1.25 µg dose.
August 14, 2018 15
Source: van Damme P, Kafeja F, Anemona A et al. Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against
typhoid fever: randomized clinical testing in healthy adults. PLoS One. 2011;6(9):e25398.

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.

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.

METHODS:
STUDY DESIGN AND PARTICIPANTS
• Observer and participant – Masked
• Done at the Centre for Clinical Vaccinology and Tropical Medicine Churchill
Hospital, Oxford, UK)
• Healthy adult volunteers aged between 18 and 60 years, with no previous
history of typhoid vaccination, infection, or prolonged residency in a typhoid-
endemic region
August 14, 2018 19
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.

RANDOMISATION
Participants were randomly assigned (1:1:1) to receive a single
parenteral dose of
• Vi-tetanus toxoid conjugate (Vi-TT) OR
• Vi-polysaccharide (Vi-PS) OR
• Control meningococcal ACWY-CRM conjugate vaccine (control)
Both Vi vaccines contained 25 μg of Vi-polysaccharide per 0.5 mL
dose.
August 14, 2018 20

PROCEDURES
• About 1 month post-vaccination, participants were challenged orally with 1–5
× 10⁴ colony forming units (CFUs) of S Typhi Quailes strain (a wild-type
strain)
• Typhoid fever was diagnosed if pre-determined criteria were met:
– A positive blood culture with S Typhi collected more than 72 h post-
challenge
OR
– A fever of 38˚C or higher persisting for 12 h or longer
(participants were denied access to antipyretics before diagnosis)
August 14, 2018 21

RESULTS
• Calculated vaccine efficacy of Vi-TT was 54.6% (95% CI 26.8–71.8)
• Estimated vaccine efficacy of Vi-PS was 52.0% [95% CI 23.2–70.0];
p=0.0010)
• Clinical manifestations of typhoid fever seemed less severe among diagnosed
participants following Vi-TT vaccination.
August 14, 2018 22

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%
August 14, 2018 24

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
August 14, 2018 25

DISCUSSION
Immunisation with a Vi-TT vaccine:
• Is safe & well tolerated
• Halves the total number of typhoid infection cases (in the context
of a controlled human infection model of typhoid fever)
It is likely that the protective effect of Vi-TT in endemic settings is
higher
August 14, 2018 26

ZYVAC TCV
CLINICAL TRIAL
PHASE II / III CLINICAL TRIAL
RESULTS: IMMUNOGENICITY &
SAFETY
27CTRI/2016/05/006975
ZyVac TCV composition: Each dose of 0.5 ml contains:
Purified Vi-capsular polysaccharide of S.typhi 25 μg.
conjugated to Tetanus toxoid (Carrier protein) 16 to 50 μg
2-Phenoxyethanol (as preservative) 2.50 mg, Isotonic buffer solution q.s.

Typhoid Vi Conjugate Vaccine I.P.
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

3-May-18
4
FLOW CHART OF THE STUDY
Typhoid Vi conjugate vaccine of M/s CHL
Typhoid Vi conjugate vaccine of M/s BBIL
Visit 1 2 3 4
Day Day 0 Day 7 ±
3 days
Day 21 ±
7 days
Day 42 +
14 days
Screening &
Randomization
Follow-up Follow-up End of study

Immunogenicity Results
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

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*
4.9%
(-3.5% to 13.3 %)

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*
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
• INDIAN CARRIER PROTEIN (TT) could result in less Adverse Events as
compared to IMPORTED CARRIER PROTEIN(TT)
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)

Safety Results
34
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
• 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.
35

Which of the following is accurate regarding
culture for typhoid fever?
1. Stool culture alone may be used to diagnose
typhoid fever
2. Blood, intestinal secretions, and stool culture
results are only positive in 20%-30% of patients
who present in the first week of onset
3. Culture of bone marrow aspirate is 90%
sensitive until at least 5 days after antibiotics are
initiated
4. A urine culture is the criterion standard
diagnostic tool for typhoid fever

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
Centers for Disease Control and
prevention
(CDC)
• If you are traveling to a
country where typhoid
is common, you should
consider being
vaccinated against
typhoid
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),

WHO Typhoid Position paper - 2018
Vaccine use in outbreaks and emergency settings
• Recommended
Revaccination
• With TCV Unclear
Vaccination of special populations, contraindications and precautions
• Professional food handlers
• Travellers from non-endemic to endemic areas
• Health-care workers
• Vaccination of pregnant women
• Vaccination of HIV-infected and other immunocompromised
persons

August 14, 2018 42
Source: Burki T. Typhoid conjugate vaccine gets WHO prequalification. Lancet Infect Dis. 2018 Mar;18(3):258.

Proprietary and confidential — do not distribute August 14, 2018 43
Source: SAGE meeting. Evidence review on the immunogenicity, efficacy/effectiveness and safety of typhoid conjugate vaccines. Available from:
http://www.who.int/immunization/sage/meetings/2017/october/4_Levine_Typhoid_SAGE_16Oct2017.pdf?ua=1 ; accessed on 4th June 2018 @ 10: 20 AM.

August 14, 2018 44Source: SAGE meeting. Evidence review on the immunogenicity, efficacy/effectiveness and safety of typhoid conjugate vaccines. Available from:
http://www.who.int/immunization/sage/meetings/2017/october/4_Levine_Typhoid_SAGE_16Oct2017.pdf?ua=1 ; accessed on 4th June 2018 @ 10: 20 AM.

Which of the following is accurate regarding
treatment of typhoid fever?
• Treatment should be initiated only after
confirmatory tests
• Cholecystectomy is almost always successful
in eradicating the carrier state
• Uncomplicated typhoid fever should be
treated with aztreonam and/or imipenem
• Ceftriaxone may be indicated for complicated
typhoid fever

Which of the following is accurate
regarding treatment of typhoid fever?
• Treatment should be initiated only after
confirmatory tests
• Cholecystectomy is almost always successful
in eradicating the carrier state
• Uncomplicated typhoid fever should be
treated with aztreonam and/or imipenem
• Ceftriaxone may be indicated for complicated
typhoid fever

• Recommended dose of Ceftriaxone, and the
maximum dose?

Vaccine Manufacturing Capabilities
Confidential 51
▪ 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
52
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

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 and Dr. Himpriya, Abbott Vaccines
Missed something ?
Check www.slideshare.com/gauravg
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