Sushant Sahastrabuddhe International Vaccine Institute

1. Role of PDPs in vaccine development:
Experience from IVI’s Typhoid program
Sushant Sahastrabuddhe, MBBS, MPH, MBA
Associate Director General
16 SEP 2022

2. 2
Dr. Sushant Sahastrabuddhe is affiliated to IVI, S. Korea and has received multiple
grants for development of vaccines against Typhoid, paratyphoid A, cholera,
Chikungunya, and COVID-19.
The ideas and experiences presented are personal views of the speaker and do not
reflect the views of the affiliated organizations.
Disclaimer

3. 3
Background and Need for PDPs
Global focus on R&D is not
aligned with the priorities of the
resource poor settings where
there is high disease burden
Less market incentive for
‘diseases of the poor’
Only 10 percent of global health
research is devoted to conditions
that account for 90 percent of the
global disease burden, often
referred to as the ‘10/90’ gap
Product Development
Partnerships (PDPs) try to bridge
the gap by integrating the public
health needs with private sector
incentives

4. 4
Salient features of PDPs:
• Nonprofit in nature
• Use portfolio approach to R&D
• Partnership across public and private sectors
• Work along the product development continuum from early discovery to product
implementation, covering specific research gaps or the full innovation cycle.
What are PDPs?
Definition: Public health driven not-for-profit organizations that drive neglected disease drug [product]
development in conjunction with industry groups (Moran et al., 2005)

5. 5
• Global focus on R&D is not aligned with the priorities of the resource poor settings
where there is high disease burden
• Less market incentive for ‘diseases of the poor’
• Only 10 percent of global health research is devoted to conditions that account for 90
percent of the global disease burden, often referred to as the ‘10/90’ gap
• Product Development Partnerships (PDPs) try to bridge the gap by integrating the public
health needs with private sector incentives
Background and Need for PDP

6. 6
What are PDPs?
Definition: Public health driven not-for-profit organizations that drive neglected disease drug
[product] development in conjunction with industry groups (Moran et al., 2005)

7. 7
• Reduce industry and donor risks by spreading the funding
across portfolio of candidates
• Strong governance structures and professional portfolio
management
• Ensures programs are conducted effectively and efficiently by
reviewing projects as they progress through defined transition
points
• Leverage resources from public and private partners
• Affordable pricing and adequate levels of supply, and include
provisions for technology transfer or access to intellectual
property
• Affordability & adoptability as central criteria for new products
• Harnessing private sector capacity for public ends (CSR)
• Global coordination of scarce investments
Advantages and disadvantages of PDPs
• Untested institutional model: will it
work?
• Financial sustainability unclear
• Developing country participation is
limited
• Risk that private interests undermine
public goals
• Limited to ND (diseases without a
market)

8. IVI’s typhoid conjugate vaccine
development program: PDP case study

9. http://www.appl-
lachaise.net/appl/article.php3?id
_article=2038
S. TYPHI IS OBSERVED AND CULTURED
FOR THE FIRST TIME IN THE EARLY
1880’S
THE WIDAL AGGLUTINATION TEST WAS DESCRIBED
IN 1896
FIRST USED IN MUNICIPAL HOSPITALS LATER THAT YEAR (JOHNSTON
1896) INCLUDING THE NEW YORK CITY HEALTH DEPARTMENT
(GUERARD 1897)
PWD
Historical
Collection,
from
The
Principles
of
Bacteriology,
by
A.C.
Abbott,
M.D.
Seventh
Edition.
Philadelphia:
Lea
Brothers
&
Co.,
1905.
AR Guerard. JAMA. 29. 1897.

10. 10
Various estimates put the burden of typhoid fever globally between 12 million to 22 million cases per year and
mortality between 120,000 to 600,000 deaths per year:
• Ivanoff et al. (1994) 17 million cases and 600,000 deaths
• Crump et al. (2004) 21.6 million cases and 216,000 deaths
• Mogasale V et al (2014) 12 million cases and 129,000 deaths
• IHME (2016): 148,000 deaths
Global Burden of Typhoid Fever
10
Mogasale V et al, 2014, Lancet Global Helath

11. 11
Typhoid Through the Centuries
Enteric Fever Cases
Developing Countries
Developed Countries
1800 1900 2000 2100
1850 1950 2050
Widal
Diagnostic
(1896)
Development of
heat-inactivated
phenol-preserved
whole-cell typhoid vaccine
Typhoid
immunization
available
Chloramphenicol
(1948+)
Acetone-
inactivated
whole-cell typhoid
vaccine
(1960s)
Ty21a
(live oral)
Purified
Vi PS
Quinolones and
3rd gen.
cephalosporins
150 years
Better and improved
vaccines?
?
MDR ?
Isolation of
S. typhi
organisim
(1880)
Industrialization
Urbanization 50% 60% 75%
Municipal water treatment / Sanitation
Urbanization 50% 60% 75%
Municipal water treatment / Sanitation

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• Typhoid vaccines are available for over a century, but
their use was limited because of unfavorable TPP
• Newer vaccines (Polysaccharide and oral) with better
efficacy are available since last 30-40 years, but their use
is also limited (multiple doses, moderate efficacy and
inability to administer in kids younger than 2 years)
Typhoid vaccines
Typhoid
vaccination
for
US
soldiers
during
WWI.
Image
from
the
History
of
Medicine
(NLM).
The
History
of
Vaccines.
http://www.historyofvaccines.org/
Doctor administering a typhoid vaccination at a school in San Augustine County, Texas.
Photograph by John Vachon, April 1943.

13. TCV (Vi-DT) Development Program
SK Vi-DT:
To accelerate clinical development for SK’s Vi-DT
up to licensure and WHO PQ
 Phase I study - completed
 Phase I long-term follow-up study - Ongoing
 Phase II study - completed
 Phase II long-term follow-up study - ongoing
 Support SK’s CMC activity
 Pre-clinical study - completed
 Phase III NPL study - completed
 Phase III PHL study - completed
 Support for licensure and WHO PQ - ongoing
Biofarma Vi-DT:
To provide technical support to Biofarma
for a typhoid conjugate vaccine (Vi-DT)
from the early phase of development to
the licensure in Indonesia and WHO PQ
 Phase I study – completed
 Phase II study – completed
 Phase III study – completed
 Local licensure/ WHO PQ – ongoing

14. Project Progress : SK TCV
Phase I study (completed)
 Objective:
o To generate safety and immunogenicity data in 2-45 years of
age participants;
o To gather preliminary safety and immunogenicity data of Vi-DT vaccine, compared to Vi-Polysaccharide
vaccine
 Progress/outcome: Vi-DT was safe, generally well tolerated, and immunogenic; Results published in
“Vaccine”
Phase I long-term follow-up study (ongoing)
 Objective:
o To assess the long-term immunogenicity at years 3, 4, and 5
after immunization
 Progress/outcome:
o Participants from the phase I study were approached for participation and the first subject in was on
Oct 30, 2019. All 3 years (Year 3, 4, and 5) visits completed
o Interim CSR excluding SBA assay results is developed; SBA assay for Ph1 and Ph1 LTFU samples would
be completed in December 2022 and the final CSR having its analysis will be developed

15. Project Progress : SK TCV
Phase II study (completed)
 Objectives:
o To assess the safety and immunogenicity of the Vi-DT vaccine in infants 6 to 23 months old (Target
population)
o Long-term follow-up with 24 months booster to assess antibody kinetics post last vaccination for
children who received a single dose of Vi-DT
 Progress/outcome:
o Completed interim and primary analysis; published interim data (“Vaccine”) and primary analysis
(“Lancet EClinicalMedicine”)
o Study completed & final clinical study report available, final data manuscript published in “NPJ Vaccine”
[Seroconversion following a single dose of Vi-DT persisted at week 110. The GMT following booster dose
in the single dose group increased to 351.76 (265.01, 466.93) (p<0.001).
Phase II long-term follow-up study (ongoing)
 Objective: To assess the long-term immunogenicity at years 3, 4, and 5 after immunization
 Progress: The first subject enrolled was on Aug 24, 2021. Visit for year 4 is ongoing in 2022.

16. Project Progress : SK TCV
Phase III Nepal study (completed)
 Objective:
o Demonstrate non-inferiority of Vi-DT compared to
Typbar TCV® (WHO PQ’ed vaccine) and a lot to lot
consistency in the target age group of 6 months to
45 years old
 Progress/outcome:
o Vi-DT Vaccine (data pooled 3 lots) demonstrated
Immune Non-Inferiority against to Typbar-TCV
Group in terms of seroconversion rates by overall
and by age strata.
o Three lots of Vi-DT Vaccine demonstrated
Equivalent Immune Consistency in terms of GMTs
by overall and by age strata
o Comparable seroconversion rates with Vi-TT
vaccine at 24 weeks
o No immune interference with measles-containing
vaccines
o Manuscript published in Lancet ID
Phase III Philippines study (completed)
 Objective:
o Demonstrate the immune equivalence of multi
dose formulation against single dose formulation
of Vi-DT vaccine (18 – 45-year age) at 4 weeks
after a single dose
o Generate safety profile in 6 months to 45 years
old
 Progress/outcome:
o Demonstrated Immune Equivalence of multi-
dose (MD) formulation against single dose (SD)
formulation of Vi-DT in terms of GMT
o Demonstrated Immune Equivalence of multi-
dose (MD) formulation against single dose (SD)
formulation of Vi-DT in terms of Seroconversion
rate
o Confirmed satisfactory safety profile for Vi-DT in
all age as well as by age strata

17. 2019
Activity Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov
Central Training
(completed)
Site Specific Training
(completed)
Mock Drills/ Dry Run
(completed)
Hands on Training
(completed)
• Simulate real situation of the trial as per study protocol,
operation manual and site-specific SOPs
• All sites staff
• 3 times per site
Phase III Nepal - Site Trainings
• Basic knowledge of clinical trials
• Site PI and study coordinator from each site & Government officials
• 3 times (combined for all sites
• Operational aspects of clinical trials in addition to the basic training
• All sites staff
• 3 times per site
• Real experience of know how
• Site CRC, lab personnel/study nurses,
and Field Supervisor
• 1 time per site
★ SIV
★ IM

18. Central Trainings
• 3 central trainings completed successfully
• Topics covered: GCP, clinical trial overview, study design, visit procedures and safety reporting

19. Phase III Nepal - Site Specific Trainings
 3 Site Specific Trainings are being planned per site, and 1st & 2nd SST are completed
 Topics covered: GCP, study Design, visit procedures, safety reporting, IP management, study logs & forms filling, eCRF introduction,
role play & dummy runs
2nd SST for
Kanti Children Hospital
(25th & 26th Aug 2019)
2st SST for
Nepalgunj
(27th & 28th Aug 2019)
2st SST for
BPKIHS
(29th & 30th Aug 2019)
2st SST for
Dhulikhel Hospital
(1st & 2nd Sep 2019)

20. Brief overview of Vi-DT BioFarma clinical trials
Phase Design Sample size Test vaccine/
Comparator
Country Status Safety
Database
(test vaccine)
Ia Safety &
Immunogenicity
(Age de-escalation)
100 Subjects;
18-40 years (50)
2-5 years (50)
Vi-DT, 0.5
μg/Influenza
Vi-DT, 0.5 μg/PCV
Indonesia Completed Approx. 50
subjects
IIb Safety &
Immunogenicity
600 Subjects;
12-40 years (200)
2-11 years (200)
6-23 months (200)
Vi-DT, 0.5 μg/Vi
Polysaccharide
/IPV
Indonesia Completed;
Year 3 follow-up of Phase II
long-term study is ongoing
Approx. 300
subjects
IIIc Immune non-
inferiority to TCV &
Superiority to Vi-
Polysaccharide
3071 subjects
6 mn-60 years
Vi-DT, 0.5 μg/Vi
Polysaccharide/TCV
Indonesia Completed Approx. 2700
subjects
Total Approx. 3050
a ClinicalTrials.gov Identifier: NCT03109600; b NCT03460405; cNCT04204096

21. Project Progress : Biofarma TCV
 Phase I (completed): To generate safety and immunogenicity data in adults and children (100 subjects; 2 to
5 years old age and 18 to 40 years old age)
o Progress/result: 100% seroconversion (defined as a four-fold rise in titer) after the first dose in both
adult and children Vi-DT group; while 88% in the control group. No rise in GMT after the second dose;
Data published in “PLoS One”.
 Phase II: Year 3 follow-up of Phase II long-term study is ongoing
o A booster dose vaccination initially planned in the 2nd year to see antibody kinetics, was done in the
3rd year due to the COVID-19 situation in Indonesia. A booster dose vaccination is only given to the
children group.
 Phase III: Total target enrollment (3,071) was completed as of June 19.
o Completed P3 clinical study report
o Submitted the dossier to Indonesian NRA (BPOM) in April 2022 for local licensure. Expected to get the
licensure in November 2022.

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Sharing the updates with scientific community

23. 23
Phase 4
studies
National
licensure
Phase III
Phase II
Phase I
Bharat
(licensed 2013)
Preclinical stage
Biological E (B)
LIBP
Typhoid conjugate vaccine pipeline
NIH
Vi-rEPA
development
-
not
commercialized
(Phase
I-PhaseIII
efficacy,
Infant
co-admin)
Vi-rEPA
Vi-DT Vi-TT
Vi-CRM197 Under review
BioMed
(licensed 2008)
EuBiologics
Incepta (A)
(A) IVI technology transfer
(B) NVGH technology transfer
1994-2010
Slide courtesy: Dr Adwoa Bentsi-Enchill
PT Biofarma (A)
SK Bioscience (A)
Zydus
(Licensed 2018)
Finlay Inst

24. 24
Policy:
•WHO position paper: 2008;
revised in 2018
•Recommended use of TCV
Vaccine supply:
•4 licensed in India
•3 of them prequalified by WHO
Financing:
•Gavi board has approved $85M
for TCV in November 2017 and
the call is open for eligible
countries to apply
Policy and Financing
24

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As for any new vaccine introductions, the demand is not
clear and depends on various uptake scenario in the
endemic countries
Gavi’s forecast:
• Higher scenario: peaking at above 150 million doses in 2022, with a
period of several years where demand could be well over 100 million
doses per year, stabilizing later at levels above 60 million doses per year
• Even with the lower scenario, demand is going to stabilize at >10M
doses/year
Multiple prequalified candidates will alleviate the supply
insecurities and create healthy price competition
Vaccine Demand and Supply
25