The Impact of MEnAfriVac in the Meningitis Belt and Prospects for Meningoccocal Disease prevention through EPI and Higher Valetn Vaccines

1. The impact of MenAfriVac in the Meningitis Belt and
Prospects for Meningococcal Disease Prevention
through EPI and Higher Valent Vaccines
Dr Marie-Pierre Preziosi
Initiative for Vaccine Research, Department of Immunization, Vaccines and Biologicals
Meningitis and Septicaemia in Children and Adults 2015, Meningitis Research Foundation
Royal Society of Medicine, London, 4- 5 November 2015

2. 1
1996
Ministers of Health and Interior
from 16 African countries
recognized epidemic meningitis as a high priority

3. 2
• 1996 Epidemic
meningitis ,
high priority in
Africa
• 1999 Conjugate
meningococcal
vaccines
needed
• 2001 Project
Launch
• 2002 African
political will
for affordable
vaccines, and
Business model
defined
• 2003-04 Tech
transfer to SIIL
• 2005 Phase I trial
• 2006-2013
Comprehensive
vaccine
development in
India & Africa
• 2003-05
Enhanced disease
surveillance and
stockpile for
epidemic
response
• 2007-2008
Launch of carriage
studies
• June 2010 WHO
Prequalification
(1-29 year-olds)
following DCGI
licensure Jan. 2010
• 2010- 2014
Regulatory approval
at national level
• 2010 WHO/GACVS
Recommendation &
WHO/SAGE Policy
• 2014 Regulatory
approval, policy for
indication variation
• Sept. 2010 Phase1
introduction in 3
selected districts
• Dec. 2010
Nationwide
introduction in 3
countries
• 2010-2013
Enhanced
manufacturing
capacity (SIIL)
• 2016 Introduction
in routine
• 2010-2016 Mass
campaigns 1-29
year-olds in 26
countries in Africa
• 2011 Burkina Faso
initial measurement
of vaccine impact
• 2012 Chad
demonstration and
quantification of the
vaccine effect
• 2014 Impact
evaluation
framework defined
Research/
Design
Develop/
Validate
Approve/
Recommend
Introduce/
Optimize Scale-up/ Apply
An Integrated approach
Meningitis Vaccine Project (MVP) & partners 2001-2014

4. • Inducing strong herd protection
 Large single dose mass vaccination
campaigns with high coverage, targeting
1–29 year-olds in 26 belt countries
• Protecting new birth cohorts
 Routine EPI immunization or periodic
follow-up campaigns
• Enhancing surveillance and
outbreak response capacity
 Throughout vaccine introduction + beyond
 Rapid response to outbreaks (W, C, X and A
in the unprotected)
 Adequate care/treatment of meningitis cases
 Outbreak containment: emergency stockpile
MenAfriVac introduction strategy

5. MenAfriVac rollout 2010–2016

6. MenAfriVac rollout 2010–2016
19
55
103
154
217
237
277
0
50
100
150
200
250
300
2010 2011 2012 2013 2014 2015 2016
Millions of Persons Vaccinated

7. MenAfriVac use in a controlled temperature chain (CTC)
• 2012: relabeled to allow for use in a CTC
– Pilot use in North Benin: successful implementation
• 2014: over 1.5 million persons vaccinated during
campaigns in 14 districts, 3 countries: Côte
d’Ivoire, Mauritania and Togo
– Wastage due to CTC (temperature or time): very low < 0.1%
– Reported vaccine coverage: very high > 95%
– Safety: no serious related AEFI
– Implementation: protocol well understood, good compliance
– HCW's Acceptance of the CTC approach : excellent
• GAVI financial support
• Implementation requires ad-hoc preparation,
training, supervision, monitoring and specific
indicators

8. Meningitis pathogen trends in the belt, 2006-2015
MenAfriVac introduction
Courtesy C. Lingani, WHO/AFRO IST-West

9. Vaccine effect on disease, on carriage &
transmission … THE evidence !
Lancet 2013
Emerging Infectious Diseases 2015

10. MenAfriVac campaigns,
A huge success
• Excellent coverage
– High population acceptance
– Reported coverage usually >95%
– Age group > 15 years often less well covered
– Mop-up campaigns conducted in areas with lower coverage
(Senegal, Cameroon)
• No new serious AEFI attributable to the vaccine
detected
• Vaccine wastage < 5%
• Operational costs 0.65 USD / target person usually
enough

11. Introduction into Routine Childhood
Immunization Programmes

12. Comparison of strategies A-D
http://www.who.int/immunization/sage/meetings/2014/october/presentations_background_docs/en/
Karachaliou A, Conlan AJK, Preziosi MP and TrotterC. Modelling long-term vaccination strategies with MenAfriVac® in the African meningitis belt. Clinical Infectious
Diseases 2015; 61(Suppl.5): S594-600.
If routine EPI is NOT TIMELY…
Epidemic likely in 2025 or before...

13. WHO updated recommendations
• Countries completing mass vaccination campaigns introduce
meningococcal A conjugate vaccine into the routine childhood
immunization programme within 1-5 years following campaign
• A one-time catch-up campaign should be conducted for birth
cohorts born since the initial mass vaccination and outside the
age range targeted by the routine immunization programme
WHO recommends that
SOURCE: Weekly epidemiological record, No.8, 20 February 2015, vol. 90, (pp. 57–68), available at http://www.who.int/wer/en/

14. WHO updated recommendations
 A 1-dose schedule at 9-18 months of age based on local
programmatic and epidemiological considerations*
 Any children who missed vaccination at the recommended age should be
vaccinated as soon as possible thereafter
 For infants < 9 months of age, if compelling reasons exist,
a 2-priming dose infant schedule should be used starting at
3 months of age, with doses at least 8 weeks apart
WHO recommends
* Recommendation for RI based on the high level of herd immunity following mass campaigns, epidemiological evidence
on the age distribution of disease, and programmatic and economic considerations.

15.  MenAfriVac 5 μg should be used for routine immunization of
infants and young children from 3 to 24 months of age
 MenAfriVac (10 micrograms) should continue to be used
for catch-up and periodic campaigns from 12 months of age
onwards*
*Unless bridging studies have been conducted and show that MenAfriVac 5 μg can be used in older age groups
WHO recommends that
WHO updated recommendations

16. Totals Up to 2018
2015 SDF v12 0 0 5 14 7 26
2015 SDF v11 0 1 9 10 6 26
2010 SDF 9 2 8 4 2 25
Routine introduction date assumptions1,2
Niger
Nigeria
Mali
Sudan North
Ghana3
Burkina Faso
Chad
Cent. Afr. Rep.
Kenya
Tanzania
Cameroon
Guinea-Bissau
Mauritania
Benin
DR Congo
Ethiopia
Gambia
Senegal
Uganda
2015 2016 2017
1. Base scenario, Strategic Demand Forecast (SDF)
2. If a country chooses to administer the routine vaccine dose at 9 months of age: the catch-up campaign should be conducted if possible 3 months after the
routine introduction; if administered at 18 months of age: the catch-up campaign should be conducted if possible 7 months before the routine introduction
3. Ghana program is partially approved
<=2014 2018
Rwanda
Burundi
Cote d’Ivoire
Eritrea
Guinea
South Sudan
Togo
Introduced
Board Approved
Recommendation
Expected
Application received
Status of applications to Gavi

17. Plans for Multivalent
Meningococcal Conjugate Vaccines

18. Multivalent meningococcal conjugate vaccines
• WHO prequalified vaccines
 Menactra, Sanofi Pasteur
meningococcal ACWY conjugate vaccine - DT carrier, liquid
 Menveo, GSK (ex Novartis)
meningococcal ACWY conjugate vaccine - CRM carrier, liquid-lyophilised
combined vaccine
• Licensed, not yet WHO PQ vaccines
 Nimenrix, GSK
meningococcal ACWY conjugate vaccine - TT carrier, lyophilised vaccine
• In development
 Sanofi Pasteur
meningococcal ACWY conjugate vaccine - TT carrier
 Serum Institute of India
meningococcal ACWYX conjugate vaccine - TT and CRM carrier

19. Polyvalent meningococcal vaccine project
Courtesy Dr Mark Alderson, PATH
Funding UK Department for
International Development DFID, 2008
Partnership between PATH and SIIL
Goal Develop and license a
thermostable, affordable polyvalent
meningococcal conjugate vaccine for
sub-Saharan Africa, pentavalent ACWYX
A meningococcal vaccine that covers multiple strains has the potential
to eliminate meningococcal meningitis from the meningitis belt
PATH/Gabe Bienczycki

20. Early development issues
• Serum Instituted of India faced major IP issues since polyvalent
meningococcal conjugate vaccines are heavily “patented” with
extensive pharma “know how”
• No published guidelines for Group X meningococcal vaccines
• Srinivas Reddy Chilukuri, Peddi Reddy, Nikhil Avalaskar, Asha
Mallya, Sambhaji Pisal, Rajeev M. Dhere. Process development
and immunogenicity studies on a serogroup ‘X’ Meningococcal
polysaccharide conjugate vaccine. Biologicals 2014; 42: 160-8.

21. Product optimization
Fermentation/purification
• Yields of crude PS range from 600 mg/L for X to 900 mg/L for Y and W
• Purified PS yields 350 – 650 mg/L
Conjugation
• Conjugation yields between 20-35% with new conjugation technology
Formulation/configuration
• Lyophilization, with stabilizers
• Requirement for adjuvant to be assessed clinically
(aluminium phosphate, 125 µg Al3+)
• Detailed stability studies on Men A and Men C

22. Conjugation Scheme
CPPT Conjugation IP (PCT/US2010/061133) Exclusively Licensed to SIIL

23. Target Product Profile
Active (Lyophilized)
Composition/Dose Men/Poly
Men A -TT 5 μg
Men C-CRM 5 μg
Men Y-CRM 5 μg
Men W-CRM 5 μg
Men X -TT 5 μg
Presentation Lyophilized, 1 & 5 Dose
Stabilizer < 5%
Diluent / Dose
Alum (Al+++) 125 μg / Dose (0.5 ml)
Vehicle Sodium chloride in WFI
Preservative No
Men X Ps-TT Conjugate properties confirmed at NIBSC
Remaining conjugates under testing at NIBSC, UK & University of Cape Town, SA

24. Summary
A, C, Y, W and now X polysaccharides comply to WHO specifications
The lyophilized Men A-TT and Men C-CRM conjugates showed
excellent stability even when stored at 40ºC for six months
Three formulations and a licensed comparator were tested rabbits.
The SBA results consistently showed that the lead candidate
vaccine was equivalent or better than the comparator for groups A,
C, Y and W. The Men X Ps -TT conjugate generated high SBA titers.
Lead formulation was tested with/without aluminum phosphate
(AI3+, 125 µg/dose); IgG and SBA titers were higher with alum
One and five dose presentations are proposed for the pentavalent
without preservative. All conjugates vaccine components are at
5μg with/without 125 μg of alum per human dose

25. SIIL MCV-5 Clinical/Regulatory Plans
Clinical development will be predominantly in Africa
The vaccine will be initially licensed for export in India
Target is WHO Prequalification
 Phase 1/2 single dose in adults and 2 doses in toddlers ±alum
Menactra as comparator vaccine. Target start date: Jan, 2016
 Phase 2/3 infants 2 doses, 9 months and 15-18 months of age
Menactra as comparator vaccine
 Phase 2/3 2-55 years of age in India and Africa in parallel
Menveo as comparator vaccine
Immunoassays at PHE Manchester (Ray Borrow)

27. AARSH
Recherche en Santé
Humaine
In collaboration with health authorities of India and of 26 countries in sub-Saharan Africa