The impact of MenAfriVac in the Meningitis Belt and Prospects for Meningococcal Disease Prevention through EPI and Higher Valent Vaccines

Dr Marie-Pierre PreziosiInitiative for Vaccine Research, Department of Immunization, Vaccines and Biologicals

Meningitis and Septicaemia in Children and Adults 2015, Meningitis Research FoundationRoyal Society of Medicine, London, 4- 5 November 2015

2

1996 Ministers of Health and Interior

from 16 African countries recognized epidemic meningitis as a high

priority

3

• 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

• 2007-2008Launch 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 approachMeningitis Vaccine Project (MVP) & partners 2001-2014

• 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

MenAfriVac rollout 2010–2016

MenAfriVac rollout 2010–2016

2010 2011 2012 2013 2014 2015 20160

50

100

150

200

250

300

19

55

103

154

217

237

277

Millions of Persons Vac-cinated

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

Meningitis pathogen trends in the belt, 2006-2015

MenAfriVac introduction

Courtesy C. Lingani, WHO/AFRO IST-West

Vaccine effect on disease, on carriage & transmission … THE evidence !

Lancet 2013

Emerging Infectious Diseases 2015

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

Introduction into Routine Childhood Immunization Programmes

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...

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/

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.

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

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

NigerNigeria

MaliSudan North

Ghana3

Burkina FasoChad

Cent. Afr. Rep.Kenya

TanzaniaCameroon

Guinea-BissauMauritania

BeninDR CongoEthiopiaGambiaSenegalUganda

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

RwandaBurundi

Cote d’IvoireEritreaGuinea

South SudanTogo

IntroducedBoard ApprovedRecommendationExpected

Application received

Status of applications to Gavi

Plans for Multivalent Meningococcal Conjugate Vaccines

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

Polyvalent meningococcal vaccine projectCourtesy 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

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.

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

Conjugation Scheme

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

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

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

SIIL MCV-5 Clinical/Regulatory Plans

Clinical development will be predominantly in Africa

The vaccine will be initially licensed for export in IndiaTarget 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)

AARSH

Recherche en Santé Humaine

In collaboration with health authorities of India and of 26 countries in sub-Saharan Africa