Meningococcal conjugate vaccines

Mary Ramsay Consultant Epidemiologist Immunisation, Hepatitis and Blood Safety Department HPA Centre for Infections

Meningococcal serogroup C (MCC) conjugate vaccination in the UK

•  The first conjugate vaccine for meningococcal disease was introduced into the UK in 1999 •  Based on successful approach used for Hib vaccines

•  Incidence too low to undertake efficacy trials •  Licensed on the basis of immune responses

•  Vaccine produced protective levels of serum bactericidal antibodies •  Superior to plain polysaccharide vaccine

•  Evidence of immunological memory •  Response to challenge dose of plain polysaccharide vaccine •  Increase in antibody avidity with time

Miller E, Salisbury D, Ramsay M. Vaccine 2001;20 Suppl 1:S58-67.

MCC vaccine implementation in the UK

•  Vaccine given with the routine schedule at 2, 3 and 4 months of age • Coverage of >90% rapidly achieved

•  Based on pre-vaccine epidemiology, catch-up for all children <18 years of age completed in 2000 • Coverage exceeded 85% in all cohorts up to 16 years

•  Immediate dramatic impact on disease rates •  Impact now sustained for over 10 years

•  Vaccine introduced in several European countries between 2000 and 2002

Incidence of invasive meningococcal disease and number of serogroup C infections England and Wales

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Serogroup C IMD

all meningococcal disease

Post marketing studies of MCC vaccines in UK

•  Short term protection high in all age groups (>=90%) –  correlated well with immunological correlate (rSBA >=1:8)

•  Protection declines over time in younger vaccinees –  Remains high if vaccinated as older child / adolescent

Age at vaccination Within 1 year More than 1 year Infants (routine) 97 % 68 % Toddlers (catch-up) 89 % 71 % 3 to 18 years 96 % 93 %

•  Andrews N, Borrow R, Miller E. Clin Diagn Lab Immunol 2003;10:780-6. •  Campbell H, Andrews N, Borrow R, Trotter C, Miller E. Clin Vaccine Immunol

2010;17:840-7.

Further studies in Europe

•  Antibody levels and individual protection decline with time –  Particularly in young infants –  Persistence of antibody strongly related to age at vaccination

•  Despite this declining protection, major reduction in MenC incidence in all age groups in all countries –  Different vaccines used

NeisVac-C (Baxter) Tetanus toxoid Meningitec (Pfizer) CRM197 Menjugate (Novartis) CRM197

–  Different schedules used

Schedules used for routine introduction of meningococcal serogroup C conjugate vaccine (MenC)

Country Routine schedule

Year introduced Catch-up

Belgium 12 months 2002 To 17 years

Ireland 2, 4 and 6 months 2000 To 23 years

Netherlands 14 months 2002 To 18 years

Spain 2, 4 and 6 months 2000 To 19 years (15 regions)

To 6 years (4 regions)

UK 2, 3, 4 months 1999 To 18 years

Percentage reduction in MenC incidence in European countries over time

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100%

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Belgium (2001)

Ireland (2000)

Netherlands (2001)

Spain (2000)

UK (1999)

Summary of impact in Europe

•  All countries achieved very high coverage (>90%) for routine and catch-up vaccination –  Rapid and dramatic decline in disease rates

•  Impact of programme less rapid and dramatic in Spain –  Probably due to less extensive initial catch up campaign in some

autonomous regions (to six years of age)

•  Main reason for dramatic impact was indirect (herd) protection –  Reduced acquisition of nasopharyngeal carriage –  Required vaccination of in older children and teenagers

Maiden MC et al. J Infect Dis. 2008;197:737-43.

Nasopharyngeal carriage rates of serogroup C Neisseria meningitidis, UK adolescents

-71% -81%

Quadrivalent (MCV4) meningococcal vaccines

•  In 2005, the first conjugate against serogroups A, C, W135 and Y was licensed in USA –  Menactra – diphtheria conjugate (Sanofi)

•  Used as adolescent vaccine (>11yrs) in USA –  Impact of vaccine modest in comparison to MCC experience

•  USA preliminary effectiveness for Menactra from case control study

Overall 74% (35-90%) Within one year 99% (0-100%)

One to two years 80% (-3, 96%) Two to five years 46% (-66%-83%)

Updated recommendations for use of meningococcal conjugate vaccines – Advisory board on Immunization Practices (ACIP), 2010. MMWR, Jan 28, 2011, Vol 60, No. 3.

Reason for modest impact observed in the USA

•  No indirect protection (herd immunity) as coverage low and took some years to accumulate

•  Evidence of rapid decline in protection •  GMTs slightly lower with this conjugate

•  Other quadrivalent vaccines now available / close to licensure •  Different conjugate proteins (CRM197 and tetanus) •  May have better immunogenicity than product used in

USA

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The Meningitis Vaccine Project (MVP) MenAfrivacTM, a new group A meningococcal conjugate vaccine

•  PsA-TT, MenA polysaccharide (Ps) conjugated to tetanus toxoid (TT)   Lee CH, Kuo WC, Beri S, Kapre S, Joshi JS, Bouveret N, LaForce FM, Frasch CE. Preparation and characterization of an

immunogenic meningococcal group A conjugate vaccine for use in Africa. Vaccine 2009;27: 726-32

•  Comprehensive product development according to GMP/GLP/GCP •  2005- 2010: 7 trials conducted in 8 sites / 5 countries •  India, Mali, The Gambia, Senegal, Ghana

•  Regulatory pathway, indication 1 to 29 year olds   Marketing authorization in country of manufacture, Drugs Controller General of

India – 2009   WHO prequalification certificate – 2010   Licensure in 3 countries of the African meningitis belt: Mali, Niger, Burkina

Faso – 2010   Non-inferiority to the reference licensed meningococcal polysaccharide

vaccine (percentage of vaccinees having a 4-fold or greater increase in SBA titer)

14 14 14 * For all studies, reference was a PsACWY Vaccine (Mencevax®), except for study PsA-TT-001 and PsA-TT-005, where the reference vaccine was a PsAC

vaccine (Menomune® and MenA+C®, respectively)

Group A rSBA Geometric Mean Titers (GMT) with 95%CI Pre-vaccination and 28 days after immunization ITT PsA-TT-001, PsA-TT-002, PsA-TT-003, PsA-TT-003a and PsA-TT-005

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PsA Vaccine*

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V1 V1 V3 V3 V1 V1 V3 V3 V1 V1 V3 V3 V1 V1 V3 V3 V1 V1 V3 V3 V1 V1 V3 V3 PsA- TT PsACWY PsA-

TT PsACWY PsA- TT PsACWY PsA-

TT PsACWY PsA- TT PsACWY PsA-

TT PsACWY PsA- TT PsACWY PsA-

TT PsACWY PsA- TT PsACWY PsA-

TT PsACWY PsA- TT PsAC PsA-

TT PsAC

12-23 months 2-10 years 2-10 years 11-17 years 18-29 years 18-35 years PsA-TT-002 PsA-TT-003a PsA-TT-003 PsA-TT-003 PsA-TT-003 PsA-TT-001

Immune Response MenAfrivacTM 1 to 29 year-olds indication

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Immune Persistence MenAfrivacTM 1 to 29 year-olds indication

Group A rSBA Titers Reverse Cumulative Distribution Curves in 12-23 month-olds Pre-vaccination, 1 month and 10 months after immunization - ITT PsA-TT-002

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2 4 8 16 32 64 128 256 512 1024 2048 4096 8192 16384 32768 65536 1E+05MenA rSBA titers

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Baseline PsACW YBaseline PsA-TT

4 weeks PsACWY4 weeks PsA-TT40 weeks PsACWY40 weeks PsA-TT

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•  Safety •  9943 subjects in trials, 6920 subjects received the PsA-TT vaccine •  safe and well tolerated, no safety concern in any age group

•  Immunogenicity after a single dose of MenAfriVacTM •  superior immune response vs. licensed polysaccharide vaccines in all

age groups (1 to 29 year-olds indication) •  bactericidal antibody sustained to 2 years and evidence of immune

memory •  Response consistent between vaccine lots

•  Samba Sow, Brown J. Okoko, Aldiouma Diallo, Simonetta Viviani, Ray Borrow, George Carlone, Milagritos Tapia, Adebayo K. Akinsola, Pascal Arduin, Helen Findlow, Cheryl Elie, Fadima Cheick Haidara, Richard A. Adegbola, Doudou Diop, Varsha Parulekar, Julie Chaumont, Lionel Martellet, Fatoumata Diallo, Olubukola T. Idoko, Yuxiao Tang, Brian Plikaytis, Prasad S Kulkarni, Elisa Marchetti, F. Marc LaForce, Marie-Pierre Preziosi. Immunogenicity and Safety of a Meningococcal A Conjugate Vaccine in Africans. 2011: in press.

Summary of Results from studies so far MenA conjugate vaccine safety and immunogenicity

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•  Mass vaccinations of 1-29 year olds with a single dose of Men A conjugate vaccine to induce strong herd immunity

•  Protection of new birth cohorts   Follow-up campaigns every 5 years of 1-4 year olds or   Routine immunization in infants   Infant indication, development ongoing

  Preliminary data in < 1 year-olds are promising and analyses are currently ongoing to confirm the most appropriate dosage and schedule

  Detailed results will be available to present at the next SAGE session

MenAfriVacTM Introduction Strategy

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Impact evaluation

  Disease and Group A disease rates •  Case-based surveillance (Burkina Faso and Niger) •  Weekly reporting from 13 countries WHO/IST •  SOPs and laboratory support from WHO and CDC

  CSF Bacteriologic data   Case control studies (Burkina Faso, Mali)   Linked carriage studies (pre- and post

vaccinations studies in Burkina Faso, Mali & Niger)

Conclusions

•  Conjugate vaccines produce high short term protection (superior to polysaccharide vaccines) –  Particularly in infants and toddlers –  Age dependent decline in protection over time

•  For major impact need high coverage in age group where carriage occurs –  Important to vaccinate adolescents and young adults

•  Circulating antibody is important for individual protection –  High initial levels correlate with longer protection –  Advantage in picking most immunogenic vaccines

•  Role of boosting (natural and vaccine) not yet clear –  Booster doses have been added in many countries

Acknowledgements

•  WHO - Marie-Pierre Preziosi, Carole Tevi-Benissan

•  CDC - Nancy Messonnier, Amanda Cohn •  HPA - Ray Borrow, Helen Campbell

•  EU-IBIS collaborators in Europe – Sabine de Greef, Rosa de Cano Portero,

Germaine Hanquet, Margaret Fitzgerald