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1 What would be the best schedule for prevention of meningococcal disease in all ages? Ray Borrow Public Health England, Manchester, UK

2 MCC vaccine programme - UK In November 1999, the UK became the first country to introduce a national vaccination program with meningococcal C conjugates (MCC) targeting the entire under 18 years population. Introduced into UK infant immunisation schedule at 2, 3 & 4 months of age with no booster in the second year of life. Done on basis of phase 2 immunogenicity + safety data BUT without a randomised controlled trial of efficacy. In 22, extended up to 25 years of age. Miller E et al. Vaccine 22;2:S58-S67.

3 Number of cases Annual cases of laboratory confirmed meningococcal capsular groups B & C disease England & Wales 1992 to Year Group B Group C Public Health England Meningococcal Reference Unit, unpublished data

4 EU MCC vaccine schedules, before 23 Country Routine Catch-up Year UK 2, 3, 4 months Under 18 years (to 24y in 21) 1999 Ireland 2, 4, 6 months Under 23 years 2 Spain 2, 4, 6 months Under 6 years (regional variation) 2 Netherlands 14 months 1 to 19 years 22 Belgium 12 months 1 to 5/ 1 to 18 years (regional variation) 22 Iceland 6, 8 months Up to age

5 Percentage reduction in meningococcal serogroup C in European countries over time 5

6 Serogroup distribution for invasive meningococcal disease, Europe, 26

7 Evidence of herd protection: Rate per 1 5 of group C disease in year olds before and after campaign Pre vaccine 65% reduction in rate in unvaccinated cohort 2/1 unvaccinated vaccinated 98/99 /1 /1 Ramsay ME et al. BMJ 23;326:365-6.

8 % VE (95% CI) Within 1 year Is infant priming sufficient? (2,3,4 month schedule) Significant decline in MCC vaccine effectiveness in England >1 year from routine MCC infant immunisation P<.1 More than 1 year Campbell H et al. Clin Vaccine Immunol 21;17:84 7. Auckland C et al. J Infect Dis 26;194: Vaccine failures primed for immunological memory but response not rapid enough SBA titre Vaccine failures P=.3 Unvaccinated cases

9 SBA GMT and 95% CIs Borrow et al., J. Infect. Dis. 22; Richmond et al., J. Infect. Dis MenC SBA GMTs (95% CI) pre- and post- three dose MCC infant schedule and challenge with plain polysaccharide vaccine

10 2 months DTaP/IPV/Hib + pneumococcal Post 1 dose (2 mth) Post 2 doses (2 & 3 mths) Post 2 doses (2 & 4 mths) 3 months DTaP/IPV/Hib + MCC 4 months DTaP/IPV/Hib + MCC + pneumococcal 12 months Hib/MCC The UK infant immunisation schedule; months MMR + pneumococcal

11 Borrow R et al., Clin. Vaccine Immunol. 21 % with MenC SBA titre >= Meningitec Menjugate Proportions of subjects with SBA titre > 8, by primary MCC vaccine (2 doses) and time since MCC/Hib-TT booster Pre-boost 1 month post-boost 12 months post-boost 24 months post-boost NeisVac-C Meningitec Menjugate NeisVac-C Meningitec Menjugate NeisVac-C Meningitec Menjugate NeisVac-C

12 Number of cases Number of cases of invasive MenC disease in England and Wales, 1998/99 to 213/14 Monovalent MenC vaccine introduced in autumn 1999 Year Public Health England Meningococcal Reference Unit, unpublished data

13 % Importance of catch-up campaigns 1 Carriage rates of N. meningitidis and N. lactamica by age in Stonehouse, Gloucestershire, UK, Age (years) N. meningitidis N. lactamica Cartwright KAV et al. Epidemiol Infect 1987;99:

14 3 2 1 Meningococci (% of isolates) Importance of catch-up campaigns 2 Reduction in capsular group C carriage following introduction of meningococcal serogroup C conjugate vaccines Serogroup C Serogroup B Maiden MC et al. J Infect Dis. 28;197: % -81% Serogroup W Serogroup Y

15 Ishola D, Borrow R, Findlow H, et al. Clin Vaccine Immunol 212; 19: % with SBA titre >= <6 mths 6-11 mths Proportions of sera with MenC SBA titres 8 by age in England & Wales, pre and post-introduction of MCC vaccines yrs 5-9 yrs 1-14 yrs yrs 2-24 yrs yrs yrs yrs yrs 65+ yrs

16 Findlow H et al., Paed Infect Dis J 212;31: Menjugate or NeisVac-C at 3 months 1 1 % of subjects with SBA Is a single primary dose of MCC sufficient? Proportion of subjects with SBA 8 following a single dose of MCC at 3 months of age and a booster of MenC/Hib-TT at 12 months of age. Menitorix (MenC/Hib-TT) at 12 months 1 month 1 mth post 2 mth months post post Pre-booster pre-booster 1 mth 1 post-booster month post-booster (4mths) (5mths) (12 mths) (13 mths) Age: 4 months 5 months 12 months 13 months Menjugate NeisVac-C

17 UK schedule, 213 Dose 1- MCC (3 months) Dose 2- MCC/Hib-TT (12 months) Dose 3- MCC (13/14 years) Simplifies infant immunisation schedule. Maintains herd protection

18 Laboratory confirmed cases Laboratory confirmed cases of meningococcal disease in England, Wales and Northern Ireland, 1995 to date W Y C B

19 Number of laboratory confirmed cases Cumulative cases of MenW by epidemiological year (July June) In England & Wales 25/6 to 214/15 25/26 26/27 27/28 28/29 29/21 21/ / / / /215 To Jan 2th cases cases cases W:2a:P1.5,2 cc11 Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Month

20 Serogroup W in Argentina & Chile In Argentina serogroup W represented less than 6% of the confirmed cases up to 26, rising to 13% in 27 and represented around 5% from 28 onwards. In Chile in 211 incidence was.4/1, increasing in 212 to.8/1,, with more than 55% of the cases due to serogroup W * Other serogroups Serogroup W CFR 4 2 EPIDEMIOLOGIA-MINSAL * Preliminary data

21 In Chile in October 212, strategic vaccination of children aged 9 months to 5 years was initiated. < >6 Years

22 Chile Age (years) Results from the Chilean carriage study in 213 Author s statement: No evidence of association of meningococcal W carriage in adolescent so additional risk factors need to be investigated. % Serogroup B C W Y NG/ Total other 1-13 (N= 1291) (N = 1723) (N = 573) UK (N = 1464)

23 cc11 core genome (cg)mlst 1.

24 W:cc11

25 n CFR 13% W:cc11 - E&W post-hajj W:cc11 England and Wales 25 to year 26 (n=1) UK Hajj 25 (n=1) 27 (n=1) 211 (n=1) Current Sth Africa 29 to 213 (n=117) 27 (n=2)

26 W:cc11 - E&W post-hajj UK Hajj Current Sth Africa Current UK Argentina Brazil

27 Action: Secretariat to write to the Department of Health on behalf of the JCVI informing them of their advice with regard to the use of MenACWY vaccine in place of MenC vaccine in the adolescent and fresher vaccination programmes.

28 Randomised trial: immunogenicity of a CRM or TT conjugated quadrivalent meningococcal vaccine, in teenagers who received a CRM or TT conjugated serogroup C vaccine at preschool age Original study: Children aged years vaccinated in with Menjugate, Meningitec, or NeisVac-C Randomised as teenagers aged 16 to 19 years Booster vaccine MenACWY-TT (GSK) MenACWY-CRM (Novartis) Priming vaccine Menjugate Meningitec NeisVac-C Menjugate Meningitec NeisVac-C

29 Serogroup-specific SBA GMTs, pre and postquadrivalent conjugate

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31 Group 4CMenB (979 subjects) Control (987 subjects) MenACWY (988 subjects) Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Day 1 Month 1 Month 2 Month 4 Month 6 Month 12 Swab 4CMenB Swab JE vaccine Swab MenACWY Carriage Study Design Swab 4CMenB Swab JE vaccine Swab Placebo Swab Swab Swab Swab MenACWY Swab Swab Swab Swab MenACWY Swab Swab Swab Swab

32 Combined Serogroups C, W, Y Serogroup Y MenACWY-CRM Carriage at Cumulative V3 V6 Vaccine Groups Efficacy % Control (95% CI) MenACWY- CRM Number % % 5.5% 7.4% N ( ) Number % % 4.5% 6.5% N ( )

33 Conclusions MCC vaccine, introduced into several EU\EEA countries have led to the reduction of disease due to serogroup C. Largest impact through interruption of carriage. Serogroup W ST-11 has increased in South America and the UK. Switch from monovalent C conjugates to quadrivalent conjugates in adolescents. Catch-up in adolescents would aid in herd protection against W. Role of Bexsero & Trumenba against non-b???

34 Argentina: Adriana M. Efron Brazil: Maria C. Gorla Canada: Raymond S. W. Tsang France: Muhamed-Kheir Taha South Africa: Mignon du Plessis Spain: Julio Vazquez Turkey: Mehmet Ceyhan Acknowledgements UK: Xilian Bai, Helen Campbell, Helen Findlow, Jamie Findlow, Dorothea Hill, David Ishola, Shamez Ladhani, Jay Lucidarme, Martin Maiden, Liz Miller, Mary Ramsay, Robert Read, David Salisbury, Caroline Trotter. Meningitis Research Foundation