Vaccines. Robert Read University of Southampton University Hospital Southampton

Vaccines Robert Read University of Southampton University Hospital Southampton

Disclosures Non personal, non specific; Novartis-GSK Member, JCVI Editor in Chief, Journal of Infection, and Current Opinion in Infectious Diseases

Question In the under 5s, since 2013 there has been `replacement` invasive pneumococcal disease caused by A serotype 4 B serotype 6 C serotype 9V D serotype 14 E serotype 22F

Question Since september 2015, adolescents have been receiving routinely the following meningococcal vaccine for the given reason A rmenb to cover serogroup B B rmen B to cover serogroup Y C MenC to cover serogroup C D conjacwy to cover serogroup W E conjacwy to cover serogroup Y

Routine Immunisation Schedule 2015

Selective immunisation programmes 2015

NIHR Southampton Respiratory Biomedical Research Unit The nasopharynx the root of all.. Pneumonia Otitis Media Sinusitis Chronic Bronchial Sepsis Meningitis

NIHR Southampton Respiratory Biomedical Research Unit The nasopharynx the root of all.. Pneumococcal carriage Ifedayo et al 2012 Meningococcal carriage Christensen et al 2010

Vaccine Name acronym nature serotypes 23-valent pneumococcal polysaccharide vaccine 7-valent pneumococcal glyco-conjugate vaccine 10-valent pneumococcal glyco-conjugate vaccine pneumovax PPV23 Plain Pneumococcal vaccines polysaccharide Prevnar PCV7 Conjugated to diphtheria protein (CRM197) Synflorix PCV10 Conjugated to NTHi protein D, or tetanus/diphthe ria proteins 1, 2, 3, 4, 5, 6b, 7F, 8,9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F 4, 6B, 9V, 14, 18C, 19F and 23F 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F 13-valent pneumococcal glyco-conjugate vaccine Prevnar 13 PCV13 Conjugated to diphtheria protein (CRM197) 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F

Figure 1. Corrected* invasive pneumococcal disease incidence from epidemiological year 2000/01 to 2013/14, by serotype grouping and agepcv7=seven-valent pneumococcal conjugate vaccine. PCV13=13-valent pneumococcal conjugate vaccine. NVT=nonvaccine type. *Corr... Waight PA Lancet Infect Dis 2015

NIHR Southampton Respiratory Biomedical Research Unit The nasopharynx the root of all.. Pneumococcal carriage Ifedayo et al 2012 Meningococcal carriage Christensen et al 2010

Pneumococcal Carriage Rates in Children Decline 3 Years After Implementation of PCV7 Vaccination 1 Cross-sectional observation study, healthy Dutch 11- and 24-month-olds prior to and post-pcv7 introduction 40% Streptococcus pneumoniae* Carriage in Children (%) 20% 11 months 24 months 0% Pre-vaccination Post-vaccination Time period nasopharyngeal swabs collected *Streptococcus pneumoniae serotypes included in 7-valent pneumococcal conjugate vaccine. 11-month-olds: Pre-PCV7 n=319, Post-PCV7 n=329; 24-month-olds: Pre-PCV7 n=321, Post-PCV7 n=330. 1. Spijkerman J, et al. Emerg Infect Dis. 2011;17:765-767. 16

Changes in ranked serotype distribution in overall carriage in our findings from 2001/2002, 2008/2009 and 2012/2013. Van Hoek AJ, Vaccine 2014 Pneumococcal carriage in children and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England

Van Hoek AJ, Vaccine 2014

Figure 3. Number of invasive pneumococcal disease cases due to non-pcv13 serotypes in children younger than 5 years from July, 2012, to June, 2013, and from July, 2013, to June, 2014Serotypes 15B and 15C were combined because they are considered to be one rapi... Pauline A Waight, Nicholas J Andrews, Shamez N Ladhani, Carmen L Sheppard, Mary P E Slack, Elizabeth Miller Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study null, Volume 15, Issue 5, 2015, 535 543 http://dx.doi.org/10.1016/s1473-3099(15)70044-7

Fig 3. Forest Plot of PPV23 efficacy to prevent all-cause CAP by study setting. Schiffner-Rohe J, Witt A, Hemmerling J, von Eiff C, Leverkus FW (2016) Efficacy of PPV23 in Preventing Pneumococcal Pneumonia in Adults at Increased Risk A Systematic Review and Meta-Analysis. PLoS ONE 11(1): e0146338. doi:10.1371/journal.pone.0146338 http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0146338

Post Hoc Analysis of the Cumulative Episodes of the Primary and Secondary Efficacy End Points in the Per- Protocol Population. Bonten MJ et al. N Engl J Med 2015;372:1114-1125.

Neisseria meningitidis - groups Neisseria meningitidis strains are classified into 12 groups. The polysaccharide capsule is used to identify the different groups. A B C Five main groups cause the majority (95%) of all meningococcal disease around the world A, B, C, W and Y. Polysaccharide Capsule W Y MenB is responsible for ~85% of meningococcal disease in the England & Wales.

Meningococcal diseaseglobal epidemiology CANADA 1 EUROPE 5 RUSSIA 10 14% 23% 59% USA 2 13% 71% TURKEY 6 25% 26% 40% JAPAN 11 36% 28% 32% 18% 35% TAIWAN 12 21% 57% COLOMBIA 3 BRAZIL 3 SAUDI ARABIA 7 36% 35% 50% 29% 38% 29% 71% 21% 17% 78% AFRICAN MENINGITIS BELT 8 AUSTRALIA 13 ARGENTINA 4 43% 48% 10% 11% 47% 83% 27% NEW ZEALAND 14 48% SOUTH AFRICA 9 57% A B C W- 135 X Y Represents serogroups not defined for each individual country Generated from multiple refrences MEN-BEX-P-S-574-2742012

Structure of Meningococcal Outer Membrane, Showing Variability of Outer-Membrane Proteins and Capsule Used in Vaccines and Interaction with Complement. Tan LK et al. N Engl J Med 2010;362:1511-1520.

Invasive meningococcal disease in England and Wales by capsular group 2002/03 to 2011/12 (data provided by Public Health England)

Meningococcal conjugate vaccine production Vaccine 1999 C 2010 A C Y W 2010 A Polysaccharide capsule? B MenB polysaccharide is polysialic acid, a compound identical to that found on the surface of human neuronal cells. Consequently: (i) Poorly immunogenic. (ii) Potential to induce an autoimmune response.

Serogroup C Conjugate Vaccine Successfully Reduced Carriage of Serogroup C Meningococci (UK) 1 Immunised adolescents 15 19 years of age Serogroup C 3 Meningococci (% of isolates) 2 1 0 25 20 15 10 5 0 Serogroup B 1. Maiden MC, et al. J Infect Dis. 2008;197:737-743. 71% 81% Meningococci (% of isolates) 1999 2000 2001 10 8 6 4 2 0 10 8 6 4 2 0 Serogroup W-135 Serogroup Y 28

Figure 2 Areas of Chad vaccinated with PsA TT in 2011, or in epidemic or alert situation during Jan June 2012 Green shading shows the districts where mass vaccination of people aged 1 29 years was undertaken at the end of 2011, before the 2012 meningitis... DM Daugla, JP Gami, K Gamougam, N Naibei, L Mbainadji, M Narbé, J Toralta, B Kodbesse, C Ngadoua, ME... Effect of a serogroup A meningococcal conjugate vaccine (PsA TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study The Lancet null 2013 null http://dx.doi.org/10.1016/s0140-6736(13)61612-8

serogroup A carriers 32/4278 pre Serogroup A carriers 1/2001 post Figure 3 Incidence of reported cases of meningitis in Chad, 2009 12 Vaccination with PsA TT was undertaken in patients aged 1 29 years at the end of 2011 (arrow). PsA TT=serogroup A meningococcal polysaccharide tetanus toxoid conjugate vaccine. DM Daugla, JP Gami, K Gamougam, N Naibei, L Mbainadji, M Narbé, J Toralta, B Kodbesse, C Ngadoua, ME... Effect of a serogroup A meningococcal conjugate vaccine (PsA TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study The Lancet null 2013 null http://dx.doi.org/10.1016/s0140-6736(13)61612-8

Novel antigens discovered by reverse vaccinology Based on the genome sequence of MC58, 570 ORFs that potentially encoded novel surface exposed or exported proteins were identified ~350 proteins successfully expressed in E. coli, purified, and used to immunise mice IHT-C 2,200,000 2,100,000 2,000,000 1,900,000 1,800,000 1,700,000 1,600,000 1,500,000 1,400,000 1,300,000 1,200,000 Bexsero 1 100,000 200,000 1,000,000 1,100,000 300,000 900,000 IHT-A 400,000 500,000 600,000 700,000 800,000 IHT-B 28 novel protein antigens identified expression and purification purified proteins Sera used to confirm surface exposure of novel proteins immunisations Slide provided by Novartis Vaccines

Novartis MenB vaccine, Bexsero Previously known as 4CMenB or rmenb+omv. Contains 4 main antigens. Three recombinant proteins discovered by reverse vaccinology. OMVs from the New Zealand outbreak strain (NZ 98/254). + fhbp (Variant 1) NadA NHBA PorA http://www.inpharm.com/news/101223/novartis-meningococcal-vaccine-bexsero

Routine Immunisation Schedule 2015

Study Methods Pre-licensure study to assess effect on carriage at an individual level Phase III, multi-centre, RCT 2,968 students from universities at 10 different UK sites 3 month enrolment (Sep Dec 2010) Subjects received either: 2 doses of 4CMenB (BEXSERO) 1 dose of MenACWY-CRM (MENVEO)/1 dose of saline placebo 2 doses of Japanese encephalitis (IXIARO) (control) Nasopharyngeal swabs taken at baseline, and at Months 1, 2, 4, 6 and 12 Carriage isolate characterisation performed at HPA (PHE) and Oxford University

Carriage Study Design Group 4CMenB (BEXSERO) (974 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 (BEXSERO) Swab 4CMenB (BEXSERO) Swab Swab Swab Swab MenACWY (MENVEO) Control (985 subjects)* Swab IXIARO (JEV) Swab IXIARO (JEV) Swab Swab Swab Swab MenACWY (MENVEO) MenACWY (MENVEO) (984 subjects)* Swab MenACWY (MENVEO) Swab Placebo Swab Swab Swab Swab *Subset (~600 subjects) evaluated for immunogenicity

Primary Analysis at 1 Month After the Vaccination Series (Read et al Lancet 2015) 4CMenB co-primary Carriage prevalence of virulent sequence types (ST)* of N. meningitidis capsular group B at 1 month following administration of 2 doses of 4CMenB Visit 3 [Month 2] Vaccine Groups Efficacy % 4CMenB Control (95% CI) Number 87 75-18.2% % 9.50% 8.08% N 916 928 (-73.3 19.4) *Virulent ST types are those capsular group B ST types (or clonal complex members) causing disease in the UK (2006-2010). MenACWY-CRM co-primary Carriage prevalence of N. meningitidis combined serogroups A, C, W and Y at 1 month following administration of a single dose of MenACWY-CRM Vaccine Groups Efficacy % MenACWY-CRM Control (95% CI) Visit 2 [Month 1] Number 56 58 16.0% % 5.87% 6.12% N 954 947 (-27.3 44.5) Analyses adjusted for baseline carriage, treatment group, centre and significant risk factors as identified within the multivariate model.

MenACWY-CRM Carriage at Cumulative Later Sampling Points MenACWY-CRM secondary Carriage prevalence and calculated efficacy of combined serogroups CWY and serogroup Y across cumulative later timepoints (Visits 3 6) Vaccine Groups MenACWY- CRM Control Efficacy % (95% CI) C, W, Y Serogroupable Number 193 260 % 5.5% 7.4% N 3520 3504 36.2% (15.6 51.7) Y Serogroupable Number 157 227 % 4.5% 6.5% N 3520 3504 39.0% (17.3 55.0) MenACWY-CRM reduces nasopharyngeal carriage of N. meningitidis serogroup CWY strains Analyses adjusted for baseline carriage, treatment group, centre and significant risk factors as identified within the multivariate model.

4CMenB Carriage at Cumulative Later Sampling Points 4CMenB secondary Carriage prevalence and calculated efficacy for carriage of combined capsular groups BCWY or all N. meningitidis strains across cumulative later timepoints (Visits 4 6) B, C, W, Y Capsular group Vaccine Groups Efficacy % 4CMenB Control (95% CI) Number 449 539 26.6% % 18.0% 20.9% N 2489 2576 (10.5 39.9) Any N. meningitidis Number 797 885 % 32.0% 34.4% N 2489 2576 18.2% (3.4 30.8) 4CMenB reduces nasopharyngeal carriage of N. meningitidis capsular group BCWY strains Non-significant trends for virulent B strains (12.6%; p=0.350) and all ST B strains (15.6%; p=0.225) Analyses adjusted for baseline carriage, treatment group, centre and significant risk factors as identified within the multivariate model.

Serogroup W disease

Serogroup W disease, by age

Routine Immunisation Schedule 2015

Question In the under 5s, since 2013 there has been `replacement` invasive pneumococcal disease caused by A serotype 4 B serotype 6 C serotype 9V D serotype 14 E serotype 22F

Thankyou

Vaccines for Underlying medical conditions2015