Issues in evaluating the impact of a new

meningococcal B vaccineRay Borrow

Professor of Vaccine Preventable Diseases,Vaccine Evaluation Unit,Public Health England,

Manchester Royal Infirmary,Manchester, UK

ray.borrow@phe.gov.uk

UK and the serogroup B challenge, introduction

• 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.

• Use subcapsular antigens, which are;

(i) Surface exposed.

(ii) Conserved.

(iii) Induce bactericidal activity.

http://www.inpharm.com/news/101223/novartis-meningococcal-vaccine-bexsero

• Bexsero (previously known as 4CMenB or rMenB+OMV) contains 4 main antigens.

• Three recombinant proteins discovered by genome mining/reverse vaccinology combined with OMV from the New Zealand outbreak strain (NZ 98/254).

Novartis investigational MenB 4CMenB vaccine (Bexsero®)

PorA (presented as

part of an OMV)

NadAfHBP 1 NHBA

Bexsero (Novartis)clinical program

• Phase 3 studies in infant, toddlers and adolescents complete.

• Over 5000 infants/toddlers and 2000 adolescents/adults vaccinated.

• Acceptable safety and tolerability profile in all age groups.

• Co-administered infant vaccines elicit expected immune responses when given with Bexsero.

Bai X, Findlow J & Borrow R. Expert Opin Biol Ther 2011;11:969-85.

Bexsero: Proposed immunisation schedules by population

*The safety and immunogenicity of 4CMenB in individuals older than 50 years have not been studied.The safety and immunogenicity of 4CMenB in individuals older than 50 years have not been studied.

The proposed UK infant immunisation schedule is a primary series at 2,3 and 4 months with a booster at 12 months of age

Information provided by Novartis Vaccines

Potential UK schedules

Infant schedule?

Infant schedule and catch-up?

Not recommended?

Infant & adolescent schedule?

Infant schedule, catch-up and adolescent schedule?

Adolescent schedule?

Predicting strain coverage

Polysaccharide based vaccines

• Simply calculated as the proportion of isolates with given polysaccharide.

• Genotypic typing information alone is insufficient to calculate coverage.

Pfizer and Novartis have both developed assays to determine coverage of their respective vaccines.

Subcapsular vaccines

• More complicated due to:

Multiple protein variants (vaccine induced antibody is not equally cross-reactive against all variants).

Protein expression differs between isolates.

Meningococcal Antigen Typing System (MATS)

concept (Novartis)Are any of the Bexsero components in the circulating strains:

(i) expressed to a sufficient degree, and

(ii) similar enough to the antigens in the vaccine such that the antibodies generated by Bexsero will kill the bacteria?

MATS determines the minimum amount of recognisable antigen needed to result in bacterial killing for each of the four

components

Meningococcal Antigen Typing System (MATS)

Donnelly J et al. PNAS. 2010;107:19490-5.

Using MATS to predict whether strains are covered by 4CMenB. Positive Bactericidal

Thresholds (PBT): Example - fHbp

10

Shown are the 36 fHbp expressing strains in which NadA, NHBA and PorA are either absent or mismatched

Donnelly J et al. PNAS. 2010;107:19490-5.

Killed in SBA: infant serum pool titer ≥ 8Not killed in SBA

Serum pools from 13-month-olds immunised with 4CMenB were tested in SBA against diverse MenB strains.

The PBT is defined as the value above which ≥ 80% strains are killed in SBA, maximising statistical predictive power.

Separate PBT for each antigen based on corresponding subsets of strains with 3 of 4 antigens absent or mismatched.

Donnelly J et al. PNAS. 2010;107:19490-5.

Using MATS to predict whether strains are covered by 4CMenB. Positive Bactericidal

Thresholds (PBT): Example - fHbp

Coverage by the PorA (OMV) component of the vaccine is determined by conventional typing, it presence by either serotyping or genotyping of PorA P1.4

PorA coverage

PorA P1.4 (presented as part of an OMV)

37 different variants of P1.4 (P1.4, P1.4-1 etc)

From PorA sequenced case isolates submitted to PHE MRU (1985 to 2008), 492 belonged to P1.4 family.

P1.4 n = 478 (97.2%) All mab +veP1.4-1 n = 13 (2.6%) All mab -veP1.4-5 n = 1 (0.2%) Mab -ve

Distribution of MATS relative potency for fHbp among different invasive MenB strains sorted by fHbp variant and peptide: Europe 2007/8

PBT with 95% CI

Box and whiskers denote quartile ranges for each distribution.

VARIANT 1 VARIANT 2 VARIANT 3 Family B Family A

Strains with fHbp peptides belonging to variant 1 generally had MATS RPs > PBT.Strains with fHbp belonging to variants 2 and 3 had MATS RPs < PBT.

Vogel U et al. Lancet Infect Dis 2013;13:416-25.

Distribution of MATS relative potency for NHBA among different invasive MenB strains sorted

by NHBA peptide: Europe 2007/8

PBT with 95% CI

Box and whiskers denote quartile ranges for each distribution.

Within each NHBA peptide variant, MATS RPs varied over a 5 to 10-fold range indicating significant variation in the level of NHBA expression among isolates harboring the same peptide.

Vogel U et al. Lancet Infect Dis 2013;13:416-25.

027%

123%

234%

316%

Predicted coverage of Bexsero against English and Welsh MenB isolates 2007/08 (no of antigens)*

*> MATS PBT for fHBP, NadA and NHBA, and homologous serotype for PorA.

Overall coverage

estimate of 72.9%

Novartis Meningococcal Antigen Typing System (MATS)

N=535

Vogel U et al. Lancet Infect Dis 2013;13:416-25.

123%

027%

234%

316%

1995199619971998199920002001200220032004200520062007200820092010201120122013 (To June 13)2014Serogroup B Cases1995199619971998199920002001200220032004200520062007200820092010201120122013 (To June 13)2014Serogroup C Cases1995199619971998199920002001200220032004200520062007200820092010201120122013 (To June 13)2014Serogroup W135 cases1995199619971998199920002001200220032004200520062007200820092010201120122013 (To June 13)2014Serogroup Y cases1995199619971998199920002001200220032004200520062007200820092010201120122013 (To June 13)2014EPIDEMIOLOGICAL YEARSALL CASES1998/991999/2000 2000/20012001/2002 2002/2003 2003/2004 2004/20052005/20062006/20072007/2008 2008/20092009/20102010/20112011/20122012/2013 (to May 24)2013/2014Serogroup B Cases1998/991999/2000 2000/20012001/2002 2002/2003 2003/2004 2004/20052005/20062006/20072007/2008 2008/20092009/20102010/20112011/20122012/2013 (to May 24)2013/2014Serogroup C Cases1998/991999/2000 2000/20012001/2002 2002/2003 2003/2004 2004/20052005/20062006/20072007/2008 2008/20092009/20102010/20112011/20122012/2013 (to May 24)2013/20140

500

1000

1500

2000

2500

3000

143313431107

975981909753568489385391339349271249252276231144

5148482576753638

526

398389

325306274252309

19821018517496

13

376

888874

1070

1108

1065

804738

603721

548697654

596469498379

203

PCR only

Culture and PCR

no

of

ca

se

sLaboratory Confirmed Cases of

Meningococcal Disease, England & Wales - by Calendar Year

50% PCR only

confirmed

PHE MRU unpublished data

If no systemic isolate?

• Cannot determine expression from non-culture PCR-based techniques.

• Need an isolate.

• Use nasopharyngeal isolates where available.

Nasopharyngeal isolates from cases

Cartwright KA, Jones DM. Value of throat swabs from index cases of meningococcal meningitis. J Clin Pathol 1990;43:438.

Nasopharyngeal isolates from cases

NICE guides do not stipulate submission of nasopharyngeal isolates from cases.

HPZone* prompts for collection of throat swabs for suspected meningococcal cases.

* HPZone is a web based support tool designed to provide staff at local Health Protection Units with timely & comprehensive information on cases, outbreaks, incidents and threats.

Typing data currently generated

• For cultures: Meningitis Research Foundation whole genome project.

2010/11 514 isolates 2011/12 417 isolates

• For non-culture:

• PorA

• fHbp

Culture vs non-culture genotyping: PorA

7-2, 4, 37 22, 14, 36 22, 9, 35-1

19-1, 15-11, 36 18-1, 3, 38 19, 15, 36

17-1, 23, 37 22, 14-6, 36-2 12-1, 9, 35-1

18-7, 9, 35-1 7, 16, 35 7, 30, 38

19-2, 13-1, 36 5-1, 10-8, 36-2 18-1, 14, 36

5, 2, 36-2 17, 16-3, 36 21, 16, 37-1

5-1, 2-2, 36-2 7-1, 1, 35-1 12-1, 16, 37-1

18-1, 34, 38 19-1, 3-5, 38 7-2, 13-1, 35-1

Other =1

Group B case isolates2012 (Jan-Nov)Total 223

7-2, 4, 37 22, 14, 36 22, 9, 35-1

19-1, 15-11, 36 np 18-1, 3, 38

7, 30, 38 19, 15, 36 7-1, 1, 35-1

17-1, 23, 37 5, 2, 36-2 21, 16, 37-1

22, 14-6, 36-2 5-1, 10-1, 36-2 22, 9, ?

5-1, 10-8, 36-2 7, 16, 35 17, 16-3, 36

22, 4, 37 5-1, 2-2, 36-2 12-1, 16, 37-1

18-7, 9, 35-1 other

Group B PCR+ve onlypositive cases 2012 (Jan-Oct)Total 216

Non-culture genotyping: fHbp

• To provide a complete picture of fHbp diversity and distribution, a PCR-based sequencing assay has been developed to amplify and sequence the meningococcal DNA within non-culture confirmed samples.

• A nested-PCR protocol consisting of two consecutive PCR rounds is used to increase the sensitivity and specificity of the assay.

• This assay is being used in an ongoing project to determine the fHbp allele of all non-culture cases between 2011-2015.

Approximately half of 2011 samples have been sequenced.

The non-culture profile generally reflects that of the cultured isolates.

There is noticeably lower incidence of fHbp peptides 2.22 (A10) and 2.25 (A15) in the non-culture samples.

These peptide variants are associated with groups W and Y, respectively.

Interim non-culture fHbp results

2011 Culture Isolates 2011 Non-Culture (244 samples)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Other

37

47

21

22

16

45

1

19

14

25

15

13

4

Jan to June Jan to May, Nov to Dec

B76.3%

Y14.8% W

5.1% C2.5%

other1.0%cnl/NG0.4%

2010/11 isolates

B83.8%

Y8.3%

W3.5% C

2.3%

other0.2%

cnl/NG2.0%

2010/11 allCulture only Culture/non-culture

Capsular group for culture only proven versus culture/non-culture

laboratory confirmed cases, 2010/11

Lucidarme J et al. The Meningitis Research Foundation Meningococcal Genome Library. Neisserialvaccines2013, Varadero, Cuba, May 2013.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

clonal complex (n)

NK

>66

26-65

16-25

6-15

3-5

2

1

<1

Y W

Age (years)

Clonal complex versus age group

Lucidarme J et al. The Meningitis Research Foundation Meningococcal Genome Library. Neisserialvaccines2013, Varadero, Cuba, May 2013.

Post-licensure studies of meningococcal serogroup B

vaccine, Bexsero®

•Descriptive studies

•Effectiveness studies

Descriptive studies

• Summary of the epidemiology of meningococcal disease, by vaccination status, age, etc.

• Focus on the epidemiology not only of meningococcal serogroup B, but, also include other serogroups.

- evaluate cross protection against other serogroups.

- any capsule replacement after introduction of the

vaccine.

Effectiveness studies

• Analyses for effectiveness of 4CMenB will be performed prospectively eg by the screening method.

• The screening method has been used to successfully assess meningococcal serogroup C conjugate vaccine1, Haemophilus influenzae type b conjugate vaccine2 , and influenza vaccine3 effectiveness in the UK.

• The screening method is based on a comparison of the proportion vaccinated among the cases and the population and control is achieved by using an estimate of vaccine coverage.

• If the screening method is inapplicable then a case control method would be used.

1. Trotter CL et al. Lancet 2004;364:365-7.2. Ramsay ME et al. J Infect Dis 2003;188:481-5.3. Fleming DM et al. J Epidemiol Community Health 2010;64:1062-7.

A case of N. meningitidis is defined by culture of N. meningitidis or identification of meningococcal DNA from a normally sterile site.

Cases can be further classified as:

1) A case of serogroup B N. meningitidis is defined as isolation of serogroup B N. meningitidis or positive capsular group B specific PCR from a normally sterile site.

Definitions - 1

Definitions - 2

2) A serogroup B Bexsero-vaccine-type confirmed case can be defined as either: Isolation of serogroup B N. meningitidis with at least one vaccine antigen above the positive bactericidal threshold (PBT) as measured by the MATS assay from a normally sterile site, or

Positive for meningococcal DNA and capsular group B specific PCR on a normally sterile site plus isolation from a throat swab of serogroup B N. meningitidis with at least one vaccine antigen above the PBT as measured by the MATS assay, or

Positive for meningococcal DNA and capsular group B specific PCR on a normally sterile site and PorA P1.4 identified on genosubtyping.

3) Non-serogroup B Bexsero-vaccine-type confirmed case is defined as either:

Isolation of non-B serogroup N. meningitidis with at least one vaccine antigen above the PBT as measured by the MATS assay from a normally sterile site, or Positive for meningococcal DNA and non-B serogroup specific PCR on a normally sterile site plus isolation from a throat swab of the same serogroup N. meningitidis with at least one vaccine antigen above the PBT as measured by the MATS assay, or

Positive for meningococcal DNA and non-B serogroup specific PCR on a normally sterile site and PorA P1.4 identified on genosubtyping.

Definitions - 3

Definition of a Bexsero vaccine failure

A confirmed case as defined above and …

… the confirmation that the patient was age appropriately and fully vaccinated as recommended and with 1 month delay for a full effect of the immunisation.

Clinical case of N. meningitidis

Reported to PHE MRU

Serogroup B vaccine-type

Serogroup B Non-serogroup B

vaccine-type

No N. meningitidis

confirmation

PCR only confirmed N.

meningitidis from sterile site

Culture confirmed N. meningitidis from

sterile site

MATS on throat swab

PorA P1.4 genotyping

MATS on sterile site

Case identification

Carriage studies - 1Reduction in capsular group C carriage following

introduction of meningococcal serogroup C conjugate vaccines

0

1

2

3

0

2

4

6

8

10

0

5

10

15

20

25

0

2

4

6

8

10

Meningococci(% of isolates)

1999 2000 2001

Serogroup C

Serogroup YSerogroup B

Serogroup W

-71% -81%

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

Carriage studies - 2

• A phase III study (NCT01214850) enrolled 2968 students in 10 universities across England from September-December 2010.

• Students received either one dose of a licensed quadrivalent meningococcal conjugate vaccine, Menveo® (n = 956) followed by saline placebo, or two doses of either meningococcal Bexsero® (n = 932) or Ixiaro® (n = 948).

• Oropharyngeal samples were taken before vaccination and at 5 subsequent visits over one year. 

• Primary analysis at one month after the vaccination series did not reveal significant impact of either vaccine however across the cumulative later timepoints:

Menveo was associated with a carriage-reduction efficacy of 38.0% (95% CI: 15.9 – 54.2) against serogroup Y. Bexsero was associated with a decrease in carriage of genogroup MenBCWY strains (24.2% [95% CI: 7.8 – 37.6].

Read R et al. ESPID 2013

Seroprevalence studies - 1

Ishola D, Borrow R, Findlow H, et al. Clin Vaccine Immunol 2012; 19:1126-30.

<6

mth

s

6-1

1 m

ths

1-4

yrs

5-9

yrs

10

-14

yrs

15

-19

yrs

20

-24

yrs

25

-34

yrs

35

-44

yrs

45

-54

yrs

55

-64

yrs

65

+ y

rs

0

10

20

30

40

50

60

70

80

90

100

1996-99

% w

ith S

BA

titr

e >

=8

2000-2004 2009

Proportions of sera with MenC SBA titres ≥8 by age in England & Wales, pre and post-introduction of MCC

vaccines

Seroprevalence studies - 2

0

10

20

30

40

50

60

70

80

age (years)

incid

en

ce

pe

r 1

00

,00

0 p

er

ye

ar

0%

10%

20%

30%

40%

50%

60%

% w

ith

SB

A titre

s >

=4

incidence group B per 100,000 per year

SBA>=4

Age-specific incidence of group B disease compared to the percentage of individuals with SBA ≥4 against strain

NZ98/254 (B:4:P1.7-2,4)

Trotter C, Findlow J, Balmer P, Holland A, Barchha R, Hamer N, Andrews N, Miller E, Borrow R. Clin Vaccine Immunol 2007; May 9; 14:863-8.

• For Bexsero use strains 44/76-SL (fHbp); 5/99 (NadA); NZ98/254 (PorA). • No useable strain for NHBA for seroprevalence studies though a UK NHBA MATS +ve/fHbp & NadA MATS -ve with mismatched PorA is being investigated.

Conclusions

• Approximately 50% of cases cultured confirmed thus can fully characterise utilising MATS.

•Non-culture confirmed cases:

- Nasopharyngeal isolates

- Non-culture PorA, P1.4

- non-culture fHbp but no information on expression

• Need means of quantifying expression levels direct from non-culture PCR positive samples.

• Both nasopharyngeal carriage and seroprevalence need to be monitored.