Group B Meningococcal (MenB) vaccines explained

Jim ButterySAEFVIC

Monash Children’s HospitalMonash University

Key points

• Meningococci

• Why group B are harder

• Epidemiology: – When/who most need

protection

• Meningococcal immunity understanding

• 4cMenB: Bexsero– What we know

– Known unknowns

– When will we know?

Background

• Severe disease

• Uncommon disease

• Common carriage

• Group B

– Covered in non-immunogenic sugar

• All other groups ACWY

– Sugar immunogenic

– Successful vaccines

Meningococcus

How serious a disease is N meningitidis ?

Meningococcal disease has a

case fatality rate of

approximately 10%, however

more deaths are caused by

septicaemia than by meningitis

http://www.dh.sa.gov.au/pehs/Youve-got-what/specific-

conditions/meningococcal-photos.htm

4CMenB

GpB PS- polymer of sialic acid: • chemically identical to polysaccharides found in human tissues during development• (2→8)-α-Neu5Ac as a self antigen of humans• potential cause of immunopathology

Nasophayngeal colonisation

Scanning electron micrograph:

attachment of N. meningitidis

by pili to the microvilli of

noncilited cells

in the nasopharynx

Colonisation• Common• transient• Increased in adolescence• Majority- totally asymptomatic

Invasive Meningococcal Disease

Age –specific notification rates of invasive meningococcal disease, Australia 1991-1999.

Immature Immune System1

Impaired Immune System2,3

Nasopharyngeal Irritation3 Social Factors3,4

Most cases of meningococcal disease occur in previouslyhealthy persons without identified risk factors

Infants

Waning Ab

PS response

Prematurity

Asplenia

Complement deficiency

Humoral deficiency

HIV/AIDS

Smoking

Respiratory-tract

infection

Close contact - case

Crowding

Mult kissing contacts

Pubs/Discos

1. Rosenstein NE,et al. N Eng J Med. 2001;344:1378–1388; 2. Figueroa JE, et al. Clin Microbiol Rev. 1991;4:359–395; 3. Bilukha OO, et al. MMWR Recomm Rep. 2005;54:1–21; 4. Imrey PB, et al. J Clin Microbiol. 1995;33:3133–3137.

Risk factors: meningococcal disease

Meningococcal Epidemiology Victoria

Meningococcal notifications

Courtesy Lucinda Franklin/Kath Taylor, DH Victoria

Invasive meningococcal disease

MenC vaccineintroduced

Meningococcal immunity

Goldschneider et al. J. Exp. Med. 129:1307, 1969

Bactericidal activity in an Army recruit population& susceptibility to group C meningococcal disease

BOOT CAMP ENTRY

492 recruits at Fort Dix, NJ – 1968

• 438 had bactericidal antibody -

No disease

• 54 were initially lacked bactericidal

antibody– SBA: SERUM BACTERICIDAL ACTIVITY

OUTCOME: 54 WITH NO SBA

• 24 became exposed to the

group C epidemic strain

• 11 developed SBA

– No disease

• 13 failed to develop SBA

– 5/13 – group C IMD

(38.5 % attack rate)

Ref: Goldscneider et al J Exp Med 127: 1969

Disease

Bactericidalantibody

Highest incidence of meningococcal meningitisoccurs at lowest bactericidal antibody prevalence

Group B immunity

• SBA other serogroups directed against capsular PS

• ELISA developed to correlate with SBA

– All other vaccines developed using these

– NEVER LICENSED ON EFFICACY

• Can’t use PS for Gp B

• SBA against other bits…

Reverse Vaccinology Allowed the Identification of Novel MenB Antigens

Genomic-based approach to vaccine development

1. Tettelin H, et al. Science. 2000;287:1809–1815; 2. Rappuoli R. Vaccine. 2001;19:2688–2691; 3. Pizza M, et al. Science. 2000;287:1816–1820.

Complete N. meningitidis genome sequence

Bioinformatic analysis

Protein expression in E. coli

Vaccine*

Confirmation ofbactericidal activity

Final candidates selectedfor vaccine development

Confirmation of surface exposure

Protein purificationand immunization

2158

570350

2891

3

4CMenB: Bexsero™

Capsular PS: shared by allProteins: more variable between strains of Group B

Aust strains will share 0-4 of vaccine peptides

• NadA: Neisserial adhesin A Protein

–Promotes adherence to and invasion of human epithelial cells1-3

• fHBP: factor H Binding Protein

–Binds factor H, which enables bacterial survival4,5 in the blood

• NHBA: Neisseria Heparin-Binding Antigen Fusion Protein

–Binds heparin, which may increase the serum resistance of bacteria6-8

• NZ PorA P1.4: porin A

–Major outer membrane vesicle protein—induces strain-specific bactericidal response

Summary of Antigenic Components of BEXSEROImportant for meningococcal survival, function, or virulence

1. Comanducci M, et al. J Exp Med. 2002;195:1445–1454; 2. Capecchi B, et al. Mol Microbiol. 2005;55:687–698; 3. Mazzon C, et al. J Immunol. 2007;179:3904–3916; 4. Madico G, et al. J Immunol. 2006;177:501–510; 5. Schneider MC, et al. J Immunol. 2006;176:7566–7575; 6. Serruto D, et al. Proc Natl Acad Sci USA. 2010;107:3770–3775; 7. Welsch JA, et al. J Infect Dis. 2003;188:1730–1740; 8. Plested JS, et al. Clin Vaccine Immunol. 2008;15:799–804.

BEXSERO® studies: RCT

*BEXSERO was evaluated in 13 studies, including 9 randomized controlled clinical trials.

Data on file, Novartis Vaccines and Diagnostics.

Infants and children 2 months to <2 years of age

• 5850 received at least 1 dose of BEXSERO

• 3285 received booster dose in second year of life

1703 adolescents and adults ≥11 years of age

Approximately 7800 subjects (from 2 months of age) received at least 1 dose of the vaccine*

250 children 2 to 10 years of age

MATS: infant immuno & persistence

Immunogenicity varies between proteinsImmune response wanes: amount also varies

BEXSERO® Can Be Co-Administered With Other Vaccines

Vaccine Antigens

Diphtheria

Tetanus

Acellular pertussis

Inactivated poliomyelitis

Hepatitis B

Haemophilus influenzae type b

Heptavalent (7-valent) pneumococcal conjugate

Measles

Mumps

Rubella

Varicella

TGA Approved Product Information, 14 August 2013

Inconsistent results were seen across studies for responses to inactivated poliovirus type 2 and pneumococcal conjugate serotype 6B and lower antibody titers to the pertussis pertactin antigen were also noted, but these data do not suggest clinically significant interference.

Note: Bexsero has not been studied in concomitant administration with Prevenar13, Rotavirus vaccine or MenC conjugate vaccine

*No increase in the incidence or severity of the adverse reactions was seen with subsequent doses of the vaccination series.†Routine vaccines: PCV7 and DTaP-HBV-IPV/Hib; BEXSERO+Routine: N=2478; MenC+Routine: N=490; Routine: N=659.‡ Fever was categorized as severe if temperature was ≥40°C. All other reactions were categorized as severe if subject was unable to perform normal daily activities.

BEXSERO® Tolerability in Infants Solicited systemic reactions when BEXSERO is

given with routine vaccines—post–dose 1

0

20

40

60

80

100

1. Vesikari T, et al. Lancet. 2013;381:825-835; 2. Data on file, Novartis Vaccines and Diagnostics; 3. TGA Approved Product Information, 14

August 2013

Routine 2-4-6†

BEXSERO+Routine 2-4-6†

MenC+Routine 2-4-6†

Severe‡

Post–dose 1

Changed eating habits

Sleepiness Vomiting Diarrhea Irritability Unusual crying

Rash Fever ≥38.5°C

% o

f in

fan

ts

0

20

40

60

80

100

Tenderness Erythema Induration Swelling

% o

f in

fan

ts

Post–dose 1*

BEXSERO 2-4-6 + Routine 3-5-7†

Injection-site data

shown in figure

BEXSERO 2-4-6 BEXSERO

Routine 3-5-7† PCV7

Routine 3-5-7† DTaP-HBV-IPV/Hib

1. Gossger N, et al. JAMA. 2012;307:573-582; 2. Data on file, Novartis Vaccines and Diagnostics.

BEXSERO® Tolerability in InfantsSolicited local reactions when BEXSERO is

given separately from routine vaccines—post–dose 1

*No increase in the incidence or severity of the adverse reactions was seen with subsequent doses of the vaccination series;Hatched lines represent severe (erythema, swelling and induration were categorized as severe if local reaction was >50 mm). Tenderness was categorized as severe if subject cried when injected limb was moved).†Routine vaccines: PCV7 and DTaP-HBV-IPV/Hib; BEXSERO: N=626; Routine: N=613.

0

20

40

60

80

100

When Fever Occurred, it Generally Followed a Predictable Pattern, With the Majority Resolving the Day After Vaccination

BEXSERO® given with routine vaccines—post–dose 1

Post–dose 1 (2-4-6 month dosing schedule)

6 hrs 24 hrs 48 hrs 72 hrs

≥40°C

39°C–<40.0°C

38.5°C–<39°C

BEX

SER

O+R

ou

tin

e*

Men

C+R

ou

tin

e*

Ro

uti

ne*

Time

*Routine vaccines: PCV7 and DTaP-HBV-IPV/Hib; BEXSERO+Routine: N=2433–2478; MenC+Routine: N=486–490;

Routine only: N=643–659. Fever was defined as rectal temperature ≥38.5°C.

1. Vesikari T, et al. Lancet. 2013;381:825-835; 2. Data on file, Novartis Vaccines and Diagnostics; 3. TGA Approved Product Information, 14 August 2013

% o

f in

fan

ts

Inform your patients about the likelihood of fever lasting one to two days

NPP: no prophylactic paracetamol (N=182); PP: with prophylactic paracetamol (N=178-179).

Routine vaccines: PCV7 and DTaP-HBV-IPV/Hib.

Prophylactic Paracetamol at the Time of and Closely After Vaccination Reduced Fever

When BEXSERO® is given concomitantly with routine infant vaccines

0

10

20

30

40

50

NPP PP NPP PP NPP PP

% o

f su

bje

cts

6 hrs 48 hrs 72 hrs

Time

Post–dose 1

(of 2-3-4 month dosing schedule)

≥40°C

39°C–<40.0°C

38.5°C–<39°C

1. Prymula R, et al. Presented at: 29th Annual Meeting of the European Society for Paediatric Infectious Disease

(ESPID); June 7-10, 2011; The Hague, The Netherlands. Poster #631; 2. Data on file, Novartis Vaccines and Diagnostics;

3. TGA Approved Product Information, 14 August 2013

Advise your patients that the prophylactic administration of paracetamol at the time and closely after vaccination can reduce the incidence and intensity of post-

vaccination febrile reactions

Prophylactic Paracetamol Did Not Impact Immunogenicityof Routine Vaccines

Predicted Coverage of MenB Strains Indicates BEXSERO® Has the Potential to Impact MenB Disease

Canada: Bettinger J, et al. Presented at: 5th Vaccine & ISV Annual Global Congress; October 2-4, 2011; Seattle, WA; US: Kim E, et al. Presented at: 19th IPNC. September 9-14, 2012.

Würzburg, Germany. Poster P270; Brazil: Lemos AP, et al. Presented at: 19th IPNC. September 9-14, 2012. Würzburg, Germany. Poster P272; Europe: Vogel U, et al. Lancet Infect Dis. 2013;13:416-425; Greece: Data on file, Novartis Vaccines and Diagnostics; Australia: Nissen M, et al. Presented at: 19th IPNC. September 9-14, 2012. Würzburg, Germany. Poster P269.

85%

73%82%

85%87%

85%

82%

87%

85%

73%

69%88%

74%

76%

66%

91%

81%

http://www.immunise.health.gov.au/

In March 2014, the Department of Health’s Technical Advisory Group on Immunisation issued

‘Advice for immunisation providers regarding the use of Bexsero® ‘

http://www.immunise.health.gov.au/

Recommendations

Based on their higher disease risk, 4CMenB is recommended for:

Infants and young children, particularly those aged <24 months

Adolescents aged 15 to 19 years

Children and adults with medical conditions that place them at a high risk of IMD, such as functional or anatomical asplenia or complement component disorders (see Chapter 4.10 of The Australian Immunisation Handbook, 10th edition1)

Laboratory personnel who frequently handle Neisseria meningitidis.

4CMenB is also recommended for all children and young adults who wish to reduce their risk of MenB IMD.

DOH - Australian Technical Advisory Group on Immunisation (ATAGI) - Advice

http://www.immunise.health.gov.au/

Age at commencement of

vaccine course

Primary immunisation

Interval between primary doses

Age for booster dose

2 months* 3 doses, delivered at ~2*, 4 and 6 months of age;

(intervals ~2 months, at least 1 month)12 months

3 to 5 months 3 doses 1–2 months 12 months

6 to 11 months 2 doses 2 months12 months, or 2 months after

previous dose, whichever is later

12 months to 10 years

2 doses 2 months No booster required†

11 years and above‡ 2 doses 1–2 months No booster required†

* 4CMenB is registered for use in persons ≥2 months of age; however, the 1st dose of 4CMenB may be administered as early as

6 weeks of age to align with the NIP infant schedule.

† The need for a booster dose for this age group is as yet uncertain.

‡ There are currently no data on the use of 4CMenB in individuals aged over 50 years, however, based on first principles, ATAGI

recommends that 4CMenB can be used in older persons who are at high risk of IMD.

Table 1. Recommended schedule of 4CMenB by age group

MATS: adolescent immuno & persistence

• Will it work?– Modified serology says yes– But untested given not directed against PS

• Will it provide herd immunity?– 12.6% (−15.9%, 34.1%) reduction in NP carriage

• Will protection last?• Will there be “escape strains”?• Will it increase fever/ febrile convulsions?• Will Australians follow paracetamol advice

– Will that change febrile seizure risk anyway?

• How will we register adolescent doses?

Known unknowns

BEXSERO Approvals and Recommendations

Approved for use in >30 countries

Clinical Recommendation

Approval (No recommendation as of Oct 2014)

Reimbursement (National)

Reimbursement (Regional)

Outbreak Use (Regional)

35APPROVALS

12RECOMMENDATIONS

CAN

AUS

IRL

USA

CHL

UK

ESP

FRA

POR

GER POL

CZE

AUT

SVK

ITA

ROM

HUN

BUL

GRE

SVNCRO

LTU

LVA

EST

DNK

FIN

SWE

NOR

BEL

NED

LUX

LIE

CYP

ISL

MLT

URU

Bexsero Regional Program in QuébecPost-marketing studies started with launch on 5 May 2014

Saguenay – Lac St. Jean region

• Programme:

– all persons aged 2months to <20 years of age

– Between May 5 and June 17, 43,740 persons received their first dose of Bexsero

• Safety study:

– Online safety survey of 12,332 vaccinees

– Diary cards to assess fever, paracetamol use, school absenteeism, etc.

– Within 8 days and 6 months after vaccination

– Antipyretic use high (93% in persons 2years age and under)

– No signal of concern to date

• Effectiveness study, incl. vaccine registry:

– Routine surveillance monitors for potential vaccine

Antipyretic prophylaxis significantly reduced the risk of fever in infants and children aged under 5 years

Proportion of vaccinees who reported fever on days 1 and 2by age and number of antipyretic prophylaxis doses

• In children under the age of 2 years, administration of 2 or more doses of antipyretic reduced thelikelihood of fever by approximately 50% within the first 48 hours.

• There was a greater reduction in the risk of fever with a higher number of doses of antipyreticprophylaxis.

• Antipyretic prophylaxis significantly reduced the risk of fever in the children aged 2-4 years, andto a lesser extent in the children aged 5-11 years.

• The prophylactic effect was more pronounced in those who had co-administration of othervaccines than in those who received 4CMenB alone.

35%

0 dose30%

1 dose25%

20% 2 or more doses

15%

10%

5%

0%

2-11 months

12-23 months

2-4 years

5-11 years

12-16 years

>=17 years

Initial Dose of a Multicomponent Serogroup B Meningococcal Vaccine in the Saguenay-Lac-Saint-Jean Region, Quebec, Canada: An InterimSafety Surveillance Report. http://www.inspq.qc.ca/pdf/publications/1902_SerogroupB_Meningococcal_Vaccine.pdf

Thank you

Acknowledgements: Victor Carey- several slidesLucinda Franklin- DH Vict