group b meningococcal (menb) vaccines explained...• nz pora p1.4: porin a –major outer membrane...
TRANSCRIPT
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