Meningococcal Group B Vaccine For The Prevention Of Invasive Meningococcal Disease Caused By Neisseria meningitidis Serogroup B

Figures & data

Table 1 Main Characteristics Of Available MenB Vaccines:^27,131 4cmenb And rLP2086

	4CMenB Vaccine	rLP2086 Vaccine
Age	From 6 to 8 weeks	From 10 years
Posology	Infants: 3+1/2+1 (from 3 months) From 2 to 10 years: 2 doses From 10 years: 2 doses (Separated 1 month)	Infants: Not authorized for use From 2 to 10 years: Not authorized From 10 years: 2 doses (0–6 months) or 3 doses (0–1/2–6 months)
Cross-protection	In vitro: The genes encoding for the antigens fHbp, NHBA, and NadA can be present and expressed in other serogroups, suggesting a potential impact of MenB vaccines against non-B strains Clinical: Neisseria gonorrhea	In vitro: The genes encoding for fHbp antigen can be present and expressed in other serogroups, suggesting a potential impact of MenB vaccines against non-B strains Clinical: unknown
Number of components/antigens	4 different components/antigens Recombinant fusion protein comprised NHBA (peptide 2) and accessory protein 953 derived from N. meningitidis strains NZ98/254 and 2996, respectively Recombinant N. meningitidis group B NadA protein (fragment of the full-length protein derived from N. meningitidis strain 2996 (peptide 8 variant 2/3)) Recombinant fusion protein comprised fHbp (variant 1.1) and the accessory protein 936 derived from N. meningitidis strains MC58 and 2996, respectively Outer membrane vesicle N. meningitidis group B NZ98/254 (B:4:P1.7–2,4) (expressing outer membrane protein PorA serosubtype P1.4)	2 components, variants of 1 single antigen Recombinant fHBP subfamily A (A05) Recombinant fHBP subfamily B (B01)
Nasopharyngeal impact	± Preliminary data	No data available
Duration of protection	Immune persistence data 7,5 years^Citation79	Immune persistence data – 4−5 years^Citation109
Special groups	Complement deficiencies, asplenia, splenic dysfunction, and those receiving eculizumab	No data available
Effectiveness	UK data (2+1) – after 2 doses: 83% against all strains, 94% against vaccine strains – after Booster: 82% (−81–97%) Canada data (Quebec) 2 months-20 years– 78% reduction	No data available
Strain coverage prediction	MATS assess if strain expressed antigens are recognized by the vaccine induced antibodies (basing on the variant and quantity of expressed antigen), 70% – UK strains 78% – EU strains 91% – US strains	MEASURE assess level of expressed antigen regardless of if the antigen is or not recognized by the vaccine induced antibodies (in 2.150 strains from EU, US, and Canada, 91% of the strains expressed sufficient levels of fHbp susceptible to bactericidal activity by vaccine antibodies)
Bactericidal activity	Serum bactericidal antibodies were measured with hSBA assays using 3 strains selected to measure responses to fHbp, NadA, or PorA. Proportion of subjects who achieved a 4-fold or greater increase in hSBA titer for each of the 3 strains was 88% against representative strains in the UK (higher estimation than with MATS)	The vaccine was then tested for hSBA against the representative strains of different fHbp type, (PMB3302 (A04), PMB1256 (B03), PMB2001 (A56), PMB2707 (B44), PMB1321 (A22), and PMB2948 (B24). Proportion of subjects who achieved hSBA titers >1:8–16 (depending on the strain) was 80% against different representative strains
Antigenic expression	% invasive strains expressing each vaccine antigen at levels that predict bactericidal activity 63.2% – fHbp variant 1 59.3% – NHBA 1.5% – NadA 20.2% – PorA P1.4.	>96% of the MenB strains in Europe express fHbp A o B (2 variants A 30% and B 70%)
Presence of the gene	>99% of the invasive strains of Men B contains genes from at least 1 component of 4CMenB	>99% of the invasive strains of Men B contains genes from at least 1 component of rLP2806

Table 2 Protein Targets Of Currently Licensed Vaccines

Protein Name	Class 1 Outer Membrane Protein	Factor H-binding Protein	Neisseria Adhesin A	Neisseria Heparin Binding Antigen
Gene Name	PorA	fHbp	NadA	NHBA
GNA Code	–	GNA1870	GNA1994	GNA2132
Gene-Protein Acc code (PubMed)	Q9JPT2	C6KHT4	A0ELI2	A0A024A437
Function	Ion membrane channel. Main antigen in the outer membrane^Citation48,Citation51	Downregulation of complement cascade by recruitment of factor H^Citation24,Citation48,Citation51	Bacterial adhesion and penetration into epithelium^Citation52,Citation55,Citation132	Bacterial adhesion Binds to human heparin (resistance to antibodies)^Citation52,Citation132^–^Citation134
Diversity (sub-classifications)	High diversity (VR1 and VR2 regions extremely variable)	Two main groups (fHbp A and fHbpB)^Citation24,Citation48,Citation51	Genetically diverse with high antigenic diversity^Citation135,Citation136	Genetically diverse with high antigenic diversity^Citation137
Immunogenicity and Antibody activity	Highly immunogenic^Citation48 Limited cross-reactivity^Citation138	Immunogenic and has cross-reactivity but with autoantibodies (IgM) to factor H (clinical significance unknown)^Citation68,Citation139,Citation140	Immunogenic but and antibodies can be crossreactive, though not consistently expressed in many circulating strains^Citation135	Immunogenic but has contrasting evidence on bactericidal action of the antibody^Citation48,Citation134,Citation141
Others	Determines the serosubtype of Neisseria meningitides	Rare meningococcal strains were discovered to have no fHbp expression (Immune pressure selection)^Citation137,Citation142	Bactericidal activity of antibodies against NadA dependent on antigen expression rather than diversity^Citation135,Citation136	–
rLP2086 antigen	No	Yes*	No	No
4CMenB antigen^Citation143	Yes	Yes	Yes	Yes

Notes: *RLP2086 final formulation includes two peptide variants, one of each family (A and B).

Table 3 Key Clinical Trials On 4cmenb Vaccine

	Findlow 2010^Citation28 (UK)	Snape 2010^Citation73 (UK)	Kimura 2011^Citation69 (Italy And Germany)	Gossger 2012^Citation30 (Belgium, United Kingdom, Czech Republic, Germany, Italy, And Spain)	Vesikari 2013^Citation71 (Finland, Czech Republic, Germany, Austria And Italy)
Study Characteristics
Study Design	Phase II	Phase II	Phase II	Phase II2B	Phase III
Study subjects and age	Infants (2 months)	Infants (6–8 months)	Adults (18–50 years)	Infants (2 months)	Infants (2 months)
Schedule (3 dose regimen)	2, 4, 6, and 12 months of age	Day 0, day 60, and 12 months of age	Day 0, day 60, and 4 months	2, 4, and 6 months of age	2, 4, 6, and 12 months of age
Sample size (total)	147	60	54	1885	3630
(II) Immunogenicity endpoints (strain-specific)*
Proportion of patients with hSBA titers >1:4
44/76-SL NZ98/254 5/99 M01 240101 M00 242922 M01 240364 M01 24035	87% (34/39) 85% (34/40) 61% (35/57) 47% (18/38) 63% (24/38) 12% (4/33) – (0/32)	100% (24/24) 100% (24/24) 96% (23/24) 100% (22/22) 70% (16/23) 100% (2/2) 90% (18/20)	97% (38/39) 100% (39/39) 92% (36/39)	99% (521/525)** 79% (417/528)** 99% (517/520)**	100% (1181/1181) 100% (1184/1184) 84% (992/1183)
(H) Geometric mean titers
44/76-SL NZ98/254 5/99	30.0 (19.0–46.0) 126.0 (77.0–205.0) 19.0 (11.0–33.0)	189 (136–263) 906 (700–1172) 44 (32–62)	95 (68–131) 269 (205–354) 30 (18–50)	83 (77–90) 12 (10–13) 520 (475–570)	91 (88–95) 634 (606–664) 13–15)
(III) Safety Endpoints
Serious AEs (total)	18% (9/50)	3% (1/30)	– (0/50)	10% (63/625)	8% (210/2480)
AEs (total)	100% (50/50)	100% (30/30)	100% (50/50)	99% (620/625)	99% (2469/2480)
Pyrexia Tenderness Erythema Swelling	23% (11/48) 75% (36/48) 98% (47/48) 75% (36/48)	10% (6/30) 60% (18/30) 93% (28/30) 67% (20/30)	– (0/50) 100% (50/50) 56% (28/50)-	83% (514/624) 85% (529/624) 86% (535/625) 53% (328/625)	78% (1945/2480) 89% (2200/2480) 87% (2166/2480) 54% (1342/2480)

Notes: *Immunogenicity taken 1 month after 3rd dose, adverse events taken after 1 month of the 3rd dose; **Titers >1:5; ***No disaggregated data available.

Table 4 Key Clinical Trials On rLP2086 Vaccine

	Richmond 2012^Citation72 (Australia, Poland And Spain)	Nissen 2013^Citation31 (Australia)	Marshall 2013^Citation32 (Australia)	Vesikari 2016^Citation33 (Czech Republic, Denmark, Finland, Germany, Poland, Spain, Sweden)
Study characteristics
Study Design	Phase II	Phase II	Phase II	Phase III
Study subjects and age	Adolescents 11–18 years	Children 8–14 years	Adults 18–40 years	Adolescents 11–19 years
Dosing schedule	0, 2, and 6 months	0, 1, and 6 months	0, 1, and 6 months	0, 1, and 6 months	0, 2, and 6 months
Sample size (total)	538	127	55	426	414
(II) Immunogenicity endpoints based on strain (variant of fHBP)
Proportion of patients with hSBA titers 1:16
PMB2001 (A56) PMB80 (A22) PMB2707 (B44) PMB2948 (B24)	95% (20/21) – 76% (16/21) –	**	**	88% (289/329) 62% (207/332) 30% (101/333) 45% (148/328)	98% (332/339) 88% (303/344) 59% (194/331) 64% (214/337)
(E) Geometric mean titers
PMB2001 (A56) PMB80 (A22) PMB2707 (B44) PMB2948 (B24)	**	**	**	152.9 55.1 40.3 29.1	159.6 56.3 35.0 25.6
(III) Safety endpoints
Serious AE	5% (1/22)	7% (3/45)	**	3% (12/426)	3% (14/414)
AEs	8% (18/22)	9% (42/45)	–	27% (113/426)	28% (115/414)
Pyrexia Tenderness	– –	7% (3/45) –	– –	1% (7/426) 1% (6/426)	<1% (3/414) <1% (4/414)

Notes: *Dosage at 60 ug per antigen, immunogenicity taken at 1 month after 3rd dose, adverse events until 30 days from 3rd dose; **No disaggregated data available.

Table 5 Real-World Data Of MenB Vaccination In Different Countries

	US	UK	Canada	Spain
Immunization Program
Program	Campaign	Routine	Campaign	Recommended by the Spanish Pediatric Association
Area	Select colleges and universities	Nationwide	One region	Nationwide (private setting)
Eligible population	Adolescents (16–18 years)	Infant (2 months to 18 months)	Infants (2 months to 18 months) Children and Adolescents (>1 year to 20 years)	Infants, children, and adolescents (2 months to20 years)
Vaccine	rLP2086 or 4CMenB	4CMenB	4CMenB	4CMen B
Vaccine schedule	3 doses (rLP2086) 2 doses^Citation144	3 doses (2 months4 months12 months)	4 doses (2 months–4 months–6 months–12 months) 2 doses (2 months apart)	4 doses (2 months–4 months–6 months–12 to 15 months)
Immunization coverage (a) Dose 1 (b) Dose 2	~60% No data	95.5% 88.6%	83% 77%	(a) - (b) 33.5% (estimated average for at least 2 doses before 2 years of age)
Vaccine Effects and Safety
Effectiveness	—	VE 82·9% (95% CI 24.1 to 95.2)	VE 79% (95% CI: −231% to 99%)	—
Impact	Asymptomatic carriage remained stable across immunization campaign(20–24%)	50% incidence rate reduction (from pre-vaccine period)	For vaccine target: 96% incidence reduction (from baseline) decline from 11.4 to 0.4 cases/100,000 For non-vaccine target, 56% decline 1.1 to 0.5 case/100,000	Reduction of 41.7% for 0–5 months and 65.4% for 6–11 months compared to baseline (year before availability of 4CmenB in Spain)
Safety	—	Local reaction 41% Fever 40%	Absenteeism 6.2% Medical consultation 9.2%	—
Comments	Low coverage from lack of information Poor immunization program in adolescents Low incidence of IMD precluding efficacy assessment	Two dose priming is cost-effective Effectiveness seen within 10 mos of routine implementation	Large-scale population-based safety monitoring reveals acceptable safety profile	Vaccine was given in private market.
Sources	McNamara JID 2017^Citation114 Soeters CID 2017^Citation116 Fisher J Adol Health 2018^Citation145	Bryan Lancet Child Adolesc Health 2018^Citation104 Parikh Lancet 2016^Citation101	Serres INSPQ^Citation105 Serres Vaccine 2018^Citation103 De Wals CID 2017^Citation102 INSPQ^Citation125	RENAVE 2017–2018,^Citation126,Citation130 Moreno-Perez, 2015^Citation127 Abad 2012^Citation146 GTV 2019^Citation129

Note: *Impact through a cost-effectiveness assessment modeling.

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