Advances towards licensure of a maternal vaccine for the prevention of invasive group B streptococcus disease in infants: a discussion of different approaches

Figures & data

Figure 1. Schematic representation of the presence of immunoglobulins in infants due to maternal vaccination. (a) Maternal IgG is selectively transported across the placenta by the neonatal Fc receptor (FcRN). (b) Maternal vaccines augment or induce maternal antibody levels to protect the infant from infectious disease in the first few months of life.

Figure 2. Global prevalence of GBS serotypes causing neonatal disease (2004–2013). (a) Distribution of serotypes by region. (b) Overall global distribution. Adapted from Buurman et al.⁴⁶

Figure 3. Serotype-specific IgG geometric mean fold rise (GMFR) from baseline at 1, 3 and 6 months following GBS6 vaccination for 120 μg (20 μg CPS/serotype/dose) dose level formulated without aluminum phosphate.

Table 1. Summary of prior seroepidemiological studies for GBS

	Serotype						Region	EOD/LOD	Healthy controls	Ref
	Ia		III		V
	Proposed protective threshold (serum source)	Cases	Proposed protective threshold (serum source)	Cases	Proposed protective threshold (serum source)	Cases
1	5 μg/mL^a (maternal) 4 μg/mL^a (cord)	50	10 μg/mL^a (maternal) 7 μg/mL^a (cord)	26	–	–	USA	EOD	Colonized infants	49, 66
2	0.5 μg/mL^a (maternal)	17	0.5 μg/mL^a (maternal)	9	0.5 μg/mL^a (maternal)	7	USA	EOD	Infants from colonized mothers	48
3	6 μg/mL^b (maternal)	27	3 μg/mL^b (maternal)	29	–	–	South Africa	EOD + LOD	Infants from colonized mothers	62
4	1 μg/mL^b (maternal)	8	1 μg/mL^b (maternal)	23	–	–	Europe	EOD	Infants from colonized mothers	64
5	2.31 μg/mL^b (maternal) 0.93 μg/mL^b (cord/infant)	19	3.41 μg/mL^b (maternal) 1.08 μg/mL^b (cord/infant)	39	–	–	South Africa	EOD + LOD	Infants from colonized mothers	67

^aInferred by conditional logistic regression analysis.

^bCalculated by Bayesian analysis.

Abbreviations: EOD, early onset disease; LOD, late onset disease; Ref, reference.

Table 2. Assay formats and reference standards that have been used to quantify anti-GBS capsule polysaccharide IgG antibodies in published seroepidemiological studies

	Assay format	Immobilized antigen	Sera	Ref
1	Monoplex direct binding ELISA	In-house preparation of type Ia CPS	Derived from an individual immunized with a 4-valent CPS vaccine (Serum 20, NABI Inc.)	49
2	Monoplex direct binding ELISA	In-house preparation of type III CPS adsorbed with methylated HSA	Derived from an individual immunized with 4-valent CPS vaccine that includes III (Serum 19, NABI Inc.)	66
3	Monoplex direct binding ELISA	In-house CPS preparation conjugated to HSA	Sera from individuals immunized with five monovalent CPS-TT conjugates (Ia, Ib, II, III, V). Calibrated by immunoprecipitation, RABA and correction with IgM/IgA concentrations by ELISA	48
4	Multiplex Luminex immunoassay	Novartis (GSK)-produced CPS, chemically coupled to microspheres	Purified pooled human gammaglobulin (South Africa) calibrated to Baker et al. reference standards	67, 71
5	Monoplex direct binding ELISA	GSK-produced CPS conjugated to HSA	Baker et al. reference standards	64

Abbreviations: CPS, capsular polysaccharide; CPS-TT, capsular polysaccharide tetanus toxoid conjugate vaccine; ELISA, enzyme-linked immunosorbent assay; GSK, GlaxoSmithKline; HSA, human serum albumin; RABA, radio-antigen binding assay; Ref, reference; TT, tetanus toxoid.

Figure 4. Overview of potential approaches to licensure of a maternal GBS6 vaccine. Effectiveness study refers to a clinical endpoint trial that is conducted under real-world settings after vaccine licensure. Disease endpoint clinical trial refers to an efficacy trial with GBS disease as the primary study endpoint. Accelerated approval is not applicable to Option 3.

Buurman ET, Timofeyeva Y, Gu J, Kim JH, Kodali S, Liu Y, Mininni T, Moghazeh S, Pavliakova D, Singer C, et al. A novel hexavalent capsular polysaccharide conjugate vaccine (GBS6) for the prevention of neonatal group B streptococcal infections by maternal immunization. J Infect Dis. 2019;220(1):105–15. doi:10.1093/infdis/jiz062.

 PubMed Web of Science ®Google Scholar

Lin FY, Philips JB 3rd, Azimi PH, Weisman LE, Clark P, Rhoads GG, Regan J, Concepcion NF, Frasch CE, Troendle J, et al. Level of maternal antibody required to protect neonates against early-onset disease caused by group B Streptococcus type Ia: a multicenter, seroepidemiology study. J Infect Dis. 2001;184(8):1022–28. doi:10.1086/323350.

 PubMed Web of Science ®Google Scholar

Lin FY, Weisman LE, Azimi PH, Philips JB 3rd, Clark P, Regan J, Rhoads GG, Frasch CE, Gray BM, Troendle J, et al. Level of maternal IgG anti–Group B streptococcus type III antibody correlated with protection of neonates against early-onset disease caused by this pathogen. J Infect Dis. 2004;190(5):928–34. doi:10.1086/422756.

 PubMed Web of Science ®Google Scholar

Baker CJ, Carey VJ, Rench MA, Edwards MS, Hillier SL, Kasper DL, Platt R. Maternal antibody at delivery protects neonates from early onset group B streptococcal disease. J Infect Dis. 2014;209(5):781–88. doi:10.1093/infdis/jit549.

 PubMed Web of Science ®Google Scholar

Dangor Z, Kwatra G, Izu A, Adrian P, Cutland CL, Velaphi S, Ballot D, Reubenson G, Zell ER, Lala SG, et al. Correlates of protection of serotype-specific capsular antibody and invasive Group B Streptococcus disease in South African infants. Vaccine. 2015;33(48):6793–99. doi:10.1016/j.vaccine.2015.10.019.

 PubMed Web of Science ®Google Scholar

Fabbrini M, Rigat F, Rinaudo CD, Passalaqua I, Khacheh S, Creti R, Baldassarri L, Carboni F, Anderloni G, Rosini R, et al. The protective value of maternal group B streptococcus antibodies: quantitative and functional analysis of naturally acquired responses to capsular polysaccharides and pilus proteins in European maternal sera. Clin Infect Dis. 2016;63(6):746–53. doi:10.1093/cid/ciw377.

 PubMed Web of Science ®Google Scholar

Madhi SA, Izu A, Kwatra G, Jones S, Dangor Z, Wadula J, Moultrie A, Adam Y, Pu W, Henry O, et al. Association of group B streptococcus (GBS) serum serotype-specific anticapsular immunoglobulin G concentration and risk reduction for invasive GBS disease in South African infants: an observational birth-cohort, matched case-control study. Clin Infect Dis. 2021;73(5):e1170–e80. doi:10.1093/cid/ciaa1873.

 PubMed Web of Science ®Google Scholar

Dangor Z, Lala SG, Cutland CL, Koen A, Jose L, Nakwa F, Ramdin T, Fredericks J, Wadula J, Madhi SA. Burden of invasive group B Streptococcus disease and early neurological sequelae in South African infants. PLoS One. 2015;10(4):e0123014. doi:10.1371/journal.pone.0123014.

 PubMed Web of Science ®Google Scholar