Progress to reduce under five mortality rates by 2030, as part of the sustainable developmental goals, has been modest for many African countries (1), and children living in sub-Saharan Africa are ten-fold more likely to die in the first month after birth compared to high-income countries (1, 2). Many of the deaths in this age group are at and/or around birth; in 2021, of the five-million deaths in children less than 5 years of age, 46% occurred in the neonatal period (1, 2). In this neonatal period, the leading causes of death are from preterm related complications (17%), intrapartum related events (11%) and pneumonia, sepsis or meningitis (8%) (2).

In terms of specific infectious causes, Streptococcus agalactiae, commonly referred to as Group B Streptococcus (GBS), is the commonest reported cause of early-onset disease (EOD; i.e.: disease in the first 6 days after birth) in neonates (3–7). However, adverse perinatal outcomes are not limited to EOD in neonates, and late-onset disease (LOD) also occurs mostly within the neonatal period. Whilst considerable mortality is associated with EOD and LOD, survivors may also develop moderate or severe neurodevelopmental impairment (NDI) (8–10). Prior to birth, there may be miscarriages and stillbirth from invasive GBS disease in-utero (11, 12), and GBS colonisation has been associated with preterm labour (13, 14). Pregnant women may also develop GBS sepsis (15).

Worldwide, based on maternal GBS colonization, and using Bayesian modelling, there were an estimated 394,000 cases of invasive GBS disease (EOD and LOD) and 58,300 (95%CI: 26,500–125,800) deaths in early infancy (8). The majority of cases of invasive GBS disease, 231,800 (95%CI: 114,100–455,000) cases, were EOD. The burden of disease and death from GBS EOD is high in African countries, with 90,800 (95%CI: 43,000–186,600) of all EOD cases in sub-Saharan Africa (8) and the incidence of EOD almost double the worldwide estimate (16). Consequently, almost half of all early-onset GBS deaths occur in sub-Saharan Africa, where the case fatality is also high (23%, vs. 6% in developed countries) (8). Factors driving the incidence of EOD in African countries include higher prevalence of maternal GBS colonization, and limited or no intrapartum antibiotic prophylaxis (IAP). IAP is commonly given in high-income countries, based on either clinical risk-based screening or microbiological screening to prevent EOD (16, 17). It should also be noted that there are data gaps in Africa, with less than a quarter of African countries contributing data to estimates (8, 16).

The adverse consequences of EOD GBS disease in neonates are not limited to disease and death. There may also be neurodevelopmental impairment (NDI). In high-income countries, survivors of invasive GBS disease (sepsis and/or meningitis) compared to matched controls have a two-fold increased risk of moderate or severe NDI by 10 years of age (9). There is a paucity of long-term outcome data from Africa, but in a recent multi-country matched cohort study undertaken in South Africa, India, Mozambique, Kenya, and Argentina, 38% (8.8% were moderate or severe) of survivors (n = 138) of invasive GBS disease had NDI compared to 22% of non-GBS (n = 390) children (10). Specifically, survivors of GBS EOD commonly developed NDI (10, 18).

In addition to this burden, there is also a substantial burden from GBS causing stillbirth from infections in-utero, with 20,300 (95%CI: 9,000–40,500) out of 46,200 (95%CI: 20,300–111,300) GBS stillbirths in 2020 in sub-Saharan Africa (8). Furthermore, babies born with intrapartum hypoxia from invasive GBS disease may present with neonatal encephalopathy (19, 20).

Maternal GBS colonization increases the risk of preterm labour (13), although data are limited; of the 15 million preterm births that occurred globally in 2020, approximately 518,100 (95%CI: 36,900–1,142,300) were estimated to be associated with GBS, most of which were from sub-Saharan Africa (8). Prematurely born infants also have an increased risk of acquiring invasive GBS disease (21); and being premature and acquiring invasive GBS disease was independenty associated with death and NDI in survivors (18, 22–24).

The acute healthcare cost and impact on the family of a neonate having a sepsis and/or meningitis is important. In a recent study from South Africa (a third of participants had EOD), the mean household and hospital cost of having a child with culture-confirmed GBS, E-coli or Staphyloccal infection was 52 and 684 international dollars, respectively (25). Average hospitalization cost for confirmed sepsis ranged from $55 to $129 in most high-income countries (26). Extra care for a child with invasive GBS disease is also required, and if the child has NDI this will be long-term. In cases of infant deaths from GBS EOD, parents of infants experience grief and express frustrations over the death of the child, and fears of future pregnancy (27).

Streptococcus agalactiae is an encepsulated Gram positive coccus exclusively in the “B” Lancefield grouping of Streptococci. Approximately 18% (95%CI: 17–19%) of pregnant women are gastrointestinal and/ or genitourinary tract colonised with GBS globally (28); colonization rates are reported to be higher (22–25%) in Southern Africa (28–30), and approximately half of pregnant women are colonized at some point during their pregnancy (31). Of the 20 million pregnant women that had rectovaginal colonization in 2020, 6 (30%) million were living in sub-Saharan Africa (8).

There are ten GBS serotypes (Ia, Ib, II-X), serotype III being the commonest cause of invasive disease followed by Ia and V (16). Geographical differences in the prevalence of serotypes have been reported, and in Africa, serotype III is the commonest for EOD (16); most of the hypervirulent clonal complex 17 is serotype III (32).

There are several risk factors for EOD, GBS colonisation of the pregnant women is the only unequivocal risk factor (33). Other risk factors for EOD include prolonged rupture of membranes (>18 h; PROM), maternal fever during labor, premature labour, previous infant with invasive GBS disease, maternal GBS bacteriuria, chorioamnionitis, absence of screening for GBS colonisation, unavailability of intrapartum antibiotic prophylaxix (IAP), unavailability of a skilled birth attendant (8, 22, 34).

GBS colonization is usually asymptomatic, and maternal GBS colonization status is unknown to most African pregnant women as this is not routinely tested for in pregnancy. During the prenatal or perinatal period, ascending GBS into amniotic cavity can adversely affect the pregnant women resulting in chorioamnionitis or invasive maternal disease (15). For the foetus or newborn, the possible outcomes are EOD (pneumonia, sepsis, meningitis and/ or neonatal encephalopathy), stillbirth, or prematurity (11–13, 19, 20, 24) (Figure 1).

Currently, prevention of invasive GBS EOD is dependant on the availability of intravenous antibiotics that can be administered to a pregnant women at least 4 h before delivery by adequately trained health care workers (35). There are two screening approaches (microbiological or clinical risk-based) to determine which pregnant women should get IAP. Many high-income countries use the microbiological screening approach in which pregnant women have a vaginal-rectal swab in the 36 or 37th week of gestation, and are offered IAP if they are GBS colonized (36). This strategy resulted in a 80% reduction in EOD in the United States from the early 1990’s to 2010 (37). The risk-based approach targets pregnant women that have selected clinical risk factors (premature labour, PROM, maternal fever or previous child with GBS). Both strategies have limitations; microbiological screening is insensitive and colonisation status changes during pregnancy. Clinical risk factors are non-specific, and only identified with close monitoring and comprehensive assessments, otherwise sensitivity is low. Microbiological screening also requires processing of specimens, logistical support and timely feedback of results. Microbiolgical screening is likely more effective at reducing EOD than risk-based approaches (38), but implementation challenges make either strategy challenging to implement in resource limited African settings. In African countries, IAP is not provided due to an absence of microbiological screening, and (i) a large proportion of home deliveries, (ii) no intravenous treatment available at primary health care facilities where a large proportion of women deliver, (iii) inability to administer antibiotics 4 h before delivery because of late presentations to labour ward, or staff shortages that delay medical interventions, and (iv) failure to recognise pregnant women with risk factors when they are present (39). Importantly, the risk of EOD to a neonate born to GBS colonized pregnant women is 1.1% with no IAP compared to 0.3% where IAP coverage is high (34).

Point of care / real-time molecular PCR testing in labour wards with IAP to colonized women has also been associated with a reduction in EOD (40). The sensitivity and specificity of PCR testing to detect GBS colonization in pregnant women has been reported as 93 and 97%, respectively (41). The advantages of these point of care testing would be a non-reliance on laboratory service and the immendiate availability of results to the midwife / obstetrician, but this will need to be offset by the high cost of these tests.

Recent studies have investigated the role of probiotics, garlic and zinc in the prevention of GBS colization but results are inconclusive (42–44).

Maternal vaccination is now recognized as the optimal strategy to reduce disease in pregnant women, and foetus or young infant. There is considerable precedent for vaccines in pregnancy providing protection at the most critical time after birth, and WHO has recommended tetanus, pertussis, influenza and Covid-19 vaccinations during pregnancy (45). Vaccinating pregnant women against pertussis and influenza has been shown reduce disease in infants of vaccinated mothers, and has been associated with a 75% reduction in stillbirths and a 30% reduction in preterm birth (46–48). Other vaccines such as those for Cholera and Typhoid are recommended in specific situations, and a number of maternal vaccines are currently under development (45).

Vaccination of pregnant women to prevent invasive GBS disease in infancy is an important, pragmatic, future preventative strategy for Africa and other low- and middle-income countries (LMICs). The WHO has provided a comprehensive value assessment for a GBS vaccine (49–51). A GBS vaccine would also likely prevent stillbirths and LOD (51), and may reduce GBS-associated preterm birth. A maternal GBS vaccine would need to be safe, effective, affordable, and accepted by policymakers as important, with demand from pregnant women and their partners. Studies from high-income countries suggest there is likely to be demand, but studies from countries in Africa are needed; in a study from the United Kingdom, after receiving information about GBS, two thirds of women reported that they would consider taking a GBS vaccine during pregnancy, underpinning the need for interventions to support uptake (52).

In terms of health impact and cost-effectiveness, a maternal GBS vaccine with 80% efficacy could prevent, worldwide, 127,000 (uncertainty range (UR): 63,300 – 248,000) EOD cases, 87,300 (UR: 38,100 – 209,000) LOD cases, 31,100 (UR: 14,400 – 66,400) deaths, 17,900 (UR: 6,380 – 49,900) cases of moderate and severe NDI, 185,000 (UR: 13,500 – 407,000) preterm births, and 23,000 (UR: 10,000 – 56,400) stillbirths per year (53). The effect will be greatest in sub-Saharan where two-fifths of the above will be prevented by vaccinating a fifth of women (53). A GBS vaccine is likely to be cost effective in most settings, including African countries (54–56). Asssuming the cost of the vaccine was $50, $15 and $3.50 in high, upper-middle, and in low/lower-middle-income countries, respectively, a single dose of the vaccine would cost $1.7 billion but save $385 million in healthcare costs worldwide (53).

The mechanism of protection against invasive disease through maternal vaccination is from an increase in type-specific antibody levels in the vaccinated pregnant women that can be transplacentally transferred to the foetus over the weeks (most tranfer occurs in the last trimester) until delivery. The transplacental transfer of type-specific maternal IgG antibodies (IgG1 > IgG4 > IgG3 > IgG2) is an active process from the maternal to foetal circulation using the neonatal Fc receptor (FcRn) (45). Protein based vaccines induce mostly IgG1 and IgG3 responses, whereas capsular polysaccharide vaccines induce IgG2. The rate of IgG transfer is negatively affected by infections such as malaria and HIV, which are common in some areas of African countries. For a maternal GBS vaccine to be effective, the vaccine would need to be: (i) immunogenic and elicit functional responses, and (ii) administered at the appropriate gestational age for optimal concentrations of IgG to be transported across the placenta to the foetus (this is dependant on IgG subclass, transfer rate and gestational time to birth). Importantly, a vaccine to prevent invasive GBS disease can reduce the emergence of antimicrobial resistance; recent data from the US shows a low but increasing proportion of isolates with reduced beta-lactam susceptibility (57).

The burden of invasive GBS disease, the commonest cause of EOD in neonates, is high in Africa, where IAP preventative strategies are not feasible, although data gaps remain. However, after many decades of GBS vaccine development, maternal GBS vaccines are moving into late stage clinical trials. If these vaccine candidates are successful and a GBS vaccine is licensed based on a correlate of protection, studies of effectiveness will need to follow to assess the burden of GBS vaccine preventable disease. These studies should be complemented by routine clinical surveillance (97). This will require sentinel surveillance sites with standardized laboratory methods and monitoring systems to investigate neonates with signs of infection and confirmation of GBS, similar to those used in the estimation of pneumococcal and rotavirus vaccination effectiveness (98). These WHO surveillance sites were designed to measure baseline burden of disease or cost-effectiveness, estimate VE after vaccine introduction, monitor trends in serotype/ genotype distribution and serotype replacement after vaccine introduction, and detect other infectious diseases. Such sites exist in African countries, but sustainability is challenging.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

ZD wrote the first draft. AS, VB, and GK provided critical review. All authors contributed to the article and approved the submitted version.

AS is employed by the Bill and Melinda Gates Foundation.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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