The prevention of life-threatening human infection through vaccination is a remarkable achievement in the history of medicine. This saga also is one that applies to the prevention of neonatal disease through active immunization of pregnant women, with tetanus as the foremost example. Working in Papua, New Guinea, Schofield et al1 in 1961 demonstrated that active immunization of pregnant women with two or three doses of tetanus toxoid prevented neonatal tetanus in their offspring. Additional studies from several developing countries have reported efficacy of tetanus toxoid immunization of pregnant women in preventing neonatal tetanus2 and led to the current World Health Organization recommendation that previously unimmunized pregnant women should routinely receive two doses of vaccine prior to delivery. While prevention of neonatal tetanus in this country has been achieved by immunization prior to pregnancy, the lessons learned from tetanus are useful in approaching the immunological prevention of other infections prevalent in young infants.
Lancefield group B streptococcus (GBS), Streptococcus agalactias, was first recognized as a human pathogen in textbooks on microbiology and pediatrics in the 1970s. For two decades, GBS has been the most frequent etiologic agent isolated from the blood or cerebrospinal fluid of neonates.' Recent age- and race-adjusted projections for the US population suggest that more than 15000 cases and 1500 deaths each year can be attributed to GBS.3 Approximately 50% of these cases occur during the first 3 months of life, and 20% occur in pregnant women. Systemic GBS infection in iniants (sepsis, pneumonia, meningitis, etc) has an estimated attack rate of 1 to 4 per 1000 live births.3,4
Two clinically and epid em io logically distinct patterns of GBS infant disease have been defined by age at onset (Table 1). The first, early-onset infection, appears during the first 6 days of life 80% to 90% in the first 24 hours), is acquired from the maternal genital tract intrapartum, can be predicted in an estimated 75% of cases by one or more maternal (actors enhancing risk (labor prior to 37 weeks gestation, rupture of membranes >18 hours, chorioamnionitis, etc) and results in a mortality rate of approximately 5% to 10%.4,5
Characteristics of Group B Streptococcal Perinatal Disease
The second, late-onset infection, appears between 7 days and 3 months of age, occurs at a rate about three times less than early-onset infection, is transmitted both vertically and horizontally (nosocomial or community), is not associated with maternal factors other than preterm delivery, and has a lower mortality rate. Infant survivors of meningitis (an estimated 10% of total cases) may be left with permanent neurologic sequelae (approximately 1300 cases annually).4 Further, pregnancy-related GBS morbidity (urinary tract infection, chorioamnionitis, postpartum endometritis, and wound infection following cesarean section) occurs in an estimated 55 000 pregnant women annually.6 These are associated with excess morbidity, including early-onset GBS in the neonate, and the need for intravenous antibiotic therapy and longer hospital stays.
The recognition of GBS as a cause of substantial numbers of serious perinatal infections led to research regarding its prevention. The two methods investigated are those that have been applied to other serious bacterial infections, namely chemoprophylaxis and immunoprophylaxis. While neither is likely to be 100% successful, immunoprophylaxis offers the greater potential in preventing maternal and infant (early- or late-onset) disease and of providing cost-effective7 and durable protection. The principle underlying this approach is that sufficient amounts of IgG antibodies with specificity for the four major GBS capsular polysaccharides (Ia, Ib, II, and III) are protective.8 Thus, immunization of women with a GBS vaccine would confer through placental transfer protective levels of antibodies in newborn infants, protecting them throughout the age-restricted period of susceptibility.9
Group B streptococci possess two distinct cell surface polysaccharides: the group B cell wallassociated antigen that is common to all strains and the serologically distinct capsular polysaccharides (Ia, Ib, II, III, IV, and V). Antibodies to the group B antigen fail to protect in animal models of lethal GBS infection,10 and the level of naturally occurring human antibody to the group B antigen correlates poorly with resistance to human infection.11 By contrast, the GBS capsular polysaccharides are important virulence factors, and antisera raised to these antigens are protective against GBS experimental infection4'10 and in human disease.8
Each of the six capsular polysaccharides has been purified and immunochemically characterized. They are composed of repeating polymers of three monosaccharides - glucose, galactose, and N-acetylgtucosamine - with one (Ia1 Ib, III, IV, and V) or two (type II) side chains with a terminal acid moiety on one chain.4 Several studies have shown that the side chain sialic acid is important in the immunospecificity of these polysaccharides and exerts conformational control over the immunodominant epitope of the type III polysaccharide.12
Because antibodies directed against the capsular polysaccharide antigens of GBS are protective, the first endeavor to produce a suitable GBS vaccine was to purify type-specific polysaccharides from the types producing the largest number of neonatal cases ( Ia, Ib, II and III) to determine their safety and antigenicity in healthy adults. This approach was explored in some detail,9 and the results are summarized in Table 2. Such polysaccharides were well tolerated when tested in healthy nonpregnant adults9 and pregnant women.13 They induce primarily IgG class and IgG1 and IgG2 subclasses of immunospecific antibody that is placentally transported in women vaccinated during pregnancy,13 and they evoke antibodies that enhance opsonization and phagocytosis of GBS by human neutrophils and that protect animals against lethal GBS challenge. However, these polysaccharide vaccines are quite variable in their ability to induce an immune response in adults (response ranges from 56% to 90% ).9'13 One reason for this poor antigenicity is that most (80% to 90%) healthy adults of childbearing age have low levels of type'Specific GBS antibodies in their sera,* suggesting lack of priming by these antigens. Such individuals are more likely to have a poor immune response to GBS polysaccharide vaccine, while those with high levels routinely develop higher levels of antibody following vaccination with GBS polysaccharides.9
Antibody Response to Group B Streptococcal Polysacchartde Vaccines In Healthy Adults*
The poor antigenicity of GBS capsular polysaccharide vaccines has led to considerable effort to develop improved vaccine candidates. One method commonly used to enhance immunogenicity of carbohydrate antigens is coupling them to a protein carrier as was done with the polyribose phosphate of Hemophilus influenzoe type b. The first group B Streptococcal conjugate vaccines were described in 1990.14,15 Both were type III polysaccharide-tetanus toxoid conju' gates and induced substantial levels of IgG-specific antibodies in animals given two or three doses of vaccine. The first used random activation of polysaccharide fragments before conjugation, while Wessels et al15 selectively activated the side chains of the linked sialic acid moieties before direct coupling by reductive amination. Approximately 25% of the sialic acid residues were reduced, leaving the antigenic properties of the type III polysaccharide intact. When tested in rabbits, this conjugate vaccine induced high levels of IgG antibodies to the type III capsule while polysaccharide alone did not elicit an immune response. Further, type III conjugate vaccine-induced antibodies provided complete protection to mice challenged with a lethal dose of type III GBS.15 Similar results have been observed with type Ia, Ib, and II GBS polysaccharide-tetanus toxoid conjugate vaccines.16,17 Phase 1 and 2 clinical studies using these candidate vaccines in healthy, nonpregnant women are underway, and hopefully the results will parallel those found in animals.
The development of suitable GBS vaccines requires precise knowledge about the distribution of GBS serotypes causing perinatal disease so that antibodies to appropriate antigens are elicited. Current informa' tion suggests that if tetanus toxoid is used as the carrier protein, a pentavalent GBS vaccine containing polysaccharides from type Ia, Ib, II, III, and V strains of GBS would be necessary to prevent >95% of disease. It is possible that an alternate carrier protein, such as the cell surface protein c that is common in the majority of GBS strains other than type III, might provide a useful monovalent vaccine if conjugated to the type III GBS polysaccharide. Both the alpha and beta components of c protein have been characterized, and antibodies against each are protective.18
A final concern for the development of GBS conjugate vaccines, once they are demonstrated to be safe and optimally antigenic in healthy adults, is their delivery to the population most likely to benefit from immunization. The strategy of targeting women for vaccination during pregnancy is practical because most seek prenatal care, have low levels of antibodies to GBS and are, with their neonates, the population at risk, and have high levels of vaccine- induced antibody that will be available for placental transport within 2 weeks of vaccination.9 This strategy would prevent both early- and late-onset infant disease as well as pregnancy- associated systemic infections. However, in this country, maternal immunization is a difficult, if not impossible, proposition no matter what the obvious benefits, primarily because of fear of litigation by manufacturers, and by obstetricians, who would administer vaccines that could be blamed, true or not, for any adverse pregnancy outcome.
Use of GBS vaccines in adolescent females is another option, one that might use the recommendation for a second dose of measles, mumps, and rubella vaccine at 12 years of age as an opportunity to provide GBS immunity. In that circumstance, vaccine -induced antibody would have to be durable, given the length of the childbearing years. A recent analysis suggests that vaccine prevention of GBS infant disease is much more cost effective than any strategy for maternal intrapartum chemoprophylaxis. Perhaps the current political climate, emphasizing the importance of infant immunization, may foster less resistance to the former strategy, namely maternal vaccination. If not, it could be well into the next century before GBS perinatal disease will be conquered by vacci' nation.
1. Schofield FD. Tucker VM, Westhnxik GR. Neonatal tetanus in New Guinea: effect of active immunization in pregnancy. Br Med J. 1961:2:785-789.
2. Rahman M. Chen LC. Yunus M, et al. Use of tetanus toxoid for rhe prevention of neonatal tetanus, 1: reduction of neonatal mortality by immuniiation of nonpregnant und pregnant women in rural Bangladesh. BuIi World Health Organ. 19B2;60:261-267.
3. Zangwil KM, Schuchat A. Wenger JD. Group B streptococcal disease in the United States, 1990: report from a multisiaie active surveillance system. MMWR. 1992:41:25-32.
4. Baker CJ, Edwards MS. Group B streptococcal injections. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. Philadelphia, Pa: WB Sounders Co. In press.
5. Schuchat A, Oxtohy M, Cochi SL, et al. Population-based risk factors for neonatal group B streptococcal disease: results of a cohott study in metropolitan Atlanta. J Infect Dis. 1990; 162:672-677.
6. Schwani B, Schuchat A, Oxtoby MJ, Cochi SL, High-tower A, Broome CV. Invasive group B streptococcal disease in adults. JAMA. 1991;266:11U-1114.
7. Mohle-Boetam JC, Schuchat A, Plikaytis BD, Smith JEJ, Brtxime CV Comparison of preventive strategies for neonatal group B streptococcal infection: a cost-effectiveness analysis. JAMA. 1993;2 70:1442- !448.
8. Baker CJ, Kasper DL. Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection. NEngiJ Med. 1976;294: 753-756.
9. Baker CJ, Kasper DL. Group B streptococcal vaccines. Beiseins m Infectious Diseases. 1985;7;458-467.
10. Lancefield RC, McCartv M, Everly WN. Multiple mouse-protective antibodies directed against group B streptococci: special reference KI antibodies effective against protein antigens. J Exp Med. 1975;142:165-179.
11. Anthony BF, Concepcion NF, Concepcion KF. Human antibody to the groupspecific polysaccharide of group B Streplococcus . J Infect Dis. 1985:151:221-216.
12. Jennings H. Further approaches for optimizing polysaccharide-protem conjugate vaccines for prevention of invasive bacterial disease. J Infect Dis. 1992;165 (suppl 1):S156-S159.
13. Baker CJ. Rench MA, Edwards MS, Carpenter R, Hays B, Kasper DL, Immunization of pregnant women with a polysaccharide vaccine of group B Streptococcus. N Engl J Med. 1988;319:1180-1185.
14. Lagergard T, Shiloach J, Robhins JB, Schneerson R. Synthesis and immunological properties of conjugates composed of group B Streptococcus type III capsular polysaccfiaride covalently bound to tetanus toxoid. Infect Immun. 1990; 58:687-694.
15. Wessels MR, Paoletti LC, Kasper DL, et al. Immunogen icity in animals of a polysaccharide-protein conjugate vaccine against type III group B Streptococcus . J Clin Invest. 1990; 86:1428-1433.
16. Paoletti LC, Wessels MR, Michon F, DiFabio J, Jennings HJ, Kasper DL. Group B Streptococcus type II polysacchaiide- tetanus toxoid conjugate vaccine. Infect Immun. 1992;60:4009-4014.
17. Wessels MR, Paoletti LC, Rodewald AK, et al. Stimulation of protective antibodies against type 1a and 1b group B streptococci by a type 1a polysacc ha ride-tetanus toxoid conjugate vaccine. Infect Immun. 1993:61:4760-4766.
18. Michel JL, Madoff LC, Kling DE, Kasper DL, Ausubel FM. Cloned alpha and beta C-proiein antigens of group B streptococci elicit protective immunity. Inject Immun. 1991;59:2023-2036.
Characteristics of Group B Streptococcal Perinatal Disease
Antibody Response to Group B Streptococcal Polysacchartde Vaccines In Healthy Adults*