A Time to Save

A Time to Save Abstract Group B Streptococcus (GBS), characterized by Lancefield in 1933, was not recognized as a human pathogen until the early 1970s when it emerged and replaced Escherichia coli as the most common cause of sepsis and meningitis among neonates and young infants. This article briefly gives a personnel account of the discovery of clinical syndromes of GBS distinguished by age at onset, vertical mode of transmission for early-onset disease, meningeal tropism for GBS capsular (CPS) type III strains, and protective CPS epitopes. It also reviews the difficult evolution of the now routine program for antenatal GBS culture screening and intrapartum antibiotic prophylaxis, development of the first GBS candidate vaccines, clinical trials documenting the immunogenicity and safety of CPS tetanus toxoid conjugate vaccines, ongoing need to prevent morbidity and mortality in neonates and young infants, and critical need for commercial vaccines for routine use in pregnant women. It is a great honor to provide a lecture that bears the name of a giant in vaccinology, Stanley A. Plotkin. I am certain that Dr. Plotkin does not know that my journey in this field is related to one of his seminal contributions to science, namely rubella vaccine. After my first year of medical school, a summer job found me surrounded by dozens of babies with congenital rubella syndrome. Thanks to Dr. Plotkin and others, this devastating congenital infection has been eliminated from our country. However, although the horrors cast upon these babies and the tears in their mothers eyes are a lasting memory, this historical tie with infectious disease and vaccinology was not what launched me towards my ultimate professional goal—that came later. With the patience of both Dr. Plotkin and the audience, this lecture will tell a story of my long journey, one that continues, because the destination remains elusive. I have been told that the title of my lecture is vague. This was my intent. It is meant to introduce an enemy, one that continues to rob our babies of life and rob its survivors of normal function. This foe is what used to be a new and emerging infection, but now it is an old but still devastating pathogen, Streptococcus agalactiae or Lancefield’s group B Streptococcus (GSB). Time always has been my enemy. This is irrational—time is neutral. From childhood, I was always hurrying, trying to be faster and get more than others. Time continues to a problem because my decades-old dream of preventing invasive GBS early- and late-onset infant infections remains unrealized. A TIME TO DISCOVER During the first month of my pediatric residency, I was assigned to the nurseries of a Houston hospital that was delivering approximately 14 000 newborns annually. I worked long hours, moving into the call room for 3 weeks when the supervising neonatologist went on vacation to South Africa. I noted that many, mostly term neonates, critically ill either at birth or presenting with sudden onset of apnea within the first day or 2 of life, had a Gram-positive β-hemolytic organism isolated from their blood cultures. I was curious because dogma was that the major cause of neonatal bacterial infections was Gram-negative bacteria, in particular Escherichia coli. I mentioned this to the neonatologist upon his return and on later rotations to faculty on the pediatric wards where older quite ill infants were being hospitalized with sepsis and often with meningitis due to the same Gram-positive organism. My observation was discounted perhaps because we were so busy just trying to keep children alive. Not getting an explanation spurred my signature response—you must be wrong about a new and important cause of young infant sepsis and I’ll just have to show you. Oddly, these infections did not seem to occur once an infant attained the age of 3 months, so I collected just the meningitis cases, thinking that surely meningitis, a severe manifestation of this new infection in neonates and young infants, would attract some attention. Upon beginning a fellowship in Infectious Diseases, I asked the division chief, “Can I continue the work on this new β-hemolytic organism?” The answer was clear—“We already have an assigned project for you” (aka, “no”). Being prudent, I worked on my more interesting project on nights and weekends when I was not on call. A TIME TO DEFY Initial obedience to work on my assigned fellowship research project was secretly associated with ongoing investigation. I wrote a letter to Dr. Rebecca Lancefield (she refused to be addressed as other than “Mrs. L” when I subsequently met her) hoping that she was still working since she started her postdoctoral studies with Oswald Avery at Rockefeller University in 1918. I suspected that the Gram-positive organism was Lancefield’s GBS, an established bovine but almost unheard of human pathogen. Lancefield wrote back and asked whether I had any of the strains—yes, of course. I had 13 cerebrospinal fluid isolates on taped closed blood agar plates in my apartment. I mailed these to her; 12 of the 13 were capsular (CPS) type III! She had only 1 type III GBS strain in her entire collection that began in the 1930s so she was amazed and excited. She invited me to the Rockefeller. My Houston chief, upon seeing the handwritten letter from Lancefield, finally agreed to my change in focus. With a small travel grant, I set off, armed with an undergraduate degree in English literature and virtually no training in “real” science, but I was fueled by Lancefield’s excitement and encouragement as well as my own unconcealed enthusiasm. I learned so much in 6 weeks, but most of all, I learned to dream the seemingly impossible. Could I find a way to prevent these infections? Meanwhile, I published the meningitis cases, coined the terms “early and late-onset” GBS infections in neonates (bimodal age at onset) [1], and returned to Houston. I prepared reagents, defined the capsular types of GBS causing colonization in pregnant women, and determined the mode of transmission of early-onset disease (EOD). I then noted the discrepancy between the relatively high prevalence of genital GBS colonization in pregnant women (approximately 25%) and the low attack rate for disease among exposed neonates (approximately 1%–2%) [2]. Group B Streptococcus gradually became accepted as an important pathogen in neonates and young infants, adding to rather than replacing the predominance of E coli, and thereby increasing the number of neonatal sepsis cases. I also discovered the importance of type III as a cause of meningeal invasion, whether disease onset was early or late [3]. I had begun on a treacherous uphill hiking trail but had finally moved to a wide, smooth, paved road. The highway would be taken by others because I thought that answers to my remaining questions required years more of training, and it was time to get a job. A TIME TO TEAR DOWN DOGMA Having no credentials other than as an Infectious Diseases (ID) clinician, I applied for a second fellowship in internal medicine infectious diseases where I would work with Maxwell Finland at Harvard to learn what we now call hospital epidemiology and infection control. After an accidental meeting with a bacterial “capsule” man, Dennis Kasper (an internal medicine trained ID fellow) and me (a pediatric trained now medicine ID fellow) had a chance to find the “real” type III GBS capsule, not one ravaged by Lancefield’s hot acid extraction method. I met with Dr. Finland, and he astonished me by his support for my plan to abandon hospital epidemiologist training so I could chemically characterize the most destructive GBS, namely capsular type III. I called Mrs. L—she basically said “you are probably right about that acid extraction destroys an extra piece of the CPS”, and I was granted permission to tear down her dogma, a challenge that required my learning immunochemistry. I gently provoked whole GBS to release their capsules so I could characterize the type III CPS chemical structure and define the “native” CPS with its acid labile, terminal sialic acid component [4]. This discovery allowed me to develop an assay to measure antibodies to its native (and hopefully protective) epitope. I compared serum samples from women colonized with type III GBS at delivery whose newborns remained healthy to samples from women who developed type III GBS early- or late-onset disease. The result was that if a mother had sufficient antibody to the III capsule, disease was averted [5, 6]. I asked myself, could that “native” CPS be used as a polysaccharide vaccine (like the pneumococcal polysaccharide that was given to older adults) and be given to pregnant women stop this baby killer? Aside from my failure to comprehend how absurd my idea of giving a vaccine to pregnant women was in the 1970s, an era in which no vaccines were recommended for use during pregnancy, I now knew why so many infants were exposed to GBS at delivery and so few became ill. Fortunately, 4 decades later, we do have recommendations for routine use of 2 vaccines in every pregnancy, inactivated influenza and tetanus and diphtheria toxoid-acellular pertussis (Tdap). Nevertheless, my story continues into the late 1970s. A TIME TO DREAM Undaunted by the hurdles to pursing maternal immunization as a prevention strategy, I published additional data proving that the native type III capsule contained the protective epitope on its surface, and Kasper and I moved on to characterizing CPSs of other prevalent GBS disease serotypes (each had an acid labile, sialic acid component) and testing these as potential vaccines in healthy adults [7]. We assumed that our GBS polysaccharide vaccines given to young healthy adults would be immunogenic and functional based on the then contemporary analogy with the efficacy of 14-valent pneumococcal polysaccharide vaccine in South African gold miners [8]. A good lesson resulted—assumptions often are wrong and can be substitutes for careful thinking. More than 85% of pregnant women had very low concentrations of antibodies to type Ia, II, and III GBS polysaccharides in their sera, indicating that this population had never encountered these antigens and were not “primed” for an anamnestic response [9]. We needed a new approach, CPS-protein conjugate vaccines that could provide the needed T-cell help. Awaiting design and preparation of these vaccines by the Kasper laboratory (and funding for clinical trials), I continued to care for a seemingly unending number of neonates and infants with early- and late-onset disease, trying to comfort their parents that someday we might be able to prevent this suffering. Even though the 25%–50% mortality of the 1970s diminished with recognition of maternal risk factors for EOD, prompt diagnostic evaluations followed by prompt initiation of empirical antibiotic therapy and improvements in intensive care, I felt a sense of urgency, driven hard by my hard-wired impatience. With the publication in the mid-1980s of 2 randomized, controlled trials demonstrating that EOD GBS could be prevented by administration of intravenous intrapartum penicillin or ampicillin prophylaxis (IAP) [10, 11], I anticipated adoption of national recommendations where women carrying GBS would be identified and given prophylaxis as “best practice”, but nothing happened. Why not? Obstetricians also had begun to notice that GBS caused some cases of chorioamnionitis, postpartum endometritis, bacteremia, and, rarely, septic shock. A TIME FOR DIPLOMACY I approached George Peter, at the time editor of the American Academy of Pediatrics (AAP) Red Book, and Caroline Hall, chair of AAP’s Committee on Infectious Diseases, and they “hired me” to write a policy statement on this topic. This was to be done in collaboration the American College of Obstetricians and Gynecologists (ACOG). Numerous meetings with ACOG’s Maternal Fetal Medicine Committee and more than a year was required to reach consensus, the AAP statement was published in Pediatrics in November 1992 [12]. Surprisingly, in January 1993 the ACOG Newsletter masthead read, “GBS screening not recommended” [13]. I was more than discouraged until a young epidemic intelligence service (EIS) officer from the Centers for Disease Control and Prevention (CDC), Dr. Anne Schuchat, approached me more than a year later and informed me that GBS was a public health problem. I was thrilled to have a partner and someone else who could share the burden. More diplomacy ensued, slowly bringing ACOG back and several more “stakeholders” to the table at the invitation of the CDC. I was there, the only person not representing an organization and the one ironically chosen to crayon proposals on the overhead projector. Finally, in 1996, consensus guidelines for the prevention of early-onset GBS infections (imperfect but representing considerable progress) were published. Unfortunately, they allowed a choice for a strategy based on maternal risk or antenatal culture [14]. These were imperfect because the published contemporary literature indicated that approximately 50% of EOD cases arose from women with no identifiable risk factors during labor except GBS colonization. By the way, the EIS officer with the vision to prevent GBS disease is now deputy director of the CDC. Subsequent CDC evidence comparing the 2 prevention approaches proved the substantially greater effectiveness of prophylaxis using culture-based rather than the risk-based screening. In 2002, culture-based antenatal screening for GBS became the standard of obstetrical care in the United States [15, 16]. However, this was noted as an interim prevention strategy because immunoprophylaxis (a vaccine for pregnant women) was theoretically deemed to be more effective, cost-saving, and safe [17]. Prevention of early-onset GBS disease by IAP is now nearly 30 years old with a remarkable more than 80% reduction in EOD (Figure 1). However, it is concerning that IAP intervention has reached a plateau for the past 8 years, has had no impact on late-onset disease, and is based on the assumption that β-lactam resistance among GBS will not occur [18]. We used to think the same thing about the pneumococcus and penicillin resistance. Figure 1. View largeDownload slide Data for incidence of early-onset Group B Streptococcus (GBS) disease by year interval from the Centers for Disease Control and Prevention (CDC) Active Bacterial Core network. AAP, American Academy of Pediatrics. Adapted from: Verani JR, et al. Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep2010; 59(RR-10):1–36. Figure 1. View largeDownload slide Data for incidence of early-onset Group B Streptococcus (GBS) disease by year interval from the Centers for Disease Control and Prevention (CDC) Active Bacterial Core network. AAP, American Academy of Pediatrics. Adapted from: Verani JR, et al. Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep2010; 59(RR-10):1–36. TIME TO SHOW PHARMA Leaving IAP and surveillance to the CDC, the National Institute of Allergy and Infectious Diseases, based on the assumption that if they provided contract funding, and that if I performed GBS conjugate vaccine phase 1 and 2 clinical trials in childbearing age healthy women, Pharma would be convinced that development of a GBS would be worthwhile. It was a lot more work, work away from the bench. These trials spanned a decade and were followed by a small randomized, placebo-controlled trial in pregnant women using III-TT CPS monovalent conjugate vaccine. The result in pregnant women was a 4-fold or greater rise in CPS-specific immunoglobulin (Ig)G in 95% of women, vaccine-induced IgG transport to their neonates, and persistence of moderate levels of III CPS-specific maternal antibodies at age 2 months that promoted opsonization, phagocytosis, and killing using the individual infant’s endogenous complement [19]. Still nothing came from Pharma but questions. What about liability if a vaccine was associated with adverse outcomes with either the pregnancy or the neonates? If a vaccine was developed, would it be recommended for use in pregnant women? Were the findings from the 1970s concerning low levels of maternal CPS-specific antibodies at delivery being associated with GBS infant disease still true? A TIME TO CONFIRM SOMETHING AGAIN This last question prompted a 3:1 matched case control-study confirming that biology had not changed, and at least for the most prevalent GBS CPS types, namely Ia and III, with a trend for V, women with moderate to high concentrations of CPS-specific IgG in their sera at delivery did not have babies with early-onset GBS disease [20]. In addition, the maternal delivery serum concentrations that result in at least a 90% risk reduction in EOD are easily achievable by the Ia, III, and V candidate vaccines we evaluated. Similar data have been published by several other groups of investigators, including those from South Africa where GBS EOD incidence is at least 3 per 1000 live births [21–23]. Not surprising to me at least, GBS also accounts for an estimated 2%–4% of 3rd trimester stillbirths in Soweto, South Africa. A TIME TO SAVE So where are we? Group B Streptococcus is still happening in the United States and is finally recognized as a major killer in the first months of life in low- and middle-income countries throughout the globe [24]. It is now also the most frequent cause of bacterial meningitis in the US pediatric population [25]. All of these numbers cause me to remember what was said by a former US Surgeon General, Julius Richmond, MD.: “Statistics are people with tears wiped dry”. Group B Streptococcus affects real children, some who never leave the hospital; some who leave with devastating neurological injuries; some whose parents breathe relief that their child was a fortunate one. I remain convinced that the future will bring a GBS vaccine so that we can have healthy pregnant women, fetuses, neonates, and young infants. Now it’s time to explain the title and to conclude. “There is a time for everything” “…a time to tear down (dogma) and a time to build, a time to weep (chemistry) and a time to laugh (CPS), a time to embrace (CPS vaccine) and a time to refrain (inadequate responses), a time to search (conjugate vaccine) and a time to give up (IAP), a time to be silent (vaccine trials) and a time to speak (WHO 2016 GBS landscape meeting), a time for war and a time for peace.” “…there is nothing better for a man (woman) than to enjoy his (her) work, because that is his (her) lot. For who can bring him (her) to see what will happen after him (her).” [26] Isn’t it time to save our babies and to help their mothers? To the person who nominated me for this award, especially for her moniker describing me as having “true grit”, I am deeply appreciative, as I am to the Pediatric Infectious Diseases Society. Notes Acknowledgments. Numerous individuals assisted in this journey but foremost among them are my 2 mentors, Drs. Rebecca C. Lancefield, and Maxwell Finland, colleagues including Drs. Dennis L. Kasper, Morven S. Edwards, and Pamela McInnes, my brilliant Research Associate, Marcia A. Rench, research assistants Bette W. Manulik, Mary A. Hall, Melissa H. Ward, and Kristen T. Ewing, fellows who worked in my laboratory, and my wonderful, patient administrator, Robin D. Schroeder. Potential conflicts of interest. The author: No reported conflicts. The author has submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1 Baker CJ Barrett FF Gordon RC Yow MD. Suppurative meningitis due to Streptococci of Lancefield group B: a study of 33 infants. J Pediatr  1973; 82: 724– 9. Google Scholar CrossRef Search ADS PubMed  2 Baker CJ Barrett FF. Transmission of group B Streptococci among parturient females and their neonates. J Pediatr  1973; 83: 919– 925. Google Scholar CrossRef Search ADS PubMed  3 Baker CJ Barrett FF. Group B streptococcal infections in infants. The importance of the various serotypes. JAMA  1974; 230: 1158– 60. Google Scholar CrossRef Search ADS PubMed  4 Baker CJ Kasper DL Davis CE. Immunochemical characterization of the “native” type III polysaccharide of group B Streptococcus. J Exp Med  1976; 143: 258– 70. Google Scholar CrossRef Search ADS PubMed  5 Baker CJ Kasper DL. Correlation of maternal antibody deficiency with susceptibility to neonatal infection with group B Streptococcus. N Engl J Med  1976; 294: 753– 756. Google Scholar CrossRef Search ADS PubMed  6 Baker CJ Kasper DL Tager IRABet al.  . Quantitative determination of antibody to capsular polysaccharide in infection with type III strains of group B Streptococcus. J Clin Invest  1977; 59: 810– 8. Google Scholar CrossRef Search ADS PubMed  7 Baker CJ Kasper DL. Group B streptococcal vaccines. Rev Infect Dis  1985; 7: 458– 67. Google Scholar CrossRef Search ADS PubMed  8 Austrian R Douglas RM Schiffman Get al.  . Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Physicians  1976; 89: 184– 94. Google Scholar PubMed  9 Schneerson R Robbins JE Chu CYet al.  . Semi-synthetic vaccines composed of capsular polysaccharides of pathogenic bacteria covalently bound to proteins for the prevention of invasive diseases. Prog Allergy  1983; 33: 144– 58. Google Scholar PubMed  10 Boyer KM Gotoff SP. Prevention of early-onset neonatal group B streptococcal disease with selective intrapartum chemoprophylaxis. N Engl J Med  1986; 314: 1665– 9. Google Scholar CrossRef Search ADS PubMed  11 Tuppurainen N Hallman M. Prevention of neonatal group B streptococcal disease: intrapartum detection and chemoprophylaxis of heavily colonized parturients. Obstet Gynecol  1989; 73: 583– 7. Google Scholar PubMed  12 American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn: Guidelines for prevention of group B streptococcal (GBS) infection by chemoprophylaxis. Pediatrics  1992; 90: 775– 778. PubMed  13 American College of Obstetricians and Gynecologists. Group B streptococcal infections in pregnancy: ACOG’s recommendations. ACOG Newsletter  1993; 37: 1. 14 Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease: a public health perspective. MMWR Recomm Rep  1996; 45: 1– 24. 15 Schrag S Gorwitz R Fultz-Butts K Schuchat A. Prevention of perinatal group B streptococcal disease: revised guidelines from CDC. MMWR Recomm Rep  2002; 51: 1– 22. Google Scholar PubMed  16 Verani JR McGee L Schrag SJet al.  . Prevention of perinatal group B streptococcal disease–revised guidelines from CDC, 2010. MMWR Recomm Rep  2010; 59: 1– 36. Google Scholar PubMed  17 Institute of Medicine. New Vaccine Development Establishing Priorities: Diseases of Importance in the United States . Washington, DC: National Academies Press, 1985. 18 CDC. Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network. Group B Streptococcus , 2014. Available at: http://www.cdc.gov/abcs/reports-findings/survreports/gbs14.pdf. Accessed 26 August 2016. 19 Baker CJ Rench MA McInnes P. Immunization of pregnant women with group B streptococcal type III capsular polysaccharide-tetanus toxoid conjugate vaccine. Vaccine  2003; 21: 3468– 72. Google Scholar CrossRef Search ADS PubMed  20 Baker CJ Carey VJ Rench MAet al.  . Maternal antibody at delivery protects neonates from early onset group B streptococcal disease. J Infect Dis  2014; 209: 781– 8. Google Scholar CrossRef Search ADS PubMed  21 Lin FY Philips JB3rd Azimi PHet 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: 1022– 8. Google Scholar CrossRef Search ADS PubMed  22 Lin FY Weisman LE Azimi PHet 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: 928– 34. Google Scholar CrossRef Search ADS PubMed  23 Dangor Z Kwatra G Izu Aet al.  . Correlates of protection of serotype-specific capsular antibody and invasive Group B Streptococcus disease in South African infants. Vaccine  2015; 33: 6793– 9. Google Scholar CrossRef Search ADS PubMed  24 Edmond KM Kortsalioudaki C Scott Set al.  . Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis. Lancet  2012; 379: 547– 56. Google Scholar CrossRef Search ADS PubMed  25 Thigpen MC Whitney CG Messonnier NEet al.  . Bacterial meningitis in the United States, 1998–2007. N Engl J Med  2011; 364: 2016– 2025. Google Scholar CrossRef Search ADS PubMed  26 Ecclesiastes 3:1–8, 3:22. The Holy Bible. New International Version . Grand Rapids: Zondervan Bible Publishers; 1973. © The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Pediatric Infectious Diseases Society Oxford University Press

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Abstract

Abstract Group B Streptococcus (GBS), characterized by Lancefield in 1933, was not recognized as a human pathogen until the early 1970s when it emerged and replaced Escherichia coli as the most common cause of sepsis and meningitis among neonates and young infants. This article briefly gives a personnel account of the discovery of clinical syndromes of GBS distinguished by age at onset, vertical mode of transmission for early-onset disease, meningeal tropism for GBS capsular (CPS) type III strains, and protective CPS epitopes. It also reviews the difficult evolution of the now routine program for antenatal GBS culture screening and intrapartum antibiotic prophylaxis, development of the first GBS candidate vaccines, clinical trials documenting the immunogenicity and safety of CPS tetanus toxoid conjugate vaccines, ongoing need to prevent morbidity and mortality in neonates and young infants, and critical need for commercial vaccines for routine use in pregnant women. It is a great honor to provide a lecture that bears the name of a giant in vaccinology, Stanley A. Plotkin. I am certain that Dr. Plotkin does not know that my journey in this field is related to one of his seminal contributions to science, namely rubella vaccine. After my first year of medical school, a summer job found me surrounded by dozens of babies with congenital rubella syndrome. Thanks to Dr. Plotkin and others, this devastating congenital infection has been eliminated from our country. However, although the horrors cast upon these babies and the tears in their mothers eyes are a lasting memory, this historical tie with infectious disease and vaccinology was not what launched me towards my ultimate professional goal—that came later. With the patience of both Dr. Plotkin and the audience, this lecture will tell a story of my long journey, one that continues, because the destination remains elusive. I have been told that the title of my lecture is vague. This was my intent. It is meant to introduce an enemy, one that continues to rob our babies of life and rob its survivors of normal function. This foe is what used to be a new and emerging infection, but now it is an old but still devastating pathogen, Streptococcus agalactiae or Lancefield’s group B Streptococcus (GSB). Time always has been my enemy. This is irrational—time is neutral. From childhood, I was always hurrying, trying to be faster and get more than others. Time continues to a problem because my decades-old dream of preventing invasive GBS early- and late-onset infant infections remains unrealized. A TIME TO DISCOVER During the first month of my pediatric residency, I was assigned to the nurseries of a Houston hospital that was delivering approximately 14 000 newborns annually. I worked long hours, moving into the call room for 3 weeks when the supervising neonatologist went on vacation to South Africa. I noted that many, mostly term neonates, critically ill either at birth or presenting with sudden onset of apnea within the first day or 2 of life, had a Gram-positive β-hemolytic organism isolated from their blood cultures. I was curious because dogma was that the major cause of neonatal bacterial infections was Gram-negative bacteria, in particular Escherichia coli. I mentioned this to the neonatologist upon his return and on later rotations to faculty on the pediatric wards where older quite ill infants were being hospitalized with sepsis and often with meningitis due to the same Gram-positive organism. My observation was discounted perhaps because we were so busy just trying to keep children alive. Not getting an explanation spurred my signature response—you must be wrong about a new and important cause of young infant sepsis and I’ll just have to show you. Oddly, these infections did not seem to occur once an infant attained the age of 3 months, so I collected just the meningitis cases, thinking that surely meningitis, a severe manifestation of this new infection in neonates and young infants, would attract some attention. Upon beginning a fellowship in Infectious Diseases, I asked the division chief, “Can I continue the work on this new β-hemolytic organism?” The answer was clear—“We already have an assigned project for you” (aka, “no”). Being prudent, I worked on my more interesting project on nights and weekends when I was not on call. A TIME TO DEFY Initial obedience to work on my assigned fellowship research project was secretly associated with ongoing investigation. I wrote a letter to Dr. Rebecca Lancefield (she refused to be addressed as other than “Mrs. L” when I subsequently met her) hoping that she was still working since she started her postdoctoral studies with Oswald Avery at Rockefeller University in 1918. I suspected that the Gram-positive organism was Lancefield’s GBS, an established bovine but almost unheard of human pathogen. Lancefield wrote back and asked whether I had any of the strains—yes, of course. I had 13 cerebrospinal fluid isolates on taped closed blood agar plates in my apartment. I mailed these to her; 12 of the 13 were capsular (CPS) type III! She had only 1 type III GBS strain in her entire collection that began in the 1930s so she was amazed and excited. She invited me to the Rockefeller. My Houston chief, upon seeing the handwritten letter from Lancefield, finally agreed to my change in focus. With a small travel grant, I set off, armed with an undergraduate degree in English literature and virtually no training in “real” science, but I was fueled by Lancefield’s excitement and encouragement as well as my own unconcealed enthusiasm. I learned so much in 6 weeks, but most of all, I learned to dream the seemingly impossible. Could I find a way to prevent these infections? Meanwhile, I published the meningitis cases, coined the terms “early and late-onset” GBS infections in neonates (bimodal age at onset) [1], and returned to Houston. I prepared reagents, defined the capsular types of GBS causing colonization in pregnant women, and determined the mode of transmission of early-onset disease (EOD). I then noted the discrepancy between the relatively high prevalence of genital GBS colonization in pregnant women (approximately 25%) and the low attack rate for disease among exposed neonates (approximately 1%–2%) [2]. Group B Streptococcus gradually became accepted as an important pathogen in neonates and young infants, adding to rather than replacing the predominance of E coli, and thereby increasing the number of neonatal sepsis cases. I also discovered the importance of type III as a cause of meningeal invasion, whether disease onset was early or late [3]. I had begun on a treacherous uphill hiking trail but had finally moved to a wide, smooth, paved road. The highway would be taken by others because I thought that answers to my remaining questions required years more of training, and it was time to get a job. A TIME TO TEAR DOWN DOGMA Having no credentials other than as an Infectious Diseases (ID) clinician, I applied for a second fellowship in internal medicine infectious diseases where I would work with Maxwell Finland at Harvard to learn what we now call hospital epidemiology and infection control. After an accidental meeting with a bacterial “capsule” man, Dennis Kasper (an internal medicine trained ID fellow) and me (a pediatric trained now medicine ID fellow) had a chance to find the “real” type III GBS capsule, not one ravaged by Lancefield’s hot acid extraction method. I met with Dr. Finland, and he astonished me by his support for my plan to abandon hospital epidemiologist training so I could chemically characterize the most destructive GBS, namely capsular type III. I called Mrs. L—she basically said “you are probably right about that acid extraction destroys an extra piece of the CPS”, and I was granted permission to tear down her dogma, a challenge that required my learning immunochemistry. I gently provoked whole GBS to release their capsules so I could characterize the type III CPS chemical structure and define the “native” CPS with its acid labile, terminal sialic acid component [4]. This discovery allowed me to develop an assay to measure antibodies to its native (and hopefully protective) epitope. I compared serum samples from women colonized with type III GBS at delivery whose newborns remained healthy to samples from women who developed type III GBS early- or late-onset disease. The result was that if a mother had sufficient antibody to the III capsule, disease was averted [5, 6]. I asked myself, could that “native” CPS be used as a polysaccharide vaccine (like the pneumococcal polysaccharide that was given to older adults) and be given to pregnant women stop this baby killer? Aside from my failure to comprehend how absurd my idea of giving a vaccine to pregnant women was in the 1970s, an era in which no vaccines were recommended for use during pregnancy, I now knew why so many infants were exposed to GBS at delivery and so few became ill. Fortunately, 4 decades later, we do have recommendations for routine use of 2 vaccines in every pregnancy, inactivated influenza and tetanus and diphtheria toxoid-acellular pertussis (Tdap). Nevertheless, my story continues into the late 1970s. A TIME TO DREAM Undaunted by the hurdles to pursing maternal immunization as a prevention strategy, I published additional data proving that the native type III capsule contained the protective epitope on its surface, and Kasper and I moved on to characterizing CPSs of other prevalent GBS disease serotypes (each had an acid labile, sialic acid component) and testing these as potential vaccines in healthy adults [7]. We assumed that our GBS polysaccharide vaccines given to young healthy adults would be immunogenic and functional based on the then contemporary analogy with the efficacy of 14-valent pneumococcal polysaccharide vaccine in South African gold miners [8]. A good lesson resulted—assumptions often are wrong and can be substitutes for careful thinking. More than 85% of pregnant women had very low concentrations of antibodies to type Ia, II, and III GBS polysaccharides in their sera, indicating that this population had never encountered these antigens and were not “primed” for an anamnestic response [9]. We needed a new approach, CPS-protein conjugate vaccines that could provide the needed T-cell help. Awaiting design and preparation of these vaccines by the Kasper laboratory (and funding for clinical trials), I continued to care for a seemingly unending number of neonates and infants with early- and late-onset disease, trying to comfort their parents that someday we might be able to prevent this suffering. Even though the 25%–50% mortality of the 1970s diminished with recognition of maternal risk factors for EOD, prompt diagnostic evaluations followed by prompt initiation of empirical antibiotic therapy and improvements in intensive care, I felt a sense of urgency, driven hard by my hard-wired impatience. With the publication in the mid-1980s of 2 randomized, controlled trials demonstrating that EOD GBS could be prevented by administration of intravenous intrapartum penicillin or ampicillin prophylaxis (IAP) [10, 11], I anticipated adoption of national recommendations where women carrying GBS would be identified and given prophylaxis as “best practice”, but nothing happened. Why not? Obstetricians also had begun to notice that GBS caused some cases of chorioamnionitis, postpartum endometritis, bacteremia, and, rarely, septic shock. A TIME FOR DIPLOMACY I approached George Peter, at the time editor of the American Academy of Pediatrics (AAP) Red Book, and Caroline Hall, chair of AAP’s Committee on Infectious Diseases, and they “hired me” to write a policy statement on this topic. This was to be done in collaboration the American College of Obstetricians and Gynecologists (ACOG). Numerous meetings with ACOG’s Maternal Fetal Medicine Committee and more than a year was required to reach consensus, the AAP statement was published in Pediatrics in November 1992 [12]. Surprisingly, in January 1993 the ACOG Newsletter masthead read, “GBS screening not recommended” [13]. I was more than discouraged until a young epidemic intelligence service (EIS) officer from the Centers for Disease Control and Prevention (CDC), Dr. Anne Schuchat, approached me more than a year later and informed me that GBS was a public health problem. I was thrilled to have a partner and someone else who could share the burden. More diplomacy ensued, slowly bringing ACOG back and several more “stakeholders” to the table at the invitation of the CDC. I was there, the only person not representing an organization and the one ironically chosen to crayon proposals on the overhead projector. Finally, in 1996, consensus guidelines for the prevention of early-onset GBS infections (imperfect but representing considerable progress) were published. Unfortunately, they allowed a choice for a strategy based on maternal risk or antenatal culture [14]. These were imperfect because the published contemporary literature indicated that approximately 50% of EOD cases arose from women with no identifiable risk factors during labor except GBS colonization. By the way, the EIS officer with the vision to prevent GBS disease is now deputy director of the CDC. Subsequent CDC evidence comparing the 2 prevention approaches proved the substantially greater effectiveness of prophylaxis using culture-based rather than the risk-based screening. In 2002, culture-based antenatal screening for GBS became the standard of obstetrical care in the United States [15, 16]. However, this was noted as an interim prevention strategy because immunoprophylaxis (a vaccine for pregnant women) was theoretically deemed to be more effective, cost-saving, and safe [17]. Prevention of early-onset GBS disease by IAP is now nearly 30 years old with a remarkable more than 80% reduction in EOD (Figure 1). However, it is concerning that IAP intervention has reached a plateau for the past 8 years, has had no impact on late-onset disease, and is based on the assumption that β-lactam resistance among GBS will not occur [18]. We used to think the same thing about the pneumococcus and penicillin resistance. Figure 1. View largeDownload slide Data for incidence of early-onset Group B Streptococcus (GBS) disease by year interval from the Centers for Disease Control and Prevention (CDC) Active Bacterial Core network. AAP, American Academy of Pediatrics. Adapted from: Verani JR, et al. Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep2010; 59(RR-10):1–36. Figure 1. View largeDownload slide Data for incidence of early-onset Group B Streptococcus (GBS) disease by year interval from the Centers for Disease Control and Prevention (CDC) Active Bacterial Core network. AAP, American Academy of Pediatrics. Adapted from: Verani JR, et al. Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep2010; 59(RR-10):1–36. TIME TO SHOW PHARMA Leaving IAP and surveillance to the CDC, the National Institute of Allergy and Infectious Diseases, based on the assumption that if they provided contract funding, and that if I performed GBS conjugate vaccine phase 1 and 2 clinical trials in childbearing age healthy women, Pharma would be convinced that development of a GBS would be worthwhile. It was a lot more work, work away from the bench. These trials spanned a decade and were followed by a small randomized, placebo-controlled trial in pregnant women using III-TT CPS monovalent conjugate vaccine. The result in pregnant women was a 4-fold or greater rise in CPS-specific immunoglobulin (Ig)G in 95% of women, vaccine-induced IgG transport to their neonates, and persistence of moderate levels of III CPS-specific maternal antibodies at age 2 months that promoted opsonization, phagocytosis, and killing using the individual infant’s endogenous complement [19]. Still nothing came from Pharma but questions. What about liability if a vaccine was associated with adverse outcomes with either the pregnancy or the neonates? If a vaccine was developed, would it be recommended for use in pregnant women? Were the findings from the 1970s concerning low levels of maternal CPS-specific antibodies at delivery being associated with GBS infant disease still true? A TIME TO CONFIRM SOMETHING AGAIN This last question prompted a 3:1 matched case control-study confirming that biology had not changed, and at least for the most prevalent GBS CPS types, namely Ia and III, with a trend for V, women with moderate to high concentrations of CPS-specific IgG in their sera at delivery did not have babies with early-onset GBS disease [20]. In addition, the maternal delivery serum concentrations that result in at least a 90% risk reduction in EOD are easily achievable by the Ia, III, and V candidate vaccines we evaluated. Similar data have been published by several other groups of investigators, including those from South Africa where GBS EOD incidence is at least 3 per 1000 live births [21–23]. Not surprising to me at least, GBS also accounts for an estimated 2%–4% of 3rd trimester stillbirths in Soweto, South Africa. A TIME TO SAVE So where are we? Group B Streptococcus is still happening in the United States and is finally recognized as a major killer in the first months of life in low- and middle-income countries throughout the globe [24]. It is now also the most frequent cause of bacterial meningitis in the US pediatric population [25]. All of these numbers cause me to remember what was said by a former US Surgeon General, Julius Richmond, MD.: “Statistics are people with tears wiped dry”. Group B Streptococcus affects real children, some who never leave the hospital; some who leave with devastating neurological injuries; some whose parents breathe relief that their child was a fortunate one. I remain convinced that the future will bring a GBS vaccine so that we can have healthy pregnant women, fetuses, neonates, and young infants. Now it’s time to explain the title and to conclude. “There is a time for everything” “…a time to tear down (dogma) and a time to build, a time to weep (chemistry) and a time to laugh (CPS), a time to embrace (CPS vaccine) and a time to refrain (inadequate responses), a time to search (conjugate vaccine) and a time to give up (IAP), a time to be silent (vaccine trials) and a time to speak (WHO 2016 GBS landscape meeting), a time for war and a time for peace.” “…there is nothing better for a man (woman) than to enjoy his (her) work, because that is his (her) lot. For who can bring him (her) to see what will happen after him (her).” [26] Isn’t it time to save our babies and to help their mothers? To the person who nominated me for this award, especially for her moniker describing me as having “true grit”, I am deeply appreciative, as I am to the Pediatric Infectious Diseases Society. Notes Acknowledgments. Numerous individuals assisted in this journey but foremost among them are my 2 mentors, Drs. Rebecca C. Lancefield, and Maxwell Finland, colleagues including Drs. Dennis L. Kasper, Morven S. Edwards, and Pamela McInnes, my brilliant Research Associate, Marcia A. Rench, research assistants Bette W. Manulik, Mary A. Hall, Melissa H. Ward, and Kristen T. Ewing, fellows who worked in my laboratory, and my wonderful, patient administrator, Robin D. Schroeder. Potential conflicts of interest. The author: No reported conflicts. The author has submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1 Baker CJ Barrett FF Gordon RC Yow MD. Suppurative meningitis due to Streptococci of Lancefield group B: a study of 33 infants. J Pediatr  1973; 82: 724– 9. Google Scholar CrossRef Search ADS PubMed  2 Baker CJ Barrett FF. Transmission of group B Streptococci among parturient females and their neonates. J Pediatr  1973; 83: 919– 925. Google Scholar CrossRef Search ADS PubMed  3 Baker CJ Barrett FF. Group B streptococcal infections in infants. The importance of the various serotypes. JAMA  1974; 230: 1158– 60. Google Scholar CrossRef Search ADS PubMed  4 Baker CJ Kasper DL Davis CE. Immunochemical characterization of the “native” type III polysaccharide of group B Streptococcus. J Exp Med  1976; 143: 258– 70. Google Scholar CrossRef Search ADS PubMed  5 Baker CJ Kasper DL. Correlation of maternal antibody deficiency with susceptibility to neonatal infection with group B Streptococcus. N Engl J Med  1976; 294: 753– 756. Google Scholar CrossRef Search ADS PubMed  6 Baker CJ Kasper DL Tager IRABet al.  . Quantitative determination of antibody to capsular polysaccharide in infection with type III strains of group B Streptococcus. J Clin Invest  1977; 59: 810– 8. Google Scholar CrossRef Search ADS PubMed  7 Baker CJ Kasper DL. Group B streptococcal vaccines. Rev Infect Dis  1985; 7: 458– 67. Google Scholar CrossRef Search ADS PubMed  8 Austrian R Douglas RM Schiffman Get al.  . Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Physicians  1976; 89: 184– 94. Google Scholar PubMed  9 Schneerson R Robbins JE Chu CYet al.  . Semi-synthetic vaccines composed of capsular polysaccharides of pathogenic bacteria covalently bound to proteins for the prevention of invasive diseases. Prog Allergy  1983; 33: 144– 58. Google Scholar PubMed  10 Boyer KM Gotoff SP. Prevention of early-onset neonatal group B streptococcal disease with selective intrapartum chemoprophylaxis. N Engl J Med  1986; 314: 1665– 9. Google Scholar CrossRef Search ADS PubMed  11 Tuppurainen N Hallman M. Prevention of neonatal group B streptococcal disease: intrapartum detection and chemoprophylaxis of heavily colonized parturients. Obstet Gynecol  1989; 73: 583– 7. Google Scholar PubMed  12 American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn: Guidelines for prevention of group B streptococcal (GBS) infection by chemoprophylaxis. Pediatrics  1992; 90: 775– 778. PubMed  13 American College of Obstetricians and Gynecologists. Group B streptococcal infections in pregnancy: ACOG’s recommendations. ACOG Newsletter  1993; 37: 1. 14 Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease: a public health perspective. MMWR Recomm Rep  1996; 45: 1– 24. 15 Schrag S Gorwitz R Fultz-Butts K Schuchat A. Prevention of perinatal group B streptococcal disease: revised guidelines from CDC. MMWR Recomm Rep  2002; 51: 1– 22. Google Scholar PubMed  16 Verani JR McGee L Schrag SJet al.  . Prevention of perinatal group B streptococcal disease–revised guidelines from CDC, 2010. MMWR Recomm Rep  2010; 59: 1– 36. Google Scholar PubMed  17 Institute of Medicine. New Vaccine Development Establishing Priorities: Diseases of Importance in the United States . Washington, DC: National Academies Press, 1985. 18 CDC. Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network. Group B Streptococcus , 2014. Available at: http://www.cdc.gov/abcs/reports-findings/survreports/gbs14.pdf. Accessed 26 August 2016. 19 Baker CJ Rench MA McInnes P. Immunization of pregnant women with group B streptococcal type III capsular polysaccharide-tetanus toxoid conjugate vaccine. Vaccine  2003; 21: 3468– 72. Google Scholar CrossRef Search ADS PubMed  20 Baker CJ Carey VJ Rench MAet al.  . Maternal antibody at delivery protects neonates from early onset group B streptococcal disease. J Infect Dis  2014; 209: 781– 8. Google Scholar CrossRef Search ADS PubMed  21 Lin FY Philips JB3rd Azimi PHet 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: 1022– 8. Google Scholar CrossRef Search ADS PubMed  22 Lin FY Weisman LE Azimi PHet 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: 928– 34. Google Scholar CrossRef Search ADS PubMed  23 Dangor Z Kwatra G Izu Aet al.  . Correlates of protection of serotype-specific capsular antibody and invasive Group B Streptococcus disease in South African infants. Vaccine  2015; 33: 6793– 9. Google Scholar CrossRef Search ADS PubMed  24 Edmond KM Kortsalioudaki C Scott Set al.  . Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis. Lancet  2012; 379: 547– 56. Google Scholar CrossRef Search ADS PubMed  25 Thigpen MC Whitney CG Messonnier NEet al.  . Bacterial meningitis in the United States, 1998–2007. N Engl J Med  2011; 364: 2016– 2025. Google Scholar CrossRef Search ADS PubMed  26 Ecclesiastes 3:1–8, 3:22. The Holy Bible. New International Version . Grand Rapids: Zondervan Bible Publishers; 1973. © The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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Journal of the Pediatric Infectious Diseases SocietyOxford University Press

Published: Mar 1, 2018

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