National Center for Immunization & Respiratory Diseases

GBS Young Infant Disease Burden, Trends and Prevention Strategies: High Income Countries

Stephanie Schrag, D Phil US Centers for Disease Control and Prevention

FDA Vaccines and Related Biological Products Advisory Committee Meeting, May, 2018

DISCLOSURES Not involved in any clinical trials involving GBS vaccines sponsored by

either GSK or Pfizer. Serve on two committees as part of my official Federal duties that are

related to the matter coming before the committee.

1. Chair of the WHO GBS vaccine development working group

2. Member of the World Health Organization/London School of Hygiene and Tropical Medicine advisory group to develop a value proposition for vaccines against GBS

Sixty year anniversary: Emergence of GBS sepsis and meningitis in infants 1958: Yale Hospital, Connecticut1; Charity Hospital, New Orleans2

1962–3: Boston City Hospital3

1965–72: St Louis Children’s Hospital4

1969–71: Several Colorado Hospitals (incidence: 2/1000 live births) 5

1970–72: Baylor College Affiliated Hospitals, Texas6

UK, 1968: First infant GBS report7; rapid emergence in 1970s

1Nyhan, WL et al. 1958 Pediatrics; 2Hood, M et al, AMHOG 1961; 3Eickhoff, TC et al. 1964. N Engl J Med 1964; 4Barton, LL et al,1973. J Peds; 5Franciosi R. et al. 1973. J Peds; 6Baker, CJ et al. 1973. J Peds; Ismail, A. et al. Neonatology, 2011

GBS Disease in Infants Before Prevention Efforts

These charts show the age distribution of invasive GBS disease in infants before prevention efforts, by age in months, weeks, or (for early-onset cases only) days. Approximately 80% of infant infections occur in the first days of life. Late-onset infections occur in infants between 1 week and 89 days of age.

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< 1wk

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Late onset: 7–89 days of life

Early-onset (EOGBS):0–6 days of life

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A Schuchat. Clin Micro Rev. 1998;11:497–513.

Early-onset GBS Risk Factors: Maternal Colonization

~10–30% pregnant women colonized with GBS– Higher prevalence among African Americans

Can be transient, intermittent or persistent; genitourinary or gastrointestinal tract serves as reservoir

Acquired vertically– GBS ascends to amniotic cavity during labor

• Aspiration leads to pneumonia/bacteremia– Exposure during passage through birth canal

• Colonization of skin/ mucus membranes– GBS can also cross intact amniotic membranes

Maternal to Infant Transmission (in absence of intervention)

Approximately 10–30% of women are colonized with GBS. About half of the infants born to colonized mothers are themselves colonized. The majority of colonized infants (98%) are asymptomatic. In the absence of intervention, about 2% of colonized infants will develop early-onset disease (e.g., sepsis, pneumonia, meningitis).

GBS colonized mother

Non-colonized newborn

Colonized newborn

AsymptomaticEarly-onset sepsis,

pneumonia, meningitis

50% 50%

98% 2%

~10-30%

Intrapartum antibiotic prophylaxis (IAP) to prevent GBS disease in first week of life

Clinical trials and well-designed observational studies (1980s) – IV penicillin or ampicillin– Given to GBS-colonized women (+/- additional risk factors)

Efficacy against invasive early-onset disease: 100%– Effectiveness in observational studies: 86–89%

1970s: Work towards a maternal GBS vaccine launched

Allardice et al. 1982, Am J Obstet Gynecol; Boyer and Gotoff. 1986. N Engl J Med; Lim et al., 1986, J Clin Micro; Tupperainen et al., 1989. Obstet Gynecol ; Garland et al, 1991, Aust NZ J Obstet Gynecol; Matorras et al. 1991 Eur J Obstet Gynecol Reprod Biol.

Debate: How best to target women for IAP

Risk-based strategies– GBS bacteriuria, prolonged membrane rupture, premature rupture of

membranes, preterm delivery, intrapartum fever, previous infant with GBS disease

– Flexibility in risk factors considered (narrow vs more comprehensive) Microbiologic screening for GBS colonization

– 50% more effective than risk-based approach1

– Requires laboratory capacity and cost of antenatal screens Concerns: Antimicrobial resistance and disruption of newborn microbiome

– Deliveries exposed to IAP, US: 12% pre-prevention; 32% IAP era – Similar under screening or broad risk-based approach

1Schrag et al. 2002. NEJM 347

US perinatal GBS disease prevention guidelines

In 1996, CDC published “Prevention of Perinatal Group B Streptococcal Disease: A Public Health Perspective,” which recommended either risk-based or microbiologic screening. In 2002, CDC published “Prevention of Perinatal Group B Streptococcal Disease: Revised Guidelines from CDC,” which recommended universal microbiologic screening. The most recent guidelines, “Prevention of Perinatal Group B Streptococcal Disease: Revised Guidelines from CDC, 2010” made small refinements to the 2002 guidelines.

1996: Either risk-based or microbiologic screening

2002: Universal microbiologic screening

2010: Small refinementsMMWR, Vol 59(RR-10)

Rapid transition to universal screening: Proportion of women screened for GBS pre- and post-2002

A bar chart showing how quickly 10 states transitioned to universal screening after CDC’s guidelines were published in 2002. From 1998 through 1999, these states screened about 48% of pregnant women. By 2003 through 2004, this number had increased to 85%.

Van Dyke et al., N Engl J Med. 2009

•Increased from 48% to 85% •98% had available result at labor

Proportion of women with indication receiving IAP increased under universal screening

A bar chart showing how the proportion of pregnant women with an indication who went on to receive intrapartum antibiotic prophylaxis (IAP) increased under universal screening. From 1998 through 1999, 74% of women with an indication actually received IAP. By 2003 through 2004, this number had increased to 85%.

Van Dyke et al., N Engl J Med. 2009

•Increased from 74% to 85%

Active Bacterial Core Surveillance (ABCs) System

• Surveillance began in 3 sites, 1989

Oregon

CaliforniaColorado

New Mexico

Minnesota

Georgia

New York

ConnecticutMaryland

Tennessee

• Live births in 10 current ABCs sites ~10% of US births• GBS from a normally sterile site, all ages• Early-onset GBS disease: 0-6 days of life; Late-onset: 7-89 days

www.cdc.gov/abcs

Invasive early- and late-onset disease trends, US ABCs

A line graph showing invasive early- and late-onset disease trends from 1990 through 2015 from Active Bacterial Core surveillance. In 1990, the incidence of early-onset disease was more than 1.7 cases per 1,000 live births. The incidence decreased dramatically through 1999 (a little more than 0.4 cases per 1,000 live births) and continued to decrease gradually through 2015 (a little more than 0.2 cases per 1,000 live births). During this same time period, late-onset disease incidence has remained relatively stable at around 0.3 cases per 1,000 live births.

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Early-onset disease Late-onset disease

Universal screening

Minor guidelines revisions

First consensus guidelines

Schrag and Verani. Vaccine 2013; Nanduri S et al. ISSAD 2018

GBS disease serotype distribution over time, ABCs

Pie charts showing that GBS serotype distribution her time according to ABCs data. Serotypes S disease, followed by II and V, then Ib. Seset GBS disease, followed by Ia, V, Ib, and

1999–2005n=1743n=997

as rov Ia aGB roty-on II.

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93

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2006–2015

-ons

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ained relatively sta III cause most early-on II causes about half of

Phares, C. et al. JAMA 2008; Nanduri, S. et al., ISSAD 2018

Early

Late-

Antimicrobial susceptibility, young infant GBS disease, ABCs Beta-lactam non-susceptibility rare

– 1% of adult invasive isolates non-susceptible to beta-lactams, 2015/16 Resistance to second line agents common in 2015

– Erythromycin: 49% of isolates– Clindamycin (constitutive): 26% of isolates

Metcalf, BJ et al., Clin Microbiol Infect 2016; Nanduri, S et al., ISSAD 2018; McGee; L. et al ISSAD 2018

US remaining infant GBS disease, ABCs, 2006–15

Estimated US cases, 2015: 840 early-onset, 1265 late-onset Estimated US deaths, 2015: 58 early-onset, 68 late-onset

Phares, C. et al. JAMA 2008; Nanduri, S. et al., ISSAD 2018

Early-onset , % (n=1277) Late-onset , % (n=1388)

Age at onset <2d: 94% Median: 34 days (IQR 20-49d)

Gestational age <35 wks 20 33.6

Gestational age 35-<37 wks 7 8

Case fatality risk 6.9 5.4

Syndrome

Meningitis 9.5 31.3

Pneumonia 6 1.9

Bacteremia (no focus) 83.1 61.1

Comparison to other US diseases where maternal immunization is in use or under consideration

1Nanduri, S. et al., ISSAD 2018; 2NNDSS 2010; 3Hall, C. et al. Pediatrics, 2013; 4Byington, C. et al., Pediatrics 2015

Condit ion (infants <3 months) Incidence per 1000 live births (est imated UScases)

Proport ionhospitalized (%)

Case fatality risk (US deaths)

Invasive GBS, 2015 1 0.47 (2105) 100 6% (126)

Pertussis 2012 (peak year pre-maternal Tdap ) 2

0.57 (2269) 60 1% (15)

Average RSV hospitalizat ions ~ 4.4/10003 (17,500) 100 <<1%4

Sequelae among GBS infection survivors: 18% have moderate to severe impairment* post-meningitis

12/18 studies were from high income countries

*Neurodevelopmental impairment assessed at 18 months of follow-upKohli-Lynch, M. et al. 2017. CID 65: Suppl 2

Additional disease burdens that might be prevented by a maternal GBS vaccine Maternal GBS disease: an estimated 175 maternal invasive cases in US per

year1

GBS associated stillbirths: approximately 1% of stillbirths2; limited data

1Phares, C. et al., JAMA 2008; 2Seale, A. et al. Clin Infect Dis 2017

Cost-effectiveness of a potential maternal GBS vaccine, USHealthcare sector perspective, 2013 U.S.$

Screen/IAP prevents EOGBS: $70,275/QALY, compared with no prevention.

Maternal GBS immunization, pentavalent vaccine, 70% effective against covered serotypes, prevents EOGBS and LOGBS: $56,609/QALY, compared with no prevention.

BUT … at coverage typical of current maternal vaccines (~50%), GBS vaccine would prevent fewer cases of disease than Screen/IAP … unless the vaccine were 90% effective.

A combination strategy, vaccination with Screen/IAP for unvaccinated women, would prevent more disease than either alone, at costs/QALY similar to Screen/IAP.

Kim S-Y et al., Vaccine 2017

Global adoption of policies for GBS prevention

LeDoare, K. et al. 2017. CID 65. Suppl 2.

Trends in early and late-onset disease, United Kingdom and Ireland

Lamagni, T. et al. 2013. CID O’Sullivan et al., ESPID, 2016

Incidence / 1000 live births 2000–2001 2014–2015

Overall 0.72 0.95

EOD 0.48 0.55

LOD 0.24 0.38

Invasive early and late-onset trends, Netherlands

Bekker et al. 2014. Lancet Infect Dis

1990 1995 2000 2005 2010

Risk-based IAP

Most recent high income country incidence estimate, young infant GBS disease*: 0.46/1000 live births (EOD: 0.37, LOD: 0.21)

*Invasive disease, day 0-89 of lifeMadrid, L. 2017. CID 65; Suppl 2.

Global GBS serotype distribution, meta-analysis

Madrid, L. et al., CID 2017: 65 (Suppl2). Based on data from 2000-2017 (N=6500 isolates)

Early-onset Late-onset

High income country experience: where are we today? Remaining disease burden of significance

– US: Despite 80% decline in early-onset disease incidence– UK, Netherlands: Increasing young infant GBS disease

Further major declines through improved IAP unlikely in US– Does not prevent late-onset disease

Beta-lactam non-susceptibility has emerged but remains rare – If it becomes more common it could threaten current prevention and

treatment strategies Long-term consequences of newborn microbiome disruption due to IAP poorly

understood– CDC has funded two large observational evaluations

Emerging incidence of invasive GBS disease among non-pregnant adults, ABCs: 10.9/100,000 in 2016

US estimate: 27,729 cases of invasive GBS disease and 1,541 deaths in 2016

www.cdc.gov/abcs

For more information, contact CDC1-800-CDC-INFO (232-4636)TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

ABCs Surveillance Officers

Acknowledgements• Entire ABCs team• Srinivas Nanduri • Paul HeathThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.