Maternal Immunization Efficacy and Safety Saad B. Omer William H. Foege Professor of Global Health Professor of Epidemiology & Pediatrics Emory University, Schools of Public Health & Medicine
Pregnancy Pre-partum Birth 6 wks (2 mo) After Birth 10 wks (4 mo) 14 wks (6 mo) Some infections more dangerous in pregnancy (e.g. influenza, Hepatitis E) 5 3 mil. deaths (0-27 days) Mortality data: Liu et al., Lancet; 2012
3 Omer, New Eng. J. Med., 2017
4 Influenza
Pregnancy & infancy as risk factors for severe disease attributable to seasonal influenza Odds ratios for a cardiopulmonary event during influenza season among pregnant women aged 15-44 years (referent group: postpartum women) Bhat N et al. N Engl J Med. 2005 Dec 15;353(24):2559-67 Neuzil KM, Reed GW, Mitchel EF, et al.. Am J Epidemiol.. 5
63% reduction in infant influenza after maternal vaccination in pregnancy Shehzad Noorani 17 Zaman et al., New Eng Journal of Medicine, 2008
Distribution of the Number of Weeks of Exclusive Breastfeeding 18 Omer, et al., New Eng Journal of Medicine, 2009
Synergy between Influenza Virus & S. pneumoniae (pneumococcus) Influenza infection predisposes to pneumococcus Altered immune system particularly innate immune system Most deaths in the 1918 influenza pandemic due to secondary pneumococcal infection 20
One-two punch of maternal influenza immunization + infant pneumococcal conjugate vaccine
% Efficacy Efficacy of PCV +TIV for Respiratory Illness with Fever 100 80 Full Study Period Flu Circulation Period 60 40 37 41 20 0 5-20 -40-60 Mother PPSV23; Infant Hib Mother PPSV23; Infant PCV7 Mother Control Mother Control Infant Control Infant PCV Mother TIV Infant Control Mother TIV; Infant Hib Mother TIV Infant PCV Mother TIV; Infant PCV7 TIV: Trivalent (inactivated) influenza vaccine; PCV7: 7-valent pneumococcal conjugate vaccine 10 Omer et al., J. Infect. Dis., 2013
WHO Strategic Advisory Group of Experts (SAGE) Recommendation: Countries considering the initiation or expansion of seasonal influenza vaccination programmes give the highest priority to pregnant women 24 Wkly Epidemiol Rec., 2012
Three Bill & Melinda Gates Foundation Trials Mali Nepal South Africa 25 UN Photo/John Isaac UNFPA/Anna Adhikari UN Photo/P Mugabane
Vaccine Efficacy against laboratory confirmed influenza in infants -Data from RCTs 14 Omer, New Eng. J. Med., 2017
Vaccine Efficacy against laboratory confirmed influenza in mothers -Data from RCTs 15 Omer, New Eng. J. Med., 2017
Birth weight (g) 3100 3000 Baseline Mean Birth weight in Trial Countries 2983 3059.9 2900 2800 2700 2600 2717 2632 2500 2400 Nepal 1 Mali 2 South Africa 3 Bangladesh 4 1) Mullany et al., 2007; 2) Teguete et al., 2012; 3) Sabet et al., 2009; 4) UNICEF 2005 16
17 Steinhoff M, IDSA, 2015; Tapia M et al., The Lancet,,2016; Madhi S et al., NEJM, 2014; Steinhoff M et al., Canadian Medical Association Journal, 2012.
Steinhoff et al., CMAJ, 2012 18 Distribution of birth weight by vaccine group and circulation period - Bangladesh Mother's Gift Trial
Location specific nuances Nepal was the only trial to have low birth weight as a (co-)primary outcome Gestational age at vaccination was lower for the Nepal trial compared to other 3 trials Baseline birth weight was lower in the populations where the Nepal trial was conducted compared to other study sites 32
Maternal Influenza Vaccine Evidence of impact on lab confirmed infant influenza Emerging evidence for impact on severe outcomes in infants Appreciating location specific nuances Seasonality Baseline rates of outcomes of interest Evidence-based decision-making
22 Pertussis Vaccine
Pertussis Burden WHO estimate: 16 million cases/year 95% in developing countries Infants too young to be completely vaccinated at high-risk More severe disease in young infants compared to older children & adults Combined tetanus, diphtheria, and (acellular) pertussis (Tdap) vaccine recommended for pregnant women in multiple countries. (without a phase III clinical trial) 39 WHO, 2011: CDC, 2012
40 Kharbanda et al. JAMA. 2014
Time Since Prior Tetanus-Containing Vaccine & RR of Tdap Safety Outcomes 2.97 Local Reactions 3.00 Small for Gestational Age 3.00 Preterm Delivery 0.99 0.77 1.00 0.99 0.96 1.00 1.15 1.06 0.49 0.33 <2 years 2-5 years 0.33 <2 years 2-5 years 0.33 <2 years 2-5 years Reference group: >5 years since prior tetanus-containing vaccine 25 Sukumaran et al., JAMA, 2015
26 GBS Vaccine
Invasive GBS disease in infants Early-onset GBS (EOGBS) occurs before age 7 days sepsis without a focus (80%-95%) pneumonia (10%-15%) meningitis (5%-10%) Late-onset GBS (LOGBS) occurs in infants aged 7 to 89 days old Meningitis more frequent (21% 35%)» 30% of cases have permanent sequelae (eg, hearing loss, developmental delay). 27 Healy & Baker in Vaccines, 6th Ed.
Epidemiology of Group B Streptococcal infection in pregnant women (United States) Universal screening No change in lateonset disease in infants or disease in pregnancy 43 Phares et al. JAMA. 2008 May 7;299(17):2056-65
Invasive Group B Streptococcal Infection in Pregnant Women Pregnancy Outcomes Among Women with Invasive GBS Active, population-based surveillance in 10 U.S. states Identified 409 invasive GBS infections in pregnant women 61% 4% 5% SAB or Stillbirth Infant Clinical Infetion Induced Abortion 29 Phares et al. JAMA. 2008 May 7;299(17):2056-65
Proportions of Cases of Bacterial Meningitis Caused by Each Pathogen U.S. Emerging Infections Program 2003 2007 30 Thigpen, et al. NEJM, 2011
Potential mechanisms of maternal GBS colonization leading to adverse pregnancy outcomes Supportive data Maternal GBS colonization Preliminary data Intra-amniotic, urinary tract, or systemic GBS infection Bacterial virulence factors Subclinical local or systemic inflammation Preterm birth 47
Association between Group B Streptococcal colonization and preterm delivery 3.4 1.7 Cross-Sectional Case Control Pooled Cross-Sectional + Case Control Cohort Studies 0.85 32 Valkenburg-van den Berg et al. Acta Obstet Gynecol Scand. 2009;88(9):958-67
GBS Vaccine Progress Trivalent Type Ia, Ib and III Vaccine to Prevent GBS Infection (Novartis) Purified CPS conjugated to CRM197 Phase I & II trials Further clinical development plans evolving 33
34 RSV Vaccine
55 Hall et al. NEJM, 2009
36 Hall et al. NEJM, 2009
Global Neonatal and Infant Deaths in 2010 57 Lozano R et al. Lancet, 2012
Estimated case fatality ratio in children <5 years admitted to hospital for RSV-associated severe ALRI <1 year <5 years Industrialised countries 0 7% (0 3 4 8) 0 3% (0 2 0 4) Developing countries 2 1% (1 6 2 2) 2 1% (1 3 3 4) 38 Nair et al. Lancet, 2010
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41 Ethics
legitimacy of a mother s interests in the welfare of her fetus/infant 43
Characteristics of an Interests-based Approach Mother s agency front and center Inclusion of women in decision-making Limits options for mandatory maternal immunization Chamberlain et al., Science, 2017
Thank You @SaadOmer3 45