Update on influenza maternal immunization. Joachim Hombach WHO Initiative for Vaccine Research

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1 Update on influenza maternal immunization Joachim Hombach WHO Initiative for Vaccine Research

2 Influenza Burden of Disease WHO global estimate: 3-5 million severe cases, deaths <5 year old children: deaths (2008); 99% of global mortality due to influenza occurs in low & middle income countries <1 year old children: around 2.8% of global mortality in that age group Pregnant women 9x increased risk of influenza seasonal hospitalization compared to non-pregnant (Canada) Pregnant women at high risk of death during the 2009 influenza pandemic Most common risk factor severe disease in South Africa WHO factsheet; Nair 2011 Lancet, Lozano 2012 Lancet, Schanzer 2 J Obstet Gynaecol Can 2007, Jamieson 2009 Lancet, Archer 2009 Euro Surveill

3 WHO's Seasonal Influenza Vaccine Recommendations WHO position paper Identification of risk groups (pregnant women, children, aged 6 59 months, elderly, individuals w. spec. chronic med. conditions, health-care workers) Strategic Advisory Group of Experts (SAGE) WHO to plan maternal immunization agenda Global Advisory Committee on Vaccine Safety (GACVS) Inactivated vaccines safe in pregnant women and offspring WHO. Vaccines Against Influenza, WHO position paper 3 November WER 47, 2012, 87, WHO Maternal Influenza Immunization Project Support adoption of maternal immunization in countries Address uncertainties related to evidence, regulation, implementation and supply

4 WHO Position Paper: Maternal Immunization Additional considerations for targeting pregnant women include: operational feasibility opportunity to strengthen maternal immunization programs (tetanus and maybe others: pertussis, RSV, GBS; HepE) Will require effective educational programmes and communication Address issues of vaccine supply 4 WHO. Vaccines Against Influenza, WHO position paper November Wkly Epidemiol Rec. No. 47, 2012, 87,

5 Antenatal care coverage (2013) 5 Data from: WHO. World Health Statistics 2014 MDG 5 Antenatal care coverage (%) Income group At least 1 visit At least 4 visits Low income Lower middle income Upper middle income 93 - High income - - Global Graphic source: UNICEF global databases, 2014, based on Multiple Indicator Cluster Surveys (MICS), Demographic and Health Surveys (DHS) and other nationally representative sources.

6 Tetanus vaccination in pregnancy (2013) 103 countries provide Tetanus Toxoid-containing vaccine to prevent against maternal and neonatal tetanus (MNT). In these 103 countries 82% of newborns at birth are protected from tetanus derived from vaccination coverage (at least 2 doses of T. Toxoid or T.diphtheria Toxoid vaccine). 25 countries Have not yet eliminated MNT (mainly in Africa and Asia) 6 WHO Immunization coverage fact sheet N 378 (November 2014)

7 Countries with Influenza Vaccination Recommended in the National Immunization Programme Introduced* to date (78 countries or 40%) * Includes partial introduction Data source: WHO/IVB Database, as of 05 March 2015 Map production Immunization Vaccines and Biologicals (IVB), World Health Organization Introduced* in parts of the country (2 countries or 1%) Not Available, Not Introduced/No Plans (114 countries or 59%) Not applicable The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO All rights reserved.

8 JRF 2012: countries reporting influenza vaccination of pregnant women Country_Name WHO_region Target population Year Target_group_number Doses Administered Percent_coverage Mauritius AFRO Pregnant women South Africa AFRO Pregnant women Argentina AMRO Pregnant women Bolivia (Plurinational State of) AMRO Pregnant women Brazil AMRO Pregnant women Chile AMRO Pregnant women Costa Rica AMRO Pregnant women Cuba AMRO Pregnant women Ecuador AMRO Pregnant women El Salvador AMRO Pregnant women Mexico AMRO Pregnant women Nicaragua AMRO Pregnant women Panama AMRO Pregnant women Paraguay AMRO Pregnant women Uruguay AMRO Pregnant women Venezuela (Bolivarian Republic of) AMRO Pregnant women Iran (Islamic Republic of) EMRO Pregnant women Belarus EURO Pregnant women Denmark EURO Pregnant women Romania EURO Pregnant women Thailand SEARO Pregnant women Lao People s Democratic Republic (the) WPRO Pregnant women Marshall Islands (the) WPRO Pregnant women

9 Maternal Influenza Immunization at WHO Numerous activities involving multiple WHO departments and collaboration with several partner institutions Designed to address implementation obstacles to maternal influenza immunization program implementation Burden of Disease Vaccine Safety Vaccine performance Impact and Economics Implementation Regulatory aspects Manufacturing Data Review and Synthesis 9

10 Evidence

11 BMGF-Sponsored Maternal Immunization Trials RCT Endpoint 11 Nepal (Steinhoff) Safety and efficacy in mothers and infants Mali (Levine) Safety and efficacy in mothers and infants South Africa (Madhi) Years Safety and efficacy in mothers (without HIV) and infants. Safety and immuno in mothers with HIV and infants. Sample Size 3,000 5,440 HIV-:2,100 HIV+:180 (year 1)/ 789 (year 2) Vaccines Vaxigrip/placebo Vaxigrip/ Menactra Geography Rural Urban Urban Vaxigrip/placebo Infant Mortality 47/1,000 l-b 102/1,000 l-b 44/1,000 l-b HIV prevalence <1% 2.3% 29% Climate/Flu Seasonality Subtropical/Year Round Tropical/ Unknown Adegbola R. Am J Obstet Gynecol Clinicaltrials.gov Temperate/ Seasonal

12 South Africa Maternal Influenza Vaccine Trial HIV-uninfected cohort (2116 women/newborn pairs) Two year study, no change in vaccine formulation between years Influenza attack rate 3.6% vs. 1.8/1.9% Vaccine efficacy among women was 55%, and among infants it was 46%. No difference in newborn weight, prematurity No safety signals. HIV-infected cohort (194 women/newborn pairs) Single year study Influenza attack rate 17% vs. 7% Vaccine efficacy among women was 71%, despite poor immunogenicity in this cohort Too few outcomes in children to calculate VE in that group. No safety signals. Madhi, SA et al., NEJM 4 Sept

13 Burden of disease WHO working group - March 2015 to evaluate Influenza data to inform vaccine impact and economic modelling Review of influenza disease parameters in pregnant women, children <6 months, and fetus Flu epidemiologists, vaccinologists, perinatal epidemiologists, clinical experts Informed by multiple reviews: Burden of disease Impact of pregnancy interventions on birth outcomes Methods of vaccine studies in pregnancy Maternal immunization vaccine effectiveness 13

14 Areas of work include analysis of 14 Disease burden Economic burden Economic evaluation Health Economics (2) - Responding to guidance needs - IVR develops a guideline on economic evaluation to support countries on how to generate evidence A manual will guide researchers in any single country on how to perform and report a study to inform evidence-based decision based on disease burden A costing tool will help planners at country level to estimate the financial resources required to introduce seasonal influenza vaccines Courtesy: Raymond Hutubessy, WHO IVR Health Economics Lead

15 Maternal Immunization - recent vaccine safety products - In 2014, WHO Global Advisory Committee on Vaccine Safety (GACVS) reviewed influenza vaccine safety in pregnancy and found no safety concerns 1 Harmonizing maternal immunization AEFI definitions and guidance (with Brighton Collaboration) WHO consultation 7/2014, and follow-up by Brighton Collaboration Survey of National Pharmacovigilance Centres about maternal immunization AEFI surveillance systems and experts Investigating how to use publicly available data from EMA and FDA for pooled vaccine safety analysis Reports of ethics and manufacturer liability considerations 15 y_pregnancy_nov2014.pdf

16 Policy and Implementation

17 Implementation - Main areas of work - Introduction guidance summarizing evidence and providing implementation help Conducting country case studies to identify best practices for routine maternal immunization (Malawi, El Salvador, WPRO) (PATH) Integration of maternal immunization into WHO ANC guidance (in progress) Small project to integrate maternal immunization as an indicator into subnational ANC data collection tools (planning phase) Strengthening and development of NITAGs in Eastern Europe, Uganda, and Senegal MNTE case study 17

18 Creating an enabling regulatory environment WHO consultation on influenza vaccines for pregnant and lactating women: clinical data requirements for product labelling (15-16 July 2014); Identifying tools to promote more permissive pregnancy lactation sections in labels Explore the option of model package inserts for prequalified vaccines Explore the application of programmatic suitability criteria Developing guidance on vaccine clinical evaluation in pregnancy WHO TRS 924 update should include revised section on rationale of clinical studies in pregnant women 18

19 Manufacturing & supply (1) - Rationale - Year-round availability particularly critical for pregnant women given vulnerability to influenza Limited contact points during pregnancy through antenatal care visits Timing of campaigns for other populations Vaccine should be made available Before the peak of influenza season Whenever pregnant women present for antenatal care Bull World Health Organ 2014;92:

20 Manufacturing & supply (2) - Ensuring year round supply of vaccines - Tropical and subtropical countries having influenza peaks earlier than countries temperate regions in the same hemisphere or no peaks at all Year round supply may require influenza vaccines during periods when prior formulations have expired & subsequent formulations are not available Consultation considered regulatory and vaccine provision options to tailor vaccine use to local epidemiologic contexts. Particularly beneficial for regions with prolonged influenza virus activity may be: Switching between NH and SH formulation Influenza vaccines with shelf lives extended to e.g. 15 months vaccines could be provided to countries where year-round use of influenza vaccines/switching would otherwise not be possible Late filling & finishing from bulk is another option for creating flexibility for shelf lives 20

21 With many thanks to IVR s influenza team: Justin Ortiz Philipp Lambach Mark Perut