Jan 29-30, 2015
Berlin, Germany


Report reviewed by:

Convening organizer:
Ajoke Sobanjo-ter Meulen, Senior Program Officer, Bill and Melinda Gates Foundation

Session chairs:

Jon Abramson, Professor of Pediatrics, Wake Forest Medical School

Keith Chirgwin, Deputy Director, Bill and Melinda Gates Foundation

Elizabeth Mason, Former Director MNCAH, WHO

Helen Rees, Executive Director, Wits Reproductive Health and HIV Institute

Nina Schwalbe, Principal Advisor for Health, UNICEF

Greg Widmyer, Deputy Director, Bill and Melinda Gates Foundation

Abbreviations ............................................................................................................................................ 4

Executive Summary ................................................................................................................................ 6

Part 1: Introduction and Investment Case ....................................................................................... 8
   Conclusions and Key Takeaways ................................................................................................ 11

Part 2: Evidence Base ......................................................................................................................... 12
   Conclusions and Key Takeaways ................................................................................................ 18

Part 3: Regulatory ................................................................................................................................. 19
   Conclusions and Key Takeaways ................................................................................................ 23

Part 4: Policy ........................................................................................................................................... 24
   Conclusions and Key Takeaways ................................................................................................ 31

Part 5: Market Dynamics ..................................................................................................................... 32
   Conclusions and Key Takeaways ................................................................................................ 37

Part 6: Funding ....................................................................................................................................... 38
   Conclusions and Key Takeaways ................................................................................................ 44

Part 7: Implementation ......................................................................................................................... 45
   Conclusions and Key Takeaways ................................................................................................ 50

List of Conclusions and Key Takeaways ........................................................................................ 51

Coordination and Collaboration......................................................................................................... 54

Appendix A: List of Session Chairs and Speakers ...................................................................... 57
Appendix B: List Panel Chairs and Participants........................................................................... 70
Appendix C: Complete Meeting Participant List........................................................................... 71


  AFRO     African regional office (WHO)
  ALRI     Acute lower respiratory-tract infection
  ANC      Antenatal care
  AVAREF   African Vaccine Regulatory Forum
  BMGF     Bill and Melinda Gates Foundation
  CAGR     Compound annual growth rate
  CEA      Cost-effectiveness analysis
  CFR      Case fatality ratio
  CHERG    Child health epidemiology research group
  CIDA     Canadian International Development Agency
  DALY     Disability-adjusted life years
  DFID     Department for International Development (UK)
  EMA      European Medicines Agency
  ENAP     Every Newborn Action Plan
  EPI      Expanded Program on Immunization
  FDA      Food and Drug Administration
  GAVI     The Global Alliance for Vaccines and Immunizations
  GBD      Global burden of disease
  GBS      Group B streptococcus
  GFF      Global Financing Facility
  HHS      U.S. Department of Health and Human Services
  HPV      Human papillomavirus
  IDA      International Development Association
  IHME     Institute of Health Metrics and Evaluation
  IPTp     Intermittent preventive treatment in pregnancy
  ITN      Insecticide treated net
  JE       Japanese encephalitis
  JHU      Johns Hopkins University
  LBW      Low birth weight
  LIC      Low income countries
  LMIC     Lower-middle income countries
  LRI      Lower respiratory-tract infection
  LSHTM    London School of Hygiene & Tropical Medicine
  MDG      Millennium development goal
  MenA     Meningitis A
  MI       Maternal immunization
  MNCAH    Maternal, newborn, child and adolescent Health
  MNCH     Maternal, newborn, and child health
  MNH      Maternal and neonatal health

MNTE       Maternal and Neonatal Tetanus Elimination
MoH        Ministry of Health
NGO        Non-governmental organizations
NIH        National Institutes of Health
NITAG      National Immunization Technical Advisory Group
NMR        Neonatal mortality rate
Norad      Norwegian Agency for Development Cooperation
NRA        National Regulatory Authority
PCV        Pneumococcal vaccine
PDP        Product development partnership
PDVAC      Product Development for Vaccines Advisory Committee
PLLR       Pregnancy and Lactation Labeling Rule
PMTCT      Prevention of mother to child transmission
PQ         Pre-Qualification
PT         Pertussis toxoid
PW         Pregnant women
RH/MNCAH   Reproductive health / Maternal, newborn, child, and adolescent health
RMNCH      Reproductive, maternal, newborn, and child health
ROI        Return on investment
Rota       Rotavirus
RSV        Respiratory syncytial virus
SAGE       Strategic Advisory Group of Experts
SDG        Sustainable Development Goal
SIA        Supplemental Immunization Activities
SGA        Small for gestational age
TBA        Trained birth attendant
Tdap       Tetanus Diphtheria and Pertussis
TPP        Target product profile
TT         Tetanus toxoid
UNFPA      United Nations Population Fund
UNICEF     United Nations Children's Fund
USAID      United States Agency for International Development
WHO        World Health Organization
WRHI       Wits Reproductive Health and HIV Institute

Executive Summary
While concerted global efforts have led to the steady reduction of under-5 childhood
mortality by ~5% per year over the past two decades, mortality reduction in neonates has
been more gradual, declining on average ~3% per year since 1990. Due to this difference,
neonatal deaths have risen from 35% of under-5 deaths in 1990 to 44% today, a trend
that is expected to continue. Maternal immunization has emerged as a promising
intervention to address infection-related neonatal and young infant deaths in developing
countries, and is increasingly supported by global health stakeholders and industry. In
addition to addressing difficult to reach neonatal and young infant deaths, maternal
immunization may also provide substantial health benefits to fetuses, reduce morbidity &
associated healthcare costs, and provide a number of socio-economic benefits. Given the
growing evidence base, maturing product development pipelines and global policy
momentum, now is a pivotal time for the alignment of key stake-holders on a strategic
path to impact for maternal immunization in developing countries.

On January 29-30, 2015, the foundation convened a meeting of global health
stakeholders in maternal immunization in Berlin. The convening attracted major donors,
as well as over 110 key leaders in vaccine manufacturing, regulatory agencies, academia,
multilateral organizations, and country-level ministers of health from Africa and Asia.
Representatives from the foundation's Pneumonia, MNCH, Vaccine Delivery, Vaccine
Development, and LSP groups were also present. The meeting focused on maternal
immunization as an intervention for addressing five pathogens: Influenza, Respiratory
Syncytial Virus, Pertussis, Tetanus, and Group B Streptococcus. Goals for the convening
included (1) Understanding the challenges, knowledge gaps and potential impact of
maternal immunization at both the platform and pathogen level, (2) Setting strategic
priorities for the maternal immunization community, and (3) Fostering alignment between
the MNCH and Vaccine communities on an end-to-end “Path to Impact” for maternal
immunization. Major conclusions included:

      A stronger evidence base is needed, including burden of disease, maternal
       immunization efficacy and safety for mother, fetus and infant, and effects on
       morbidity & associated healthcare costs, in order to build a stronger investment
       case for manufacturer and donor investment, policy recommendations, licensure,
       and country-level uptake.
      Integration of maternal immunization into the ANC channel is preferred, but
       research needed to identify the most attractive integration models for given
       countries and pathogens. These models should benefit women, fetuses and
       infants, provide benefits beyond mortality (e.g. maternal health and socio-
       economic benefits), strengthen existing healthcare systems rather than
       fragmenting them, and be sustainably funded.
      The foundation & external stakeholders are engaged and willing to take on next
       steps, including sharing of learnings from existing maternal immunization efforts
       (e.g. MNTE, pertussis in Argentina), funding to improve the maternal immunization

evidence base and accelerate maternal vaccine development, development of
      maternal vaccine TPPs by WHO PDVAC and other stakeholders, and integration
      of SAGE and maternal immunization policy guidelines with WHO ANC guideline

The convening enabled discussions across pathogens, platforms, and stakeholder
groups that led to novel strategic-level insight, especially between the vaccine and MNCH
communities, and created momentum for collaboratively addressing key challenges on
the maternal immunization path to impact.

Part 1: Introduction and Investment Case

Maternal Immunization in the Context of a Global Health Agenda
Keith Klugman (BMGF), France Donnay (BMGF)

Global under-5 (U5) mortality has declined from 90 deaths per 1,000 live births in 1990
to 48 deaths per 1,000 live births in 2012, a decline of ~5% per year. Neonatal mortality
has only declined by ~3% per year, however, and by 2035 is projected to make up ~55%
of all U5 mortality. Accelerated action in addressing neonatal mortality will therefore be
required to continue making substantial progress in global health, and to reach the
Sustainable Development Goals (currently under development) by 2030.

                                       Global  under-five (U5),
                                                                 infant and
                                                                        and Neonatal
                                                                            neonatal mortality
                                       90                                                               Under-f ive mortality rate
  Deaths per 1,000 Live Births

                                                                                                        Inf ant mortality rate
                                                                                                        Neonatal mortality rate
                                                                                        Under-five: ~5% annual decline

                                                          Neonatal: ~3% annual decline
                                                                                                                                      MDG 4
                                  25                                                                                                 target: 30

                                   1990           1995            2000             2005                  2010                  2015
From "Maternal Immunization in the Context of a Global Health Agenda" presentation, Keith Klugman & France Donnay

                                                                                          Global neonatal mortality 1
Maternal immunization is an approach
that sits at the crossroads of the Vaccine
and Maternal, Newborn, and Child
Health Communities (MNCH), in which
pregnant women are vaccinated in order
to protect newborns who are too young
to be vaccinated themselves. Neonatal
mortality includes ~600k infection-
related deaths per year, part of which
may be addressed by the maternal
immunization        interventions    under
consideration at this convening. In
addition, maternal immunization may
address part of the ~965k deaths from
pre-term birth, prevent a portion of the
10-50% of still-births estimated to be
                                                                            1. McClure EM, "Stillbirth in Developing Countries: A review of
                                                                           causes, risk factors and prevention strategies”, J. of Matern Fetal
                                                                                     Neonatal Med. (2014); 2. WHO-CHERG 2013
caused by infectious disease, and provide protection to mothers & infants < 5 months of

To realize these benefits, outstanding issues regarding maternal immunization uptake,
cost-effectiveness, affordability, and integration with antenatal care, particularly in low-
income and lower-middle income countries (LIC/LMIC), will need to be addressed. The
goal of the 2015 stakeholder convening will be to understand the challenges, knowledge
gaps and potential impact of five maternal immunization initiatives, and to align on next
steps to drive toward health impact. In particular, three desired outcomes were

      Identify challenges & potential solutions to achieve maternal immunization impact
      Set strategic priorities for the maternal immunization community
      Encourage increased collaboration of the Vaccine and MNCH communities

Investment Case
Ajoke Sobanjo-ter Meulen (BMGF)

Brief summary: Implementation of maternal immunization must be supported by a strong
investment case that demonstrates cost-effective health benefits. The foundation recently
completed a health impact and cost effectiveness analysis, which showed that maternal
immunization has significant potential to avert neonatal and infant deaths (~40-85k per
year) and morbidity (~4-8M disability adjusted life years (DALYs) per year) by 2040.
Maternal immunization may also decrease the rate of pre-term and still-births, provide
socio-economic benefits and, if implemented properly, strengthen the existing antenatal
care (ANC) system. In order to build a more robust investment case, the pathogen-
specific evidence base must be strengthened, and challenges in affordability, ANC
coverage, and Vaccine/MNCH integration addressed.

Maternal immunization progress and future directions: Maternal immunization has
existed for over a century, with acceptance and investment increasing over the last
decade in response to expanding safety and efficacy data. The foundation began
significant investment in maternal immunization in 2009, primarily with evidence base and
vaccine development focused on influenza and Respiratory Syncytial Virus (RSV). In
2014 the foundation expanded its maternal immunization program to five pathogens:
Influenza, RSV, Pertussis, Tetanus, and Group B Streptococcus (GBS). The foundation
aims, and plans to leverage this convening, to drive toward an end-to-end path to impact
for maternal immunization, starting with evidence generation and product development,
and ending with the delivery and monitoring of maternal immunization impact.

Long history of progress in maternal immunization

Source: "Maternal Immunization: Path to Impact" presentation by Ajoke Sobanjo-ter Meulen

The foundation's forecast of maternal immunization health impact: The foundation
recently completed a health impact and cost effectiveness analysis of maternal
immunization, based on a high-level model of disease burden, vaccine efficacy, and
vaccine procurement and delivery costs. The model predicts a total of ~0.7-1.6 M deaths
averted by 2040 if Pertussis, GBS, Influenza, and RSV vaccines are introduced into ANC
channels in all current LIC/LMICs. By 2030, annual deaths averted are estimated at ~40-
85k deaths (~1% of global under-5 burden) while DALYs averted are estimated at ~ 4-8
M DALYs. Cost per death averted is estimated to be high relative to most GAVI-funded
vaccines, but comparable in cost per DALY averted to other MNCH interventions. Model
results indicate the need for a stronger evidence base, affordable vaccine prices,
increased ANC coverage, and collaboration between Vaccine and MNCH communities.

          Range of deaths and DALYs averted after introduction of maternal immunization
            against four pathogens (RSV, GBS, influenza and pertussis) in LIC / LMIC

Source: BCG analysis. Note: Introduction date assumptions: Influenza – 2017, Pertussis – 2020, RSV – 2020, GBS – 2025.

          Table of model assumptions used to predict future morbidity and mortality impact


               Timeline                                  2015–2040

 Disease       Geographical coverage                     All low and lower-middle income countries (82 LIC/LMIC)
 burden        Base burden data                          Based on IHME GBD, and CHERG1

               Future disease trends                     Global neonatal mortality decline (~-3%)2

               Delivery channel                          Assume antenatal care with ANC1 coverage rate (~30-100%)3

 Health        Duration of protection                    BMGF projection by vaccine (3-5 months)
 impact        Vaccine efficacy                          BMGF projection by vaccine (45-70%)4

               Vaccine intro. date                       BMGF assumption by vaccine (2017-2025)

               Vaccine / delivery cost                   $2.40 base assumption for price+delivery cost of all vaccines5
               Averted cost of care                      No averted cost of care included (pending)

                                                         Univariate sensitivity analysis applied on burden, vaccine
 General       Sensitivity analysis
                                                         efficacy, vaccine cost, duration of protection, etc.
Source: BCG analysis. 1. Global burden of disease, Child Health Epidemiology Research Group. 2. Average neonatal decline from
Liu, Li, et al. "Global, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an
updated systematic analysis." The Lancet (2014). 3. GAVI strategic demand forecast 4. Influenza calculated from current BMGF MI
trials. 5. Based on assumed COGS, markup, and delivery cost

           Introduction and Investment Case: Conclusions and Key Takeaways

     1. Neonatal mortality is a growing proportion of under-5 mortality and immunization
        provides an opportunity to prevent a portion of infection related neonatal mortality
        that is not addressed through any other intervention in LIC/LMIC settings.
        Therefore, the potential for maternal immunization to address unmet health needs
        will grow over time.
     2. The foundation's impact model predicts significant mortality and morbidity
        aversion, on the higher end of cost per death averted compared to GAVI vaccines,
        and moderate cost per DALY averted compared to current MNCH interventions.
     3. A better understanding of the disease burden, especially in LIC/LMIC is required
        to assess the full potential health impact of maternal immunization.
     4. Additional benefits, currently uncaptured in the model, include the potential impact
        on infection-related pre-term and still-births, and non-DALY morbidity burden with
        associated healthcare costs.

Part 2: Evidence Base

Context and Session Goals

The foundation has focused its efforts in maternal immunization on five pathogens:
Influenza, Tetanus, Group B Streptococcus (GBS), Pertussis, and Respiratory Syncytial
Virus (RSV). The investment case for maternal immunization and the willingness of
manufacturers and healthcare providers to allocate resources will depend on the strength
of the disease burden evidence base and potential health impact of vaccination for each
pathogen. This session discusses the current evidence base for each pathogen, including
addressable mortality and morbidity from each disease in neonates, infants, and mothers,
current vaccine candidate development status and likely profile, and potential effects on
fetal outcomes (e.g. pre-term and still birth). The goal of the session is to use the current
evidence base to identify key information gaps for each of the five pathogens addressable
by maternal immunization.

Influenza Evidence Base
Shabir Madhi (National        Institute   for   Communicable    Diseases,    University   of

Brief summary: Influenza is estimated to cause ~30k-110k deaths annually in children,
the vast majority in low-income and lower-middle income countries (LIC/LMICs). It also
poses significant health risks to pregnant women, and may negatively affect fetal
outcomes. Influenza may impact pre-term and still-birth rates, but significant knowledge
gaps in these areas prevent estimation of the potential health impact.

Burden of disease in pregnant women and infants: In 2008, influenza was estimated
to have caused the deaths of between ~30k-110k children. ~99% of these deaths
occurred in LIC/LMIC. Among pregnant women, recent evidence has suggested that
pregnancy is not a risk factor for influenza. However, pregnancy appears to increase the
risk of cardio-pulmonary events in pregnant women and may therefore represent a
significant risk to both mother and child. Among children, one South African study
demonstrated a case fatality rate (CFR) due to influenza-associated severe acute lower
respiratory infection of ~4.5% for infants under six months of age, an estimate that may
be higher among neonates and in lower income countries. Despite the high fatality rate,
the relatively low incidence of severe influenza associated disease resulted in lower
overall mortality burden than respiratory syncytial virus (CFR of ~1.2%) in South Africa.

Vaccine efficacy in pregnant women and neonates: Maternal immunization has the
potential to improve health outcomes for pregnant women, fetuses, and neonates. For
pregnant, HIV- women, efficacy was estimated at ~50% (15-71% CI). Greater efficacy in
women has been reported for pandemic flu. In young infants, maternal immunization was
also estimated to be effective (~53% in Bangladesh and S. Africa, 25-71% CI). Beneficial

effects of maternal influenza immunization on fetal outcomes are unconfirmed, as mixed
results have been reported for rates of premature birth and SGA (small for gestational
age). Significant knowledge gaps affecting estimates of impact for maternal influenza
immunization include the disease burden for young infants at the country level, the impact
of vaccination on severe illness, and potential fetal benefits (pre-term, still birth, and SGA
rates). Additional knowledge gaps that may affect impact in developing countries include
the difficulty of strain matching in environments of year-round influenza as well as the
logistical challenges of timely vaccine delivery.

                              Summary of key gaps and next steps for influenza

 Key gaps                                    Implications if not addressed      Desired actions
 Evidence for severe disease                 Poor awareness and demand          Active surveillance studies of
 burden in young infants,                    among different countries due      severe illness in regions with
 including at country level                  to lack of evidence                high burden to improve
                                                                                current evidence
 Impact of vaccination on                    Questionability of extrapolation   Effectiveness studies on
 severe illness                              of current efficacy data           severe illness, including HIV-
                                                                                exposed infants
 Potential fetal benefits of MI              Underestimation of potential       Clinical studies looking at
                                             health impact of MI                birth outcomes in SEARO
 Unpredictable efficacy of                   Uncertain health impact of         Invest in development of
 currently available Vx                      maternal immunization and          universal vaccine to
          Role of strain matching           more complicated logistics         circumvent need of strain
 Logistical challenges in                    Low adoption at country-level      Improve timeline for vaccine
 timelines of vaccine availability                                              availability and regulatory
 and formulation                                                                framework for approval in
Source: “Influenza Evidence Base" presentation, Shabir Madhi

Maternal and Neonatal Tetanus Elimination (MNTE)
Dr. Azhar Abid Raza (UNICEF New York)

Brief summary: The Maternal and neonatal tetanus elimination (MNTE) program has
made substantial progress, with 35 nations achieving elimination (defined as
has a case fatality rate of ~70-100%. ~60% of the total MNT deaths are concentrated in
India, Nigeria, Pakistan and DRC.

Progress toward elimination: MNT elimination is achievable through vaccination and
has been achieved in 88 countries (defined as < 1 case per 1,000 live births in every
district). Of these, 35 achieved elimination between 2000 and 2014. 8 did so by
strengthening routine immunization and reproductive health services, while the rest used
supplemental immunization activities (SIA) or integrated campaigns. In 2014, 24 countries
had yet to achieve elimination. Four strategies have been applied to achieve and maintain
elimination: (1) SIA to target women of reproductive age, (2) Vaccination of pregnant
women through ANC or referral through midwives, (3) Enablement of clean delivery, and
(4) Surveillance systems to maintain elimination.

Lessons learned: Lessons learned include the need for strong political commitments
and secure financial flow, the need for planning and training to ensure campaign
effectiveness, and the need for community engagement to prevent misconceptions and
delays in implementation. Important operational principles learned from the MNTE effort
include the utility of supplemental immunization activities to target vulnerable populations
lacking regular health coverage, and the difficulty of surveillance in such populations,
particularly for neonates. During the Q&A, an audience member asked whether mothers
will opt for vaccination when the only health risk of the pathogen is to their child. UNICEF's
observation was that for tetanus this has not been a problem, and that acceptance has
been excellent so long as disease burden is clear (i.e. mothers are aware of the health
risks of tetanus to their child).

                      Summary of operational challenges and next steps for tetanus

 Operational Challenges                                           Next Steps
 Most vulnerable population often not reachable                   Explore possible integrations and innovations to
 through regular service - High-risk approach                     counter prevailing access and security issues.
 proved effective
 Wide variations exist in access to services                      Demand creation by engaging communities and
 within & between countries                                       health workers
 Missed opportunities during referral (EPI                        Expand partnerships and resource mobilization
 center ↔ ANC Clinic)                                             efforts to bridge funding gap of US$ 90 million.
 TT Vaccination coverage – credited to                            Stay vigilant; periodically monitor progress in
 EPI efficiency                                                   all countries
 Difficulties in monitoring protection –                          Strengthen existing health services to achieve
 serosurveys not an easy alternative.                             >80% TT/Td coverage and >70% access to
                                                                  clean delivery
 Gaps in neonatal tetanus Surveillance while                      Programmatic integrations to minimize missed
 limited data on maternal tetanus.                                opportunities
Source: "Maternal and Neonatal Tetanus Elimination (MNTE)" presentation, Dr. Azhar Abid Raza

Group B Streptococcal Infections in Neonates and Young Infants
Carol J. Baker, M.D. (Baylor College of Medicine, Executive Director of the Center for
Vaccine Awareness and Research at Texas Children’s Hospital)

Brief summary: Group B streptococcus (GBS) causes pneumonia, meningitis and sepsis
in neonates and is associated with high rates of mortality and morbidity. Incidence of
GBS in LIC/LMIC is not well established and under reporting is believed to be significant.
Vaccine development is in the clinical stage with promising safety and immunogenicity
but efficacy is yet to be established.

Background and disease burden: GBS disease burden is estimated at 0.5 per 1,000
live births globally, but is believed to be underreported due to lack of laboratory
confirmation capacity in many countries. Surveillance studies have shown that GBS is
more common in AFRO (~2 cases per 1000 live births), but uncommon in SEARO (~0.02
cases per 1000 live births). The studies that make up the surveillance data have varying
detection mechanisms and methodology, and more consistent data is needed to confirm
the true disease burden in many places. The case fatality rate is at least 10% (higher in
AFRO). Among the ~25% who develop meningitis, ~50% of survivors are left with severe
disability. GBS is also thought to cause stillbirth in 1% of infected women. In the United
States and other high income countries, intrapartum prophylactic antibiotics are given to
GBS colonized mothers - an effective strategy, cost and operationally prohibitive in
LIC/LMIC. More accurate disease burden and impact estimates represent a key
knowledge gap, as infection rates and confirmation of sepsis are difficult to assess owing
to poor surveillance and detection.

Status and future of GBS vaccine: There are at least 2 GBS vaccines in development,
as Novartis currently has one GBS vaccine in clinical development and another
manufacturer has a vaccine in pre- clinical development. In the former, phase 2 trials in
non-pregnant and pregnant women indicate safety and immunogenicity, but efficacy has
yet to be demonstrated. It is unclear whether this vaccine will continue on to a clinical
case driven phase 3 efficacy trial due to the need for a very large study population
(~80,000 pregnant women). While the Novartis vaccine is trivalent and has a ~85%
serotype coverage, there is interest in increasing valency to improve vaccine coverage.
Although GBS vaccines will likely be marketed in developed countries, assessing clinical
efficacy in populations with low disease burden and alternative prophylactic antibiotic
treatments may prove difficult. Thus, a GBS vaccine may be a candidate for surrogate
efficacy endpoints (e.g. immunogenicity), or clinical trials in developing countries where
disease burden is higher.

Summary of key gaps and next steps for GBS

 Gaps                                                               Actions
 Epidemiology: disease burden and health                            Laboratory defined sepsis (blood/CSF cultures
 impact in the developing world                                     “always”)
 Multivalent vaccine to provide greatest                            Active, population-based, laboratory surveillance
 efficacy (Ia, Ib, II, III, IV, V)                                  of early- and late-onset disease and CPS type %
 Novel licensing pathway for resource rich                          Initial R & D of multivalent cost-favorable vaccine
Source: "Group B Streptococcal Infections in Neonates and Young Infants" presentation by Carol J. Baker, M.D.

Jussi Mertsola (Turku University Hospital, Finland)

Brief summary: Pertussis infection occurs in all age groups, but pertussis mortality
primarily affects young infants in the first few months of life. Existing vaccines have good
safety and efficacy profiles, however, short duration of protection and high vaccine cost
(for acellular vaccinations) pose issues for LIC implementation.

Background and disease burden: Pertussis is estimated to cause ~60,000 deaths per
year in children under 5, though there may be significant underreporting due to the
variable range of symptoms and lack of laboratory confirmation. ~90% of mortality occurs
in the first few months of life and may therefore be addressable by maternal immunization.
Immunity wanes over time and is mostly lost by 8.5 years after the last vaccination,
necessitating rational planning of infant vaccination timing, consideration of boosters, and
appropriate post-vaccination surveillance. It is possible that this limited immunity is due
to the use of acellular pertussis vaccines; however, the safety profile of whole-cell
vaccines is generally not considered favorable for use in pregnant women.

Vaccine status: Immunity to pertussis wanes over time, which has resulted in spikes in
pertussis cases and a resurgence in neonatal pertussis mortality in developed countries
over the last two decades. A recent UK study showed that maternal immunization with
trivalent Tdap was ~90% effective against pertussis in infants under three months of age.
Safety in pregnant women has also been established, with no evidence of accelerated
time to delivery, increased risk of stillbirth, hemorrhage, or low birth weight. PAHO
countries have also provided Tdap via maternal immunization, and may provide important
learnings for future maternal immunization efforts. Lower-cost alternatives to trivalent
Tdap, such as PT-only Tdap and a pertussis-toxoid-only vaccine, are being considered
for maternal immunization applications in LIC/LMIC. During the Q&A session, several
attendees raised the point that pertussis vaccines are already provided in many AFRO
countries. It will therefore be important to determine what vaccine is given during
pregnancy, how this will affect current vaccination schedules, and whether boosters will
be necessary.

Summary of key gaps and next steps for pertussis

 Key gaps                                 Implications if not addressed      Desired actions
 Disease burden in first                  Lower impact of pertussis MI       Conduct active surveillance
 months of life in LIC/LMIC                                                  studies to quantify disease
          Potential under                                                   burden in infants
           reporting due to                                                         Use lab confirmation to
           lack of laboratory                                                        identify positive cases
           confirmed cases
 Impact of maternal                       Dampening of immune response       Conduct controlled trials to
 immunization on childhood                to childhood vaccination leading   evaluate the impact of maternal
 DTwP vaccination                         to increased burden in infants     immunization with aP on
                                          and children                       childhood vaccination with wP
Source: "Pertussis" presentation, Jussi Mertsola

Respiratory Syncytial Virus
Eric A.F. Simões, MB, BS, DCH, MD (University of Colorado, Denver)

Brief summary: Deaths from Respiratory syncytial virus (RSV) occur primarily in children
under 6 months of age, and early live cases can result in significant morbidity. High
maternal antibody titers are effective in protecting against the virus and vaccines against
RSV are currently in clinical development. One monoclonal antibody providing passive
immunity against RSV is in use in developed countries for vulnerable populations.

Background and disease burden: Globally, near-ubiquitous infection with RSV is
estimated to cause between ~66k-199k deaths annually in children under 5, concentrated
primarily in the first 6 months of life. Case fatality rates are estimated to be between ~2-
10%, with higher rates concentrated in LIC/LMIC. Even in non-fatal cases, RSV can result
in asthma and recurrent wheezing later in life. RSV is seasonal and patterns of infection
vary between regions.

Early evidence for maternal immunization and vaccine status: High maternal
antibody titers have been shown to reduce the risk of neonatal RSV and resulting asthma,
indicating the potential of maternal immunization to address a high percentage of
neonatal RSV deaths. Achieving high antibody titers over the period required to provide
neonatal protection may be challenging, however, due in part to natural antibody longevity
and in part to the effects of background disease burdens such as HIV and malnutrition.
Novavax currently has an RSV F protein-based vaccine in phase II clinical trials that has
shown good immunogenicity and safety in women of child-bearing age. A multi-dose
monoclonal antibody (palivizumab) is effectively used in high-income countries in
premature infants to increase passive immunity against RSV. MedImmune is currently
developing an alternative to palivizumab for prophylaxis in healthy infants that is single-
dose, and may therefore be simpler, less expensive, and more attractive for LIC/LMIC.

                                  Summary of key gaps and next steps for RSV

Key gaps                                Implications if not addressed                  Desired actions
 Accurate identification of              Under estimation of the disease                Active surveillance studies with
 RSV burden in infants in                burden and MI impact                           Focus on first 6 months especially
 the developing world                                                                   Indian subcontinent, China,
 Understanding the kinetics              Overestimate the potential                     RSV neut antibody kinetics
 of RSV antibody transfer                impact of MI                                   studies in different epidemiologic
 and longevity                                                                          backgrounds
 Disease burden in                       Might impact licensure in                      Active surveillance studies
 pregnant women                          industrialized nations                         focusing on pregnant women
 Effect of MI on recurrent               Potential missed economic                      Long term follow up with subjects
 wheezing                                opportunity and burden                         in clinical trials
Source: "Respiratory Syncytial Virus" presentation, Eric A.F. Simões, MB, BS, DCH, MD

                         Evidence Base: Conclusions and Key Takeaways

    1. Evidence base in LIC/LMIC must be strengthened for neonates and young infants,
       who have the poorest data quality but highest predicted disease burden.
    2. Efforts to improve the evidence base, both for burden of disease and vaccine
       efficacy, should include birth outcomes, fetal health, severe disease and
       hospitalization, and information from autopsies.
    3. Diagnostic tools and guidelines must be improved and standardized to accurately
       estimate disease burden, especially for pertussis.
    4. Tetanus may provide a good learning agenda for the maternal immunization

Part 3: Regulatory

Context and Session Goals
Keith Chirgwin (BMGF, Deputy Director of Regulatory Affairs)

Maternal immunization poses a unique challenge for regulators, who must consider the
safety and efficacy not only for the pregnant woman who receives the vaccine, but also
for the fetus and infant. Developers of maternal immunization vaccine candidates must
design clinical trials to take into account specific requirements for licensure of a vaccine
intended for pregnant women. After primary licensure, the vaccines must also achieve
marketing authorization in the target low-income and lower-middle income countries (LIC
/ LMIC), a path that may be aided by World Health Organization (WHO) prequalification
and regional regulatory partnerships such as the African Vaccine Regulatory Forum
(AVAREF) and the African Medicines Regulatory Harmonization Programme (AMRH).
The current vaccine candidates are at different points in clinical development, which
provides an opportunity for companies to engage early with regulators, and design clinical
programs that will achieve impact in LIC/LMIC soon after licensure. The goal of this
session is to determine the unique challenges for maternal immunization in safety,
efficacy, labeling, and regulatory pathways into LIC/LMIC, and to outline a path forward.

                        Regulatory pathways in LIC/LMIC and current vaccine status

Source: "Context and Session Goals" presentation, Keith Chirgwin 1. Lower middle income countries/lower income countries 2. EMA
program which allows EMA to issue a scientific opinion for medicines not intended to be used in the EU. 3. Most advanced candidate.
4. Pre-qualification, 5. Pertussis toxoid, 6. 3-Valent Note: NRA – National Regulatory Agency; EMA – European Medicines Agency;

Vaccines for Use in Pregnancy, US Food and Drug Administration (FDA)
Marion Gruber (US FDA)

Brief summary: Current FDA labels do not include prescribing information for pregnancy
unless clinical trials have been performed in pregnant women, but this does not preclude
the use of such vaccines during pregnancy. Indications for use in pregnant women would
require clinical trials in pregnant women to demonstrate safety and efficacy. Depending
on the specific vaccine, the FDA may consider alternative efficacy endpoints. Additionally,
the FDA can provide advice to sponsors for the development of vaccines not intended for
use in the US through its investigational new drug (IND) program.

Labeling for maternal immunization vaccines in the US: US labeling provisions
require that prescribing information summarizes the information essential for safe and
effective use without implying indications or uses. As a result, although there are no
vaccines specifically licensed for use during pregnancy in the US, this does not preclude
their use for maternal immunization. Re-labeling a vaccine to include an indication
specifically for pregnant women, however, would require clinical trials demonstrating
safety and efficacy in this population. Starting in June 2015, the updated Pregnancy and
Lactation Labeling Rule (PLLR) will alter labeling to allow manufacturers to provide a
concise narrative of risks and benefits of administration during pregnancy based on
human or animal data. This is intended to assist healthcare professionals in advising
women on the use of drugs during pregnancy and lactation.

Considerations for demonstrating safety and efficacy in pregnant women: In order
to identify pregnant women as an intended subgroup in indications, product-specific
safety and efficacy data in pregnant women must be generated in controlled studies with
pre-specified endpoints. This applies equally to vaccines already recommended by global
health bodies for use in pregnancy (influenza, Tdap) and to new vaccines (RSV, GBS).
Clinical trials in pregnant women must assess safety in both mother and infant, including
maternal adverse event monitoring, pregnancy outcomes, perinatal events, and postnatal
events (infant growth and development). Assessments of clinical efficacy will depend on
the intended indication, for example prevention of disease in mother, infant, or both.
Alternative efficacy endpoints, for example maternal immune response, may be
permissible but would require discussion with the FDA. Assuming sufficient safety and
efficacy can be demonstrated, the FDA is willing to provide US licensure for vaccines
intended for use outside of the US.

Ethical Considerations for Maternal Vaccine Research in Low Resource Settings
Amina White (NIH Department of Bioethics)

Brief summary: Ethical guidelines for conducting maternal immunization research in low
resource settings (e.g. LIC/LMIC) were provided, including how to ensure that the host
country is not exploited and that all participants are provided a favorable risk/benefit

Avoiding exploitation of the host country: It is unethical to exploit developing countries
for the purposes of conducting a clinical trial. Exploitation occurs when a country receives
an unfair level of benefit or is forced to carry an unfair burden of risk. A specific situation
in which the latter may occur is in the design of clinical trial control groups: experimental
intervention should not be tested against a no-treatment control but against the best
proven therapy that is globally available and plausible to provide. Exceptions to this rule
may be warranted if no effective intervention exists, if there is minimal harm in withholding
the proven intervention, or compelling scientific methodological reasons require it (and
there is no added risk of serious harm) (CIOMS 2002, 2013 Declaration of Helsinki). It is
also important to avoid "helicopter research" performed in a community that will not
receive the benefits of that research (e.g. in the case of clinical trials performed in
LIC/LMIC but ultimately meant to benefit HIC alone).

Ensuring a favorable risk/benefit profile for participants: All clinical trials involve a
level of risk and the potential for benefit. Acceptable study risks are determined in relation
to the prospect of benefit, and risks must be kept as low as possible without compromising
study objectives. In the specific case of pregnant women, accurate risk assessment is
challenging due to the tendency to overestimate the risk of intervention and
underestimate the risk of failing to intervene. The Council for International Organizations
of Medical Sciences (CIOMS) has also provided ethical guidelines specific to pregnant
women, which states that research in pregnant women is acceptable when it is relevant
to the health needs of the pregnant woman, fetus, or pregnant women in general and,
when appropriate, reliable evidence from animal models is available regarding risks of
teratogenicity and mutagenicity. In general, a good guideline to establishing a reasonable
risk/benefit profile is to ask the question, "would an informed doctor recommend
participation in the study, based solely on the risks and potential benefits to the

Additional considerations: During the Q&A, several important questions were raised
that were not decisively answered, but merit further discussion: (1) What balance should
be struck between community ethics and individual ethics when deciding whether to
conduct a clinical trial, and how does the physician's role as advocate for individual
patients affect this balance? (2) How should the recommendations of international and
local institutional review boards (IRBs) be weighted when they conflict, and how can local
IRBs be engaged better and earlier? (3) Is it ethical to use vaccines off-label in pregnant
women indefinitely, or are clinical studies ethically necessary?

Panel: Safety, Efficacy, and Labeling
Panel Lead: Keith Chirgwin (BMGF)
Panel Participants: Patrick Zuber (WHO), Laurent Brassart (EMA), Boonchai
Somboonsook (Thai FDA)

Brief summary: Panel participants discussed the clinical path to safety, efficacy, and
labeling to support maternal immunization uptake in LIC/LMIC.

What should be considered in evaluating safety to support maternal immunization
indications? There is a clear desire to establish safety more rigorously through
controlled, randomized trials and careful monitoring of perinatal and postnatal adverse
events. Doing so will require better measurements of the background adverse event rate
in pregnant women, particularly in LIC/LMIC, in order to accurately evaluate the risks of
maternal immunization. Ethical study design is a top priority, with recommendations that
phase I trials to establish safety be performed in healthy, non-pregnant adults. The Thai
FDA perspective is that approval of vaccines for maternal immunization by a strong NRA
would also increase confidence and likelihood of uptake by LIC/LMIC.

What should be considered in evaluating efficacy to support maternal
immunization indications? The evaluation of efficacy in maternal immunization should
ideally include several features. First, trials should be performed on pregnant women, and
show clear efficacy either for the mothers, infants, or both. Immune response may be an
acceptable endpoint if trial design precludes efficacy as an endpoint. Second, trials should
ideally be randomized and controlled. Finally, it is important to show that protection of
mothers and/or infants is of sufficient duration to have a significant impact.

What is considered appropriate labeling to support a recommendation for routine
use of a vaccine in pregnant women? Labeling for use in pregnant women must require
rigorous safety and efficacy standards, and must be as clear as possible to assist
healthcare professionals in safely and effectively administering the vaccine. Where
labeling for pregnant women is not warranted due to lack of data, it is unclear whether a
statement should be made to indicate that the product has not been tested in pregnant
women. Doing so may avoid undue risk to pregnant mothers and to manufacturers
seeking to avoid liability. However, there are cases in which the risks of not being
vaccinated may outweigh the risks of vaccination, and such labels may do more harm
than good. In these cases, the major challenge is to accurately communicate the risks of
intervention versus nonintervention. Pharmaceutical companies must also be proactive
in updating labels whenever possible to incorporate the latest safety and efficacy data.

Regulatory Pathway (WHO Prequalification)
Carmen Rodriguez Hernandez (WHO), Olivier Lapujade (WHO)

Brief summary: The WHO prequalification program verifies the quality, efficacy and
safety of vaccines to facilitate registration and use in developing countries. Attaining
prequalification is essential for implementation of maternal immunization in LIC/LMIC, as
it is required for major funding mechanisms.

What is prequalification? Prequalification (PQ) is a service offered by the WHO to UN
purchasing agencies. It provides an independent opinion on the quality, efficacy and
safety of vaccines, and ensures that they are suitable for the target population. To achieve
this, PQ evaluates the NRA of the export country, clinical data from vaccine trials, the
vaccine manufacturing process, and the quality of the actual product to determine

whether it meets WHO requirements. If the vaccine is prequalified and licensed, the WHO
also performs ongoing tests to ensure continued vaccine quality.

Process of prequalification: Selection of new vaccines for PQ is performed on a priority
basis determined in part by demonstrated need and efficacy. Once selected for PQ, a
vaccine must go through 30-90 days of screening followed by ~ 270 days of internal time,
something that is currently being optimized to reduce time to licensure. For already
prequalified vaccines that require re-labeling, for instance in the case of adding an
indication for pregnant women, only ~90 days would be required. This can be done
simultaneously with NRA labeling approval to reduce total labeling time.

Relevance to maternal immunization: The UN already supplies WHO prequalified
vaccines for maternal immunization including vaccinations against tetanus and influenza.
For vaccines with existing WHO prequalification but without a label supporting use in
pregnant women, a labeling change will require that the responsible NRA for PQ to
approve a label change followed by a type A approval by WHO PQ. Supporting data for
such a label change may include clinical, pharmacovigilance, or other data. Challenges
to WHO PQ for vaccines intended for use in pregnant women include a lack of currently
available data supporting safety and efficacy, and reluctance from manufacturers due to
liability concerns.

                    Regulatory: Conclusions and Key Takeaways

   1. Clinical trials must satisfy stringent ethnical concerns, and provide sufficient safety
      and efficacy data, to result in an indication for maternal immunization.
   2. There is limited data available on maternal immunization, and what is available
      may not be reflected in labeling. This may in part be addressed by the FDA
      pregnancy and lactation labeling rule (PLLR).
   3. Accurate measures of disease burden and efficacy are crucial to establishing
      whether maternal immunization has a favorable risk/benefit profile.
   4. A major challenge in effectively labeling vaccines for maternal immunization will
      be to accurately communicate the risks of intervention versus the risks of
      nonintervention, in order to avoid obstructive fears of vaccination in the face of
      serious disease.

Part 4: Policy

Context and Session Goals
Jon Abramson (SAGE, Wake Forest Medical School), Elizabeth Mason (Former Director

Brief summary: Maternal immunization policy straddles both Vaccine and Maternal,
Newborn, and Child Health (MNCH) policy. As such, it is important to understand the
policy setting landscapes for both, including key players and issues at the global level,
and considerations for translating global policy to the country level. The goal of this
session was to determine the requirements for maternal immunization policy
recommendations by Vaccine and MNCH policy-makers at the global and country level.

                                     Matrix view of potential policy-makers

Source: "Context and Session Goals" presentation, Jon Abramson. 1. Strategic Advisory Group of Experts on Immunization. 2.
Reproductive health/ Maternal, newborn, child and adolescent health. 3. Reproductive maternal newborn child health

Vaccine policy: The Strategic Advisory Group of Experts on Immunization (SAGE) at the
World Health Organization (WHO) is the normative global policy setter for Vaccines.
SAGE receives inputs from multiple committees and partners to understand the evidence
base and impact of a vaccine, in order to weigh the risks and benefits of a vaccination
strategy and make its final recommendation. Other key players include regional and
national technical advisory groups (NITAGs). Translating global policy recommendations
to country-level policy is not always straightforward, as each country needs to prioritize
and weigh the risk / benefit for each vaccine. The process for this assessment is often
delayed in part because some NITAGs are more functional than others. Vaccine policy
has typically focused on saving young children, but integration with MNCH will bring with
it new emphasis on saving mothers as well, and on improving training for midwives and
birth attendants.

MNCH policy: Global MNCH policy is determined primarily by United Nations agencies
such as the WHO. National governments then set country level policy based on global
recommendations, as well as inputs from expert advisory groups, donors and NGOs.
Maternal mortality reduction has not made the same progress in the last few decades as
under-5 mortality reduction. MNCH sees the potential integration of maternal
immunization into the package of standard care for pregnant women as a significant step
forward for their objectives. This approach has received interest from the WHO.

Historical Vaccine Learnings
Kate O'Brien (Johns Hopkins University)

Brief summary: This presentation detailed key learnings for driving adoption of new
vaccines in the developing world, and how these learnings can be applied to maternal
immunization policy discussions.

Difficulty of accelerating vaccine adoption in LIC/LMIC: There are multiple
stakeholders and activities that must be coordinated in an iterative fashion to enable
policy recommendations, program introduction, and impact generation. During the Q&A,
the idea of establishing maternal immunization as its own program similar to the
expanded program on immunization (EPI) was largely dismissed in favor of greater
integration with existing healthcare systems. Each vaccine also poses unique policy
challenges, as does the setting (country) in which it will be used, requiring customized
approaches to ensure success.

Factors that influence the pace and extent of new vaccine adoption: Evidence of
disease burden is the starting point for driving vaccine demand and adoption. Strategic
planning for the investments needed to demonstrate disease burden starts with literature
review, an assessment of how new data can change estimates, targeted study design,
and adaptation of existing data to facilitate policy-making within countries. However,
compelling disease burden and the existence of an efficacious vaccine are not sufficient
criteria to drive country-level adoption. Adequate financing, consistent supply, and
appropriate policy are also required. Financing solutions must be creative, long term, and
tightly linked to the recommendations for vaccine usage; a particular concern raised
during the Q&A was the financing situation for MICs that have graduated from GAVI and
must therefore secure sustainable vaccine funding themselves. Supply issues can also
disrupt adoption/impact and should be forecasted early and proactively. Finally, a strong
global recommendation and appropriate country-level policy are essential for driving
adoption both directly, and indirectly through facilitating financing and supply. Policy
decisions will be influenced by technical alignment and consensus within the Vaccine and
MNCH communities.

Factors that influence country-level policy setting

Source: "Historical Vaccine Learnings" presentation by Kate O'Brien

Implications for maternal immunization: Maternal immunization is largely considered
to be in the "establish and organize evidence" phase. Key considerations for maternal
immunization therefore include technical consensus on disease burden and the safety
and efficacy of vaccines, a vaccine administration schedule, planning for adequate
vaccine supply and financing, foresight into operational issues, plans for monitoring of
impact and safety, and alignment of the specific implementation plan with global policy
recommendations. Country-level policy decisions pose a particular challenge, and hinge
on coverage, acceptability, feasibility, and affordability.

Panel: Vaccine Policy - From Global to Regional/Country
Panel lead: Helen Rees (WRHI and University of Witwatersrand)
Panel participants: Azhar Raza (UNICEF), Fredrick Were (University of Nairobi, Kenya),
Carla Vizzotti (MoH, Argentina), Adenike Grange (Former MoH, Nigeria)

Brief summary: The main drivers of vaccine decision-making at a country level are
burden of disease, safety, and cost benefit considerations. Confidence in the level of
disease burden and vaccine safety may be bolstered by global recommendations (e.g.
from the WHO), inclusion of maternal immunization within trusted existing programs, and
efforts to increase buy-in at the community and healthcare provider levels. Understanding
of country culture, structure and leadership will be important to successfully achieve buy-
in at the country level. Appropriate representation of MNCH and vaccine policymakers on
regional and country NITAGs would greatly improve country-level policy setting.

How can we drive global maternal immunization policy at the regional / country
level? Driving maternal immunization policy at the country level will first require
understanding the country's epidemiology, concerns and objectives. While most countries
are concerned with the evidence base, efficacy and safety of vaccines in pregnant
women, individual countries often have unique considerations or objectives that may not
be fully understood by outside countries or policy makers.
Common country-level concerns include cost-benefit, whether long-term financing is
secure enough to ensure a sustainable maternal immunization platform, the level of
difficulty in integrating maternal immunization into existing antenatal care infrastructure
(something requiring cooperation with MNCH), and whether the various internal
stakeholders of a given country are properly aligned. In some places, there is enough
evidence to begin advocating for and implementing maternal immunization today.
Due to their epidemiological profile (an already decreasing maternal and U5 mortality)
capacity for stronger and more secure financing, as well as the relative strength of their
ANC programs and capacity for pharmacovigilance, middle income countries may be an
easier starting point for maternal immunization. Argentina's experience implementing
maternal immunization for pertussis and influenza may provide a learning experience for
the entire platform.

New WHO Antenatal Care Guidelines and Relevance to Maternal Immunization
Metin Gulmezoglu (WHO)

Brief summary: This presentation reviewed the current process for ongoing review and
revision of antenatal care (ANC) guidelines at the WHO, and specific considerations that
must be addressed for maternal immunization to be included in the new guidelines for the

History and purpose of WHO ANC guidelines: Since 2002, the WHO ANC Guidelines
have served as a roadmap for countries describing which interventions should be
included in ANC and when. Goals include health promotion, disease prevention, early
detection of and treatment for complications, birth preparedness, and complication

Process for updating of ANC guidelines: ANC guidelines identify which evidence-
based practices during the ANC period improve outcomes, and specify how these
practices must be delivered to achieve impact. These guidelines are updated using the
DECIDE framework (Developing and Evaluating Communication strategies to support
Informed Decisions and practice based on Evidence) and input from expert panels.

Importance of integrating new interventions within ANC: When considering routes to
implementation of maternal immunization, an important consideration is its relationship to
ANC. Consensus was reached that successful integration of maternal immunization into
ANC would have better outcomes than a vertical maternal immunization program, due to
the ability to leverage existing healthcare systems and the simplicity (for patients) of
integrated care. However, successful integration is not guaranteed. Integration

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