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Challenges in Infant Immunity

Workshop Summary

June 3–4, 2010

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Workshop Goals

A workshop, “Challenges in Infant Immunity,” organized by NIAID and co-sponsored by NIAID’s Division of Allergy, Immunology, and Transplantation (DAIT) and the Bill & Melinda Gates Foundation (BMGF), was convened on June 3–4, 2010. Participants discussed the subject of infant (age from birth to 12 months) immunity and how to develop improved prevention and therapeutic strategies against infection for infants throughout the world.

The specific goals of the workshop were the following:

  • Understand and assess the current scientific knowledge regarding infant immunity
  • Identify key knowledge gaps in infant immunity that affect generation and maintenance of protective immunity to infections
  • Foster collaborations amongst investigators studying infectious disease pathogenesis, vaccine design and development, and immune mechanisms in infants

This report summarizes the key knowledge gaps identified in each of four topic areas.

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Workshop Structure

Following introductory presentations by NIAID and BMGF on their perspectives of infant immunity, the workshop was divided into four sessions based on the following topic areas:

  • Development of the immune system in neonates and infants
  • Infant immunity and disease manifestations
  • Challenges in the clinic; infections/vaccines; successes, limitations, and future challenges
  • Early life immunity in the developing world

The final session was an open discussion to identify the key knowledge gaps that emerged from each topic area. 

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NIAID and BMGF Perspectives on Infant Immunity

Mercy Prabhudas, Ph.D., from DAIT, discussed the importance of understanding immune system development in infants and the unique immune characteristics at this stage that, if understood, would provide a basis for designing better interventions for improving the health and mortality of this vulnerable population. Globally, approximately 4,000,000 children less than 6 months of age die each year at a rate of 450 deaths per hour. In addition, high hospitalization costs for infected infants are incurred in the United States with an annual estimated cost of $690,000,000.

Although the infant immune system most often suffices to allow survival to adulthood, a significant number of newborns and infants are vulnerable to severe infections due to impaired responses to a range of pathogens and vaccine. For example, polysaccharide-encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis, are leading causes of serious infection in young children worldwide. Moreover, vaccines are lacking for some childhood pathogens, such as respiratory syncytial virus, that often cause acute infections in infants. Furthermore, studies evaluating bacterial and viral vaccines have shown that immunity wanes after vaccination and requires multiple boosters to maintain immunological memory and protection in this population. The need for more comprehensive study of the newborn and infant immune system is particularly important in light of the fact that the majority of vaccines are given in the pediatric age range, yet the basis for age-specific vaccine efficacy is very poorly understood.

An integral part of NIAID's mission (PDF) and NIH's mission is to understand the mechanisms involved in immune regulation and immune protection. This knowledge base will enable the development of better treatments and strategies to prevent infectious, immunologic, and allergic diseases that afflict millions in the United States and around the world.

NIAID’s Advisory Council recently approved a 2012 concept on the "Infant Immune System: Implications for Vaccines and Response to Infections."

Chris Wilson, M.D., from BMGF, presented the interests and mission of BMGF that complement those of NIAID in developing ways to fight and prevent diseases in infants living in resource-limited countries. BMGF focuses on supporting studies where there are gaps in knowledge and science and creating critical technologies in areas where current tools are lacking. Dr. Wilson provided a global health perspective using vaccines to enteric infections as an example. Reduced efficacy of certain vaccines, such as rotavirus and poliovirus vaccines, appears to be related predominantly to environmental causes, including impaired nutrition, immune status, and concurrent infections, likely in concert with genetic differences. Thus, a global view and approach is essential for understanding why neonates and young infants are unduly susceptible to infection-related death and disability.

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Session 1: Development of the Immune System in Neonates and Infants

Topics in this session covered the current understanding of infant innate and adaptive immune responses, peripheral lymphoid organ development, development of the mucosal immune system, and maternal-fetal immune interactions in utero.

The speakers in this session included the following investigators:

  • Rebecca (Becky) Adkins, Ph.D. (University of Miami)
  • Tobias Kollmann, M.D., Ph.D.  (University of British Columbia, Vancouver)
  • David B. Lewis, M.D. (Stanford University)
  • Joseph (Mike) McCune, M.D., Ph.D. (University of California, San Francisco)
  • Josef Neu, M.D. (University of Florida, Gainesville)

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Summary of Key Knowledge Gaps Identified During Session 1

  • Molecular mechanisms governing early life immune system development
  • Factors that shape the ‘normal’ immune ontogeny  (e.g., host genetics vs. environment vs. both), to understand possible consequences of modification of the normal immune ontogeny
  • Regulation of immune suppression versus  immune activation in infants
  • Contribution/consequences of nutrition and the microbiome on immunity in early life
  • Epigenetic influences and how they impact the developing immune system
  • Biomarkers to better understand and predict vaccine efficacy, persistence, and immune memory in infants
  • Better tools to study human immune responses in different organ systems of the neonate (e.g., gut or respiratory tract)
  • The reevaluation of outliers, in terms of immune responses, in clinical and animal  studies

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Session 2: Infant Immunity and Disease Manifestations

The second session covered immune development in urban neighborhoods and the risk of allergic diseases; the impact of nutritional status, infant transplantation, and congenital immune deficiencies on infant immune development.  In addition, an alternative method was proposed for diagnosis of infections in infants.

The speakers in this session included the following investigators:

  • James Gern, M.D. (University of Wisconsin, Madison)
  • M. Louise Markert, M.D., Ph.D. (Duke University)
  • Sophie Moore, Ph.D. (Medical Research Council (MRC) International Nutrition Group, MRC Keneba, The Gambia)
  • Octavio Ramilo, M.D. (Nationwide Children’s Hospital and Ohio State University)
  • Stuart Sweet, M.D., Ph.D. (Washington University in St. Louis)

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Summary of Key Knowledge Gaps Identified During Session 2

  • Safe and effective vaccines for pre-term infants and infants with congenital immune deficiencies or who have undergone organ/tissue transplantation
  • Methods to prescreen infants for primary immune deficiency diseases to reduce the risk of complications from live vaccines
  • Effects of nutrients and supplements on infant immune system development and function
  • The contribution of a maternal history of asthma and seasonal effects on immunity to vaccines and infections in inner-city children with asthma
  • Effects of nutritional status on immune system development and vaccine efficacy in infants in global communities
  • Determination of pathogen-specificity of maternal antibodies in the infant and elucidation of possible mechanisms of maternal antibody-induced immune suppression in infants

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Session 3: Translational Studies: Challenges in the Clinic

Topics in this session covered the development of immunity to vaccines and infections, mechanisms to enhance vaccine efficacy, and alternative modes of immune protection for the infant.

The speakers in this session included the following investigators:

  • Carol J. Baker, M.D. (Baylor College of Medicine)
  • Hayley Gans, M.D. (Stanford University)
  • Volker Gerdts, D.V.M., Ph.D. (University of Saskatchewan)
  • Ruth Karron, M.D. (Johns Hopkins University)
  • Ofer Levy, M.D., Ph.D. (Children’s Hospital, Boston and Harvard Medical School)
  • Claire-Anne Siegrist, M.D., Ph.D. (World Health Organization Collaborating Center for Neonatal Vaccinology and the University of Geneva, Switzerland)
  • James Wynn, M.D. (Duke University)

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Summary of Key Knowledge Gaps Identified During Session 3

  • Development of large animal models, e.g., pigs and nonhuman primates, which are crucial for  studying fetal, neonatal, and infant stages of immune development, and responses to infections and vaccines
  • Development of human and animal in vitro models to study human vaccine immune responses
  • Understanding neonatal sepsis by a detailed analysis of current clinical cohorts in the US and overseas to study the following:
    • Mechanisms and biomarkers
    • The effect of intravenous immunoglobulin (IVIg) on very low birth weight (VLBW) babies using global clinical cohorts
  • Need for longitudinal studies of currently licensed vaccines and adjuvants using new immunologic assays to expand understanding of the immune response in the infant
  •  Novel methods and technologies to analyze small volumes of blood for immune system changes, and standardization of methods that can be applied across centers
  • Mechanisms of vaccine interference in infants
  • Reevaluation of vaccination schedules in infants to minimize interference and maximize efficacy
  • Effects of vaccine dosages and novel adjuvants on vaccine efficacy in infants
  • Effects of vaccination of pregnant or nursing mothers on immune status of infants
  • Development of immune-based therapies to protect children with primary immune deficiency disease
  • Mechanism of immune suppression by regulatory T cells in infants
  • T cell memory development and long-term persistence to vaccines in infants

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Session 4:  Early Life Immunity in the Developing World

Topics in this session covered infant immune responses to infections, vaccines, and co-infections, and fetal parasitic infections in developing countries.

The speakers in this session included the following investigators:

  • Willem Hanekom, M.D. (University of Cape Town, South Africa)
  • Christopher King, M.D., Ph.D. (Case Western Reserve University)
  • Martin Ota, Ph.D. (Medical Research Council, The Gambia)
  • Sarah Rowland-Jones, M.A., B,.M., B.Ch., D.M. (Medical Research Council, University of Oxford, England, and The Gambia)

Key knowledge gaps from Session 4 are summarized below.

Summary of Key Knowledge Gaps Identified During Session 4

  • The impact of co-infections on vaccine efficacy in the developing world
    • During pregnancy
    • In neonates at time of vaccination
    • Effects of anti-infectious therapies  in mothers and infants prior to vaccination
  • The effect of exposure to infections in utero and in neonatal life on subsequent innate and adaptive responses to vaccines or infections
  • Effects of vaccine dosage, co-administration of multiple vaccines, and timing of vaccination on vaccine efficacy in infants in the developing world
  • Effects of genetic and epigenetic influences within global cohorts on innate or adaptive immune responses to standardized antigenic stimuli (confounding factors that affect data analysis and interpretation)

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Last Updated January 07, 2011

Last Reviewed January 04, 2011