Human newborns are highly susceptible to infection due to functionally distinct innate and adaptive immune responses. Successful immune defense relies on a fine balance between an effective inflammatory response to infection (disease resistance) and adequate anti-inflammatory mechanisms to prevent uncontrolled inflammation (disease tolerance).
The passive transfer of maternal immunity is considered central to anti-microbial defenses in early life. The proposed mechanisms center around active transport of maternal IgG through the placenta, providing systemic immunity during the first months after birth until the infant actively acquires immunity through exposure to pathogens or vaccines. Maternal immunization has the potential to substantially reduce morbidity and mortality from infectious diseases after birth. However, many gaps in knowledge regarding the immunobiology of maternal immunization prevent the optimal design and application of this successful public health intervention. Examples of those gaps are the clinical relevance of vaccine interference by maternal antibodies in terms of the active immunity induced in the infant by natural infection or immunization, the impact of vaccine antigen and timing of vaccination in pregnancy on passive antibody transfer, etc.
Effective early life immunization is another area of intense research but remains a moving target due to dynamic changes of the immune system over the first year of life. Emerging literature suggests that vaccines can have immunomodulatory effects beyond initiating antigen-specific adaptive responses. Epidemiologic studies have linked live attenuated vaccines given during the neonatal or infantile period (particularly BCG, the Bacille Calmette-Guerin vaccine against tuberculosis) to an unanticipated reduction in all-cause mortality, which greatly exceeds a reduction in mortality attributable to vaccine-specific disease prevention. Observational studies and randomized-controlled trials in Guinea-Bissau have shown near halving of neonatal mortality in low-birth weight children vaccinated with BCG at birth. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infections and fever. These observations suggest BCG and other live vaccines induce “heterologous” protection against antigenically diverse, unrelated pathogens. Similar to vaccines, early life infections can have effects on the unique neonatal immune system. One such observation is the association of bloodstream infections in critically ill preterm newborns with enhanced pathogen-specific mononuclear cell pathogen recognition receptors (PRR) expression in the setting of subsequent Gram-positive or Gram-negative bacteremia, which suggests that the neonatal innate immune system can remember previous activation such that responses to subsequent microbial challenges are altered. Similarly, histologic chorioamnionitis affecting preterm infants is associated with a significantly reduced risk of late onset sepsis, both with coagulase-negative Staphylococcus (most common) and other bacteria, implying that perinatal inflammation may enhance functional maturation of the preterm immune system.
One of the suggested mechanisms for heterologous protection against infection is innate immune memory, also known as “trained immunity”. It is posited that human innate immune memory may be mediated by changes in the number and function of innate immune cells with low turnover, such as NK cells and macrophages, but the molecular mechanisms are now starting to be unraveled. Newer data suggest that epigenetic and metabolic reprogramming of hematopoietic progenitors may account for long-term maintenance of trained immunity and its benefits. Immunization strategies leveraging vaccine-induced innate immune memory in a controlled way could be used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous boosters in later infancy. In addition to reducing overall risk of infection in vulnerable populations, vaccine-induced heterologous immunomodulatory effects can impact multiple facets of future health, such as propensity to allergic and autoimmune diseases.
List of subjects, which will be addressed:
- The immunobiology of maternal immunization and effects on fetal/infant immunity
- Strategies to boost immunization during pregnancy
- Vaccines to prevent congenital infections: how close are we?
- Harnessing trained immunity in national immunization programs
- Details matter: putting data into action to optimize global immunization practices
- Precision vaccinology in the era of OMICS
- Sex differences in vaccine responses
- Vaccine interactions with the Microbiome: do they define health and disease?
- The BCG experience: safety, immunogenicity, heterologous effects
- Vaccines to prevent neonatal sepsis
Human newborns are highly susceptible to infection due to functionally distinct innate and adaptive immune responses. Successful immune defense relies on a fine balance between an effective inflammatory response to infection (disease resistance) and adequate anti-inflammatory mechanisms to prevent uncontrolled inflammation (disease tolerance).
The passive transfer of maternal immunity is considered central to anti-microbial defenses in early life. The proposed mechanisms center around active transport of maternal IgG through the placenta, providing systemic immunity during the first months after birth until the infant actively acquires immunity through exposure to pathogens or vaccines. Maternal immunization has the potential to substantially reduce morbidity and mortality from infectious diseases after birth. However, many gaps in knowledge regarding the immunobiology of maternal immunization prevent the optimal design and application of this successful public health intervention. Examples of those gaps are the clinical relevance of vaccine interference by maternal antibodies in terms of the active immunity induced in the infant by natural infection or immunization, the impact of vaccine antigen and timing of vaccination in pregnancy on passive antibody transfer, etc.
Effective early life immunization is another area of intense research but remains a moving target due to dynamic changes of the immune system over the first year of life. Emerging literature suggests that vaccines can have immunomodulatory effects beyond initiating antigen-specific adaptive responses. Epidemiologic studies have linked live attenuated vaccines given during the neonatal or infantile period (particularly BCG, the Bacille Calmette-Guerin vaccine against tuberculosis) to an unanticipated reduction in all-cause mortality, which greatly exceeds a reduction in mortality attributable to vaccine-specific disease prevention. Observational studies and randomized-controlled trials in Guinea-Bissau have shown near halving of neonatal mortality in low-birth weight children vaccinated with BCG at birth. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infections and fever. These observations suggest BCG and other live vaccines induce “heterologous” protection against antigenically diverse, unrelated pathogens. Similar to vaccines, early life infections can have effects on the unique neonatal immune system. One such observation is the association of bloodstream infections in critically ill preterm newborns with enhanced pathogen-specific mononuclear cell pathogen recognition receptors (PRR) expression in the setting of subsequent Gram-positive or Gram-negative bacteremia, which suggests that the neonatal innate immune system can remember previous activation such that responses to subsequent microbial challenges are altered. Similarly, histologic chorioamnionitis affecting preterm infants is associated with a significantly reduced risk of late onset sepsis, both with coagulase-negative Staphylococcus (most common) and other bacteria, implying that perinatal inflammation may enhance functional maturation of the preterm immune system.
One of the suggested mechanisms for heterologous protection against infection is innate immune memory, also known as “trained immunity”. It is posited that human innate immune memory may be mediated by changes in the number and function of innate immune cells with low turnover, such as NK cells and macrophages, but the molecular mechanisms are now starting to be unraveled. Newer data suggest that epigenetic and metabolic reprogramming of hematopoietic progenitors may account for long-term maintenance of trained immunity and its benefits. Immunization strategies leveraging vaccine-induced innate immune memory in a controlled way could be used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous boosters in later infancy. In addition to reducing overall risk of infection in vulnerable populations, vaccine-induced heterologous immunomodulatory effects can impact multiple facets of future health, such as propensity to allergic and autoimmune diseases.
List of subjects, which will be addressed:
- The immunobiology of maternal immunization and effects on fetal/infant immunity
- Strategies to boost immunization during pregnancy
- Vaccines to prevent congenital infections: how close are we?
- Harnessing trained immunity in national immunization programs
- Details matter: putting data into action to optimize global immunization practices
- Precision vaccinology in the era of OMICS
- Sex differences in vaccine responses
- Vaccine interactions with the Microbiome: do they define health and disease?
- The BCG experience: safety, immunogenicity, heterologous effects
- Vaccines to prevent neonatal sepsis