Susceptibility to infection is highest during the neonatal period, extending from birth to the age of 28 days [1]. Infection-related mortality, both overall and by type of infection, is higher in newborns than in any other age group. About 2.5 million neonatal deaths occur annually, accounting for almost half of all deaths in the under-fives. Epidemiological studies have estimated that about one third of these deaths are caused by infections, such as meningitis, encephalitis, pneumonia, sepsis, and diarrheal disease [2], [3], [4], [5], [6], [7], [8]. Microbiologically, the neonatal period is characterized by susceptibility to severe disease caused by microorganisms that display little virulence in older children and adults, including group B streptococcus (GBS), Escherichia coli (E. coli) K1 and respiratory syncytial virus (RSV) [9], [10], [11], [12]. These observations led to the development of the idea, relentlessly tested in the neonatal immunology field, that age-specific immunological mechanisms of vulnerability to ‘neonatal pathogens’ account for the high incidence of severe and fatal infections observed during the first few weeks of life. Intensive research, with its roots in the experiments on fetal immune tolerance conducted in the 1940 s and 1950 s [13], [14], has resulted in an extensive characterization of the adaptive and innate immune responses of newborns, highlighting the differences between newborns and adults [15], [16], [17], [18]. These studies paved the way for the establishment, during the 1990 s, of the widely accepted theory of ‘neonatal immune immaturity’, also known as ‘neonatal tolerance’ [19], [20], [21]. According to this theory, transitional neonatal immune responses reflect both the need for tolerance to the newly forming microbiota in various parts of the body and the need for appropriate, protective, inflammatory responses to microorganisms encountered during primary infections [22], [23], [24], [25]. The immune immaturity theory has recently been revisited, with the addition of novel hypotheses, including the ‘energy allocation hypothesis’, according to which, the neonatal immune system is not ‘immature’, with ‘immature’ defined as ‘not fully functional’ for the mounting of protective antimicrobial responses. Instead, there is an evolutionarily determined preference of tolerance over inflammation, with the immune system programmed to have a higher threshold for unleashing inflammatory responses, to ensure that as much energy as possible can be spared for growth [1], [26], [27], [28], [29]. Epidemiological, microbiological and immunological studies conducted over the last 80 years suggest that there are age-specific immunological mechanisms of vulnerability to neonatal pathogens.

These population-immunology studies focused on the ontogeny, physiology and development of the human immune system from gestation or birth, through infancy, making it possible to infer potential links to the higher incidence of specific infections at population level [9], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]. However, they were unable to identify reproducible, clinically useful immune parameters or ‘degrees’ of immune immaturity that could predict or mechanistically explain susceptibility or resistance to infection in individual newborns [1], [46]. Most of the known risk factors for vertically or horizontally transmitted severe infections act by increasing the risk of exposure to one or more microorganisms or by reducing anatomical barriers, in both full-term and preterm human newborns [47], [48], [49]. Immunologically, specific maternal antimicrobial antibodies (Abs), transmitted to the fetus via the placenta during pregnancy, are the principal factor known to explain a substantial proportion of the interindividual variability of protection against several microorganisms during the first few months of life [50]. No other known major immunological mechanism can explain susceptibility or resistance to a given infection in otherwise healthy human newborns to the same extent. Conversely, interindividual variability during the course of infection in older children and adults has increasingly been investigated by the clinical immunology field, through the use of a combined genetic and immunological approach, over the last 40 years or so, and single-gene inborn errors of immunity and their autoimmune phenocopies are now known to explain a substantial proportion of life-threatening infections in these age groups [51], [52], [53]. The fields of neonatal immunology and clinical immunology have progressed along parallel lines, but with little mutual interaction. In this review, I will analyze how our current understanding of neonatal age-dependent immunity can be reconciled with the increasingly recognized role of human genetic and immunological determinants of infection outcome. I will not discuss here the interplay between the microbiota and the early-life immune system, which is analyzed in other reviews of this issue of the Journal and elsewhere [54], [55]. I will mostly consider full-term newborn infants with no known comorbidities, unless explicitly addressing questions relating to preterm infants or fetuses. Finally, I will limit the discussion to the neonatal period, while bearing in mind that most of the considerations reported here are also valid for older infants during the first 3 to 12 months of life, a time window corresponding to ‘early life’, as defined later in this review.