Challenges for the Newborn Immune Response to Respiratory Virus Infection and Vaccination

Abstract

The initial months of life reflect an extremely challenging time for newborns as a naïve immune system is bombarded with a large array of pathogens, commensals, and other foreign entities. In many instances, the immune response of young infants is dampened or altered, resulting in increased susceptibility and disease following infection. This is the result of both qualitative and quantitative changes in the response of multiple cell types across the immune system. Here we provide a review of the challenges associated with the newborn response to respiratory viral pathogens as well as the hurdles and advances for vaccine-mediated protection.

Keywords: adaptive immunity; innate immunity; newborn; respiratory infection; respiratory viruses; vaccines.

Figure 1

The neonate immune system has alterations that span both the innate and adaptive arms, both of which are important in viral clearance. Within the innate arm, NK cells have functional deficiencies that include decreased cell adhesion due to a reduction in selectins, reduced TNFα production, and increased inhibitory receptors. The number of neonatal PDCs is reduced as well as the amount of type I IFN produced from these cells. Potent adaptive immune responses are dependent on the capacity of DCs to undergo maturation together with the robust activation, differentiation and survival of T and B cells. DCs from newborns are challenged in this process, as they have decreased capacity to respond to PAMPs through TLR and RIG-I receptors resulting in impaired costimulatory molecules (CD40, CD80 and CD86) expression as well as diminished IL-12p70 production that is essential for the differentiation of CD4 TH1 cells and CD8⁺ T cells. There is also increased IL-4 production from newborn DCs. The low levels of IL-12p70 accompanied by increased IL-4 production skews the differentiation of CD4⁺ T cell towards TH2 cells. Decreased IL-12p70 impacts the CD8⁺ T cell differentiation leading to decreased production of IFNγ. Neonates also have heightened Treg responses. There are functional defects in neonatal Tfh cells including limited expansion leading to poor GC responses and reduced production of high affinity, isotype switched Ab.

Figure 2

Eliminating the window of vulnerability of neonates to respiratory infection. The window of vulnerability describes the timeframe wherein maternal-derived antibody and infant-derived antibody levels are low and as a result there is minimal protection against pathogen infection. The combination of maternal antibody, which provides protection early following birth and infant-derived antibody, generated by vaccination in the first months following delivery, would limit the window of vulnerability. Maternal antibody level can be enhanced by vaccination during pregnancy at a time that allows maximal production and transplacental transfer of high affinity IgG (red line). Vaccination and boost of newborns soon after birth allows the production of antibody by the infant to reach protective levels (green line) prior to waning of maternal antibody to a level that is no longer protective (blue line).