The advantage of mucosal immunization for polysaccharide‐specific memory responses in early life

Abstract

The aim of vaccination is to rapidly elicit protective immunity and generate memory for sustained protection. We studied the induction and persistence of polysaccharide (PS)-specific memory in neonatal and infant mice primed with pneumococcal conjugate (Pnc1-TT) by assessing the response to native pneumococcal PS (PPS-1), the kinetics of the PPS-1-specific IgG response to a second Pnc1-TT dose and affinity maturation. A subcutaneous (s.c.) Pnc1-TT booster induced a rapid increase in PPS-1-specific IgG, indicating efficient priming for memory by a single dose of Pnc1-TT already at 1 week of age. High levels were maintained for >12 weeks. However, a PPS-1 booster induced no response in neonatal or infant mice. The adjuvant LT-K63 significantly enhanced the IgG response and affinity to Pnc1-TT by both the s.c. and the intranasal (i.n.) route in all age groups. In neonatal and infant mice, PPS-1 and LT-K63 induced a booster response only when given i.n. following either s.c. or i.n. priming with Pnc1-TT and LT-K63. In contrast, PPS-1 with or without LT-K63 administered s.c. compromised the ongoing PPS-1-specific response elicited in neonatal mice by either s.c. or i.n. priming with Pnc1-TT and LT-K63. These results demonstrate the advantage of the mucosal route for elicitation of PS-specific memory responses in early life.

Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

“…Our previous studies have shown that immunization of mice with conjugate vaccines can induce PS Abs and protective immunity in early infancy, but both immunogenicity and protective efficacy is significantly lower than in adults [34,42]. This murine infant immunization model against S. pneumoniae clearly reproduces the main features of human infant immune responses to native capsular PPS and pneumococcal conjugate vaccines, as shown for serotypes 1, 6B and 19F, as well as the relative protective efficacy of such vaccines.…”

“…Unresponsiveness of lymphoid-mediated signals at the level of neonatal follicular dendritic cell precursors has recently been shown to be a major limiting factor, leading to limitations in germinal center induction, Ab-secreting cells and Ab response [43]. Age-dependent limiting factors for Ab responses to conjugate vaccines have not yet been fully identified, but we have recently shown that the immunization route affects the recall response to PPS in mice primed with a conjugate as neonates [42]. Here, we show that a weak carrier-specific T cell response obtained after immunization with a monovalent pneumococcal conjugate vaccine in early life is responsible for the low levels of IgG Abs to the PPS.…”

The Adjuvant LT-K63 Can Restore Delayed Maturation of Follicular Dendritic Cells and Poor Persistence of Both Protein- and Polysaccharide-Specific Antibody-Secreting Cells in Neonatal Mice

“…Avidity of IgG Abs was measured by ELISA with a kaliumthiocyanate (KSCN) elution step (19). Cell wall PS-neutralized standard and sera (1:50)…”

“…Using an early-life murine model of pneumococcal vaccination and challenge that reproduces the main features of human infant response to pneumococcal conjugate vaccines (16), we have reported that coadministration of the nontoxic adjuvant LT-K63 (nontoxic mutant of Escherichia coli heat-labile enterotoxin) (17,18) with pneumococcal polysaccharide of serotype 1 conjugated to tetanus toxoid (Pnc1-TT) enhances protection against pneumococcal infection, correlating with enhanced PPS-specific Ab levels (16), avidity (19), and activation of B cells, T cells (20), and dendritic cells in spleen (21).…”

Mucosal delivery of vaccines in domestic animals

“…Other reasons for using mucosal routes of immunization include the practicability of administering the vaccine without injections, and therefore the reduction of injection site reactions, and the possibility of vaccination at a very early age of life in the presence of passively acquired maternal antibodies (Tab. I) [15].…”