Unresponsiveness to lymphoid-mediated signals at the neonatal follicular dendritic cell precursor level contributes to delayed germinal center induction and limitations of neonatal antibody responses to T-dependent antigens

The factors limiting neonatal and infant IgG Ab responses to T-dependent Ags are only partly known. In this study, we assess how these B cell responses are influenced by the postnatal development of the spleen and lymph node microarchitecture. When BALB/c mice were immunized with alum-adsorbed tetanus toxoid at various stages of their immune development, a major functional maturation step for induction of serum IgG, Ab-secreting cells, and germinal center (GC) responses was identified between the second and the third week of life. This correlated with the development of the follicular dendritic cell (FDC) network, as mature FDC clusters only appeared at 2 wk of age. Adoptive transfer of neonatal splenocytes into adult SCID mice rapidly induced B cell follicles and FDC precursor differentiation into mature FDC, indicating effective recruitment and signaling capacity of neonatal B cells. In contrast, adoptive transfer of adult splenocytes into neonatal SCID mice induced primary B cell follicles without any differentiation of mature FDC and failed to correct limitations of tetanus toxoid-induced GC. Thus, unresponsiveness to lymphoid-mediated signals at the level of neonatal FDC precursors delays FDC maturation and GC induction, thus limiting primary Ab-secreting cell responses to T-dependent Ags in early postnatal life

Induction of adult-like antibody, Th1, and CTL responses to measles hemagglutinin by early life murine immunization with an attenuated vaccinia-derived NYVAC(K1L) viral vector

Although initially developed in adult animals, novel viral vectors expressing recombinant measles antigens must eventually prove their success in the early life setting, where the efficacy of the currently used live-attenuated measles virus vaccine is limited. The immunological requirements for vaccine candidates include the generation of protective antibody responses as well as the induction of Th1 and cytotoxic T lymphocytes (CTL) responses, which is challenging in the neonatal setting. Here, we report that young BALB/c mice immunized with a single dose of a vaccinia-based NYVAC(K1L) vector generate adult-like antihemagglutinin (HA) antibody responses as well as adult-like Th1 and CTL responses. Despite this strong immunogenicity in early life, antibody responses (but not T-cell responses) to a single dose of NYVAC(K1L)-HA remained susceptible to inhibition by preexisting measles antibodies, calling for use of prime-boost strategies. NYVAC(K1L)-HA is the first attenuated live viral vector demonstrated as capable of inducing adult-like antibody, Th1, and CTL responses against measles in an early life murine immunization model, a capacity previously only reported for measles DNA vaccines

CpG oligodeoxynucleotides can circumvent the Th2 polarization of neonatal responses to vaccines but may fail to fully redirect Th2 responses established by neonatal priming

Neonatal murine responses to a panel of conventional vaccines differ qualitatively from adult responses by a particular polarization toward a Th2 pattern and a frequent limitation of the Th1 and CTL responses required for protection against intracellular microorganisms. In contrast, DNA vaccines induce adult-like Th1/CTL neonatal responses against the same vaccine Ags. In this report, we show that this can be related to their content in unmethylated CpG motifs. Oligodeoxynucleotides (ODN) containing CpG motifs activate neonatal APCs to produce IL-12 in vitro and induce adult-like Th1 responses to tetanus toxoid and measles Ags in vivo, with production of IgG2a-specific Abs and adult-like secretion of IFN-gamma and IL-5 by Ag-specific T cells. However, in spite of their capacity to trigger neonatal B cell proliferation in vitro, CpG-ODN only partially enhanced early life Ab responses. Finally, using Th1-driving CpG-ODN with the boosting dose of a protein vaccine was sufficient to redirect adult but not neonatally primed Th2 responses. These observations could be important for the development of novel vaccines that will have to be effective early in life

Adjuvant effects of CpG oligodeoxynucleotides on responses against T-independent type 2 antigens

Oligodeoxynucleotides containing CpG motifs (CpG-ODN) are potent in vitro B-cell activators and they have been successfully used to increase in vivo antibody responses to T-dependent peptide and protein antigens. In contrast, the use of CpG-ODN to enhance in vivo antibody responses to various T-independent type 2 (TI-2) antigens has recently generated contradictory results. In this study, we compared the CpG-ODN stimulatory effect on antibody responses of adult and young BALB/c mice to trinitrophenylaminoethyl-carboxymethyl (TNP) -Ficoll and to polysaccharides (PS) from several distinct serotypes of Streptococcus pneumoniae (SPn). CpG-ODN co-administration significantly enhanced antigen-specific immunoglobulin M (IgM), IgG, IgG1 and IgG2a titres to TNP-Ficoll. The depletion of CD4(+) cells by monclonal antibodies (GK1.5) identified their essential role in CpG-ODN-mediated enhancement of antibody responses. In contrast to TNP-Ficoll, CpG-ODN failed to enhance IgM and IgG responses to any of the 18 SPnPS serotypes tested. Providing T-cell epitopes by the conjugation of SPnPS to the carrier protein tetanus toxoid again allowed CpG-ODN to mediate enhancement of IgG, IgG2a and IgG3 responses to most SPnPS serotypes. Thus, antigen-presenting cell/T-cell interaction appears to largely mediate the in vivo influence of CpG-ODN on antibody responses to TI-2 antigens. In early life, additional factors limit CpG-ODN modulation of antibody responses to TI-2 antigens