Generation of a universal CD4 memory T cell recall peptide effective in humans, mice and non-human primates

Abstract

CD4T cells play a key role in humoral immunity by providing help to B cells, enabling effective antibody class switching and affinity maturation. Some vaccines may generate a poor response due to a lack of effective MHC class II epitopes, resulting in ineffective helper T cell activation and recall and consequently poor humoral immunity. It may be beneficial to provide a CD4T cell helper peptide with a vaccine particularly in the case of a poorly immunogenic antigen. Such a T cell helper peptide must be promiscuous in its ability to bind a broad range of MHC class II alleles due to broad allelic variation in the human population. We designed a chimeric MHC class II peptide (TpD) with epitopes from tetanus toxoid and diphtheria toxoid, separated by an internal cathepsin cleavage site. TpD was capable of inducing a memory recall response in peripheral blood mononuclear cells from 20/20 human donors. T cells responding to TpD showed a central memory phenotype. Immunization of mice with a synthetic nicotine nanoparticle vaccine containing TpD showed that the peptide was required for robust antibody production and resulted in a long term CD4 memory T cell recall response. As a pre-clinical model two non-human primate species, rhesus macaques and cynomolgus monkeys, were immunized with a nicotine nanoparticle vaccine and evaluated for an anti-nicotine antibody response and TpD specific memory T cells. We found that 4/4 rhesus monkeys had both sustained antibody production and TpD memory T cells for the duration of the experiment (119 days). In addition 30/30 cynomolgus monkeys dosed with nicotine vaccine nanoparticles showed dose-dependent antibody generation and T cell recall response compared to saline injected controls. In summary we have developed a potent universal memory T cell helper peptide (TpD) that is active in vitro in human PBMCs and in vivo in mice and non-human primates.

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

“…It is also argued that this epitope also bears at least one B cell epitope (323)(324)(325)(326)(327)(328)(329)(330)(331)(332)(333)(334)(335)(336)(337)(338)(339), however, there is only one study that has mentioned the presence of the B cell epitope [327]. In a study by Sun et al, it was shown that 50% of the B cell response generated by the OVA protein was antibody specific to the OVA323-339 epitope [327].…”

“…In a study by Sun et al, it was shown that 50% of the B cell response generated by the OVA protein was antibody specific to the OVA323-339 epitope [327]. As the vaccine structures (G1-6) contain the CD4 epitope (OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339], the in vivo ability of vaccine structures (G1-9) for a T cell activation proliferation was assessed. Here, OT-II proliferating cells are considered to be activated when T cells expressing CD45.2 increase in percentage over the total parental CD4 + T cells [329].…”

“…As a result, it is important for a successful vaccine to have the ability of CD4 + T cell activation to generate a subsequent antibody response [330]. activation.…”

“…The OVA protein naturally exists as a glycoprotein, however, it was discovered that the OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] and OVA 1-10 sequences of the OVA protein bore a B cell epitope that was capable of inducing a T cell response. This discovery was obtained by T cell mediated IgE responses that were observed against an assumed B cell epitope inside OVA323-339 and OVA1-10 peptides [185].…”

“…Upon T cell antigen specific activation, Th1 or Th2 pathways get activated ( Figure 5-1) [344]. The advantage of Th2 activation is that it generates long-term memory immunity, compared with Th1 which gives an immediate cellular response [330]. However, an advantage of Th1 activation is its involvement in cytotoxicity enabling the elimination of a specific pathogen [307].…”