T Cell Epitope Regions of the P. falciparum MSP1-33 Critically Influence Immune Responses and In Vitro Efficacy of MSP1-42 Vaccines

Abstract

The C-terminal 42 kDa fragments of the P. falciparum Merozoite Surface Protein 1, MSP1-42 is a leading malaria vaccine candidate. MSP1-33, the N-terminal processed fragment of MSP1-42, is rich in T cell epitopes and it is hypothesized that they enhance antibody response toward MSP1-19. Here, we gave in vivo evidence that T cell epitope regions of MSP1-33 provide functional help in inducing anti-MSP1-19 antibodies. Eleven truncated MSP1-33 segments were expressed in tandem with MSP1-19, and immunogenicity was evaluated in Swiss Webster mice and New Zealand White rabbits. Analyses of anti-MSP1-19 antibody responses revealed striking differences in these segments' helper function despite that they all possess T cell epitopes. Only a few fragments induced a generalized response (100%) in outbred mice. These were comparable to or surpassed the responses observed with the full length MSP1-42. In rabbits, only a subset of truncated antigens induced potent parasite growth inhibitory antibodies. Notably, two constructs were more efficacious than MSP1-42, with one containing only conserved T cell epitopes. Moreover, another T cell epitope region induced high titers of non-inhibitory antibodies and they interfered with the inhibitory activities of anti-MSP1-42 antibodies. In mice, this region also induced a skewed TH2 cellular response. This is the first demonstration that T cell epitope regions of MSP1-33 positively or negatively influenced antibody responses. Differential recognition of these regions by humans may play critical roles in vaccine induced and/or natural immunity to MSP1-42. This study provides the rational basis to re-engineer more efficacious MSP1-42 vaccines by selective inclusion and exclusion of MSP1-33 specific T cell epitopes.

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

“…T cell responses to epitopes within the PfMSP1 33 domain can provide help for the production of PfMSP1 19 -specific antibodies (29,59,60), but this region of MSP1 is only semiconserved among P. falciparum isolates (47) and can lead to allele-specific responses. Furthermore, there is some evidence that the presence of certain T cell epitopes within PfMSP1 33 impedes the development of memory T cells (61) and/or protective antibody responses to PfMSP1 19 (62). In the P. yoelii model, improved vaccine efficacy has been demonstrated by replacement of PyMSP1 33 with promiscuous CD4 ϩ T cell epitopes from the N-terminal regions of PyMSP1 (63).…”

A Hybrid Multistage Protein Vaccine Induces Protective Immunity against Murine Malaria

“…To test whether the strategy of using an autologous promiscuous T cell epitope to enhance the immunogenicity of linear epitopes can also be applied for nonlinear structured domains, we subsequently designed a synthetic gene encoding a chimeric recombinant protein comprising four autologous promiscuous T cell epitopes assembled in tandem and fused to the carboxy-terminal domain of the PyMSP-1 (PyMSP-1 19 ) (27). The synthetic gene was codon optimized for expression in Escherichia coli, and the chimeric protein, which we have called P. yoelii recombinant modular chimera (PyRMC), was used for comparative experiments along with a recombinant protein that only expressed the native PyMSP-1 19 . After experimental challenge, PyRMC induced protection against both hyperparasitemia and severe anemia that was robust in comparison to the protective efficacy induced by the native PyMSP-1 19 .…”

“…The synthetic gene was codon optimized for expression in Escherichia coli, and the chimeric protein, which we have called P. yoelii recombinant modular chimera (PyRMC), was used for comparative experiments along with a recombinant protein that only expressed the native PyMSP-1 19 . After experimental challenge, PyRMC induced protection against both hyperparasitemia and severe anemia that was robust in comparison to the protective efficacy induced by the native PyMSP-1 19 . Most importantly, PyRMC induced functional antibodies with the ability to protect against heterologous challenge (27).…”

Longevity of Genotype-Specific Immune Responses to Plasmodium falciparum Merozoite Surface Protein 1 in Kenyan Children from Regions of Different Malaria Transmission Intensity

“…17,18 MSP1 19 contains conserved B-cell epitopes, whereas MSP1 33 contains T-cell epitopes. [19][20][21] Immune responses to these antigens as measured by enzyme-linked immunosorbent assay and enzyme-linked immunosorbent spot assays (ELISPOT) assays may serve as useful correlates of vaccine efficacy. A recent meta-analysis of population-based cohort studies found that individuals with IgG responses to the MPS1 19 antigen had lower risk of clinical malaria than those without IgG responses.…”

“…9 However, at least one study has shown that as a vaccine candidate, MSP1 19 alone is not protective unless the MSP1 33 fragment is included to provoke cell-mediated responses. 21 Thus, a better understanding of the relative contributions of humoral and cellular immunity to MSP1 are necessary for continued development and evaluation of this vaccine candidate.…”