Analysis of human immune responses to malaria vaccines containing a universal T helper epitope of Plasmodium falciparum CS protein

Plasmodium parasites transmitted by the bite of infected mosquitoes cause 400 to 500 million cases of malaria each year with over 1 million deaths in children younger than 5 years, primarily due to infection by P. falciparum. The increase in multidrug-resistant parasites and insecticide-resistant vectors have made development of a malaria vaccine a public health priority.; To develop a vaccine for P. falciparum, minimal T and B cell epitopes of the P. falciparum circumsporozoite (CS) protein, identified by sera and cells of malaria protected volunteers, were included in synthetic and recombinant subunit vaccines. The vaccines contained the immunodominant B cell epitope and a T helper epitope from the CS repeat region combined with a universal Th epitope, T*, from the C terminus of the CS protein. Preclinical evaluation of these subunit vaccines in mice and monkeys demonstrated the induction of high levels of parasite neutralizing antibodies to CS repeats and strong T cell responses to the T* universal Th epitope. In Phase I trials of a synthetic peptide vaccine containing these minimal epitopes, the majority of the volunteers developed parasite specific humoral and cellular responses.; CD4+ T cell clones from peptide immunized volunteers were comparable in fine specificity and function to previously described clones derived from sporozoite immunized volunteers: (i) the T* epitope was immunodominant, with low frequency (<1%) of clones specific for the CS repeat epitopes; (ii) the T* specific clones were restricted by multiple HLA class II molecules and additional new restriction elements were identified; (iii) the peptide induced T cells recognized full length recombinant CS protein and secreted large quantities of gamma-IFN, a central mediator in protective immunity to malaria; (iv) the peptide-induced T* specific T cells also recognized variant T* peptides representing known polymorphisms of the CS protein.; These findings support further studies of subunit vaccines that can mimic immunity elicited by sporozoite immunization and suggest new strategies to improve the responses elicited by these vaccines.