Malaria is the most relevant parasitic disease that continues to have a significant global impact. Given the mortality burden associated with Plasmodium falciparum, malaria research efforts have been mainly devoted to the study of this parasite. However, among the five species of malaria parasites that affect humans, P. vivax is the most widely distributed and is responsible for 50% of the clinical cases outside Africa. Clinical and epidemiological evidence also indicate that vivax malaria can also be associated with severe disease and fatal complications. Available malaria control measures have shown a significant impact on reducing morbidity and mortality in the past decade. Unfortunately, these measures are not effective against P. vivax relapse infections that result from the activation of undetectable dormant stages forms that can remain latent in the liver for several weeks after the primary infection. The development of novel tools to control or prevent P. vivax malaria is therefore a global health priority. We have developed a multi-stage prime-boost vaccine regimen based on chimeric recombinant proteins and recombinant adenovirus vectors, using a stringent rodent model for proof- of-principle studies. This proposal will build on our experience producing recombinant adenovirus vectors to develop a novel vector with modified cell tropism to allow dendritic cells (DC)-specific targeting, using unique methodologies for genetic modification. We hypothesize that a tropism-modified adenovirus vector expressing a Plasmodium multi-stage chimeric antigen will improve the quality and longevity of the immune response.
Our specific aims are: 1) Construct an sdAb myeloid DC-targeted Ad encoding a multi-stage P. vivax chimeric antigen and validate cell specific gene delivery using murine DCs; 2) Characterize and compare the impact of DC targeting on the immunogenicity and efficacy in a stringent murine malaria model of protection. We will take advantage of the benefits of using the highly specific camelid-derived single domain antibody moieties (sdAb) for vector targeting to DCs. The vector will then be tested for immunogenicity in comparative proof-of- principle experiments in mice. We envision that our proposed studies will provide valuable data concerning the improvement of prime-boost immunization regimens for developing an effective vaccine against P. vivax.
Malaria caused by Plasmodium vivax is a major public health problem worldwide with the number of annual infections estimated to be between 13.4 and 24.6 million. The unique biological features of P. vivax with its resistance to traditional control measures have brought increased emphasis to the development of novel approaches to prevent or treat vivax malaria. We aim to develop an effective immunization regimen that includes a novel adenovirus vector genetically modified to change cellular tropism.
