Malaria kills over one million people each year. Most malaria deaths occur in Africa and most of the victims are children under five. An effective, affordable vaccine would greatly reduce the morbidity, mortality, and economic burden imposed by malaria. Work proposed here will investigate an approach to malaria immunization modeled on oral vaccines against human adenoviruses that have been used safely and effectively in millions of people for over three decades. The goals of the proposal are live recombinant adenovirus vaccines that are administered orally, protective in one dose, and inexpensive to produce, properties that would make them ideal for use in the resource-poor areas where most malaria deaths occur. Recombinant vaccine candidates will express pre-erythrocytic Plasmodium falciparum antigens that induce protective immunity in primates: circumsporozoite protein (PfCSP) and liver stage antigen 3 (PfLSA- 3). Antigens will be produced either as fusions with major viral capsid proteins designed to display antigenic epitopes on the surface of the recombinant particles (capsid display recombinants), by a novel system developed in this laboratory for high-level expression of genes inserted into the adenovirus major late transcriptional unit (MLTU recombinants), or both (compound recombinants). Both methods of antigen expression have been used successfully in viable recombinants in this laboratory. Recombinants will be characterized in vitro for antigen production and growth properties and selected recombinants will be evaluated for the ability to induce humoral and cell-mediated immune responses in Aotus, a primate model permissive for replication of recombinants. Aotus are also susceptible to infection by P. falciparum sporozoites and will be used to determine ability of recombinants to protect against experimental malaria challenge. These studies will address the feasibility and efficacy of enteric immunization with live adenovirus recombinants and will provide information essential in considering clinical trials of oral recombinant malaria vaccines.

Public Health Relevance

Malaria kills roughly one million children per year, most of those in developing nations in Africa. The goal of this project is to develop an inexpensive oral vaccine that protects immunized individuals against infection by Plasmodium falciparum, the cause of the most severe form of malaria. The work is focused on creating, characterizing and testing genetically engineered adenoviruses that produce malaria proteins and induce immunity to malaria after vaccination with a single tablet given by mouth.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
MO, Annie X Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Public Health
United States
Zip Code
Karen, Kasey A; Deal, Cailin; Adams, Robert J et al. (2015) A replicating adenovirus capsid display recombinant elicits antibodies against Plasmodium falciparum sporozoites in Aotus nancymaae monkeys. Infect Immun 83:268-75
Berg, Michael G; Adams, Robert J; Gambhira, Ratish et al. (2014) Immune responses in macaques to a prototype recombinant adenovirus live oral human papillomavirus 16 vaccine. Clin Vaccine Immunol 21:1224-31
Deal, Cailin; Pekosz, Andrew; Ketner, Gary (2013) Prospects for oral replicating adenovirus-vectored vaccines. Vaccine 31:3236-43
Gilson, Timra; Greer, Amy E; Vindigni, Alessandro et al. (2012) The ýý2 helix in the DNA ligase IV BRCT-1 domain is required for targeted degradation of ligase IV during adenovirus infection. Virology 428:128-35
Palma, Christopher; Overstreet, Michael G; Guedon, Jean-Marc et al. (2011) Adenovirus particles that display the Plasmodium falciparum circumsporozoite protein NANP repeat induce sporozoite-neutralizing antibodies in mice. Vaccine 29:1683-9
Greer, Amy E; Hearing, Patrick; Ketner, Gary (2011) The adenovirus E4 11 k protein binds and relocalizes the cytoplasmic P-body component Ddx6 to aggresomes. Virology 417:161-8