Every year, more than 400 million people suffer from malarial infection worldwide, leading to at least 1 million deaths, most attributable to Plasmodium falciparum, the most virulent of the human infective malaria parasites. Effective control of malaria will require development and application of an efficacious malaria vaccine. Unfortunately, efforts in developing a malaria vaccine over many decades have yielded limited success. The most advanced vaccine to date, RTS,S, which is based on a P. falciparum antigen expressed during the initial infection and during liver stage development, is currently in Phase II trials. In the most recent analysis RTS,S achieved less than 20% efficacy; other vaccine constructs and antigenic targets have had even lower success rates. Thus, new platforms for antigen delivery should be investigated to improve vaccine efficacy. Parainfluenza virus 5 (PIV5), a paramyxovirus, is thought to be a contributing factor for causing kennel cough in dogs and is not known to cause any illness in humans. Several characteristics of PIV5 make it an attractive vaccine vector. First, kennel cough vaccines containing live PIV5 have been used in dogs for over 30 years. Humans are likely exposed to this virus due to close contact to dogs. In our preliminary studies, we have found that about 30 percent of humans have neutralizing antibodies against PIV5; however, no recorded illness in humans has been attributed to the virus. Second, PIV5 can be produced in high titers in many cells, including Vero cells that have been approved for vaccine production. Third, PIV5 can infect human cell lines and primary human cells. Fourth, in our recent study, we have found that pre-existing immunity against PIV5 does not negatively affect immunity generated by a PIV5-based vaccine. Fifth, a single dose immunization of PIV5 expressing HA, an antigen of influenza virus, protects against lethal influenza virus challenge in mice, and a single dose immunization of PIV5 expressing G, an antigen of rabies virus, protects lethal rabies virus challenge in mice. Also, PIV5 expressing the NP protein of influenza virus (PIV5-NP) provides broad protection against different subtypes of influenza viruses. Compared to the most commonly used viral vectors such as adenovirus (AdV)- or vaccinia virus (VV)-based vectors expressing NP, PIV5 is the most efficacious. Together, these results demonstrate that PIV5 is an effective vaccine vector. Finally, needle free administration (intranasal and oral) immunization is an advantage as a vaccine vector for malaria since endemic areas are often resources-limited. We hypothesize that PIV5 is an effective vaccine vector for malaria. In this proposal, we plan to demonstrate the proof-of principal for using PIV5 as a vector for malaria vaccine development. We will focus our efforts on the following specific aims: 1) Generate and analyze recombinant PIV5 expressing human malaria antigen CSP; and 2) Evaluate immunogenicity and efficacy of recombinant viruses in vivo.
Malaria infects more than 400 million people, leading to at least 1 million deaths worldwide annually. Unfortunately, efforts in developing a malaria vaccine over many decades have yielded limited success and the most advanced vaccine to date, RTS,S achieved less than 20% efficacy. Parainfluenza virus 5 (PIV5), a paramyxovirus, is an excellent vaccine vector. In this proposal, we seek to demonstrate the proof-of principal for using PIV5 as a vector for malaria vaccine development.
