Abstract
An ideal malaria vaccine platform should potently induce protective immune responses and block parasite transmission from mosquito to human, and it should maintain these effects for an extended period. Here, we have focused on vaccine development based on adeno-associated virus serotype 1 (AAV1), a viral vector widely studied in the field of clinical gene therapy that is able to induce long-term transgene expression without causing toxicity in vivo. Our results show the potential utility of AAV1 vectors as an extremely potent booster vaccine to induce durable immunity when combined with an adenovirus-priming vaccine in a rodent malaria model. We generated a series of recombinant AAV1s and human adenovirus type 5 (AdHu5) expressing either Plasmodium falciparum circumsporozoite protein (PfCSP) or P25 (Pfs25) protein. Heterologous two-dose immunization with an AdHu5-prime and AAV1-boost (AdHu5-AAV1) elicited robust and durable PfCSP- or Pfs25-specific functional antibodies over 280 days. Regarding protective efficacy, AdHu5-AAV1 PfCSP achieved high sterile protection (up to 80% protection rate) against challenge with transgenic Plasmodium berghei sporozoites expressing PfCSP. When examining transmission-blocking (TB) efficacy, we found that immunization with AdHu5-AAV1 Pfs25 maintained TB activity in vivo against transgenic P. berghei expressing Pfs25 for 287 days (99% reduction in oocyst intensity, 85% reduction in oocyst prevalence). Our data indicate that AAV1-based malaria vaccines can confer potent and durable protection as well as TB efficacy when administered following an AdHu5 priming vaccine, supporting the further evaluation of this regimen in clinical trials as a next-generation malaria vaccine platform.
Highlights
In response to the threat posed by emerging resistance to artemisinin-based chemotherapy and insecticide-treated bed nets, efforts to develop potent malaria vaccines as a complementary tool in eradicating the disease have recently been intensified [1]
The luminescence signal increased gradually from day 0 to day 7, reaching the peak within 10 days (1010 p/s/cm2/sr); as expected, robust luciferase expression persisted for up to 252 days (Figures 1A,B). This result indicates that our associated virus serotype 1 (AAV1) vector system can efficiently transduce muscle cells and achieve durable expression of the transgene product in mouse muscle, consistent with other studies showing a high level of stable transgene expression after an i.m. injection of AAV serotype 1 or 2, lasting for 1–5 years [30,31,32]
Immunofluorescence Assay (IFA) analysis showed that Pfs25-VSV-G in cells infected with either virus was expressed in the cytoplasm and on the surface of the cells (Figure 4C). These results suggest that the Pfs25-VSV-G on the surface of the infected cells might retain the three-dimensional structure of the native Pfs25 protein, which is essential for the induction of antibodies with TB functionality [38]
Summary
In response to the threat posed by emerging resistance to artemisinin-based chemotherapy and insecticide-treated bed nets, efforts to develop potent malaria vaccines as a complementary tool in eradicating the disease have recently been intensified [1]. Because of the moderate efficacy of the RTS,S vaccine, the Malaria Vaccine Roadmap has updated their strategic goals from the development of vaccines with 80% protective efficacy against P. falciparum by 2020 to the development of second-generation malaria vaccines for malaria elimination in multiple settings that are highly efficacious against the disease by 2030 [1, 5] Achieving this goal would require current control strategies to be complemented by new breakthroughs in vaccine development. The development of a TBV capable of inducing long-term TB immunity for at least one transmission season (∼6 months), to be combined with effective pre-erythrocytic stage vaccines, would be an advantageous strategy [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
