Preclinical Development and Assessment of Viral Vectors Expressing a Fusion Antigen of Plasmodium falciparum LSA1 and LSAP2 for Efficacy against Liver-Stage Malaria

Abstract

Despite promising progress in malaria vaccine development in recent years, an efficacious subunit vaccine against Plasmodium falciparum remains to be licensed and deployed. Cell-mediated protection from liver-stage malaria relies on a sufficient number of antigen-specific T cells reaching the liver during the time that parasites are present. A single vaccine expressing two antigens could potentially increase both the size and breadth of the antigen-specific response while halving vaccine production costs. In this study, we investigated combining two liver-stage antigens, P. falciparum LSA1 (PfLSA1) and PfLSAP2, and investigated the induction of protective efficacy by coadministration of single-antigen vectors or vaccination with dual-antigen vectors, using simian adenovirus and modified vaccinia virus Ankara vectors. The efficacy of these vaccines was assessed in mouse malaria challenge models using chimeric P. berghei parasites expressing the relevant P. falciparum antigens and challenging mice at the peak of the T cell response. Vaccination with a combination of the single-antigen vectors expressing PfLSA1 or PfLSAP2 was shown to improve protective efficacy compared to vaccination with each single-antigen vector alone. Vaccination with dual-antigen vectors expressing both PfLSA1 and PfLSAP2 resulted in responses to both antigens, particularly in outbred mice, and most importantly, the efficacy was equivalent to that of vaccination with a mixture of single-antigen vectors. Based on these promising data, dual-antigen vectors expressing PfLSA1 and PfLSAP2 will now proceed to manufacturing and clinical assessment under good manufacturing practice (GMP) guidelines.

Pre-Erythrocytic Vaccines against Malaria

“…More recently, a viral-vectored malaria vaccine that combined Pf TRAP with the highly conserved merozoite proteins, liver-stage antigen 1 (LSA1) and the liver-stage-associated protein 2 (LSAP2), was developed. Nevertheless, neither its immunogenicity nor protective efficacy were significantly impacted with the inclusion of these two proteins [ 59 , 60 , 61 ].…”

Synthetic DNA Vaccines Adjuvanted with pIL-33 Drive Liver-Localized T Cells and Provide Protection from Plasmodium Challenge in a Mouse Model

“…When T cells lack CXCR6, a cell surface marker highly expressed by liver-infiltrating CD8 T cells, there is a reduction of liver-associated memory and sporozoite immunity [22]. Very recent studies (including this report) support that CD8 tissue resident memory T cells appear important for targeting of LS malaria following vaccination [23][24][25]. It appears that LS antigens represent important candidates for inducing protective CD8+ T cell responses in the attenuated sporozoite model.…”

“…Pre-erythrocytic subunit vaccines in clinical development have shown limited success in clinical trials. Several studies have reported that T cell immunity to LS antigens contributes to protective immunity [14,15,[23][24][25], suggesting that a combination vaccine approach targeting multiple life-cycle stages of the Plasmodium parasite may be important. Synthetic DNA delivered by adaptive electroporation (EP) is a particularly attractive vaccine platform for targeting LS antigens because of its ability to induce robust CD8+ T cell responses.…”

“…Liver resident T cell responses are considered important for providing protective responses against LS antigens [23][24][25]. The proportion of CD8+ T cells expressing CXCR6 was increased in both the spleen and liver of animals immunized with EXP1_PFN plus pIL-33 compared to antigen alone.…”

Progress in Parasite Genomics and Its Application to Current Challenges in Malaria Control

“…PfLSA-1 is high conserved in P. falciparum and is found in parasitophorous vacuole in the liver stage of the parasites. PfLSA-1 contains 17 amino acids repeats and is associated with the late liver schizont stage [105,106]. LSA-1 can induce IgG and IgM antibodies as well as CD4+ T cell production [105,107].…”