PlasmodiumPreerythrocytic Vaccine Antigens Enhance Sterile Protection in Mice Induced by Circumsporozoite Protein

Abstract

Pre-erythrocytic vaccines prevent malaria by targeting parasites in the clinically silent sporozoite and liver stages and preventing progression to the virulent blood stages. The leading pre-erythrocytic vaccine RTS,S/AS01E (Mosquirix®) entered implementation programs in 2019 and targets the major sporozoite surface antigen called circumsporozoite protein or CSP. However, in phase III clinical trials, RTS,S conferred partial protection with limited durability, indicating a need to improve CSP-based vaccination. Previously, we identified highly expressed liver stage proteins that could potentially be used in combination with CSP and are referred to as pre-erythrocytic vaccine antigens (PEVA). Here, we developed heterologous prime-boost CSP vaccination models to confer partial sterilizing immunity against Plasmodium yoelii (Py)(protein prime/adenovirus 5 (Ad5) boost) and P. berghei (Pb) (DNA prime/Ad5 boost) in mice. When combined as individual antigens with PyCSP, 3 of 8 PyPEVA significantly enhanced sterile protection against sporozoite challenge, compared to PyCSP alone. Similar results were obtained when 3 PbPEVA and PbCSP were combined in a single vaccine regimen. In general, PyCSP antibody responses were similar after CSP alone versus CSP+PEVA vaccinations. Both Py and Pb CSP+PEVA combination vaccines induced robust CD8 + T cell responses including signature IFN-γ increases. In the Pb model system, IFN-γ responses were significantly higher in hepatic than splenic CD8 + T cells. The addition of novel antigens may enhance the degree and duration of sterile protective immunity conferred by a human vaccine such as RTS,S.

Co-immunization with pre-erythrocytic antigens alongside circumsporozoite protein can enhance sterile protection against Plasmodium sporozoite infection.

“…Notably, the WSV-induced antibodies to non-CSP sporozoite antigens have been shown to inhibit sporozoite invasion of hepatocytes, implying that such antigens may elicit protective immune responses against pre-erythrocytic (PE) stage infection 16 . Similar vaccine-elicited sporozoite inhibition was recently shown more directly in the P. yoelii (Py) rodent malaria model by active co-immunization with CSP alongside a panel of PE antigens normally expressed during liver stage development 17 . However, protection in those experiments was assessed using an i.v.…”

“…Additionally, a broader screen of co-immunogens derived from antigens expressed during liver stage development identified candidates that may be useful for eliciting T-cell responses 17 .…”

Co-immunization with pre-erythrocytic antigens alongside circumsporozoite protein can enhance sterile protection againstPlasmodiumsporozoite infection

“…Notably, the WSV-induced antibodies to non-CSP sporozoite antigens have been shown to inhibit sporozoite invasion of hepatocytes, implying that such antigens may elicit protective immune responses against pre-erythrocytic (PE) stage infection (17). Similar vaccine-elicited sporozoite inhibition was recently shown more directly in the P. yoelii (Py) rodent malaria model by active co-immunization with CSP alongside a panel of PE antigens normally expressed during liver stage development (18). However, protection in those experiments was assessed using an i.v.…”

“…Additionally, a broader screen of co-immunogens derived from antigens expressed during liver stage development identified candidates that may be useful for eliciting T-cell responses 17 . Here we show that several recombinant PE antigens normally expressed in sporozoites, when used in two-protein co-immunizations alongside PyCSP, can enhance sterile protection afforded by PyCSP alone.…”

“…Others have shown that active immunization with TRAP-CSP fusion proteins had protective effects in a similar experiment using the Plasmodium berghei -infected mosquito-bite challenge, although the individual contributions of anti-TRAP and anti-CSP responses were not completely defined (26). Additionally, a broader screen of co-immunogens derived from antigens expressed during liver stage development identified candidates that may be useful for eliciting T-cell responses (18). Here we show that several recombinant PE antigens normally expressed in sporozoites, when used in two-protein co-immunizations alongside PyCSP, can enhance sterile protection afforded by PyCSP alone.…”