Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and may enhance protection of anti-CSP monoclonal antibodies

Abstract

Vaccine-induced sterilizing protection from infection by Plasmodium parasites, the pathogens that cause malaria, will be essential in the fight against malaria as it would prevent both malaria-related disease and transmission. Stopping the relatively small number of parasites injected by the mosquito before they can migrate from the skin to the liver is an attractive means to this goal. Antibody-eliciting vaccines have been used to pursue this objective by targeting the major parasite surface protein present during this stage, the circumsporozoite protein (CSP). While CSP-based vaccines have recently had encouraging success in disease reduction, this was only achieved with extremely high antibody titers and appeared less effective for a complete block of infection (i.e., sterile protection). While such disease reduction is important, these and other results indicate that strategies focusing on CSP alone may not achieve the high levels of sterile protection needed for malaria eradication. Here, we show that monoclonal antibodies (mAbs) recognizing another sporozoite protein, TRAP/SSP2, exhibit a range of inhibitory activity and that these mAbs may augment CSP-based protection despite conferring no sterile protection on their own. Therefore, pursuing a multivalent subunit vaccine immunization is a promising strategy for improving infection-blocking malaria vaccines.

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

“…When used in combination with PyCSP, PyTRAP co-immunizations consistently resulted in enhanced probability of sterile protection compared to PyCSP-alone immunizations. Taken together with our recent finding that anti-TRAP mAbs can increase chances of sterile protection afforded by anti-CSP mAbs in a humanized mouse system 22 , these data suggest that the use of recombinant TRAP in co-immunization strategies still holds promise and should be revisited.…”

“…However, developing a CSP-only malaria vaccine with high efficacy and durability of protection has been hampered by various roadblocks; and identifying additional PE vaccine antigens to augment anti-sporozoite immunity may be a promising strategy to fortify CSP-based vaccines. In our recent work, we have shown that plasma from mice immunized with recombinant TRAP-an exemplar PE antigen-inhibited sporozoites, and that passively transferred monoclonal antibodies could enhance anti-CSPmediated protection from mosquito-bite challenge 22 . 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 25 .…”

“…It is possible that protection is associated with functional antibody subsets either based on on-target epitope specificity 34 , antibody isotype 9,10 or off-target cross-reactivity 35 . We and others had previously shown that the character of the polyclonal Ab response can be diverse enough to include antibodies capable of inhibiting the parasite as well as those that don't have a detectable impact on the course of infection despite their ability to bind the antigen 22,[36][37][38][39][40] . If this is the case here, then a more careful Ab response characterization with a focus on specific "vulnerable" epitopes would be required to describe the Ab response patterns that lead to protection.…”

“…In addition, we showed that many components of the inner membrane complex could become exposed during the initial process of invasion and be accessible for recognition by antibodies 21 . Recently, we demonstrated that passively transferred monoclonal antibodies (mAbs) raised against TRAP can enhance the protective effect of anti-CSP mAbs 22 . In the present study we investigated whether active immunization with non-CSP sporozoite antigens could enhance the anti-CSP response-mediated protection using the rodent parasite model.…”

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

“…In addition, we showed that many components of the inner membrane complex could become exposed during the initial process of invasion and be accessible for recognition by antibodies (22). Recently, we demonstrated that passively transferred monoclonal antibodies (mAbs) raised against TRAP can enhance the protective effect of anti-CSP mAbs (23). In the present study we investigated whether active immunization with non-CSP sporozoite antigens could enhance the anti-CSP response-mediated protection using the rodent parasite model.…”