# A stabilized tandem antigen chimera that elicits potent malaria transmission-reducing activity

## TL;DR

A new malaria vaccine candidate combines two key proteins to block transmission more effectively.

## Contribution

A stabilized tandem antigen chimera (STAC) was developed to elicit potent transmission-blocking antibodies.

## Key findings

- STAC combines potent epitopes from Pfs230-D1 and Pfs48/45-D3 in a single construct.
- STAC-induced antibodies showed transmission-reducing activity comparable or superior to existing candidates.
- Nanoparticle-based multimerization enhanced the functional activity of the STAC vaccine in mice.

## Abstract

Malaria parasite transmission remains a barrier to elimination since asymptomatic individuals sustain the infectious reservoir. Transmission-blocking vaccine (TBV) candidates targeting Plasmodium falciparum (Pf) gametocyte surface proteins Pfs230 and Pfs48/45 have shown promise in clinical trials. Several vaccine candidates have been developed for these antigens, yet it is unclear which elicit the most robust and durable transmission-blocking responses. From structure-function relationships of monoclonal antibodies in complex with both antigens, we report the development of a stabilized tandem antigen chimera (STAC), which presents the most potent epitopes from Pfs230 domain 1 (Pfs230-D1) and Pfs48/45 domain 3 (Pfs48/45-D3) in a single construct, while masking non-functional epitopes using an engineered pseudo-native domain disposition. Iterative structure-guided optimization improved antigen yields and stability, while nanoparticle-based multimerization enhanced the functional transmission-reducing activity elicited by the immunogen in female mice. Immunizations with STAC genetically conjugated to self-assembling protein nanoparticles elicited antibodies with potent transmission-reducing activity comparable or superior to the multimerized Pfs230-D1 and Pfs48/45-D3. These findings establish STAC as a promising next-generation TBV candidate to disrupt malaria transmission and accelerate elimination efforts. More broadly, our results support the engineering of highly ordered and stable multi-domain antigens in a single protein as a strategy for the cost-efficient development of multi-component vaccines.

Several transmission-blocking vaccine candidates based on Pfs230 and Pfs48/45 are in clinical development, but it remains unclear whether they will demonstrate high efficacy. Here, the authors develop a stabilized chimeric antigen presenting potent epitopes from Pfs230 and Pfs48/45 in a single construct and demonstrate induction of transmission-reducing antibodies when female mice are immunized with the antigen in a self-assembling protein nanoparticle formulation.