LSAP2 — Affinage

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LSAP2 (PF3D7_0202100) is a Plasmodium falciparum liver-stage antigen defined by its capacity to elicit protective cellular immunity against pre-erythrocytic malaria (PMID:26139288). When delivered by viral vectors (ChAd63/MVA or simian adenovirus/MVA), LSAP2 induces sterile protection against liver-stage infection that is dependent on CD8+ T cells, established in mouse challenge models using chimeric P. berghei parasites engineered to express the P. falciparum antigen (PMID:26139288). The vaccine-induced response comprises immunodominant CD4+ and CD8+ T cell populations directed at defined peptide epitopes mapped across BALB/c, C57BL/6, and HLA-A2 transgenic mice, and the CD8+ component is polyfunctional (PMID:26659715). Protective efficacy is enhanced by co-expression or co-administration with the related antigen PfLSA1 while responses to LSAP2 itself are preserved (PMID:31740525). The corpus characterizes LSAP2 solely as a target of protective T cell immunity; its endogenous molecular function, biochemical activity, subcellular localization, and role in parasite liver-stage biology have not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps

2015 Medium
Establishing whether LSAP2 could serve as a protective vaccine target answered whether this liver-stage antigen is immunologically relevant, and identified the effector arm responsible for protection.

Evidence Viral-vectored (ChAd63/MVA) vaccination and CD8+ T cell depletion in a mouse challenge model using chimeric P. berghei parasites expressing PfLSAP2

PMID:26139288
Open questions at the time
- Does not identify the endogenous function or biochemical activity of LSAP2 in the parasite
- Single lab, single study; protection shown against chimeric P. berghei rather than P. falciparum directly
- Mechanism by which CD8+ T cells clear infected hepatocytes not resolved
2015 Medium
Mapping the epitopes and quality of the LSAP2-directed response addressed which parts of the antigen drive immunity and whether the CD8+ response is functionally competent.

Evidence IFNγ ELISpot, intracellular cytokine staining, and comparison to epitope prediction across BALB/c, C57BL/6, and HLA-A2 transgenic mice

PMID:26659715
Open questions at the time
- Only a small fraction of predicted epitopes were experimentally confirmed
- Human-relevant epitope dominance beyond HLA-A2 transgenic mice not established
- Does not link specific epitopes to the protective phenotype
2020 Medium
Testing LSAP2 in combination with PfLSA1 addressed whether multi-antigen delivery improves protection without immune interference, informing vaccine design strategy.

Evidence Simian adenovirus and MVA single- and dual-antigen vector vaccination with T cell readouts in a chimeric P. berghei challenge model in outbred and inbred mice

PMID:31740525
Open questions at the time
- Mechanism of the additive protective effect with PfLSA1 not defined
- Durability of protection and translation to P. falciparum challenge in humans not addressed
- Whether LSAP2 and PfLSA1 target the same or distinct hepatocyte populations unknown

Open questions

Synthesis pass · forward-looking unresolved questions

The endogenous molecular function, biochemical activity, subcellular localization, and biological role of LSAP2 in the parasite liver stage remain unknown.
No biochemical activity or interacting partners characterized
No subcellular localization data for the endogenous protein
No loss-of-function phenotype in the parasite established

Mechanism profile

Synthesis pass · controlled-vocabulary classification

Partners

PFLSA1 (CO-ADMINISTERED/CO-EXPRESSED ANTIGEN THAT ENHANCES LSAP2 VACCINE EFFICACY) [#1]

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus

Year	Finding	Method	Journal	Conf	PMIDs
2015	Viral vectors (ChAd63 and MVA) encoding PfLSAP2 induced sterile protection against liver-stage malaria in mice in a manner dependent on CD8+ T cells, as demonstrated using chimeric P. berghei parasites expressing the P. falciparum PfLSAP2 antigen.	Mouse malaria challenge model with chimeric P. berghei parasites expressing PfLSAP2; CD8+ T cell depletion to establish dependence	Scientific reports	Medium	26139288
2020	Co-administration of single-antigen vectors expressing PfLSAP2 and PfLSA1, or dual-antigen vectors encoding both, improved protective efficacy against liver-stage malaria compared to PfLSAP2 alone, while maintaining immune responses to PfLSAP2; protection was assessed using chimeric P. berghei parasites expressing the P. falciparum antigens.	Mouse malaria challenge model (outbred and inbred mice) with chimeric P. berghei parasites; simian adenovirus and MVA vector vaccination; T cell response measurement at peak	Infection and immunity	Medium	31740525
2015	Viral-vectored vaccination with PfLSAP2 induced immunodominant CD4+ and CD8+ T cell responses; specific immunodominant peptides for PfLSAP2 were identified experimentally in BALB/c, C57BL/6, and HLA-A2 transgenic mice using IFNγ ELISpot and intracellular cytokine staining, and only a small fraction of computationally predicted epitopes were confirmed experimentally. The induced CD8+ T cell response was polyfunctional.	IFNγ ELISpot assay, intracellular cytokine staining, epitope prediction software comparison; multiple mouse strains	PloS one	Medium	26659715

Source papers

Stage 0 corpus · 3 papers · ranked by NIH iCite citations

Year	Title	Journal	Citations	PMID
2015	Comparative assessment of vaccine vectors encoding ten malaria antigens identifies two protective liver-stage candidates.	Scientific reports	49	26139288
2020	Preclinical Development and Assessment of Viral Vectors Expressing a Fusion Antigen of Plasmodium falciparum LSA1 and LSAP2 for Efficacy against Liver-Stage Malaria.	Infection and immunity	9	31740525
2015	Identification of Immunodominant Responses to the Plasmodium falciparum Antigens PfUIS3, PfLSA1 and PfLSAP2 in Multiple Strains of Mice.	PloS one	5	26659715