Schistosoma mansoni vaccine candidates identified by unbiased phage display screening in self-cured rhesus macaques

Schistosomiasis is a neglected tropical disease that infects roughly 200 million people across 78 countries and causes substantial morbidity in low- and middle-income regions. Today the only widely used treatment is praziquantel, a single drug whose efficacy is now threatened by resistance and uneven access — making a prophylactic vaccine the highest-leverage long-term control tool. The barrier has been biological: Schistosoma mansoni is a multi-stage, multicellular parasite, and decades of one-protein-at-a-time vaccine work have surfaced only a handful of candidates (Sm-p80, Sm-TSP-2, Sm14) — none yet licensed.

This study takes a fundamentally different approach. Rather than guessing which parasite proteins might be protective, the authors built a synthetic DNA phage-display library that encodes 99.6% of all 119,747 overlapping 58-amino-acid peptides from the entire S. mansoni proteome. They then used PhIP-Seq (phage-display immunoprecipitation followed by sequencing) to read the IgG repertoires of 10 rhesus macaques across the rare “self-cure and challenge-resistant” infection phenotype, in which primates spontaneously clear the parasite and resist re-infection.

The screen revealed a temporally structured antibody response: during the early establishment phase (weeks 4–6 post-infection), antibodies preferentially recognized epitopes from extracellular gut and esophageal-gland proteins (SmCatB cathepsin-B paralogs, SmAE asparaginyl endopeptidase, and MEG micro-exon-gene products); during the late clearance phase (week 10 onwards), the response shifted toward intracellular antigens. To convert the discovery into a functional vaccine test, the team selected 36 of the most-enriched peptides, expressed them as phage-fusion proteins, and immunized mice with the pool. Vaccinated mice showed a statistically significant reduction in adult worm burden compared with phage-only controls after challenge with 120 cercariae — direct in-vivo validation that antibody-reactome-discovered antigens can confer protection.