Sporozoite antigens are the basis of a number of malaria vaccines being tested, but the contribution of antigens expressed during subsequent liver stage development to pre-erythrocytic stage immunity is poorly understood. We previously showed that, following immunisation with radiation attenuated sporozoites (RAS), a model epitope embedded in a sporozoite surface protein elicited robust CD8⁺ T cell responses, whilst the same epitope in a liver stage antigen induced inferior responses. Since RAS arrest early in their development in host hepatocytes, we hypothesised that extending parasite maturation in the liver could considerably improve the epitope-specific CD8⁺ T cell response. Here, we employed a late liver stage arrested parasite model, azithromycin prophylaxis alongside live sporozoites, to increase expression of the model epitope until full liver stage maturation. Strikingly, this alternative immunisation strategy, which has been shown to elicit superior protection, failed to improve the resulting epitope-specific CD8⁺ T cell responses. Our findings support the notion that liver stage antigens are poorly immunogenic and provide additional caution about prioritising antigens for vaccine development based solely on immunogenicity.

中文翻译：

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在红细胞前成熟过程中表达的伯氏疟原虫模型肝阶段抗原的劣势 T 细胞免疫原性

子孢子抗原是许多正在测试的疟疾疫苗的基础，但在随后的肝脏发育阶段表达的抗原对红细胞前期免疫的贡献却知之甚少。我们之前表明，在用减毒子孢子 (RAS) 免疫后，嵌入子孢子表面蛋白中的模型表位引发强烈的 CD8 ⁺ T 细胞反应，而肝脏阶段抗原中的相同表位诱导较差的反应。由于 RAS 在宿主肝细胞发育早期停滞，我们假设延长肝脏中的寄生虫成熟可以显着改善表位特异性 CD8 ⁺T细胞反应。在这里，我们采用了晚期肝期停滞寄生虫模型，阿奇霉素预防与活子孢子一起，以增加模型表位的表达，直到肝期完全成熟。引人注目的是，这种替代免疫策略已被证明可引发卓越的保护，但未能改善由此产生的表位特异性 CD8 ⁺ T 细胞反应。我们的研究结果支持肝脏阶段抗原免疫原性差的观点，并为仅基于免疫原性优先考虑抗原用于疫苗开发提供了额外的谨慎。