Bundi Caroline, Bellamy Duncan, Kibwana Elizabeth, Nyamako Lydia, Ogwang Rodney, Keter Kelvias, Kimani Domtila, Salman Ahmed M, Provstgaard-Morys Samuel, Stockdale Lisa, Hill Adrian V S, Bejon Philip, Olotu Ally, Hamaluba Mainga, Ewer Katie J, Kapulu Melissa C
Centre for Geographic Medicine Research, Coast, Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.
Ifakara Health Institute, Bagamoyo Research and Training Centre, Bagamoyo, Tanzania.
Front Immunol. 2025 Jun 26;16:1620366. doi: 10.3389/fimmu.2025.1620366. eCollection 2025.
The pre-erythrocytic malaria vaccine R21 vaccine adjuvanted with Matrix-M reported good efficacy (75%) in an ongoing phase 3 trial and was recommended World Health Organization for use in children 5-36 months. Vaccine-induced antibodies against NANP are associated with protection, however, various factors such as age, pre-existing immunity, and vaccine dose have been shown to influence vaccine responses.
Samples from adults (n =18), children (n = 17), and infants (n = 51) vaccinated with R21/Matrix-M in a phase I trial were assayed for vaccine-specific antibody responses. We measured antibodies (quantity) by MSD and ELISA; and function (quality) by complement (C1q) fixation assay, inhibition of sporozoite invasion (ISI) assay, and avidity assay. Pre-existing malaria antibody exposure was assessed using an anti-3D7 crude parasite lysate ELISA.
Vaccine-induced CSP antibodies (against full-length R21, NANP, and C terminus), exhibited complement fixation and inhibition of sporozoites. These were significantly lower in adults compared to children and infants. Additionally, children had a higher rate of decay of vaccine-induced antibodies compared to adults 2 years post-vaccination. Furthermore, a higher Matrix-M adjuvant dose resulted in significantly higher C1q fixation, and ISI than the low adjuvant dose in infants. Importantly, functional measures ISI and C1q-fixation were positively associated with the vaccine-induced antibodies overall, but avidity was not. Interestingly, in adults, previous malaria exposure was negatively associated with ISI but positively correlated with avidity and C1q fixation. At baseline, all the study participants were seropositive for anti-HBsAg IgG above the WHO-required protective threshold of 10 mIU/mL, and titers significantly increased post-vaccination.
R21/Matrix-M was immunogenic across all age groups, with age and vaccine dose significantly affecting antibody magnitude and function. These findings emphasize the importance of evaluating the right adjuvant and vaccine dose for clinical development progression. This could thus inform the development of next-generation malaria vaccines. However, additional crucial factors need further exploration.
在正在进行的3期试验中，与基质-M（Matrix-M）佐剂联合使用的红细胞前期疟疾疫苗R21显示出良好的疗效（75%），并被世界卫生组织推荐用于5至36个月的儿童。疫苗诱导的抗NANP抗体与保护作用相关，然而，年龄、既往免疫力和疫苗剂量等多种因素已被证明会影响疫苗反应。
在一项1期试验中，对接种R21/基质-M的成人（n = 18）、儿童（n = 17）和婴儿（n = 51）的样本进行疫苗特异性抗体反应检测。我们通过MSD和ELISA检测抗体（数量）；通过补体（C1q）固定试验、子孢子入侵抑制（ISI）试验和亲和力试验检测功能（质量）。使用抗3D7粗制寄生虫裂解物ELISA评估既往疟疾抗体暴露情况。
疫苗诱导的CSP抗体（针对全长R21、NANP和C末端）表现出补体固定和子孢子抑制作用。与儿童和婴儿相比，成人中的这些抗体水平显著较低。此外，与接种疫苗2年后的成人相比，儿童疫苗诱导抗体的衰减率更高。此外，在婴儿中，较高剂量的基质-M佐剂导致的C1q固定和ISI显著高于低剂量佐剂。重要的是，功能指标ISI和C1q固定总体上与疫苗诱导的抗体呈正相关，但亲和力并非如此。有趣的是，在成人中，既往疟疾暴露与ISI呈负相关，但与亲和力和C1q固定呈正相关。在基线时，所有研究参与者的抗-HBsAg IgG血清学检测结果均为阳性，高于世界卫生组织规定的10 mIU/mL保护阈值，并且接种疫苗后滴度显著升高。
R21/基质-M在所有年龄组中均具有免疫原性，年龄和疫苗剂量显著影响抗体水平和功能。这些发现强调了评估合适的佐剂和疫苗剂量对临床开发进展的重要性。这从而可以为下一代疟疾疫苗的开发提供参考。然而，其他关键因素需要进一步探索。
