Björnsson Kasper H, Bassi Maria R, Knudsen Anne S, Aves Kara-Lee, Morella Roig Èlia, Sander Adam F, Barfod Lea
Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
AdaptVac, Ole Maaløes Vej 3, 2200 Copenhagen, Denmark.
Vaccines (Basel). 2024 Jul 30;12(8):859. doi: 10.3390/vaccines12080859.
A vaccine protecting against malaria caused by is urgently needed. The blood-stage invasion complex PCRCR consists of the five malarial proteins PfPTRAMP, PfCSS, PfRipr, PfCyRPA, and PfRH5. As each subcomponent represents an essential and highly conserved antigen, PCRCR is considered a promising vaccine target. Furthermore, antibodies targeting the complex can block red blood cell invasion by the malaria parasite. However, extremely high titers of neutralizing antibodies are needed for this invasion-blocking effect, and a vaccine based on soluble PfRH5 protein has proven insufficient in inducing a protective response in a clinical trial. Here, we present the results of two approaches to increase the neutralizing antibody titers: (A) immunofocusing and (B) increasing the immunogenicity of the antigen via multivalent display on capsid virus-like particles (cVLPs). The immunofocusing strategies included vaccinating with peptides capable of binding the invasion-blocking anti-PfCyRPA monoclonal antibody CyP1.9, as well as removing non-neutralizing epitopes of PfCyRPA through truncation. Vaccination with PfCyRPA coupled to the AP205 cVLP induced nearly two-fold higher IgG responses compared to vaccinating with soluble PfCyRPA protein. Immunofocusing using a linear peptide greatly increased the neutralizing capacity of the anti-PfCyRPA antibodies. However, significantly lower total anti-PfCyRPA titers were achieved using this strategy. Our results underline the potential of a cVLP-based malaria vaccine including full-length PfCyRPA, which could be combined with other leading malaria vaccine antigens presented on cVLPs.
迫切需要一种预防由[具体疟原虫种类未给出]引起的疟疾的疫苗。血液阶段入侵复合物PCRCR由五种疟原虫蛋白PfPTRAMP、PfCSS、PfRipr、PfCyRPA和PfRH5组成。由于每个亚组分都代表一种必需且高度保守的抗原，PCRCR被认为是一个有前景的疫苗靶点。此外，靶向该复合物的抗体可以阻断疟原虫对红细胞的入侵。然而，这种入侵阻断效应需要极高滴度的中和抗体，并且基于可溶性PfRH5蛋白的疫苗在临床试验中已被证明不足以诱导保护性反应。在此，我们展示了两种提高中和抗体滴度的方法的结果：(A)免疫聚焦和(B)通过衣壳病毒样颗粒（cVLPs）上的多价展示来提高抗原的免疫原性。免疫聚焦策略包括用能够结合入侵阻断抗PfCyRPA单克隆抗体CyP1.9的肽进行疫苗接种，以及通过截短去除PfCyRPA的非中和表位。与用可溶性PfCyRPA蛋白进行疫苗接种相比，用与AP205 cVLP偶联的PfCyRPA进行疫苗接种诱导的IgG反应高出近两倍。使用线性肽进行免疫聚焦大大提高了抗PfCyRPA抗体的中和能力。然而，使用该策略获得的抗PfCyRPA总滴度显著较低。我们的结果强调了基于cVLP的疟疾疫苗的潜力，该疫苗包括全长PfCyRPA，可与cVLPs上呈现的其他主要疟疾疫苗抗原结合使用。
