Immunogenicity, Efficacy, and Safety of a Novel Synthetic Microparticle Pre-Erythrocytic Malaria Vaccine in Multiple Host Species.
Immunogenicity, Efficacy, and Safety of a Novel Synthetic Microparticle Pre-Erythrocytic Malaria Vaccine in Multiple Host Species.
复制标题
DOI：
10.3390/vaccines11121789
复制
发表时间：
2023-11-30
期刊：
影响因子：
7.8
通讯作者：
Nardin E
中科院分区：
文献类型：
--
作者：
Powell TJ;Tang J;Mitchell R;DeRome ME;Jacobs A;Palath N;Cardenas E;Yorke M;Boyd JG;Kaba SA;Nardin E
我们之前报道了用合成的微粒子疫苗(LBL-MP)免疫的小鼠产生保护性抗体反应，该疫苗含有恶性疟原虫环子孢子蛋白的保守T1BT*表位。为了进一步优化候选疫苗，开发了一种台式切向流过滤方法(LBL-by-TFF)，并用于生产不同状态的候选疫苗，这些方法包括基层交联状态、抗原肽中包含TLR2配体以及用丝氨酸或丙氨酸替代T*表位上未配对的半胱氨酸残基。在小鼠身上的研究显示，Pam3Cys修饰的候选抗体具有一致的优越性，基层交联剂的好处不大，表现为更高和更持久的抗体效价(免疫后长达18个月)，T细胞对Th1表型的反应质量得到改善，与未修饰的原型候选抗体相比，可以更好地抵御活体寄生虫的挑战。免疫原性也在非人类灵长类动物模型恒河猴身上进行了测试。底层交联型LBLMP负载T1BT*多肽，无论有无共价连接Pam3Cys，均可诱导T1B特异性抗体应答和T1BT特异性T细胞应答，主要以干扰素γ分泌为主，IL-5分泌水平较低。Pam3Cys修饰的构建体更有效，在体外肝细胞侵袭实验中产生了中和野生型恶性疟原虫的抗体反应。用Pam3Cys.T1BT*LBLMP免疫猕猴，纯化的免疫球蛋白能保护幼龄小鼠免受表达全长≥蛋白的转基因伯氏肺炎子孢子的攻击，被动免疫的小鼠在15d内无寄生虫的发生率为50-88%。在T1BT*亚基的T*区用丝氨酸取代未配对的半胱氨酸不会对小鼠的免疫效力产生不利影响，同时简化了抗原肽的生产。在一项符合良好实验室操作规范的兔子毒理学研究中，基层交联、Pam3Cys修饰、丝氨酸取代的候选疫苗被证明是安全的和免疫原性的，可以引发寄生虫中和抗体反应，并建立剂量/路线/方案，用于对这种新型合成微粒前红细胞前疟疾候选疫苗进行临床评估。
We previously reported a protective antibody response in mice immunized with synthetic microparticle vaccines made using layer-by-layer fabrication (LbL-MP) and containing the conserved T1BT* epitopes from the P. falciparum circumsporozoite protein. To further optimize the vaccine candidate, a benchtop tangential flow filtration method (LbL-by-TFF) was developed and utilized to produce vaccine candidates that differed in the status of base layer crosslinking, inclusion of a TLR2 ligand in the antigenic peptide, and substitution of serine or alanine for an unpaired cysteine residue in the T* epitope. Studies in mice revealed consistent superiority of the Pam3Cys-modified candidates and a modest benefit of base layer crosslinking, as evidenced by higher and more persistent antibody titers (up to 18 months post-immunization), a qualitative improvement of T-cell responses toward a Th1 phenotype, and greater protection from live parasite challenges compared to the unmodified prototype candidate. Immunogenicity was also tested in a non-human primate model, the rhesus macaque. Base layer-crosslinked LbL-MP loaded with T1BT* peptide with or without covalently linked Pam3Cys elicited T1B-specific antibody responses and T1BT*-specific T-cell responses dominated by IFNγ secretion with lower levels of IL-5 secretion. The Pam3Cys-modified construct was more potent, generating antibody responses that neutralized wild-type P. falciparum in an in vitro hepatocyte invasion assay. IgG purified from individual macaques immunized with Pam3Cys.T1BT* LbL-MP protected naïve mice from challenges with transgenic P. berghei sporozoites that expressed the full-length PfCS protein, with 50–88% of passively immunized mice parasite-free for ≥15 days. Substitution of serine for an unpaired cysteine in the T* region of the T1BT* subunit did not adversely impact immune potency in the mouse while simplifying the manufacture of the antigenic peptide. In a Good Laboratory Practices compliant rabbit toxicology study, the base layer-crosslinked, Pam3Cys-modified, serine-substituted candidate was shown to be safe and immunogenic, eliciting parasite-neutralizing antibody responses and establishing the dose/route/regimen for a clinical evaluation of this novel synthetic microparticle pre-erythrocytic malaria vaccine candidate.
登录
查看更多内容
影响因子：
56.3
作者：
Datoo, Mehreen S.;Natama, Hamtandi Magloire;Tinto, Halidou
通讯作者：
Tinto, Halidou
影响因子：
56.9
作者：
HOFFMAN, SL;ISENBARGER, D;BALLOU, WR
通讯作者：
BALLOU, WR
影响因子：
56.9
作者：
ENEA, V;ELLIS, J;NUSSENZWEIG, RS
通讯作者：
NUSSENZWEIG, RS
影响因子：
158.5
作者：
Mian-McCarthy, Sara;Agnandji, Selidji Todagbe;Vansadia, Preeti
通讯作者：
Vansadia, Preeti
影响因子：
3
作者：
McCoy, Margaret E.;Golden, Hannah E.;Lanar, David E.
通讯作者：
Lanar, David E.