Andrade Viviane M, Cashman Kathleen, Rosenke Kyle, Wilkinson Eric, Josleyn Nicole, Lynn Ginger, Steffens Jesse, Vantongeren Sean, Wells Jay, Schmaljohn Connie, Facemire Paul, Jiang Jingjing, Boyer Jean, Patel Aditya, Feldmann Friederike, Hanley Patrick, Lovaglio Jamie, White Kimberly, Feldmann Heinz, Ramos Stephanie, Broderick Kate E, Humeau Laurent M, Smith Trevor R F
Inovio Pharmaceuticals Inc., Plymouth Meeting, PA, USA.
Virology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD, USA.
Commun Med (Lond). 2024 Nov 28;4(1):253. doi: 10.1038/s43856-024-00684-8.
We have previously developed a DNA-based vaccine, INO-4500, encoding the Lassa lineage IV glycoprotein precursor. INO-4500, when delivered with electroporation, elicited humoral and cellular responses, and conferred 100% protection in cynomolgus non-human primates. Here, we expanded the characterization of INO-4500 assessing immunogenicity and protective efficacy of lower doses and single immunization, and the durability of immune responses.
The study was divided into three arms evaluating INO-4500 vaccination: Arm 1 - Dosing regimen; Arm 2 - Single immunization; and Arm 3-Durability of immune responses and protective efficacy. Humoral and T cell responses were assessed by IgG binding ELISA, IFNγ ELISpot and flow cytometry-based T cell activation assays. NHPs were challenged with a lethal dose of Lassa lineage IV 8 weeks (Arms 1 and 2) or one year (Arm 3) after immunization. NHPs were assigned clinical scores and monitored for survival. Viremia, virus neutralization and release of soluble mediators were assessed post-challenge, as well as disease pathology following NHPs death or euthanasia.
INO-4500 induces dose-dependent immune responses and protective efficacy. Animals receiving two doses of 2 mg of INO-4500 show complete short- and long-term LASV protection. NHPs receiving 1 mg of INO-4500 are protected from LASV challenge one year after vaccination but are only partially protected 8 weeks post-vaccination. LASV-specific memory T cells are present in vaccinated NHPs one year after vaccination. INO-4500 vaccination prevents NHPs from developing severe disease.
These studies demonstrate that INO-4500 can provide short- and long-term protection in NHPs from lethal LASV challenge.
我们之前研发了一种基于DNA的疫苗INO-4500，其编码拉沙病毒IV型糖蛋白前体。INO-4500通过电穿孔给药时，可引发体液和细胞免疫反应，并在食蟹猴这一非人灵长类动物中提供100%的保护。在此，我们扩展了对INO-4500的特性研究，评估较低剂量和单次免疫的免疫原性及保护效力，以及免疫反应的持久性。
该研究分为三个评估INO-4500疫苗接种的组：第1组 - 给药方案；第2组 - 单次免疫；第3组 - 免疫反应的持久性和保护效力。通过IgG结合ELISA、IFNγ ELISpot以及基于流式细胞术的T细胞活化分析来评估体液和T细胞反应。在免疫后8周（第1组和第2组）或1年（第3组），用致死剂量的拉沙病毒IV型攻击食蟹猴。给食蟹猴评定临床评分并监测其存活情况。在攻击后评估病毒血症、病毒中和以及可溶性介质的释放情况，在食蟹猴死亡或安乐死后评估疾病病理学情况。
INO-4500诱导剂量依赖性免疫反应和保护效力。接受两剂2毫克INO-4500的动物显示出对拉沙病毒的短期和长期完全保护。接受1毫克INO-4500的食蟹猴在接种疫苗1年后对拉沙病毒攻击具有保护作用，但在接种疫苗8周后仅受到部分保护。接种疫苗1年后，接种疫苗的食蟹猴体内存在拉沙病毒特异性记忆T细胞。接种INO-4500疫苗可防止食蟹猴发生严重疾病。
这些研究表明，INO-4500可在食蟹猴中提供短期和长期保护，使其免受致死性拉沙病毒攻击。
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