W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States.
Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States.
Front Immunol. 2024 Feb 2;15:1292059. doi: 10.3389/fimmu.2024.1292059. eCollection 2024.
Previous studies have demonstrated enhanced efficacy of vaccine formulations that incorporate the chemokine macrophage inflammatory protein 3α (MIP-3α) to direct vaccine antigens to immature dendritic cells. To address the reduction in vaccine efficacy associated with a mutation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we have examined the ability of receptor-binding domain vaccines incorporating MIP-3α to sustain higher concentrations of antibody when administered intramuscularly (IM) and to more effectively elicit lung T-cell responses when administered intranasally (IN).
BALB/c mice aged 6-8 weeks were immunized intramuscularly or intranasally with DNA vaccine constructs consisting of the SARS-CoV-2 receptor-binding domain alone or fused to the chemokine MIP-3α. In a small-scale ( = 3/group) experiment, mice immunized IM with electroporation were followed up for serum antibody concentrations over a period of 1 year and for bronchoalveolar antibody levels at the termination of the study. Following IN immunization with unencapsulated plasmid DNA ( = 6/group), mice were evaluated at 11 weeks for serum antibody concentrations, quantities of T cells in the lungs, and IFN-γ- and TNF-α-expressing antigen-specific T cells in the lungs and spleen.
At 12 months postprimary vaccination, recipients of the IM vaccine incorporating MIP-3α had significantly, approximately threefold, higher serum antibody concentrations than recipients of the vaccine not incorporating MIP-3α. The area-under-the-curve analyses of the 12-month observation interval demonstrated significantly greater antibody concentrations over time in recipients of the MIP-3α vaccine formulation. At 12 months postprimary immunization, only recipients of the fusion vaccine had concentrations of serum-neutralizing activity deemed to be effective. After intranasal immunization, only recipients of the MIP-3α vaccine formulations developed T-cell responses in the lungs significantly above those of PBS controls. Low levels of serum antibody responses were obtained following IN immunization.
Although requiring separate IM and IN immunizations for optimal immunization, incorporating MIP-3α in a SARS-CoV-2 vaccine construct demonstrated the potential of a stable and easily produced vaccine formulation to provide the extended antibody and T-cell responses that may be required for protection in the setting of emerging SARS-CoV-2 variants. Without electroporation, simple, uncoated plasmid DNA incorporating MIP-3α administered intranasally elicited lung T-cell responses.
先前的研究表明，将趋化因子巨噬细胞炎性蛋白 3α（MIP-3α）纳入疫苗配方可增强疫苗的功效，从而将疫苗抗原靶向未成熟树突状细胞。为了解决与严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）突变体相关的疫苗效力降低的问题，我们研究了包含 MIP-3α 的受体结合域疫苗在肌肉内（IM）给药时维持更高抗体浓度的能力，以及在鼻腔内（IN）给药时更有效地引发肺部 T 细胞反应的能力。
6-8 周龄 BALB/c 小鼠通过肌肉内或鼻腔内接种由 SARS-CoV-2 受体结合域单独或融合趋化因子 MIP-3α 组成的 DNA 疫苗构建体进行免疫。在一项小规模（每组 3 只）实验中，通过电穿孔肌肉内免疫的小鼠在 1 年内跟踪血清抗体浓度，并在研究结束时评估支气管肺泡抗体水平。未包裹的质粒 DNA 鼻腔内免疫（每组 6 只）后，在 11 周时评估血清抗体浓度、肺部 T 细胞数量以及肺部和脾脏中 IFN-γ 和 TNF-α 表达的抗原特异性 T 细胞。
初次接种后 12 个月，接受包含 MIP-3α 的 IM 疫苗接种的受者的血清抗体浓度显著提高，约为未接受 MIP-3α 疫苗接种的受者的 3 倍。12 个月观察期的曲线下面积分析表明，接受 MIP-3α 疫苗制剂的受者在更长时间内的抗体浓度显著更高。初次免疫后 12 个月，只有融合疫苗的受者具有被认为有效的血清中和活性浓度。鼻内免疫后，只有 MIP-3α 疫苗制剂组的受者在肺部产生的 T 细胞反应显著高于 PBS 对照组。鼻腔内免疫后获得了低水平的血清抗体反应。
尽管需要单独的 IM 和 IN 免疫接种以实现最佳免疫接种，但在 SARS-CoV-2 疫苗构建体中加入 MIP-3α 为提供稳定且易于生产的疫苗制剂提供了潜力，该疫苗制剂可为新兴 SARS-CoV-2 变体情况下的保护提供所需的延长的抗体和 T 细胞反应。未经电穿孔，简单的、未包裹的包含 MIP-3α 的质粒 DNA 鼻腔内给药可引发肺部 T 细胞反应。
