A comparative analysis of vaccine immunity induced by heterologous booster with Ad5-nCoV via different routes of administration
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摘要:
新冠疫苗异源加强接种可以解决疫苗单一使用时保护效力降低的问题。灭活新冠疫苗联合重组腺病毒载体新冠疫苗（Ad5-nCoV）的序贯接种模式和Ad5-nCoV肌肉注射给药或雾化吸入式给药两种途径已被批准用于临床。本研究在小鼠模型中，系统对比分析了不同接种策略下小鼠体内抗原特异性T细胞、记忆B细胞（MBC）、抗体水平、抗体功能、黏膜免疫应答等关键指标以揭示作用机制。将接种组分为“磷酸盐缓冲液（PBS）对照组”（3×PBS组）、“2针灭活新冠疫苗+1针灭活新冠疫苗”同源加强接种组（3×INA组）、“2针灭活新冠疫苗+1针Ad5-nCoV肌肉注射组”[2×INA+Ad5（im）组]和“2针灭活新冠疫苗+1针Ad5-nCoV滴鼻给药组”[2×INA+Ad5（in）组]。结果显示：2×INA+Ad5（im）组与2×INA+Ad5（in）组异源接种诱导的抗体、Spike特异性T细胞、Spike+MBCs水平均显著高于3×INA组同源接种，Ad5-nCoV在肌肉注射途径下诱导的Spike特异性T细胞、Spike+MBCs水平显著高于滴鼻给药途径。Ad5-nCoV滴鼻加强接种不仅明显诱导血清和支气管灌洗液免疫球蛋白A产生，同时诱导更多中性粒细胞、自然杀伤细胞、树突状细胞向肺组织中募集。本研究系统对比分析了Ad5-nCoV经不同给药途径异源加强接种后诱导的疫苗特异性免疫应答差异，为包括新冠疫苗在内的多种抗感染疫苗提供了预防接种策略指导。
Abstract:Heterologous boost COVID-19 vaccination can solved the problem of decreased efficacy caused by single dose of vaccine. Heterologous booster with adenoviral-vectored COVID-19 vaccine (Ad5-nCoV) following primary immunization with inactivated COVID-19 vaccines is a widely-used vaccination strategy in clinic, while different routes of Ad5-nCoV administration exist and pose a question which route could be more optimal. In this study, we comprehensively evaluated and compared the vaccine immunity induced in mice immunized according to three different vaccination regimens: “3×phosphate buffered solution(3× PBS)”, “2×inactivated vaccine + 1×inactivated vaccine (3×INA)”, “2×inactivated vaccine + 1×Ad5-nCoV (intramuscular)[2×INA+Ad5(im)]”and“2×inactivated vaccine + 1×Ad5-nCoV (intranasal)[2×INA+Ad5(in)]”. We found that heterologous booster with Ad5-nCoV, irrespective of the route of administration, induced significantly higher levels of anti-Spike IgG and subclasses (IgG1and IgG2c), Spike-specific T cells, class-switched Spike+ memory B cells (MBCs) than homologous booster with 3rd dose of inactivated COVID-19 vaccine. Of note, compared with the intramuscular given, intranasal given of Ad5-nCoV as a booster dose clearly induced higher levels of serum and bronchoalveolar bavage fluid anti-spike immunoglobulin A, and moreover, induced stronger infiltration of major innate effector cells like neutrophils, natural killer cells and dendritic cells into the lung tissue, which suggested that mucosal vaccine responses are generated upon intranasal booster with Ad5-nCoV. Altogether, our study analyzed the vaccine immunity induced by different COVID-19 vaccines administered using different regimens, which may guide the clinical use of other types of prophylactic vaccines aiming to mount improved vaccine responses.
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Figure 1. Evaluation of Ab responses in mice immunized with COVID-19 vaccines ($ \bar{x}\pm s $, n=8)
A: Study design; B: Longitudinal analysis of serum anti-Spike IgG titer; C: Anti-Spike IgA titer at day 169 in serum; D: Anti-Spike IgG1 and IgG2c titers and ratio of IgG2c/IgG1 at day 35 and 169; E: Anti-Spike IgG titer in bronchoalveolar bavage fluid (BALF); F: Anti-Spike IgA titer inBALF3×PBS: 3×phosphate buffered solution; 3×INA: 2×inactivated vaccine + 1×inactivated vaccine; 2×INA+Ad5（im）: 2×inactivated vaccine + 1×Ad5-nCoV (intramuscular); 2×INA+Ad5（in）: 2×inactivated vaccine + 1×Ad5-nCoV (intranasal) *P<0.05, **P<0.01, ***P<0.001
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Figure 2. Effector functions of Abs induced by COVID-19 vaccines ($ \bar{x}\pm s $, n=8)
A: Antibody dependent complement deposition (ADCD) function of Abs detected by fluorescently labeled anti-C3 Abs and median fluorescence intensities(MFIs) ; B: Antibody dependent neutrophil phagocytosis (ADNP) function of Abs determined by beads-positive primary neutrophils and phagocytic scores*P<0.05, **P<0.01
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Figure 3. Spike-specific cytokine-secreting T cells induced by COVID-19 vaccines ($ \bar{x}\pm s $, n=8)
A-B: Splenocytes were stimulated with Spike peptides pool and the number of IL-2 or IFN-γ-secreting T cells were quantified by ELISpot assay **P<0.01, ***P<0.001
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Figure 4. Evaluation of Spike-specific memory B cells in spleens after COVID-19 vaccination
A: Gating strategy of CD19+CD38+IgM-IgD- memory B cells (MBC) in spleens; B: Frequencies of Spike+ MBCs were quantified and shown ($ \bar{x}\pm s $, n=8) *P<0.05, **P<0.01
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