Key Laboratory of Medical Molecular Virology of MOE and MOH, School of Basic Medical Sciences, Fudan University, Shanghai, China.
China National Vaccine and Serum Institute, Beijing, China.
Emerg Microbes Infect. 2018 Aug 3;7(1):140. doi: 10.1038/s41426-018-0133-y.
Since the first case of human avian influenza A (H7N9) virus infection in 2013, five H7N9 epidemics have occurred in China, all of which caused severe diseases, including pneumonia and acute respiratory distress syndrome, and the fatality rates of these epidemics were as high as 30-40%. To control the prevalence of H7N9 influenza, an effective vaccine is urgently needed. In the present study, we used chitosan and recombinant human interleukin-2 as an adjuvant (JY) to promote the systemic and mucosal immune responses induced by the H7N9 vaccine. Mice were immunized intranasally with the inactivated split influenza A (H7N9) virus (A/Shanghai/02/2013) vaccine with or without JY. The hemagglutination inhibition (HI) titers of mice immunized with the JY-adjuvanted vaccine were significantly higher than those of mice immunized with the vaccine without adjuvant (21.11 ± 9.58 vs. 5.04 ± 3, P < 0.05). The JY-adjuvanted H7N9 nasal spray vaccine induced higher HI titers (8 ± 0.82 vs. 6.7 ± 0.67, P = 0.0035) than those did the poly (I:C)-adjuvanted H7N9 vaccine or the LTB-adjuvanted H7N9 vaccine (8 ± 0.82 vs. 6.9 ± 0.88, P = 0.0186). The optimal immunization regimen for the nasal spray H7N9 vaccine was determined to be a 21-day interval between the primary immunization and booster, with a dose of 4.5 μg hemagglutinin per mouse. The immunogenicities of the nasal spray H7N9 vaccine and intramuscular vaccine (containing only the inactivated split virus) were compared in mice. Two doses of the nasal spray H7N9 vaccine induced higher titers of HI (6.7 ± 0.67 vs. 5.3 ± 1.16, P = 0.004) and anti-HA IgG in sera (19.26 ± 0.67 vs. 13.97 ± 0.82, P < 0.0001) and of anti-HA sIgA (7.13 ± 2.54 vs. 0, P = 0.0000) in bronchoalveolar lavage fluid (BALF) than one dose of intramuscular H7N9 vaccine 3 weeks after the last immunization. However, when we immunized the mice with two doses of both vaccines separately, the nasal spray H7N9 vaccine induced higher titers of anti-HA IgG (19.26 ± 0.67 vs. 17.56 ± 0.57, P < 0.0001) and anti-HA sIgA (7.13 ± 2.54 vs. 4.02 ± 0.33, P = 0.0026) than did the intramuscular H7N9 vaccine, and there was no difference in HI titer between the two groups (P = 0.3745). This finding indicates that the JY-adjuvanted nasal spray H7N9 vaccine induced not only the systemic immune response but also a local mucosal response, which may improve the efficacy of H7N9 influenza prevention through respiratory tract transmission.
自 2013 年首例人感染甲型禽流感（H7N9）病毒以来，中国已发生了五轮 H7N9 疫情，均导致严重疾病，包括肺炎和急性呼吸窘迫综合征，这些疫情的死亡率高达 30-40%。为了控制 H7N9 流感的流行，迫切需要一种有效的疫苗。在本研究中，我们使用壳聚糖和重组人白细胞介素-2 作为佐剂（JY）来促进 H7N9 疫苗引起的系统和黏膜免疫反应。用含有或不含有 JY 的灭活甲型流感（H7N9）病毒（A/上海/2013/02）疫苗经鼻腔免疫小鼠。与未用佐剂的疫苗免疫的小鼠相比，用 JY 佐剂疫苗免疫的小鼠的血凝抑制（HI）滴度明显更高（21.11 ± 9.58 对 5.04 ± 3，P < 0.05）。JY 佐剂的 H7N9 鼻喷疫苗诱导的 HI 滴度（8 ± 0.82 对 6.7 ± 0.67，P = 0.0035）高于聚肌苷酸（poly（I:C））佐剂的 H7N9 疫苗或 LTβ 佐剂的 H7N9 疫苗（8 ± 0.82 对 6.9 ± 0.88，P = 0.0186）。鼻喷 H7N9 疫苗的最佳免疫方案确定为初次免疫和加强免疫之间间隔 21 天，每只小鼠剂量为 4.5μg 血凝素。在小鼠中比较了鼻喷 H7N9 疫苗和肌肉注射疫苗（仅含有灭活的分裂病毒）的免疫原性。两剂鼻喷 H7N9 疫苗诱导的 HI 滴度（6.7 ± 0.67 对 5.3 ± 1.16，P = 0.004）和血清中抗-HA IgG 滴度（19.26 ± 0.67 对 13.97 ± 0.82，P < 0.0001）和支气管肺泡灌洗液（BALF）中抗-HA sIgA 滴度（7.13 ± 2.54 对 0，P = 0.0000）均高于末次免疫后 3 周时一剂肌肉注射 H7N9 疫苗。然而，当我们分别用两剂两种疫苗免疫小鼠时，鼻喷 H7N9 疫苗诱导的抗-HA IgG 滴度（19.26 ± 0.67 对 17.56 ± 0.57，P < 0.0001）和抗-HA sIgA 滴度（7.13 ± 2.54 对 4.02 ± 0.33，P = 0.0026）均高于肌肉注射 H7N9 疫苗，两组 HI 滴度无差异（P = 0.3745）。这一发现表明，JY 佐剂的鼻喷 H7N9 疫苗不仅诱导了系统免疫反应，还诱导了局部黏膜反应，这可能通过呼吸道传播提高 H7N9 流感的预防效果。
