Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
J Virol. 2018 Apr 13;92(9). doi: 10.1128/JVI.01970-17. Print 2018 May 1.
Pandemic live attenuated influenza vaccines (pLAIV) prime subjects for a robust neutralizing antibody response upon subsequent administration of a pandemic inactivated subunit vaccine (pISV). However, a difference was not detected in H5-specific memory B cells in the peripheral blood between pLAIV-primed and unprimed subjects prior to pISV boost. To investigate the mechanism underlying pLAIV priming, we vaccinated groups of 12 African green monkeys (AGMs) with H5N1 pISV or pLAIV alone or H5N1 pLAIV followed by pISV and examined immunity systemically and in local draining lymph nodes (LN). The AGM model recapitulated the serologic observations from clinical studies. Interestingly, H5N1 pLAIV induced robust germinal center B cell responses in the mediastinal LN (MLN). Subsequent boosting with H5N1 pISV drove increases in H5-specific B cells in the axillary LN, spleen, and circulation in H5N1 pLAIV-primed animals. Thus, H5N1 pLAIV primes localized B cell responses in the MLN that are recalled systemically following pISV boost. These data provide mechanistic insights for the generation of robust humoral responses via prime-boost vaccination. We have previously shown that pandemic live attenuated influenza vaccines (pLAIV) prime for a rapid and robust antibody response on subsequent administration of inactivated subunit vaccine (pISV). This is observed even in individuals who had undetectable antibody (Ab) responses following the initial vaccination. To define the mechanistic basis of pLAIV priming, we turned to a nonhuman primate model and performed a detailed analysis of B cell responses in systemic and local lymphoid tissues following prime-boost vaccination with pLAIV and pISV. We show that the nonhuman primate model recapitulates the serologic observations from clinical studies. Further, we found that pLAIVs induced robust germinal center B cell responses in the mediastinal lymph node. Subsequent boosting with pISV in pLAIV-primed animals resulted in detection of B cells in the axillary lymph nodes, spleen, and peripheral blood. We demonstrate that intranasally administered pLAIV elicits a highly localized germinal center B cell response in the mediastinal lymph node that is rapidly recalled following pISV boost into germinal center reactions at numerous distant immune sites.
大流行减毒活流感疫苗（pLAIV）可在随后接种大流行灭活亚单位疫苗（pISV）时使受试者产生强大的中和抗体反应。然而，在 pISV 加强免疫之前，pLAIV 免疫的受试者与未免疫的受试者在 H5 特异性记忆 B 细胞方面在外周血中没有差异。为了研究 pLAIV 免疫的机制，我们用 H5N1 pISV 或 pLAIV 单独或 H5N1 pLAIV 接种 12 只非洲绿猴（AGM）组，并系统地和局部引流淋巴结（LN）检查免疫。AGM 模型重现了临床研究中的血清学观察结果。有趣的是，H5N1 pLAIV 在纵隔淋巴结（MLN）中诱导了强大的生发中心 B 细胞反应。随后用 H5N1 pISV 加强免疫，可使 H5N1 pLAIV 免疫的动物的腋窝淋巴结、脾脏和循环中 H5 特异性 B 细胞增加。因此，H5N1 pLAIV 在 MLN 中引发局部 B 细胞反应，随后用 pISV 加强免疫可在全身召回。这些数据为通过初次免疫和加强免疫接种产生强大的体液反应提供了机制见解。我们之前已经表明，大流行减毒活流感疫苗（pLAIV）在随后接种灭活亚单位疫苗（pISV）后可迅速产生强大的抗体反应，即使在最初接种后抗体（Ab）反应无法检测到的个体中也是如此。为了确定 pLAIV 免疫的机制基础，我们转向非人类灵长类动物模型，并在 pLAIV 和 pISV 初次免疫和加强免疫后，对系统和局部淋巴组织中的 B 细胞反应进行了详细分析。我们表明，非人类灵长类动物模型重现了临床研究中的血清学观察结果。此外，我们发现 pLAIV 诱导了纵隔淋巴结中强大的生发中心 B 细胞反应。在 pLAIV 免疫的动物中用 pISV 加强免疫可导致在腋窝淋巴结、脾脏和外周血中检测到 B 细胞。我们证明，经鼻给予 pLAIV 可在纵隔淋巴结中引发高度局部化的生发中心 B 细胞反应，该反应在 pISV 加强免疫后迅速被召回，在许多远处的免疫部位引发生发中心反应。
