Potent Plasmablast-Derived Antibodies Elicited by the National Institutes of Health Dengue Vaccine
Potent Plasmablast-Derived Antibodies Elicited by the National Institutes of Health Dengue Vaccine
复制标题
DOI：
10.1128/jvi.00867-17
复制
发表时间：
2017-11-01
影响因子：
5.4
通讯作者：
Watkins, David I.
中科院分区：
文献类型：
--
作者：
Magnani, Diogo M.;Silveira, Cassia G. T.;Watkins, David I.
暴露于登革病毒（DENV）被认为引发由DENV中和抗体（nAb）介导的终身免疫。然而，由原发感染产生的抗体赋予抗体型特异性保护，并且仅在后续感染后才产生针对其他血清型的免疫力。因此，在连续DENV感染后获得的这些nAb应答的诱导一直是疫苗接种的长期追求的目标。尽管如此，四价疫苗是否能引发或召回nAb仍不清楚。在这项研究中，我们描述了一名志愿者的反应，该志愿者以前曾接触过DENV，并接种了由NIH和Butantan研究所开发的活减毒四价疫苗Butantan-DV。接种后11天，我们观察到浆母细胞群体的类似70倍扩增。我们从单个分选的浆母细胞产生了21种单克隆抗体（MAbs）。这些单克隆抗体是克隆扩增的结果，并具有显着水平的体细胞超突变（SHM）。19种单克隆抗体（90.5%）在1 μ g/ml或更低的浓度下中和至少一种DENV血清型; 21种单克隆抗体中有6种中和三种或更多种血清型。尽管疫苗的四价组成，我们观察到诱导的库中的中和偏倚：DENV 3被19种中和MAb（nMAb）中的18种靶向。此外，P3 D 05 nMAb以非凡的效力中和DENV 3（达到半数最大中和的浓度[Neut（50）] = 0.03 μ g/ml）。因此，Butan-DV疫苗产生成熟的抗原选择性B细胞库。我们的研究结果表明，先前的DENV 3感染引起的预先存在的反应被召回immunity.IMPORTANCE登革热疫情提出了一个全球性的公共卫生挑战，造成广泛的经济负担，并仍然在很大程度上不受现有的控制策略。成功控制登革热流行需要有效的预防和治疗干预措施。几项疫苗临床有效性试验即将完成，一种或多种四价减毒活疫苗（LATV）在世界范围内推出的机会比以往任何时候都要高。虽然广泛接受登革病毒（DENV）中和抗体（nAb）滴度与保护相关，但LATV诱导的Ab库仍未表征。在这里，我们描述了从用四价疫苗Butantan-DV免疫的DENV血清阳性志愿者中分离有效的（Neut（50）< 0.1 μ g/ml）nAb，该疫苗目前处于III期试验中。
Exposure to dengue virus (DENV) is thought to elicit lifelong immunity, mediated by DENV-neutralizing antibodies (nAbs). However, Abs generated by primary infections confer serotype-specific protection, and immunity against other serotypes develops only after subsequent infections. Accordingly, the induction of these nAb responses acquired after serial DENV infections has been a long-sought-after goal for vaccination. Nonetheless, it is still unclear if tetravalent vaccines can elicit or recall nAbs. In this study, we have characterized the responses from a volunteer who had been previously exposed to DENV and was immunized with the live attenuated tetravalent vaccine Butantan-DV, developed by the NIH and Butantan Institute. Eleven days after vaccination, we observed an similar to 70-fold expansion of the plasmablast population. We generated 21 monoclonal Abs (MAbs) from singly sorted plasmablasts. These MAbs were the result of clonal expansions and had significant levels of somatic hypermutation (SHM). Nineteen MAbs (90.5%) neutralized at least one DENV serotype at concentrations of 1 mu g/ml or less; 6 of the 21 MAbs neutralized three or more serotypes. Despite the tetravalent composition of the vaccine, we observed a neutralization bias in the induced repertoire: DENV3 was targeted by 18 of the 19 neutralizing MAbs (nMAbs). Furthermore, the P3D05 nMAb neutralized DENV3 with extraordinary potency (concentration to achieve half-maximal neutralization [Neut(50)] = 0.03 mu g/ml). Thus, the Butantan-DV vaccine engendered a mature, antigen-selected B cell repertoire. Our results suggest that preexisting responses elicited by a previous DENV3 infection were recalled by immunization.IMPORTANCE The dengue epidemic presents a global public health challenge that causes widespread economic burden and remains largely unchecked by existing control strategies. Successful control of the dengue epidemic will require effective prophylactic and therapeutic interventions. Several vaccine clinical efficacy trials are approaching completion, and the chances that one or more live attenuated tetravalent vaccines (LATVs) will be introduced worldwide is higher than ever. While it is widely accepted that dengue virus (DENV)-neutralizing antibody (nAb) titers are associated with protection, the Ab repertoire induced by LATVs remain uncharacterized. Here, we describe the isolation of potent (Neut(50) < 0.1 mu g/ml) nAbs from a DENV-seropositive volunteer immunized with the tetravalent vaccine Butantan-DV, which is currently in phase III trials.