Phase 1 study of two merozoite surface protein 1 (MSP1(42)) vaccines for Plasmodium falciparum malaria.
Phase 1 study of two merozoite surface protein 1 (MSP1(42)) vaccines for Plasmodium falciparum malaria.
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第1阶段的研究对恶性疟原虫疟疾的两种蛋白石表面蛋白1（MSP1（42））疫苗的研究。
DOI：
10.1371/journal.pctr.0020012
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发表时间：
2007
期刊：
影响因子：
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通讯作者：
Martin, Laura B
中科院分区：
文献类型：
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作者：
Malkin, Elissa;Long, Carole A;Stowers, Anthony W;Zou, Lanling;Singh, Sanjay;MacDonald, Nicholas J;Narum, David L;Miles, Aaron P;Orcutt, Andrew C;Muratova, Olga;Moretz, Samuel E;Zhou, Hong;Diouf, Ababacar;Fay, Michael;Tierney, Eveline;Leese, Philip;Mahanty, Siddhartha;Miller, Louis H;Saul, Allan;Martin, Laura B
目的评价两种针对血期恶性疟原虫的疫苗MSP142-FVO/Alhydrogel和MSP142-3D7/Alhydrogel的安全性和免疫原性。1期开放标签、剂量递增研究。2004年7月至2005年11月，任职于堪萨斯州Lenexa的Quintiles Phase 1 Services。60名年龄在18-48岁的健康志愿者malaria-naïve。在大肠杆菌中表达了FVO和3D7恶性疟原虫中存在的两种等位基因形式对应的卵裂子表面蛋白1 （MSP142）的c端42-kDa区域，并对其进行了折叠、纯化和氢氧化铝制备。对每种疫苗，分别在0、28和180 d接种3个剂量组（5、20和80 μg）的志愿者。志愿者随访1年。评估MSP142-FVO/Alhydrogel和MSP142-3D7/Alhydrogel的安全性。通过对同源和异源MSP142、MSP119和MSP133重组蛋白的反应性以及对FVO和3D7寄生虫的识别来检测每种疫苗的抗体应答。接种3次MSP142-FVO/Alhydrogel和MSP142-3D7/Alhydrogel的志愿者中，分别有20/27（74%）和22/27（81%）检测到抗msp142抗体。无论采用何种疫苗，抗体均与MSP142-FVO和MSP142-3D7蛋白发生交叉反应。大多数抗体应答针对MSP142的c端19 kda结构域，尽管也检测到针对MSP142的n端33 kda结构域的低水平抗体。志愿者血清的免疫荧光显微镜显示对FVO和3D7恶性疟原虫分裂体和游离分裂子都有反应。从接种者血清中纯化的IgG对FVO或3D7寄生虫的体外生长抑制作用很小。MSP142/醛水凝胶疫苗是安全且耐受性良好的，但在体外没有足够的免疫原性来产生生物效应。为了制造出有效的疫苗，可能需要在醛水凝胶制剂中加入免疫刺激剂，以在人体内引起更高的疫苗诱导应答。背景：一般来说，生活在世界上疟疾常见地区的成年人会对寄生虫产生保护性免疫。这意味着他们可能会被感染，但不会因此生病。然而，有些人，如孕妇和五岁以下儿童，由于没有（或减少）天然免疫力，更有可能出现疟疾症状。一种成功的疟疾疫苗将刺激个体的免疫系统对疟原虫作出反应，从而预防严重的临床疾病。许多不同的团体目前正在开发潜在的疫苗。几种候选药物是基于一种叫做MSP1的蛋白质，这种蛋白质存在于疟原虫的血液阶段形式的表面。然而，在自然界中，寄生虫携带不同版本的MSP1蛋白，理想情况下，成功的疫苗将带来针对这些不同版本的免疫反应。进行这项试验的研究人员希望比较代表两种不同MSP1蛋白的候选疫苗的安全性和免疫反应，这两种候选疫苗覆盖了许多不同的寄生虫品系。作为一期试验，这项研究是在健康的成年志愿者中进行的。60人被分配接受疫苗注射，其中含有类似于FVO寄生虫系（称为MSP142-FVO）或3D7寄生虫系（称为MSP142-3D7）的重组蛋白，剂量为三种不同水平。该试验的主要目的是评估安全性，通过收集三次疫苗接种后每次14天内任何异常体征或症状的数据来完成。这些结果被分级，然后定义为与疫苗相关或不相关。研究人员还观察了参与者血液中针对MSP1蛋白不同变体的抗体水平，并使用体外测试来观察来自接种疫苗个体的抗体是否可以阻止疟疾寄生虫在实验室培养物中生长。试验结果：试验的安全性结果表明，志愿者经历的最常见的副作用是注射部位的疼痛。尽管有一例严重事件（一名志愿者在注射部位经历了高水平的疼痛），但绝大多数此类事件被分级为轻度。副作用发生的几率与个体接种的疫苗剂量之间没有显著的关联。接种疫苗后，检测到针对疫苗所依据的蛋白质的抗体水平，尽管这些水平随着时间的推移而下降。研究人员没有发现个体接种的疫苗剂量和抗体反应水平之间有很强的联系。然而，比较这两种疫苗时，似乎在提高免疫反应方面同样出色，并且都引起了与MSP1蛋白不同变体相对应的抗体的产生。然而，培养出的抗体在防止疟疾寄生虫在实验室培养物中生长方面似乎并不是特别有效。优势和局限性：本研究的优势包括对所研究疫苗的三种不同剂量水平进行比较，以及对基于同一蛋白质的两种疫苗进行比较，这些疫苗代表不同的寄生虫品系。该研究的局限性包括参与者人数较少，这使得该试验在检测被比较组之间副作用的巨大差异方面能力不足。试验中不包括安慰剂组，因此不可能确定这里观察到的副作用数量是否归因于疫苗。最后，将个体分配给两种不同疫苗的过程涉及交替，而不是真正的随机化，这可能会将偏倚风险降到最低。对证据的贡献：这里报道的试验是疫苗开发的重要一步。结果提供了与这两种疫苗的安全性有关的第一个证据，并且在现阶段没有引起任何安全问题。尽管疫苗引起了免疫反应，但产生的抗体在体外对疟疾寄生虫似乎没有太大影响。虽然这些疫苗是安全的，但在进行实地研究之前，可能会研究预计会产生更大免疫反应的替代MSP1疫苗配方。
To assess the safety and immunogenicity of two vaccines, MSP142-FVO/Alhydrogel and MSP142-3D7/Alhydrogel, targeting blood-stage Plasmodium falciparum parasites. A Phase 1 open-label, dose-escalating study. Quintiles Phase 1 Services, Lenexa, Kansas between July 2004 and November 2005. Sixty healthy malaria-naïve volunteers 18–48 y of age. The C-terminal 42-kDa region of merozoite surface protein 1 (MSP142) corresponding to the two allelic forms present in FVO and 3D7 P. falciparum lines were expressed in Escherichia coli, refolded, purified, and formulated on Alhydrogel (aluminum hydroxide). For each vaccine, volunteers in each of three dose cohorts (5, 20, and 80 μg) were vaccinated at 0, 28, and 180 d. Volunteers were followed for 1 y. The safety of MSP142-FVO/Alhydrogel and MSP142-3D7/Alhydrogel was assessed. The antibody response to each vaccine was measured by reactivity to homologous and heterologous MSP142, MSP119, and MSP133 recombinant proteins and recognition of FVO and 3D7 parasites. Anti-MSP142 antibodies were detected by ELISA in 20/27 (74%) and 22/27 (81%) volunteers receiving three vaccinations of MSP142-FVO/Alhydrogel or MSP142-3D7/Alhydrogel, respectively. Regardless of the vaccine, the antibodies were cross-reactive to both MSP142-FVO and MSP142-3D7 proteins. The majority of the antibody response targeted the C-terminal 19-kDa domain of MSP142, although low-level antibodies to the N-terminal 33-kDa domain of MSP142 were also detected. Immunofluorescence microscopy of sera from the volunteers demonstrated reactivity with both FVO and 3D7 P. falciparum schizonts and free merozoites. Minimal in vitro growth inhibition of FVO or 3D7 parasites by purified IgG from the sera of the vaccinees was observed. The MSP142/Alhydrogel vaccines were safe and well tolerated but not sufficiently immunogenic to generate a biologic effect in vitro. Addition of immunostimulants to the Alhydrogel formulation to elicit higher vaccine-induced responses in humans may be required for an effective vaccine. Background: Generally, adults living in parts of the world where malaria is common develop protective immunity against the parasite. This means they may get infected but not become ill as a result. However, there are individuals, such as pregnant women and children under the age of five, who are more likely to develop symptoms of malaria due to no (or reduced) natural immunity. A successful malaria vaccine would stimulate an individual's immune system to respond to the malaria parasite and prevent serious clinical disease. Many different groups are currently developing potential vaccines. Several candidates are based on a protein called MSP1 (merozoite surface protein 1) which is found on the surface of the blood-stage form of the malaria parasite. However, in nature parasites carry different versions of the MSP1 protein, and ideally a successful vaccine would bring about immune responses against these different versions. The researchers carrying out this trial wanted to compare the safety and immune responses against candidate vaccines representing two different MSP1 proteins, which covered many different parasite lines. As a phase 1 trial, the study was carried out in healthy adult volunteers. Sixty individuals were assigned to receive an injection of the vaccines, either containing a recombinant protein analogous to the FVO parasite line (termed MSP142-FVO) or the 3D7 parasite line (termed MSP142-3D7) at three different dose levels. The trial's primary objective was to assess safety, which was done by collecting data on any abnormal signs or symptoms up to 14 d after each of three vaccinations. These outcomes were graded and then defined as related to the vaccine or not. The researchers also looked at antibody levels in participants' blood against different variants of the MSP1 protein, as well as using in vitro tests to see whether antibodies from vaccinated individuals could prevent malaria parasites from growing in lab culture. What the trial shows: The safety outcomes of the trial showed that the most common type of side effect experienced by the volunteers was pain at the injection site. The vast majority of such events were graded as mild, although there was one single case of a severe event (high levels of pain experienced by one volunteer at the injection site). There was no significant association between the chance of side effects and the vaccine dosage that an individual received. Following vaccination, antibody levels against the protein on which the vaccine was based were detected, although these levels dropped over time. The researchers did not see a strong association between the vaccine dosage that individuals received and the level of antibody response. However, the two vaccines when compared seemed to be equally good at raising an immune response and both caused antibodies to be raised corresponding to different variants of the MSP1 protein. However, the antibodies raised did not seem to be particularly effective at preventing malaria parasites from growing in lab culture. Strengths and limitations: Strengths of this study include a comparison of three different dosage levels of the vaccines under study, as well as a comparison of two vaccines based on the same protein, representing different parasite lines. Limitations to the study include the small number of participants, which makes the trial underpowered to detect all but large differences in side effects between the groups being compared. A placebo arm was not included in the trial, so it is not possible to be sure that the numbers of side effects observed here can be attributed to the vaccines or not. Finally, the procedure for assigning individuals to the two different vaccines involved alternation, rather than true randomization, which could have minimized the risk of bias. Contribution to the evidence: The trial reported here is an essential step in vaccine development. The results provide the first evidence relating to safety for these two vaccines, and do not raise any safety concerns at this stage. Although the vaccines raised an immune response, the antibodies raised did not seem to have much of an effect on malaria parasites in vitro. While these vaccines are safe, alternative MSP1 vaccine formulations anticipated to bring about a greater immune response will likely be studied before proceeding to field studies.