Adenovirus-5-Vectored <em>P. falciparum</em> Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component

BackgroundA protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge. Methodology/Principal FindingsNMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected. SignificanceThe NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection. Trial Registration ClinicalTrials.gov NCT00392015背景 保护性疟疾疫苗通常需要同时诱导细胞免疫与体液抗体应答。由于腺病毒疫苗载体可在人体中同时诱导这两类免疫应答，本研究开展1/2a期临床试验，以评估5型腺病毒（adenovirus serotype 5, Ad5）载体疟疾疫苗针对子孢子攻击的保护效力。 方法/主要发现 NMRC-MV-Ad-PfC是一种编码恶性疟原虫3D7株环子孢子蛋白（circumsporozoite protein, CSP）的腺病毒载体。其为双组分疫苗NMRC-M3V-Ad-PfCA的组分之一，该双组分疫苗包含分别编码CSP与顶端膜抗原1（apical membrane antigen-1, AMA1）的两款腺病毒载体，此前Sedegah等人的研究已对其安全性与免疫原性进行评估（详见同期相关研究）。14名Ad5血清阳性或阴性的成年受试者间隔16周接种两剂NMRC-MV-Ad-PfC，接种剂量为每剂颗粒单位（原文此处存在空白）。该疫苗安全性良好，耐受性佳。所有受试者在首次免疫后28天均出现阳性酶联免疫斑点（ELISpot）应答，几何均值为272斑点形成细胞/百万（sfc/m），该应答在后续16周内有所下降；加强接种后应答再次升高，但多数受试者的峰值水平未超过首次免疫后的初始峰值，几何均值为119 sfc/m。与CD4+ T细胞应答相比，CD8+ T细胞应答占优，这与首次临床试验的结果一致。抗体应答水平较弱，与ELISpot应答类似，在加强接种后有所升高，但未超过初始峰值。预先存在的Ad5中和抗体（neutralizing antibodies, NAb）不会影响首剂接种的免疫原性，但首剂诱导的NAb倍增倍数与加强接种后较弱的抗体应答显著相关，而ELISpot应答未受此影响。在接受恶性疟原虫感染蚊虫叮咬攻击后，11名受试者中有2名的原虫血症检出时间较感染性对照组出现延迟，但无受试者获得完全无菌保护性免疫。 意义 表达CSP的NMRC-MV-Ad-PfC疫苗以两剂次接种时安全性与耐受性良好，但未提供完全无菌性保护。 试验注册 ClinicalTrials.gov NCT00392015