An Intranasal Proteosome-Adjuvanted Trivalent Influenza Vaccine Is Safe, Immunogenic & Efficacious in the Human Viral Influenza Challenge Model. Serum IgG & Mucosal IgA Are Important Correlates of Protection against Illness Associated with Infection

Introduction
A Proteosome-adjuvanted trivalent inactivated influenza vaccine (P-TIV) administered intra-nasally was shown to be safe, well tolerated and immunogenic in both systemic and mucosal compartments, and effective at preventing illness associated with evidence of influenza infection.
Methods
In two separate studies using the human viral challenge model, subjects were selected to be immunologically naive to A/Panama/2007/1999 (H3N2) virus and then dosed via nasal spray with one of three regimens of P-TIV or placebo. One or two doses, 15 μg or 30 μg, were given either once only or twice 14 days apart (1 x 30 μg, 2 x 30 μg, 2 x 15 μg) and subjects were challenged with A/Panama/2007/1999 (H3N2) virus. Immune responses to the vaccine antigens were measured by haemagglutination inhibition assay (HAI) and nasal wash secretory IgA (sIgA) antibodies.
Results
Vaccine reactogenicity was mild, predictable and generally consistent with earlier Phase I studies with this vaccine. Seroconversion to A/Panama/2007/1999 (H3N2), following vaccination but prior to challenge, occurred in 57% to 77% of subjects in active dosing groups and 2% of placebo subjects. The greatest relative rise in sIgA, following vaccination but prior to challenge, was observed in groups that received 2 doses.
Conclusion
Intranasal vaccination significantly protected against influenza (as defined by influenza symptoms combined with A/Panama seroconversion) following challenge with A/Panama/2007/1999 (H3N2). When data were pooled from both studies, efficacy ranged from 58% to 82% in active dosing groups for any influenza symptoms with seroconversion, 67% to 85% for systemic or lower respiratory illness and seroconversion, and 65% to 100% for febrile illness and seroconversion. The two dose regimen was found to be superior to the single dose regimen. In this study, protection against illness associated with evidence of influenza infection (evidence determined by seroconversion) following challenge with virus, significantly correlated with pre-challenge HAI titres (p = 0.0003) and mucosal sIgA (p≤0.0001) individually, and HAI (p = 0.028) and sIgA (p = 0.0014) together. HAI and sIgA levels were inversely related to rates of illness.
Trial Registration
ClinicalTrials.gov NCT02522754

引言
鼻内接种的蛋白体佐剂三价灭活流感疫苗（Proteosome-adjuvanted trivalent inactivated influenza vaccine, P-TIV）已被证实具备良好安全性、耐受性，在系统性免疫与黏膜免疫两类免疫区室中均具有免疫原性，且可有效预防流感感染相关疾病。

方法
在两项独立的人体病毒攻击模型研究中，受试者均为对A/Panama/2007/1999（H3N2）毒株免疫幼稚，随后通过鼻喷雾给予三种P-TIV接种方案之一或安慰剂。接种方案包括：单次30μg、两次30μg（间隔14天）、两次15μg（间隔14天），随后受试者经A/Panama/2007/1999（H3N2）毒株攻毒。采用血凝抑制试验（hemagglutination inhibition assay, HAI）与鼻腔冲洗液分泌型免疫球蛋白A（secretory IgA, sIgA）抗体检测疫苗抗原的免疫应答水平。

结果
疫苗的反应原性轻微、可预测，整体与该疫苗此前的I期临床试验结果一致。接种后、攻毒前，活性接种组受试者中57%至77%出现了针对A/Panama/2007/1999（H3N2）的血清阳转，安慰剂组仅为2%。接种后、攻毒前的分泌型免疫球蛋白A相对升高幅度最大的组别为接受两剂接种的受试者。

结论
经A/Panama/2007/1999（H3N2）毒株攻毒后，鼻内接种疫苗可显著预防流感（定义为出现流感症状且伴随A/Panama毒株血清阳转）。合并两项研究的数据后，活性接种组中，伴血清阳转的任意流感症状保护效力为58%至82%，伴血清阳转的全身性或下呼吸道疾病保护效力为67%至85%，伴血清阳转的发热性疾病保护效力为65%至100%。两剂接种方案的保护效果优于单剂接种方案。本研究中，攻毒后与流感感染证据（以血清阳转为判定依据）相关的疾病保护效果，分别与攻毒前血凝抑制抗体滴度（p=0.0003）、黏膜分泌型免疫球蛋白A水平（p≤0.0001）显著相关，且与二者联合水平亦显著相关（p=0.028；p=0.0014）。血凝抑制抗体滴度与分泌型免疫球蛋白A水平与疾病发生率呈负相关。

试验注册
ClinicalTrials.gov NCT02522754