A double-blind, randomized controlled trial to evaluate the safety and immunogenicity of an intranasally administered trivalent inactivated influenza vaccine with the adjuvant LTh(αK): A phase II study.
一项双盲、随机对照试验，评价滴鼻三价灭活流感疫苗与佐剂 LTh (α k) 的安全性和免疫原性: 一项 II 期研究。
- 作者列表："Pan SC","Hsu WT","Lee WS","Wang NC","Chen TJ","Liu MC","Pai HC","Hsu YS","Chang M","Hsieh SM
BACKGROUND:Intranasal influenza vaccines may provide protective efficacy by inducing both systemic antibodies and local secretory IgA. Live attenuated intranasal vaccines are not feasible for high-risk groups. A previously constructed inactivated vaccine with adjuvant revealed an association with neurological events in some studies. In this phase II trial, we aimed to evaluate the safety and immunogenicity of an intranasal influenza vaccine with a novel adjuvant, heat-labile enterotoxin (LT)-derived from E. coli (LTh(αK)). METHODS:This study is a multicenter, randomized controlled, double-blind, phase II trial of an intranasal influenza vaccine containing 22.5 μg of the hemagglutinin (HA) antigen of three influenza strains in combination with 2 different LTh(αK) adjuvant doses (group 1: 30 μg; group 2: 45 μg) in subjects 20-70 years old. The control vaccine was 22.5 μg of influenza HA antigen alone (group 3). The vaccine was intranasally administered on days 1 and 8. Serum anti-HA antibody and nasal secretory IgA were measured, and adverse events (AEs) were recorded prevaccination and 29 (±2) days postvaccination. RESULTS:Of 354 participants randomized in the study, 340 received two vaccine doses. AEs were mostly mild, and there was no discontinuation related to the vaccine. Only a higher frequency of diarrhea after the first dose was noted among group 2 (11.5%) than among group 3 (2.8%), and there was no significant difference after the second dose. The three groups had comparable serum anti-HA antibody immunogenicity. However, the adjuvanted vaccines induced greater mucosal IgA antibody production than the control vaccine. In a subgroup analysis, group 1 participants achieved adequate immunogenicity among both 20- to 60- and 61- to 70-year-old participants. CONCLUSION:The intranasal influenza vaccine adjuvanted with LTh(αK) is generally safe and could provide systemic and local antibody responses. Adjuvanted vaccines were significantly more immunogenic than the nonadjuvanted control vaccine in mucosal immunity. ClinicalTrials.gov Identifier: NCT03784885.
背景: 鼻内流感疫苗可能通过诱导全身抗体和局部分泌 IgA 提供保护效力。鼻内减毒活疫苗对高危人群不可行。先前构建的佐剂灭活疫苗在一些研究中揭示了与神经事件的关联。在这项 II 期试验中，我们旨在评估一种新型佐剂、不耐热肠毒素 (LT) 来源于 E 的鼻内流感疫苗的安全性和免疫原性。 coli (LTh (α k))。 方法: 本研究是一项含有 22.5 μ g 血凝素 (HA) 的鼻内流感疫苗的多中心、随机对照、双盲、 II 期试验在 20-70 岁的受试者中，三种流感毒株的抗原与 2 种不同的 LTh (α k) 佐剂剂量组合 (第 1 组: 30 μ g; 第 2 组: 45 μ g)。对照疫苗为单用流感 HA 抗原 22.5 μ g (第 3 组)。疫苗在第 1 天和第 8 天滴鼻给药。测定血清抗 HA 抗体和鼻分泌型 IgA，记录预防接种和接种后 29 (± 2) 天的不良事件 (AEs)。 结果: 在研究中随机分配的 354 名参与者中，340 人接受了两种疫苗剂量。Ae 大多较轻，没有与疫苗相关的停药。仅第 1 次给药后组 2 (11.5%) 腹泻频率高于第 3 组 (2.8%)，第 2 次给药后腹泻频率无显著差异。三组血清抗 HA 抗体免疫原性相当。然而，佐剂疫苗比对照疫苗诱导更大的粘膜 IgA 抗体产生。在亚组分析中，组 1 参与者在 20-60 岁和 61-70 岁的参与者中获得了足够的免疫原性。 结论: 以 LTh (α k) 为佐剂的鼻内流感疫苗一般是安全的，可以提供全身和局部抗体反应。在粘膜免疫方面，佐剂疫苗的免疫原性显著高于非佐剂对照疫苗。ClinicalTrials.gov 标识符: nct03784885。
METHODS:BACKGROUND:From 2015/16 through 2017/18, injectable, trivalent inactivated influenza vaccines (IIV3) and a nasal spray, tetravalent live-attenuated influenza vaccine (LAIV4) were used in parallel in Finland. To understand how well vaccination with each vaccine type protected children against influenza under real-life conditions, vaccine effectiveness in two-year-olds was estimated for all three seasons. METHODS:Each season, a nationwide register-based cohort study was conducted. The study population comprised 60,088 children in 2015/16, 60,860 children in 2016/17 and 60,345 children in 2017/18. Laboratory-confirmed influenza was the study outcome. Seasonal influenza vaccination with either LAIV4 or IIV3 was the time-dependent exposure of interest. Vaccine effectiveness was defined as 1 minus the hazard ratio comparing vaccinated with unvaccinated children. RESULTS:From 2015/16 through 2017/18, the effectiveness of LAIV4 against influenza of any virus type was estimated at 54.2% (95% confidence interval, 32.2%-69.0%), 20.3% (-12.7% to 43.6%) and 30.5% (10.9%-45.9%); the corresponding effectiveness of IIV3 was 77.2% (48.9%-89.8%), 24.5% (-29.8% to 56.1%) and -20.1% (-61.5% to 10.7%). Neither of the influenza vaccines clearly excelled in protecting children. The LAIV4 effectiveness against type B was greater than against type A and greater than the IIV3 effectiveness against type B. CONCLUSIONS:To understand how influenza vaccines could be improved, vaccine effectiveness must be analyzed by vaccine and virus type. Effectiveness estimates expressing also overall protection levels are needed to guide individual and programmatic decision-making processes. Supported by this analysis, the vaccination program in Finland now recommends LAIV4 and injectable, tetravalent inactivated influenza vaccines replacing IIV3.
METHODS::Intranasally administered influenza vaccines could be more effective than injected vaccines, since intranasal vaccination can induce virus-specific IgA antibodies in the upper respiratory tract, which is the initial site of infection. In the current study, immune responses elicited by an intranasal inactivated H5 influenza vaccine were evaluated in healthy H5 influenza virus-naive individuals. Three doses of intranasal inactivated whole-virion H5 influenza vaccine induced strong neutralizing nasal IgA and serum IgG antibodies. In addition, a mucoadhesive excipient, carboxy-vinyl polymer (CVP), had a notable impact on the induction of nasal IgA antibody responses but not serum IgG antibody responses. The nasal hemagglutinin (HA)-specific IgA antibody responses clearly correlated with mucosal neutralizing antibody responses, indicating that measurement of nasal HA-specific IgA titers could be used as a surrogate for the mucosal antibody response. Furthermore, increased numbers of plasma cells and vaccine antigen-specific helper T (Th) cells in the peripheral blood were observed after vaccination, suggesting that peripheral blood biomarkers may also be used to evaluate the intranasal vaccine-induced immune response. However, peripheral blood immune cell responses correlated with neutralizing antibody titers in serum samples but not in nasal wash samples. Thus, analysis of the peripheral blood immune response could be a surrogate for the systemic immune response to intranasal vaccination but not for the mucosal immune response. The current study suggests the clinical potential of intranasal inactivated vaccines against H5 influenza viruses and highlights the need to develop novel means to evaluate intranasal vaccine-induced mucosal immune responses. This article is protected by copyright. All rights reserved.
METHODS:BACKGROUND:Influenza is an important public health problem and existing vaccines are not completely protective. New vaccines that protect by alternative mechanisms are needed to improve efficacy of influenza vaccines. In 2015, we did a phase 1 trial of an oral influenza vaccine, VXA-A1.1. A favourable safety profile and robust immunogenicity results in that trial supported progression of the vaccine to the current phase 2 trial. The aim of this study was to evaluate efficacy of the vaccine in a human influenza challenge model. METHODS:We did a single-site, placebo-controlled and active-controlled, phase 2 study at WCCT Global, Costa Mesa, CA, USA. Eligible individuals had an initial A/California/H1N1 haemagglutination inhibition titre of less than 20 and were aged 18-49 years and in good health. Individuals were randomly assigned (2:2:1) to receive a single immunisation of either 1011 infectious units of VXA-A1.1 (a monovalent tablet vaccine) orally, a full human dose of quadrivalent inactivated influenza vaccine (IIV) via intramuscular injection, or matched placebo. Randomisation was done by computer-generated assignments with block size of five. An unmasked pharmacist provided the appropriate vaccines and placebos to the administrating nurse. Individuals receiving the treatments, investigators, and staff were all masked to group assignments. 90 days after immunisation, individuals without clinically significant symptoms or signs of influenza, an oral temperature of higher than 37·9°C, a positive result for respiratory viral shedding on a Biofire test, and any investigator-assessed contraindications were challenged intranasally with 0·5 mL wild-type A/CA/like(H1N1)pdm09 influenza virus. The primary outcomes were safety, which was assessed in all immunised participants through 365 days, and influenza-positive illness after viral challenge, which was assessed in individuals that received the viral challenge and the required number of assessments post viral challenge. This trial is registered with ClinicalTrials.gov, number NCT02918006. RESULTS:Between Aug 31, 2016, and Jan 23, 2017, 374 individuals were assessed for eligibility, of whom 179 were randomly assigned to receive either VXA-A1.1 (n=71 [one individual did not provide a diary card, thus the solicited events were assessed in 70 individuals]), IIV (n=72), or placebo (n=36). Between Dec 2, 2016, and April 26, 2017, 143 eligible individuals (58 in the VXA-A1.1 group, 54 in the IIV group, and 31 in the placebo group) were challenged with influenza virus. VXA-A1.1 was well tolerated with no serious or medically significant adverse events. The most prevalent solicited adverse events for each of the treatment groups after immunisation were headache in the VXA-A1.1 (in five [7%] of 70 participants) and placebo (in seven [19%] of 36 participants) groups and tenderness at injection site in the IIV group (in 19 [26%] of 72 participants) Influenza-positive illness after challenge was detected in 17 (29%) of 58 individuals in the VXA-A1.1 group, 19 (35%) of 54 in the IIV group, and 15 (48%) of 31 in the placebo group. INTERPRETATION:Orally administered VXA-A1.1 was well tolerated and generated protective immunity against virus shedding, similar to a licensed intramuscular IIV. These results represent a major step forward in developing a safe and effective oral influenza vaccine. FUNDING:Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, and Biomedical Advanced Research and Development Authority.