Immunogenicity and safety of MF59-adjuvanted quadrivalent influenza vaccine versus standard and alternate B strain MF59-adjuvanted trivalent influenza vaccines in older adults.
MF59-佐剂四价流感疫苗与标准和替代 B 株三价流感疫苗在老年人中的免疫原性 MF59-佐剂安全性。
- 作者列表："Essink B","Fierro C","Rosen J","Figueroa AL","Zhang B","Verhoeven C","Edelman J","Smolenov I
OBJECTIVE:Evaluate whether adjuvanted quadrivalent influenza vaccine (aQIV) elicits a noninferior immune response compared with a licensed adjuvanted trivalent influenza vaccine (aTIV-1; Fluad™) and aTIV-2 containing an alternate B strain, examine whether aQIV had immunological superiority for the B strain absent from aTIV comparators, and evaluate reactogenicity and safety among adults ≥65 years. METHODS:In a multicenter, double-blind, randomized controlled trial, adults ≥65 years were randomized 2:1:1 to vaccination with aQIV (n = 889), aTIV-1 (n = 445), or aTIV-2 (n = 444) during the 2017-2018 influenza season. Immunogenicity was assessed by hemagglutination inhibition (HI) assay conducted on serum samples collected before vaccination and 21 days after vaccination for homologous influenza strains. RESULTS:aQIV met non-inferiority criteria for geometric mean titer ratios (GMT ratios) and seroconversion rate (SCR) differences against aTIV. The upper bounds of the 2-sided 95% confidence interval (CI) for GMT ratios were <1.5 for all 4 strains (A/H1N1 = 1.27, A/H3N2 = 1.09, B-Yamagata = 1.08, B-Victoria = 1.08). The upper bounds of the 95% CI of the SCR differences were <10% for all 4 strains (A/H1N1 = 7.76%, A/H3N2 = 4.96%, B-Yamagata = 3.27%, B-Victoria = 2.55%). aQIV also met superiority criteria (upper bound of 95% CI for GMT ratios <1 and SCR differences <0) for B strain absent from aTIV comparators (B-Yamagata GMT ratio = 0.70, SCR difference = 8.81%; B-Victoria GMT ratio = 0.78, SCR difference = 8.11%). aQIV and aTIV vaccines were immunogenic and well-tolerated. The immunological benefit of aQIV was also demonstrated in age subgroups 65–74 years, 75–84 years, and ≥ 85 years and in those with high comorbidity risk scores. Reactogenicity profiles were generally comparable. Conclusion: aQIV induces a similar immune response as the licensed aTIV vaccine against homologous influenza strains and has a comparable reactogenicity and safety profile. Superior immunogenicity against the additional B strain was observed, indicating that aQIV could provide a broader protection than aTIV against influenza in older adults (NCT03314662).
目的: 评估佐剂四价流感疫苗 (aQIV) 与许可的佐剂三价流感疫苗 (aTIV-1; Fluad™) 相比是否引起非劣效免疫应答) 和含有替代 B 株的 aTIV-2，检查 aQIV 是否对 aTIV 比较中不存在的 B 株具有免疫学优势，并在 ≥ 65 岁的成人中评价反应原性和安全性。 方法: 在一项多中心、双盲、随机对照试验中，≥ 65 岁的成年人随机 2:1:1 接种 aQIV 病毒 (n = 889) 、 aTIV-1 (n = 445)。或在 444-2017 流感季节 aTIV-2 (n = 2018)。采用血凝抑制 (HI) 试验对接种前及接种后 21d 的同源流感毒株血清进行免疫原性评价。 结果: aQIV 符合几何平均滴度比 (GMT 比) 和血清转换率 (SCR) 与 aTIV 差异的非劣效性标准。所有 4 个菌株的 GMT 比值的双侧 95% 置信区间 (CI) 上限均 <1.5 (A/H1N1 = 1.27，A/H3N2 = 1.09, B-山形 = 1.08，B-维多利亚 = 1.08)。所有 4 株 SCR 差异的 95% CI 上限均 <10% (A/H1N1 = 7.76%，A/H3N2 = 4.96%，B-Yamagata = 3.27%, B-维多利亚 = 2.55%)。对于 aTIV 比较对象 (B-Yamagata GMT ratio = 95%) 中不存在的 B 菌株，aQIV 也符合优势标准 (GMT ratio <1 和 SCR 差异 <0 的上限 0.70 CI),SCR 差 = 8.81%; B-Victoria GMT 比值 = 0.78，SCR 差 = 8.11%)。AQIV 和 aTIV 疫苗具有免疫原性和良好的耐受性。在年龄亚组 65-74 岁、 75-84 岁和 ≥ 85 岁以及合并症风险评分高的人群中也证明了 aQIV 的免疫学获益。反应原性谱一般具有可比性。 结论: aQIV 诱导的免疫应答与许可的抗同源 aTIV 疫苗相似 流感毒株，具有相当的反应原性和安全性。观察到对额外 B 株具有优越的免疫原性，表明 aQIV 可以比 aTIV 提供更广泛的老年人抗流感的保护 (NCT03314662)。
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.