Safety and immunogenicity of a seasonal quadrivalent influenza vaccine (GC3110A) in healthy participants aged ≥ 65 years

BackgroundSeasonal Influenza is still considered associated with seasonal morbidity and hospitalization in the elderly population. The World Health Organization (WHO) recommended seasonal quadrivalent influenza vaccine (QIV) to reduce burden of two currently circulating influenza B lineages. Until 2019 Korean National Immunization Program (NIP) recommended trivalent influenza vaccine (TIV) after ongoing debates on cost effectiveness of QIV for elderly population. Although influenza vaccine only showed modest effect on reducing influenza in elderly, this study aimed to evaluate the immunogenicity and safety of inactivated QIV in healthy participants ≥ 65 years of age.MethodsA total of 274 healthy participants aged ≥ 65 years received a QIV. Seroconversion-based vaccine efficacy of 4 strains of seasonal influenza was assessed 21 days after vaccination and adverse events were monitored until 180 days after vaccination.ResultsThe percentages of participants seroconverted after vaccination on HI antibody against each strain were 36.5% (99/271) to A/H1N1, 47.6% (129/271) to A/H3N2, 40.6% (110/271) to B Yamagata, and 49.1% (133/271) to B Victoria. The percentages of participants seroprotected after vaccination on HI antibody against each strain were 81.2% (220/271) to A/H1N1, 98.5% (267/271) to A/H3N2, 95.2% (258/271) to B Yamagata, and 93.7% (254/271) to B Victoria. There was no serious adverse event (SAE) related with the study vaccine.ConclusionThe quadrivalent split influenza vaccine is expected to offer seroprotection against influenza A and both influenza B lineages even in the elderly population.     

Immunogenicity and safety of inactivated influenza vaccines in primed populations: a systematic literature review and meta-analysis

Several inactivated influenza vaccine formulations for systemic administration in man are currently available for annual (seasonal) immunization: split virus and subunit (either plain-aqueous, or virosomal, or adjuvanted by MF59). From a literature search covering the period 1978-2009, 33 articles could be identified, which described randomized clinical trials comparing at least two of the four vaccine formulations with respect to serum hemagglutination inhibition (HI) antibody response, local and systemic vaccine reactions and serious adverse events after vaccination, and employing seasonal vaccine components and doses. In total, 9121 vaccinees of all ages, either healthy or with underlying diseases, were involved. Most vaccinees were primed or had been vaccinated in previous years.For immunogenicity, homologous post-vaccination geometric mean HI titers (GMTs) were analyzed by a random effects model for continuous data. Unreported standard deviations (SD) were addressed by imputing assumed SD-values. Age and health state of the vaccinees appeared to have little influence on the outcome. The immunogenicity of split, aqueous and virosomal subunit formulations were similar, with geometric mean ratio values (GMR, quotient of paired GMT-values) varying around one (0.93-1.24). The MF59-adjuvanted subunit vaccine induced, on average, larger antibody titers than the non-adjuvanted vaccine formulations, but the absolute increase was small (GMR-values varying between 1.25 and 1.40).Vaccine reactions were analyzed using a random effects model for binary data. Local and systemic reactogenicity was similar among non-adjuvanted formulations. The adjuvanted subunit formulation was more frequently associated with local reactions than the non-adjuvanted formulations (rate ratio: 2.12, significant). Systemic reactions were similar among all vaccine formulations. The original articles emphasized the mild and transient character of the vaccine reactions and the absence of serious vaccine-related adverse events.This adequate amount of evidence led to the conclusion that all the currently available inactivated influenza vaccine formulations are safe, well tolerated and similarly effective to control seasonal influenza outbreaks across primed populations and age ranges.     

Safety and immunogenicity of a quadrivalent inactivated influenza vaccine in adults

Background and aims

Although two antigenically distinct B strain lineages of influenza have co-circulated globally since the mid-1980s, trivalent influenza vaccines (TIVs) contain only one, resulting in frequent mismatches. This study examined the safety and immunogenicity of an inactivated quadrivalent influenza vaccine (QIV) candidate.

Methods

This was a phase III, randomized, active-controlled, multicenter trial in adults during the 2011/2012 influenza season. Enrollment was stratified to include equal numbers of subjects 18–60 and >60 years of age. Subjects were randomized 5:1:1 to be vaccinated with the QIV, the licensed TIV, or an investigational TIV containing the alternate B strain lineage. Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination.

Results

1116 subjects were vaccinated with QIV, 226 with the licensed TIV, and 223 with the investigational TIV. For all four vaccine strains, antibody responses to the QIV were non-inferior to the response to the TIV for the matched strains. For both B strains, post-vaccination antibody responses to the QIV were superior to the responses to the TIVs lacking the corresponding B strain. The QIV met all European Medicines Agency criteria for all four vaccine strains. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for the QIV and pooled TIV groups. The most commonly reported solicited reactions were injection-site pain, headache, and myalgia, and most solicited reactions were mild or moderate and appeared and resolved within 3 days of vaccination. No treatment-related serious adverse events or deaths were reported.

Conclusions

The inactivated QIV was well tolerated without any safety concerns. For all four vaccine strains, antibody responses to the QIV were superior to the responses to TIV for the unmatched strains and non-inferior for the matched strains. QIV could therefore help address an unmet need due to mismatched B strains in previous influenza vaccines.

Clinical trial registry number

EudraCT: 2011-001976-21.     

Safety,immunogenicity, and lot-to-lot consistency of a quadrivalent inactivated influenza vaccine in children,adolescents, and adults: A randomized,controlled, phase III trial

BackgroundInactivated quadrivalent influenza vaccine (IIV4) containing two influenza A strains and one strain from each B lineage (Yamagata and Victoria) may offer broader protection against seasonal influenza than inactivated trivalent influenza vaccine (IIV3), containing a single B strain. This study examined the safety, immunogenicity, and lot consistency of an IIV4 candidate.MethodsThis phase III, randomized, controlled, multicenter trial in children/adolescents (9 through 17 years) and adults (18 through 60 years) was conducted in Australia and in the Philippines in 2012. The study was double-blind for IIV4 lots and open-label for IIV4 vs IIV3. Children/adolescents were randomized 2:2:2:1 and adults 10:10:10:1 to receive one of three lots of IIV4 or licensed IIV3. Safety data were collected for up to 6 months post-vaccination. Hemagglutination inhibition and seroneutralization antibody titers were assessed pre-vaccination and 21 days post-vaccination.Results1648 adults and 329 children/adolescents received IIV4, and 56 adults and 55 children/adolescents received IIV3. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for IIV3 and IIV4 recipients in both age groups. Injection-site pain, headache, malaise, and myalgia were the most frequently reported solicited reactions, most of which were mild and resolved within 3 days. No vaccine-related serious adverse events or deaths were reported. Post-vaccination antibody responses, seroconversion rates, and seroprotection rates for the 3 strains common to both vaccines were comparable for IIV3 and IIV4 in both age groups. Antibody responses to IIV4 were equivalent among vaccine lots and comparable between age groups for each of the 4 strains. IIV4 met all European Medicines Agency immunogenicity criteria for adults for all 4 strains.ConclusionsIn both age groups, IIV4 was well tolerated and caused no safety concerns, induced robust antibody responses to all 4 influenza strains, and met all EMA immunogenicity criteria for adults.Clinical trial registry numberNCT01481454.     

Monitoring vaccine safety using the Vaccine Safety Datalink: utilizing immunization registries for pandemic influenza

Mass vaccination campaigns during which new vaccines may be administered to many millions of people in a short period of time call for timely and accurate post-licensure surveillance to monitor vaccine safety. To address the need for timely H1N1 influenza vaccine safety information during the 2009-2010 H1N1 influenza pandemic, the Vaccine Safety Datalink (VSD) project assessed the feasibility and potential mechanisms for utilizing data from state and local immunization registries to capture vaccinations that would not otherwise be captured by the data systems of the participating VSD managed care organizations (MCOs). Three of the eight VSD sites were able to capture H1N1 immunization data electronically from the state and local registries, and one site was able to capture the immunizations through a paper-based system; however, the remaining four sites encountered various obstacles that prevented capture of such data. Additional work will be required at these sites to overcome the barriers, which included privacy and confidentiality laws, time constraints brought on by the pandemic, as well as data quality concerns.     

A novel peptide-based pan-influenza A vaccine: A double blind,randomised clinical trial of immunogenicity and safety

BackgroundFP-01.1 is a novel synthetic influenza A vaccine consisting of six fluorocarbon-modified 35-mer peptides that encapsulate multiple CD4+ and CD8+ T-cell epitopes and is designed to induce an immune response across a broad population.MethodsFP-01.1 was evaluated for safety and immunogenicity in a randomised, double-blind, placebo-controlled, dose-escalation, phase I clinical study in healthy adult volunteers (n = 49). IFNγ ELISpot assays and multicolour flow cytometry were used to characterise the immune response.ResultsFP-01.1 was safe and well tolerated at all doses tested with a similar adverse event profile in actively vaccinated subjects compared with controls. Maximum immunogenicity was in the 150 μg/peptide dose group where a robust response (243 spots/million PBMC) was demonstrated in 75% subjects compared with 0% in placebo controls. All six peptides were immunogenic. FP-01.1 induced dual CD4+ and CD8+ T cell responses and vaccine-specific T cells cross-recognise divergent influenza strains.ConclusionsThis first-in-human study showed that FP-01.1 has an acceptable safety and tolerability profile and generated robust anti-viral T cell responses in a high proportion of subjects tested. The results support the further clinical testing of FP-01.1 prior to clinical, proof-of-concept, live viral challenge studies.     

Human Phase 1 trial of low-dose inactivated seasonal influenza vaccine formulated with Advax™ delta inulin adjuvant

Influenza vaccines are usually non-adjuvanted but addition of adjuvant may improve immunogenicity and permit dose-sparing, critical for vaccine supply in the event of an influenza pandemic. The aim of this first-in-man study was to determine the effect of delta inulin adjuvant on the safety and immunogenicity of a reduced dose seasonal influenza vaccine. Healthy male and female adults aged 18–65 years were recruited to participate in a randomized controlled study to compare the safety, tolerability and immunogenicity of a reduced-dose 2007 Southern Hemisphere trivalent inactivated influenza vaccine formulated with Advax™ delta inulin adjuvant (LTIV + Adj) when compared to a full-dose of the standard TIV vaccine which does not contain an adjuvant. LTIV + Adj provided equivalent immunogenicity to standard TIV vaccine as assessed by hemagglutination inhibition (HI) assays against each vaccine strain as well as against a number of heterosubtypic strains. HI responses were sustained at 3 months post-immunisation in both groups. Antibody landscapes against a large panel of H3N2 influenza viruses showed distinct age effects whereby subjects over 40 years old had a bimodal baseline HI distribution pattern, with the highest HI titers against the very oldest H3N2 isolates and with a second HI peak against influenza isolates from the last 5–10 years. By contrast, subjects >40 years had a unimodal baseline HI distribution with peak recognition of H3N2 isolates from approximately 20 years ago. The reduced dose TIV vaccine containing Advax adjuvant was well tolerated and no safety issues were identified. Hence, delta inulin may be a useful adjuvant for use in seasonal or pandemic influenza vaccines.Australia New Zealand Clinical Trial Registry: ACTRN12607000599471     

Safety and immunogenicity of a 2009 influenza A (H1N1) vaccine in hemodialysis patients

A worldwide vaccination campaign against the 2009 pandemic influenza A (H1N1) virus was launched among high-risk subjects, including hemodialysis patients. The long-term immunogenicity of an influenza vaccine has not been investigated in hemodialysis patients. This study aimed to (1) assess the long-term immunogenicity of a monovalent non-adjuvanted influenza A (H1N1) vaccine in hemodialysis patients and (2) determine the safety of this vaccine. We conducted a prospective cohort study of 44 hemodialysis patients and 149 healthy controls in 2010. All of the participants received a single dose of the monovalent non-adjuvanted 2009 influenza A (H1N1) vaccine. The level of antibodies was measured at baseline and at 4 and 24 weeks post-vaccination using a hemagglutination inhibition assay. The outcomes were the percentages of participants who achieved seroconversion and seroprotection (titer ≥1:40) 4 and 24 weeks after vaccination. At 4 weeks post-vaccination, seroconversion was observed in 17 (38.6%) of the hemodialysis patients and 94 (63.1%) of the controls (P = 0.056), and protective titers were obtained in 22 (50%) of the hemodialysis patients and 100 (67.1%) of the controls (P = 0.426). At 24 weeks post-vaccination, immunogenicity decreased in both the hemodialysis patients and the controls, but there were no significant differences between the hemodialysis patients and the controls in the seroconversion rate (27.3% versus 36.9%, P = 0.526) or the seroprotection rate (38.6% versus 48.3%, P = 0.996). No differences in adverse events were observed between the hemodialysis patients and the controls. In summary, the 2009 influenza A (H1N1) vaccine elicits a similar immune response in both hemodialysis patients and healthy controls, but immunity declines 24 weeks after vaccination in both groups. Hemodialysis patients should at least be vaccinated annually against the influenza virus.     

流行性感冒疫苗的安全性和免疫原性观察

为了解流行性感冒（流感）疫苗,尤其是儿童剂型流感疫苗的安全性和免疫原性,于1999年末在天津市对防感灵的儿童剂型和成人剂型进行了接种后安全性和免疫原性观察,共观察25～55岁成人53名和6月龄～3岁儿童69名。结果表明副反应发生率分别为3.8％和8.7％;抗体阳转率分别为92.2％、85.8％。证实防感灵疫苗儿童剂型和成人剂型均具有良好的免疫原性和安全性。     

国产流感病毒裂解疫苗的免疫原性及安全性效果评价

目的观察国产流感病毒裂解疫苗的免疫原性及安全性。方法通过对疫苗接种者的随访调查和血清学检测,分析国产疫苗和进口疫苗间的免疫差异,从而对国产疫苗进行效果评价。结果接种国产疫苗和进口疫苗后,除个别有发热现象外,未发现其他异常反应,且两组的发热比率经检验差异无统计学意义;国产疫苗H1N1亚型、H3N2亚型和B型HI抗体阳转率、GMT增长倍数以及易感人群下降率,与进口疫苗相比差异均无统计学意义。结论国产疫苗具有很好的安全性和免疫原性。     

流行性感冒病毒裂解疫苗安全性与免疫原性研究

目的评价流行性感冒（流感）病毒裂解疫苗的安全性和免疫原性。方法按随机抽样原则,采用单一中心、开放式、接种l剂流感病毒裂解疫苗免疫的方法,开展临床试验。结果观察对象接种1剂后局部反应发生率为0．6％：发热反应发生率4．52％,且以轻度发热为主。血清学检测结果表明,接种疫苗后,流感病毒甲1、甲3、乙（亚）型的血凝抑制（Haemagglutination Inhibition,HAI）抗体总阳转（≥1：40）率分别为95．0％、87．1％、88．1％;HAI抗体几何平均滴度（Geometric Mean Titer,GMT）增长倍数分别为33．28倍、7．76倍、26．04倍;抗体保护率分别为100．0％、99．7％、98．4％。三个型别之间抗体阳转率、GMT增长倍数、保护率的差异有显著的统计学意义。结论国产流感病毒裂解疫苗应用于≥3岁人群是安全的,免疫效果显著。     

Impact of the 2004 Influenza Vaccine Shortage on Patients from Inner City Health Centers

In the fall of 2004, the FDA and British authorities suspended the license of one of only two manufacturers that provided the US supply of inactivated influenza vaccine. With a 50% reduction in supply, a severe vaccine shortage resulted. This situation necessitated the development of priority groups for vaccination including those ≥65 years, when ordinarily, influenza vaccine is recommended for those ≥50 years old. A sample of patients ≥50 years old (n = 336), who had been seen at one of four inner-city health centers, was interviewed in summer 2005 using computer-assisted telephone interviewing. Associations of survey responses were examined for three groups: those vaccinated in the 2003–2004 and 2004–2005 influenza seasons (n = 142), those vaccinated in 2003–2004 but not vaccinated in 2004–2005 because of the shortage (n = 63), and those unvaccinated in both seasons (n = 83). Bivariate and multivariate logistic regression analyses were used to determine factors significantly influencing the likelihood of vaccination status. A significantly larger proportion of patients 50–64 years of age were unvaccinated due to the shortage (73%) compared to those who were vaccinated during both seasons (36%, P < 0.001), but there were no racial disparities in vaccination rates. Compared with patients who were vaccinated during both seasons, those who were unvaccinated due to the shortage were more frequently employed, self-reported their health positively, saw their physician less frequently, rated the US government’s response to the shortage as “terrible,” and blamed the US government for the shortage. Vaccination during the influenza vaccine shortage appears to have followed preferential vaccination of the CDC-established priority group (≥65 years) and did not result in racial disparities in inner-city health centers. This paper was presented at the American Academy of Family Physicians Annual Meeting held in Washington DC, September, 2006. It received a runner-up award for Family Medicine Research.     

成年人连续三批次流感裂解疫苗接种的安全性、免疫原性观察

目的 评价流感裂解疫苗安尔来福TM的安全性和免疫原性,考核疫苗生产工艺的稳定性.方法 采用随机双盲设对照的临床试验设计,试验疫苗为连续三个批次的安尔来福TM,以进口疫苗为对照.受试者为566名18～60岁健康成年人,按照4个年龄层随机分配到4个试验组,疫苗含甲1型、甲3型和乙型流感病毒抗原各15 μg.免疫程序为1针,接种后进行30 min即时反应观察以及24、48、72 h的随访观察,免疫前及免疫后第21天采血,将成对血清设盲后进行血凝抑制(HI)抗体检测.结果 受试者以轻度不良反应为主,各试验组发热反应发生率为1.4%～2.8%,组间差异无统计学意义.4个组3个型别HI抗体阳转率均≥80.3%,GMT增长倍数≥11.1,抗体保护率≥93.4%.三个批次安尔来福TM3个型别的HI抗体阳转率、GMT增长倍数及血清抗体保护率均超过欧盟及美国FDA标准.结论 连续三批次安尔来福TM具有良好的免疫原性和安全性,疫苗生产工艺稳定.     

Impact of influenza vaccination on mortality in the French elderly population during the 2000–2009 period

With declining influenza vaccine coverage in the elderly in recent years in France, we aimed at assessing the benefits of seasonal influenza vaccination, based on available data for observed mortality, vaccine coverage and vaccine effectiveness.To estimate the annual number of deaths avoided by vaccination in the people aged 65 years or more, we used the following three elements: an estimate of vaccine effectiveness against all-cause mortality (based on the “difference-in-differences” approach which reduces the usual bias seen in observational studies), French mortality data and vaccine coverage data.We estimated an annual average of 2000 deaths currently avoided through vaccination and a vaccine effectiveness of 35% against influenza-attributable deaths. Around 2650 vaccinations are needed to prevent a death among the elderly.Communicating these results should help restoring at-risk populations’ confidence in influenza vaccination.     

流行性感冒病毒裂解疫苗的研制和质量控制

[目的 ]　研制新型的流行性感冒病毒裂解疫苗 ,并评价其免疫效果。　 [方法 ]　利用乙醚裂解流行性感冒病毒 ,制得该疫苗。　 [结果 ]　三批流行性感冒病毒裂解疫苗经中国药品生物制品检定所检定合格 ,并通过临床考核 ,取得令人满意的免疫效果。　 [结论 ]　该疫苗具有良好的安全性和免疫原性。     

2008年青岛市李沧区部分成人接种某国产成人剂型流感裂解疫苗安全性观察

[目的]观察北京某生物制品有限公司上市后流行性感冒裂解疫苗的安全性,特别是老年人群中使用的安全性。[方法]2008年11~12月李沧区选择符合接种人群,分为成年(18~60岁)、老年(>60岁)2组人群,随访观察接种后0~72 h内接种反应。[结果]接种128人,成年、老年各64人。接种0~72 h内成人组11人发生不良反应,不良反应发生率为17.19%;老年组16人发生不良反应,不良反应发生率为25.00%,二者差异无统计学意义(P>0.05)。[结论]该流感裂解疫苗具有较好的安全性,可在成年、老年人群中推广使用。     

Kinetics of the immune response after primary and booster immunization against tick-borne encephalitis (TBE) in adults using the rapid immunization schedule

A total of 222 adult subjects aged 19–51 years were enrolled in this multi-center, phase III study to evaluate immunogenicity and safety of the first booster immunization with a new tick-borne encephalitis (TBE) vaccine. This was an extension study that followed subjects who had received primary immunization 12–18 months previously with either the new or formerly licensed TBE vaccine according to the rapid immunization schedule (i.e. on Days 0, 7 and 21). Compared to the levels of primary immunization, prior to first booster, neutralizing TBE antibodies (geometric mean titers, GMTs) of both vaccination groups had remained on a high level and were far above the detection limit of the neutralization test used. All subjects showed a sharp increase of TBE antibodies following the booster. The booster was well tolerated by the subjects. Conclusion: These results in terms of both immunogenicity and safety indicate that the TBE vaccination with this new TBE vaccine can be used effectively and safely in adults. A long lasting immunity can be concluded from the strong immune response following the first booster.