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.     

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 and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults

Purpose

To evaluate the safety and immunogenicity of a prototype quadrivalent inactivated influenza vaccine (QIV) containing two influenza B strains, one of each lineage, compared with licensed trivalent inactivated influenza vaccines (TIVs) containing either a Victoria B-lineage strain (2009–2010 TIV) or a Yamagata B-lineage strain (2008–2009 TIV).

Methods

Healthy adults ≥18 years of age were eligible to participate in this phase II, open-label, randomized, controlled, multicenter study conducted in the US. Participants received a single dose of 2009–2010 TIV, 2008–2009 TIV, or QIV. Sera were collected before and 21 days after vaccine administration to test for hemagglutination inhibition (HAI) antibodies to each of the four influenza strains. Immunogenicity endpoints included geometric mean HAI antibody titers (GMTs) and rates of seroprotection (titer ≥1:40) and seroconversion (4-fold rise pre- to post-vaccination). Safety endpoints included frequency of solicited injection-site and systemic reactions occurring within 3 days of vaccination, and unsolicited non-serious adverse events (AEs) and serious AEs (SAEs) within 21 days of vaccination.

Results

One hundred and ninety participants were enrolled to each vaccine group. QIV induced GMTs to each A and B strain that were noninferior to those induced by the 2009–2010 and 2008–2009 TIVs (i.e., lower limit of the two-sided 95% confidence interval of the ratio of GMT_QIV/GMT_TIV > 0.66 for each strain). Rates of seroprotection and seroconversion were similar in all groups. Incidence and severity of solicited injection-site and systemic reactions, AEs, and SAEs were similar among groups.

Conclusion

QIV, containing two B strains (one from each B lineage), was as safe and immunogenic as licensed TIV. QIV has the potential to be a useful alternative to TIV and offer protection against both B lineages.     

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.     

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.     

A randomized control trial comparing immunogenicity, safety, and preference for self- versus nurse-administered intradermal influenza vaccine

Background

Intradermally administered influenza vaccine is as immunogenic as intramuscular vaccine at a lower unit dose. New microinjection systems could allow self-administration of vaccine, potentially reducing the cost and inconvenience.

Objective

To compare the immunogenicity, reactogenicity, success rate, and acceptability of self- versus nurse-administered intradermal trivalent seasonal influenza vaccine.

Methods

Adults (18–59 years old) were randomized to either self- or nurse-administered intradermal vaccine. Prior to vaccination, participants completed a questionnaire and had blood drawn for hemagglutination inhibition titres. Participants in the nurse-administered group were vaccinated by study personnel. The self-administered group were given an instruction sheet and administered their own vaccine. All participants completed a questionnaire and adverse event diaries for 21 days post vaccination, at which time blood was again collected.

Results

Of the 228 participants, 115 were randomized to self-administration and 113 to nurse administration. Groups did not differ by sex, age, or levels of seroprotection at baseline. Of the 114 who completed self-administration, 106 (93%) were successful on the first attempt. There were no group differences in measures of immunogenicity for any of the strains. Self-administering participants reported a lower mean pain rating at vaccination but had larger areas of redness post-vaccination. Seventy percent of all participants said they would prefer intradermal over intramuscular vaccinations in the future, if given the choice.

Conclusion

Compared to nurse-administered intradermal influenza vaccine, self-administered vaccine was immunologically non-inferior and reached all EMA immunogenicity criteria for the A strains, was highly successful and well-accepted by study participants. Together, these data provide preliminary evidence of feasibility for this method of influenza vaccine administration, which may improve vaccine uptake in adults and increase efficiency of vaccine delivery during outbreaks.     

18岁以上人群接种四价流感病毒灭活疫苗免疫原性和安全性的Meta分析

目的 评价18岁以上人群接种四价流感病毒灭活疫苗(QIV)免疫原性和安全性.方法 检索美国国家医学图书馆数据库、Cochrane协作网图书馆、中国生物医学文献数据库、中国期刊全文数据库和万方全文数据库,将有关比较18岁以上人群接种QIV和三价流感病毒灭活疫苗(TIV)免疫原性和安全性的随机对照试验纳入分析.以接种疫苗21 d后产生的针对H1N1、H3N2、B/Victoria、B/Yamagata四个疫苗株的抗体保护率(SPR)和抗体阳转率(SCR)以及不良反应发生率作为结局指标,合并组间的SPR、SCR和不良反应发生率的相对危险度(RR).结果 共纳入5篇文献.针对B/Yamagata的SPR的RR是1.12(95％ CI:1.02～1.22),SCR的RR是2.11(95％ CI:1.51～2.95).针对B/Victoria的SPR的RR是1.14(95％ CI:1.03～1.25),SCR的RR是1.78(95％ CI:1.24～2.55).接种QIV和TIV(含B/Yamagata)后接种部位疼痛发生率的RR是1.23 (95％ CI:1.05～1.44).结论 18岁以上成人接种QIV不仅可以产生与TIV相似的免疫效果和安全性,而且可以对TIV未包含的乙型流感疫苗株产生较好免疫效果.     

Safety and immunogenicity of an inactivated cell culture-derived H7N9 influenza vaccine in healthy adults: A phase I/II,prospective, randomized,open-label trial

BackgroundWe conducted a phase I/II clinical trial to evaluate the safety and immunogenicity of a Madin-Darby canine kidney (MDCK) cell-grown inactivated H7N9 influenza vaccine for pandemic preparedness purposes.MethodsBetween April 7, 2015 and May 27, 2016, healthy adults aged 20–60 years were enrolled sequentially in phase I (n = 40) and phase II (n = 160) from three hospitals in Taiwan and randomized to receive 2 doses of whole-virus H7N9 vaccine (15 or 30 μg hemagglutinin antigen (HA) with or without an aluminum hydroxide adjuvant) at 21-day intervals. Safety up to 180 days and changes in hemagglutinin inhibition (HI) titers at 21 days after each vaccination were determined.ResultsOf the 200 randomized subjects, 193 (96.5%) received 2 doses of the study vaccine and were included in the intention-to-treat analysis for safety, and 190 (95%) were included in the per-protocol analysis for immunogenicity. Most adverse events were mild and transient; no death or vaccine-related serious adverse events were reported. Overall, higher immune responses were observed in the groups administered with 30 μg HA formulation than in the other two groups administered with 15 μg HA formulation. The highest immune response was observed in subjects who received 2 doses of the adjuvanted vaccine containing 30 μg HA with HI titer, seroprotection rate, seroconversion rate, and seroconversion factor of 36.2, 64.6%, 64.6% and 5.7, respectively.ConclusionsOur study demonstrated that the H7N9 influenza vaccine containing 30 µg HA with aluminum hydroxide adjuvant was immunogenic and safe in adults aged 20–60 years.CLINICALTRIALS.GOV identifier: NCT02436928.     

流感疫苗安全性和免疫效果观察

[目的 ]　评价流行性感冒疫苗 (防感灵TM)接种后的安全性和抗体阳转情况。 [方法 ]　采用随机和双盲法选择接种组和对照组 ,分别接种流感疫苗和伤寒Vi疫苗。接种后 3天内进行安全性观察。同时 ,免后 4个月时采集静脉血检测流感血凝抑制抗体的产生情况。 [结果 ]　接种组一般副反应率为 1.70 % ,全身副反应率为0 .6 4% ,与对照组差异无显著性。A1、A3、B型的血凝抑制抗体阳转率分别为 97.7%、99.2 %和 82 .9% ,接种组GMT均明显高于对照组。 [结论 ]　流感疫苗 (防感灵TM)安全性良好 ,并且有较好的免疫原性     

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.     

新型冠状病毒灭活疫苗不同接种间隔的免疫原性和安全性研究

目的 比较公安人员按不同方案（0~14 d、0~21 d、0~28 d）接种新型冠状病毒（新冠病毒）灭活疫苗的免疫原性和安全性。方法 于2021年1-2月以山西省太原市405名公安人员为研究对象,通过随机分组将其分为3组,分别按照0~14 d、0~21 d和0~28 d方案接种2剂新冠病毒灭活疫苗,采用RT-PCR检测新冠病毒核酸,活病毒微量病变法检测新冠病毒中和抗体,分析3组的新冠病毒中和抗体GMT、血清阳转率和安全性。结果 0~14 d、0~21 d和0~28 d方案组新冠病毒中和抗体血清学阳转率均为100%,其中0~21 d组[166.70（95%CI：148.30~185.10）]和0~28 d组[179.50（95%CI：156.50~202.60）]新冠病毒中和抗体水平接近（P>0.05）,均明显高于0~14 d组[86.08（95%CI：72.36~99.80）]（P<0.001）。3个方案组不良反应发生率分别为1.48%（2/135）、0.74%（1/136）和1.49%（2/134）（P=0.750）,均为轻度不良反应。结论 公安人员按不同方案（0~14 d、0~21 d、0~28 d）接种新冠病毒灭活疫苗后均表现出较好的血清阳转率和安全性,0~21 d和0~28 d接种方案组新冠病毒中和抗体GMT高于0~14 d方案组。     

A randomized,non-inferiority trial comparing two bivalent killed,whole cell,oral cholera vaccines (Euvichol vs Shanchol) in the Philippines

BackgroundCurrently, there are two oral cholera vaccines (OCV) that are prequalified by the World Health Organization. Both (Dukoral and Shanchol) have been proven to be safe, immunogenic, and effective. As the global supply of OCV remains limited, we assessed the safety and immunogenicity of a new low cost, killed, bivalent OCV (Euvichol) in the Philippines.MethodsThe randomized controlled trial was carried out in healthy Filipino adults and children. Two doses of either the current WHO prequalified OCV (Shanchol) or the same composition OCV being considered for WHO prequalification (Euvichol) were administered to participants.ResultsThe pivotal study was conducted in total of 1263 healthy participants (777 adults and 486 children). No serious adverse reactions were elicited in either vaccine groups. Vibriocidal antibody responses to V. cholerae O1 Inaba following administration of two doses of Euvichol were non-inferior to those of Shanchol in adults (82% vs 76%) and children (87% vs 89%). Similar findings were observed for O1 Ogawa in adults (80% vs 74%) and children (91% vs 88%).ConclusionA two dose schedule with Euvichol induces a strong vibriocidal response comparable to those elicited by the currently WHO prequalified OCV, Shanchol. Euvichol will be an oral cholera vaccine suitable for use in lower income countries, where cholera still has a significant economic and public health impact.     

A Phase III randomised trial of the immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in adult and elderly subjects,assessing both anti-haemagglutinin and virus neutralisation antibody responses

BackgroundTrivalent influenza vaccines (TIVs) offer substantial protection against matching B-strains, however, protection against alternate-lineage B-strains may be enhanced by adding a second B-strain in quadrivalent influenza vaccines (QIVs). In this Phase III, double-blind, multicentre, randomised study, the immunogenicity and safety of subunit inactivated QIV versus TIV was assessed in adult (aged ≥18 to ≤60 years) and elderly (aged ≥61 years) subjects by analysing a combination of haemagglutinin inhibition (HI) and virus neutralisation (VN).MethodsSubjects (n = 1980) were recruited off season (2015/2016) from 20 centres in five European countries and randomised to receive either QIV (n = 1538), TIV with B-strain of the Victoria lineage (n = 221) or TIV with B-strain of the Yamagata lineage (n = 221). The primary aim was to demonstrate non-inferiority of QIV to TIV for immunogenicity against matched influenza strains based on post-vaccination HI titres. Secondary aims were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains and to characterise the immune response by reverse cumulative distribution (RCD) curves of antibody titres and derived serological parameters for HI and VN. Reactogenicity and occurrence of adverse events were assessed post-vaccination.ResultsQIV elicited a non-inferior immune response for matched strains (upper limit of 95% CI for HI geometric mean ratios [GMRs] <1.5) and a superior response for alternate-lineage B-strains (HI GMRs < 1; p < 0.0001) versus TIV. RCD curves demonstrated that post-vaccination HI and VN titres were higher for QIV versus TIV for both alternate-lineage B-strains. Seroconversion rates and geometric mean fold increases of the VN assay were consistent with the HI assay for all strains in QIV. Reporting rates of local and systemic reactions were similar in both vaccine groups.ConclusionsQIV was non-inferior in immunogenicity to TIV for matched strains and superior to the alternate-lineage B-strains in TIV. Safety and tolerability profiles of QIV and TIV were comparable.     

Trivalent inactivated subunit influenza vaccine Influvac: 25-Year experience of safety and immunogenicity

Between 1982 and 2006, 76 clinical studies (including the annual update studies required for licensing in Europe) were performed with the trivalent inactivated subunit influenza vaccine Influvac^®. In all, 6415 subjects were vaccinated, of whom 5034 were eligible for safety evaluation and 4534 for efficacy evaluation. Treatment-emergent adverse events occurred in 13.7% of subjects. Transient mild-to-moderate local and systemic reactions occurred in up to half of subjects. Post-marketing surveillance confirmed the well-established safety profile reported for inactivated influenza vaccines. All three serological criteria for immunogenicity of the Committee for Medicinal Products for Human Use (CHMP) were met for all three virus strain (sub)types in healthy adults, elderly (over 60 years), nursing home residents, and those at high risk of influenza-related complications. In an additional trial in children aged 3–12 years, all three CHMP criteria for adults were met for all three virus strains. Influvac^® is thus immunogenic and safe, and is a suitable vaccine to combat the annually recurring medical and economic burden of influenza epidemics.     

Immunogenicity and safety of a quadrivalent inactivated influenza virus vaccine compared with a comparator quadrivalent inactivated influenza vaccine in a pediatric population: A phase 3, randomized noninferiority study

BackgroundSeqirus 2010 Southern Hemisphere split-virion trivalent inactivated influenza vaccine (IIV3) was associated with increased febrile reactions in children. Studies in vitro concluded that increasing concentrations of splitting agent decreased residual lipids and attenuated proinflammatory cytokine signals associated with fever. We assessed immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4; produced using higher concentration of splitting agent) versus a United States-licensed comparator IIV4 in healthy children aged 5–17 years.MethodsParticipants (N = 2278) were randomized 3:1 and stratified by age (5–8 years; 9–17 years) to receive IIV4 (n = 1709) or comparator IIV4 (n = 569). Primary objective was to demonstrate noninferiority of IIV4 versus comparator IIV4 as assessed by hemagglutination inhibition (HI) geometric mean titer (GMT) ratio (upper bound of two-sided 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper bound of two-sided 95% CI ≤ 10%) for all four vaccine strains. HI antibody titers were assessed at baseline and 28 days postvaccination. Solicited and unsolicited adverse events were assessed during each 7- and 28-day postvaccination period, respectively.ResultsIIV4 met immunogenicity criteria for noninferiority. Adjusted GMT ratios (comparator IIV4/IIV4) for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.01 (95% CI; 0.93, 1.09), 1.05 (0.96, 1.15), 0.89 (0.81, 0.98), and 0.92 (0.83, 1.02), respectively. Corresponding values for differences (95% CI) in seroconversion rates (comparator IIV4 minus IIV4) were −3.1 (−8.0, 1.8), 0.4 (−4.5, 5.3), −3.4 (−8.3, 1.5), and −2.0 (−6.9, 2.9). Fever rates were numerically higher, but not statistically different, with IIV4 versus comparator IIV4. No new safety signals were reported.ConclusionIIV4 demonstrated immunological noninferiority to the comparator IIV4 with a clinically acceptable safety profile in children aged 5–17 years. Increased levels of virus splitting agent seem to have reduced fever rates observed in children with Seqirus IIV3, particularly those aged 5–8 years.Funding: Seqirus Pty Ltd; Clinicaltrials.gov identifier: NCT02545543.     

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。     

Safety and immunogenicity of seasonal trivalent inactivated influenza vaccines in pregnant women

BackgroundIn the United States, seasonal inactivated influenza vaccine (IIV) is recommended for pregnant women; however, in early 2009, immunization rates were low, partly due to limited prospective data and concerns about vaccine safety.ObjectiveWe conducted a randomized study of two licensed seasonal trivalent IIVs (IIV3) to assess their safety and immunogenicity in pregnant women.Study DesignIn this prospective, randomized clinical study, 100 pregnant women, 18–39 years of age and ≥14 weeks gestation received a single intramuscular dose of 2008–2009 Fluzone® or Fluarix®. Injection site and systemic reactions were recorded for 7 days after vaccination and serious adverse events (SAEs) and pregnancy outcomes were documented. Serum samples collected before and 28 days after vaccination were tested for hemagglutination inhibition (HAI) antibody levels.ResultsThe majority of the injection site and systemic reactions were mild and self-limited after both vaccines. No fever ≥100 °F was reported. There were no vaccine-associated SAEs. Immune responses to influenza vaccine antigens were similar for the two study vaccines, with robust HAI responses against influenza A strains, and relatively lower responses for influenza B strains.ConclusionSeasonal inactivated influenza vaccines were well tolerated and immunogenic in pregnant women.

• ClinicalTrials.gov identifier NCT00905125.

Synopsis: In this prospective clinical trial, we demonstrated that immunization with seasonal trivalent, inactivated influenza vaccine in the second and third trimester of pregnancy is immunogenic and safe.     

The safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine among patients undergoing elective surgery for closed fractures: A randomized,double-blind,placebo-controlled,multicenter phase 2 clinical trial

BackgroundVaccines are urgently required to control Staphylococcus aureus hospital and community infections and reduce the use of antibiotics. Here, we report the safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine (rFSAV) in patients undergoing elective surgery for closed fractures.MethodsA randomized, double-blind, placebo-controlled, multicenter phase 2 clinical trial was carried out in 10 clinical research centers in China. Patients undergoing elective surgery for closed fractures, aged 18–70 years, were randomly allocated at a ratio of 1:1 to receive the rFSAV or placebo at a regimen of two doses on day 0 and another dose on day 7. All participants and investigators remained blinded during the study period. The safety endpoint was the incidence of adverse events within 180 days. The immunogenicity endpoints included the level of specific antibodies to five antigens after vaccination, as well as opsonophagocytic antibodies.ResultsA total of 348 eligible participants were randomized to the rFSAV (n = 174) and placebo (n = 174) groups. No grade 3 local adverse events occurred. There was no significant difference in the incidence of overall systemic adverse events between the experimental (40.24 %) and control groups (33.72 %) within 180 days after the first immunization. The antigen-specific binding antibodies started to increase at days 7 and reached their peaks at 10–14 days after the first immunization. The rapid and potent opsonophagocytic antibodies were also substantially above the background levels.ConclusionsrFSAV is safe and well-tolerated in patients undergoing elective surgery for closed fractures. It elicited rapid and robust specific humoral immune responses using the perioperative immunization procedure. These results provide evidence for further clinical trials to confirm the vaccine efficacy.China's Drug Clinical Trials Registration and Information Publicity Platform registration number: CTR20181788. WHO International Clinical Trial Registry Platform identifier: ChiCTR2200066259.     

Interchangeability of two Enterovirus 71 inactivated vaccines in Chinese children: A phase IV,open-label,and randomized controlled trial

BackgroundIn China, three inactivated Enterovirus 71 (EV71) vaccines have been approved. Although the vaccines in an immunization series should be from a single manufacture, children sometimes have to receive EV71 vaccines from more than one manufacturers. The aim of this study was to evaluate the interchangeability and safety of vaccination with EV71 vaccines from two manufacturers among Chinese children.MethodsWe conducted an open label and randomized controlled study among children aged 6–35 months from November 2018 to January 2019. The participants were randomly assigned (1:1:1:1) to receive EV71 vaccines in one of the four different schedules (two using a single vaccine for all doses from one manufacture, and two mixed schedules using vaccines from two manufactures). Blood samples were collected pre-vaccination (Day 0) and one month after the second dose (Day 60) for neutralizing antibody assay. Immunogenicity was assessed in the per-protocol cohort and safety was assessed in the total vaccinated cohort.ResultsA total of 300 children were enrolled and randomized, of whom 89.0% (267/300) were included in the per-protocol cohort for immunogenicity analysis. The seroconversion rates of the EV71 neutralizing antibody in four groups ranged from 98.4% to 100.0%, and were not significantly different among the groups. Compared with other groups, geometric mean titer was higher in group D, in which the participants received Institute of Medical Biology Chinese Academy of Medical Sciences (CAMS) vaccine in the first dose and the Sinovac vaccine in the second dose. Safety profiles were similar among the four groups and no serious adverse events related to the vaccination were reported.ConclusionsInterchangeability of EV71 vaccines from two manufactures to complete an immunization series showed good immunogenicity and safety. The antibody response levels may vary by vaccination sequences of EV71 vaccines from the two manufacturers.Trial registration: ClinicalTrials.govNCT03873740.     

Modifying the thermostability of inactivated influenza vaccines

Background

Respiratory infections caused by influenza viruses spread rapidly, resulting in significant annual morbidity and mortality worldwide. Currently, the most effective public health measure against infection is immunisation with an influenza vaccine matching the relevant circulating influenza strains. Although a number of developments in terms of influenza vaccine production, safety and immunogenicity have been reported, limitations in our understanding of vaccine stability still exist. In this report we seek to identify compounds that increase influenza vaccine thermostability.

Methods

We use plaque inhibition on confluent MDCK cells to identify compounds which inhibit the entry of various seed strain viruses. The effect of these compounds on vaccine thermal lability is evaluated through SRID analysis. The significance of these results is tested by a two-way analysis of variance (ANOVA) method.

Results

We identify two compounds which selectively inhibit entry of different group I or group II influenza strains through prevention of the neutral-pH to low-pH conformational change of hemagglutinin. Compounds which were able to inhibit virus entry were also able to limit thermally induced potency loss in matched influenza vaccines. Furthermore, we demonstrate that this effect is independent of product formulation or the presence of multiple HA types.

Conclusions

This work provides further evidence for a link between HA conformational stability in the virus and thermostability of the corresponding vaccine preparation. It also suggests straightforward approaches to improve the stability and predictability of influenza vaccine preparations.