Vitamin D levels and influenza vaccine immunogenicity among HIV-infected and HIV-uninfected adults

BackgroundVaccination is the most important preventive strategy against influenza, however post-vaccination antibody responses are often inadequate especially among HIV-infected persons. Vitamin D deficiency has been suggested to adversely influence immune responses and is highly prevalent among HIV-infected adults. Therefore, we evaluated the association between 25-hydroxyvitamin D [25(OH)D] levels and post-influenza vaccination responses.MethodsWe conducted a prospective cohort study evaluating the immunogenicity of monovalent influenza A (H1N1) vaccination among both HIV-infected and HIV-uninfected adults (18–50 years of age) during the 2009–2010 influenza season. Antibody titers were evaluated at baseline, day 28, and 6 months post-vaccination using hemagluttination inhibition assays. Serum 25(OH)D levels were measured at day 28. Univariate and multivariate regression analyses examined the association between 25(OH)D levels [categorized as <20 ng/ml (deficiency) vs. ⩾20 ng/ml] with the primary outcome of seroconversion. Secondary outcomes included seroprotection; a ⩾4-fold increase in titers; and geometric mean titers post-vaccination. Analyses were repeated using 25(OH)D levels as a continuous variable.ResultsA total of 128 adults [64 HIV-infected (median CD4 count 580 cells/mm³) and 64 HIV-uninfected] were included. Seroconversion at day 28 post-vaccination was achieved in fewer HIV-infected participants compared with HIV-uninfected participants (56% vs. 74%, p = 0.03). Vitamin D deficiency was more prevalent among HIV-infected persons vs. HIV-uninfected persons (25% vs. 17%), although not significantly different (p = 0.39). There were no associations found between lower 25(OH)D levels and poorer antibody responses at day 28 or 6 months for any of the study outcomes among either HIV-infected or HIV-uninfected adults.ConclusionVitamin D deficiency was common among both HIV-infected and HIV-uninfected adults, but lower levels did not predict antibody responses after H1N1 (2009) influenza vaccination. Low 25(OH)D levels do not explain poorer post-vaccination responses among HIV-infected persons.     

Rapid and high seroprotection rates achieved with a tri-antigenic Hepatitis B vaccine in healthy young adults: Results from a Phase IV study

BackgroundSci-B-Vac® is a tri-antigenic recombinant Hepatitis B vaccine (TAV) containing the small (s), medium (pre-S2) and large (pre-S1) hepatitis B surface (HBs) antigens. To comply with vaccine licensure, a new reference standard batch was qualified by characterizing the seroprotection rate (SPR) for anti-HBs titers ≥10 mIU/mL, following vaccination.MethodsNinety-one healthy adults aged 20–40 years were enrolled in an open label, single-arm phase IV study receiving three IM doses of 10 μg TAV at 0, 1 and 6 months. Immunogenicity was evaluated monthly and at 7, 9 and 12 months. The primary endpoint to qualify the reference standard was an SPR ≥95% by month 7. Secondary endpoints were proportion of high responders (anti-HBs titers ≥100 mIU/mL) and geometric mean concentrations (GMC) of HBs antibodies each month. Participants were followed for safety to month 12.ResultsThe primary endpoint was met 2 months after the second dose at month 3 [SPR 98.8%; 95% CI: 93.7%, 99.7%]. Proportion of high responders at months 3 and 7 were 81.4% and 97.6%, respectively. GMC at months 3 and 7 were 413.6 mIU/mL and 6799.9 mIU/mL, respectively. TAV was safe and well-tolerated.ConclusionsThe new reference standard batch of TAV was qualified successfully, demonstrating efficacy, a favorable safety profile and a rapid onset of seroprotection, including after two vaccine doses.Clinical trial registry: NCT04179786.     

Influenza surveillance in a cohort of HIV-infected children and adolescents immunized against seasonal influenza

During the 2006–2007 season, 19 HIV-uninfected and 33 HIV-infected children and adolescents with full immunovirologic response to HAART were immunized against influenza and subsequently followed up. One month post-immunization all subjects had protective antibodies titres which persisted for the whole influenza season. Seven vaccinees (four HIV-infected and three HIV-uninfected) were found to be infected by influenza viruses during the epidemic, but disease was lab-confirmed only in two HIV-infected subjects. Both presented a benign clinical course and were infected by an A/Brisbane/10/07-H3N2-like virus. These data indicate that HIV-infected subjects benefit from routine seasonal influenza vaccination.     

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.     

Comparison of hemagglutination inhibition and microbead array assays for the measurement of influenza antibody levels in HIV-infected adults

IntroductionDetermining vaccine responsiveness is challenging in immune compromised individuals. The microbead array (MBA) assay is a rapid, inexpensive test for evaluating influenza vaccine immunogenicity. MBA performance was compared to hemagglutination inhibition assay (HAI) utilizing HIV seropositive vaccine recipient specimens.MethodsCTN 253 evaluated standard dose, single antigen, inactivated split adjuvanted (AS03(A)) H1N1 influenza vaccine (Arepanrix) vs standard dose plus booster. CTN237 evaluated three doses of a seasonal, trivalent killed split non-adjuvanted influenza vaccine (Fluviral). Samples of convenience from 75 CTN 253 and 58 CTN 237 participants were evaluated by MBA and HAI. MBA seroreactivity cut-offs of 500 and 1000 mean fluorescent intensity were used to compare those derived by HAI [titer ≥40 (seroprotection) and 4-fold titer increase from baseline (seroconversion)].ResultsCTN253: Using a MBA cut-off of 500, 75% and 59% had seroreactive titers at visit 2 and 78% and 61% at visit 3 for the single versus double dose study arms. Many participants were categorized differently by the HAI and MBA tests, with raw agreement of 59% at visit 2 and 57% at visit 3. CTN 237: Baseline MBA medians (IQR) were 803 (12-2626) for the A/Brisbane strain and 460 (14-1758) for the B/Florida strain. Using a cut-off of 500 yielded for the A/Brisbane strain seroreactivity rates of 44%, 58%, and 63% were observed for the three doses of vaccine tested. The raw agreement was 47%. B/Florida strain analyses yielded similar results. For all strains assessed in both studies, no relationship between MBA values and baseline variables was identified.ConclusionThe concordance of results between the MBA assay and the HAI assay is very low. MBA assay may be more sensitive than the HAI assay suggesting that it was either detecting more false-positive results and/or that the HAI assay had more false negative.     

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.     

Safety,immunogenicity and shedding of LAIV4 in HIV-infected and uninfected children

ObjectivesHIV-infected children have poor responses to inactivated influenza vaccines. Live vaccines (LAIVs) are highly efficacious in children, but they are not used in HIV-infected children du e to limited information. We investigated the safety, immunogenicity and viral shedding of LAIV4 in HIV-infected compared with uninfected children.DesignForty-six HIV-infected and 56 uninfected children 2 to 25 years old, who had been previously vaccinated against influenza, consented to receive a single dose of LAIV4. All grade adverse events (AEs) were recorded in the first month post-vaccination and serious AEs (SAEs) throughout the influenza season. Nasopharyngeal swabs for influenza PCR and IgA ELISA and blood for hemagglutination inhibition antibody (HAI) measurements were collected at entry, 2–5, 7–10 and 21–28 days post-vaccination.ResultsThe HIV-infected subjects had median CD4+ cells of 649 cells/μL and plasma HIV RNA of 20 copies/mL. AEs were similar in the two groups. There were no vaccine-related SAEs. Shedding of ≥1 vaccine virus was detected in 67% HIV-infected and 50% uninfected participants (p = 0.14). HAI titers did not appreciably change, but mucosal IgA antibodies significantly increased post-vaccination in both groups. High baseline HAI and IgA antibody concentrations were associated with decreased viral shedding in controls, but not in HIV-infected subjects. Similar proportions of HIV-infected vaccinees and controls reported influenza-like illnesses (12% and 6%) throughout the season.ConclusionsLAIV4 was equally safe and immunogenic and caused similar viral shedding in HIV-infected and uninfected children. A correlate of protection against vaccine viral shedding was not identified in HIV-infected participants, although both circulating and mucosal antibodies correlated with protection in controls.     

Reduced immune response to influenza A (H1N1) 2009 monovalent vaccine in HIV-infected Japanese subjects

We evaluated the immunogenicity and safety of the influenza A (H1N1) 2009 monovalent vaccine in HIV-infected Japanese subjects. A total of 182 HIV-infected and 42 HIV-uninfected subjects were enrolled, and antibody (ab) titers were measured by hemagglutination-inhibition assay at baseline and 32.3 ± 10.4 and 29.7 ± 3.3 days after vaccination, respectively. In the HIV-infected cohort, ab titers ≥1:40 at baseline and post-vaccination were 12.6% and 49.5%, respectively. The seroconversion rate, defined as either an ab titer ≤1:10 before and ≥1:40 after or ≥1:10 before and ≥4-fold increase in ab titer, was only 38.5% in the HIV-infected cohort, whereas the rate was 85.7% in the HIV-uninfected cohort. Multivariate logistic regression analysis showed that the CD4 cell count was the only significant predictor of a positive vaccine response. There were no serious adverse events in any of the subjects receiving the vaccine. Additional study is warranted to identify a more effective method of vaccinating HIV-infected Japanese subjects.     

Clinical relevance of increased antibody titres in older adults upon vaccination with squalene-adjuvanted versus non-adjuvanted influenza vaccines

In older adults, the serum antibody response to inactivated influenza vaccine (IIV) is often lower than in adolescents and non-elderly adults which may translate into suboptimal protection against influenza. To counteract this expression of immunosenescence, the use of adjuvanted IIV formulations has been explored. Four recent studies (three meta-analyses and one clinical trial) found an antibody increase of up to 1.5-fold in older adults, when a squalene-adjuvanted (MF59?) IIV was used. The clinical relevance of this increase may well continue to be a matter of debate. We would favour a threshold of 1.5 to consider an adjuvanted vaccine formulation superior to standard aqueous IIV because it exceeds the inevitable variation of antibody responses to non-adjuvanted IIV. It is also the same as the upper FDA equivalence limit for IIV lot-to-lot consistency. A corresponding threshold for the seroresponse rate difference could then be +5%.     

Immunogenicity and safety of inactivated quadrivalent influenza vaccine in adults: A systematic review and meta-analysis of randomised controlled trials

BackgroundA quadrivalent influenza vaccine (QIV) includes two A strains (A/H1N1, A/H3N2) and two B lineages (B/Victoria, B/Yamagata). The presence of both B lineages eliminate potential B lineage mismatch of trivalent influenza vaccine (TIV) with the circulating strain.MethodsElectronic database searches of Medline, Embase, Cochrane Central Register of Controlled Trials (CCRCT), Scopus and Web of Science were conducted for articles published until June 30, 2015 inclusive. Articles were limited to randomised controlled trials (RCTs) in adults using inactivated intramuscular vaccine and published in English language only. Summary estimates of immunogenicity (by seroprotection and seroconversion rates) and adverse events outcomes were compared between QIV and TIV, using a risk ratio (RR). Studies were pooled using inverse variance weights with a random effect model and the I² statistic was used to estimate heterogeneity.ResultsA total of five RCTs were included in the meta-analysis. For immunogenicity outcomes, QIV had similar efficacy for the three common strains; A/H1N1, A/H3N2 and the B lineage included in the TIV. QIV also showed superior efficacy for the B lineage not included in the TIV; pooled seroprotection RR of 1.14 (95%CI: 1.03–1.25, p = 0.008) and seroconversion RR of 1.78 (95%CI: 1.24–2.55, p = 0.002) for B/Victoria, and pooled seroprotection RR of 1.12 (95%CI: 1.02–1.22, p = 0.01) and seroconversion RR of 2.11 (95%CI: 1.51–2.95, p < 0.001) for B/Yamagata, respectively. No significant differences were found between QIV and TIV for aggregated local and systemic adverse events within 7 days post-vaccination. There were no vaccine-related serious adverse events reported for either QIV or TIV. Compared to TIV, injection-site pain was more common for QIV, with a pooled RR of 1.18 (95%CI: 1.03–1.35, p = 0.02).ConclusionIn adults, inactivated QIV was as immunogenic as seasonal TIV, with equivalent efficacy against the shared three strains included in TIV, and a superior immunogenicity against the non-TIV B lineage.     

某高校离退休人员流感疫苗预防接种效果分析

目的调查某高校离退休人员接种流感疫苗预防流感的效果。方法分析2002～2008年某高校离退休人员(60～85岁)自愿接种流感疫苗的资料。结果作为重点人群的离退休人员,流感疫苗是一种安全有效的疫苗,局部反应在11.6%左右,全身反应在1.0%左右,疫苗对免疫人群有较好的保护性,保护率为46.6%,减少就诊率26.4%。结论接种流感疫苗减少了离退休人员流感样疾病的发生率,对离退休人员具有一定的保护作用。     

Phase III, randomized controlled trial to evaluate lot consistency of a trivalent subunit egg-based influenza vaccine in adults

Vaccination is the most effective preventive strategy to control influenza. The demonstration of lot-to-lot consistency to confirm the reliability of the manufacturing process has become a mandatory step in vaccine development. This phase III, observer-blind, controlled trial assessed lot-to-lot consistency, immunogenicity, and safety of a subunit trivalent influenza vaccine (Agrippal^®, Novartis Vaccines and Diagnostics) in healthy adults aged 18–49 years. The immunogenicity and safety profile of Agrippal was compared with a control vaccine (Fluvirin^®, Novartis Vaccines and Diagnostics). A total of 1507 subjects were randomized 2:2:2:1 to receive one vaccination of one of the three lots of influenza vaccine or control vaccine. Antibody levels were measured by hemagglutination inhibition assay on days 1 and 22. Adverse reactions were solicited via diary cards for 7 days after vaccination, and unsolicited adverse events were collected throughout the study period. Equivalence of day 22 immune responses to the three lots was shown for each of the three strains. Robust immunogenic responses after one dose were observed for all vaccine groups, and both Center for Biologics Evaluation and Research criteria for licensure of influenza vaccines were met for all three virus strains. Both vaccines exhibited a robust safety profile and were well tolerated, with no differences in local and systemic solicited reactions or in unsolicited adverse events. The demonstration of consistency between manufacturing lots confirms for purposes of clinical development the reliability of the production process. The robust immunogenic responses and favorable safety profiles further support the use of trivalent subunit influenza vaccines Agrippal and Fluvirin for active immunization against influenza.     

Effects of prior influenza virus vaccination on maternal antibody responses: Implications for achieving protection in the newborns

BackgroundIn the US, influenza vaccination is recommended annually to everyone ≥6 months. Prior receipt of influenza vaccine can dampen antibody responses to subsequent vaccination. This may have implications for pregnant women and their newborns, groups at high risk for complications from influenza infection.ObjectiveThis study examined effects of prior vaccination on maternal and cord blood antibody levels in a cohort of pregnant women in the US.Study designInfluenza antibody titers were measured in 141 pregnant women via the hemagglutination inhibition (HAI) assay prior to receipt of quadrivalent influenza vaccine, 30 days post-vaccination, and at delivery (maternal and cord blood). Logistic regression analyses adjusting for age, BMI, parity, gestational age at vaccination, and year of vaccination compared HAI titers, seroprotection, and seroconversion in women with versus without vaccination in the prior year.ResultsCompared to those without vaccination in the previous year (n = 50), women with prior vaccination (n = 91) exhibited higher baseline antibody titers and/or seroprotection rates against all four strains after controlling for covariates. Prior vaccination also predicted lower antibody responses and seroconversion rates at one month post-vaccination. However, at delivery, there were no significant differences in antibody titers or seroprotection rates in women or newborns, and no meaningful differences in the efficiency of antibody transfer, as indicated by the ratio of cord blood to maternal antibody titers at the time of delivery.ConclusionIn this cohort of pregnant women, receipt of influenza vaccine the previous year predicted higher baseline antibody titers and decreased antibody responses at one month post-vaccination against all influenza strains. However, prior maternal vaccination did not significantly affect either maternal antibody levels at delivery or antibody levels transferred to the neonate. This study is registered with the NIH as a clinical trial (NCT02148874).     

我国两个地区儿童流感疫苗与肺炎疫苗接种现状与影响因素分析

目的 了解儿童流感疫苗和肺炎疫苗的接种行为与影响因素。方法 采用两阶段整群抽样,在北京市通州区和甘肃省白银市对适龄儿童家长开展横断面问卷调查,分析儿童流感疫苗和肺炎疫苗接种率及影响因素。结果 共纳入2 377名儿童,儿童流感疫苗接种率为35.93%,肺炎疫苗接种率为16.58%,两种疫苗均接种率为11.65%。接种两种疫苗的理由占比前三位分别为认为疾病严重（流感疫苗：36.02%;肺炎疫苗：49.61%）、学校、单位要求接种（流感疫苗：28.76%;肺炎疫苗：25.45%）和认为疾病易感（流感疫苗：26.41%;肺炎疫苗：13.88%）;未接种疫苗的理由前三位分别为个人方面、疫苗本身和疫苗供应。家庭居住地为农村是影响两类疫苗接种的重要因素。子女数量>1个的家庭、家庭居住地为农村和家庭人均年收入较低与两类疫苗的接种呈负相关。结论 调查地区儿童流感疫苗和肺炎疫苗接种率较低,农村家庭、多子女家庭是扩大疫苗接种的重点关注人群。加强疫苗相关知识宣教,引导家长正确认知疫苗安全性问题,协调疫苗供应与降低疫苗价格对提高流感疫苗和肺炎疫苗接种率具有促进作用。     

Immunogenicity of heterologous H5N1 influenza booster vaccination 6 or 18 months after primary vaccination in adults: A randomized controlled clinical trial

BackgroundHighly pathogenic avian influenza A/H5N1 viruses continue to circulate in birds and infect humans causing serious illness and death.MethodsIn this randomized, observer-blinded study, adults ≥18 years of age (n = 841) received 3.75 or 7.5 μg hemagglutinin antigen (HA) of an AS03-adjuvanted (AS03_A or AS03_B) A/Indonesia/5/2005 H5N1 (subclade 2.1) vaccine (priming), followed by the same HA dose of AS03-adjuvanted A/turkey/Turkey/1/05 H5N1 (clade 2.2) influenza vaccine as a booster 6 or 18 months after priming; an unprimed group received placebo at Day 0, and 3.75 μg HA of AS03_A-adjuvanted booster vaccine at 6 and 18 months. Antibody responses were assessed by hemagglutination-inhibition assay (HI). Microneutralization (MN) antibody and cellular immunoassays were assessed in a subset of participants.ResultsGeometric mean titers (GMTs) and seroconversion rates (SCRs) were higher in primed vs. unprimed subjects against the booster strain 10 days following booster vaccination at month 6 and month 18. After the booster at 18 months, the lower limit of the 97.5% confidence interval for the difference in SCR and GMT ratios between primed and unprimed subjects was >15% and >2.0, respectively, fulfilling the primary endpoint criteria for superiority against the booster strain. MN and cellular immune responses corresponded with the immunogenicity seen in HI measures.ConclusionsAdults primed with a dose-sparing oil-in-water adjuvanted H5N1 subclade vaccine had rapid and durable antibody responses to a heterologous subclade boosting vaccine given 6 or 18 months later.     

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.     

MF59-佐剂流感亚单位疫苗在中国老年人中的免疫原性和安全性研究

目的 比较MF59-佐剂流感亚单位疫苗与传统的非佐剂流感亚单位疫苗在老年人中的安全性和免疫原性.方法 采用随机、研究者设盲的对照研究,按照2:1的比例分别给予600名60岁以上老年人接种MF-59佐剂流感亚单位疫苗(复立达TM,简称佐剂流感疫苗)和传统的非佐剂流感亚单位疫苗(爱阁力保(R),简称传统亚单位疫苗),观察接种日和接种后7天内的局部反应和全身反应;使用血凝抑制试验检测接种老年人免疫前后的血凝抑制抗体(HI)滴度,计算基线无免疫保护状态受试者的抗体4倍增长阳转率、免疫后HI抗体达到保护水平(≥1:40)的保护率以及抗体GMT值和增长倍数.比较两者在安全性和免疫原性的差异.结果 两组疫苗的局部反应和全身反应相似,但传统亚单位疫苗组(n=200)中注射部位的硬结相对常见(P＜0.05),而佐剂流感疫苗组(n=400)中注射部位轻度疼痛和发热则相对较常见.对于基线无免疫保护状态的受试者,免疫后针对A/H3N2病毒株的抗体阳转率,佐剂流感疫苗组显著高于传统亚单位疫苗组(P＜0.001);除A/H1N1病毒株外,与基线相比,两组疫苗的保护率均有显著提高,但针对A/H3N2病毒株的保护率方面,佐剂流感疫苗显著高于传统亚单位疫苗(P＜0.001);两组疫苗接种后的GMT均比基线明显增加(P＜0.001),但佐剂流感疫苗组明显高于传统亚单位疫苗组.结论 中国老年人对佐剂流感疫苗耐受性良好,佐剂流感疫苗诱导的免疫原性水平比传统亚单位疫苗高,可使免疫力低下的老年人获益更大.     

Key differences in B cell activation patterns and immune correlates among treated HIV-infected patients versus healthy controls following influenza vaccination

BackgroundThere is increasing recognition of the role of B cell dysfunction in HIV pathogenesis, but little is known about how these perturbations may influence responses to vaccinations.MethodsHealthy controls (n = 16) and antiretroviral therapy (ART)-treated aviremic HIV-infected subjects (n = 26) receiving standard-of-care annual influenza vaccinations were enrolled in the present study. Total bacterial 16 S rDNA levels were assessed by quantitative polymerase chain reactions in plasma. Serologic responses were characterized by ELISA, hemagglutination inhibition assay (HI), and microneutralization, and cell-mediated responses were assessed by ELISPOT (antigen-specific IgG+ antibody-secreting cells (ASCs)) and flow cytometry at pre-vaccination (D0), day 7–10 (D7) and day 14–21 (D14) post-vaccination.ResultsDecreased peripheral CD4+ T cell absolute counts and increased frequencies of cycling and apoptotic B cells were found at baseline in HIV-infected subjects relative to healthy controls. In healthy controls, post-vaccination neutralizing activities were related to the frequencies of vaccine-mediated apoptosis and cycling of B cells, but not to CD4+ T cell counts. In patients, both baseline and post-vaccination neutralizing activities were directly correlated with plasma level of bacterial 16S rDNA. However, overall vaccine responses including antibody titers and fold changes were comparable or greater in HIV-infected subjects relative to healthy controls.ConclusionB cell function correlates with measures of recall humoral immunity in response to seasonal influenza vaccination in healthy controls but not in ART-treated patients.     

四价流感病毒灭活疫苗在18~64岁人群免疫原性和安全性的系统综述和Meta分析

目的 用Meta分析的方法评价四价流感病毒灭活疫苗在18~64岁人群的免疫原性（抗体保护率和抗体阳转率）。方法 检索Medline、Cochrane Library、Science Direct数据库,将近10年内发表的比较18~64岁人群接种四价流感病毒灭活疫苗和三价流感病毒灭活疫苗免疫原性的临床随机对照试验纳入分析。采用Revman 5.3软件对纳入文献数据进行Meta分析。结果 共纳入8篇文献,针对甲型流感株（A/H1N1、A/H3N2）的抗体保护率和抗体阳转率,两种疫苗的反应差异无统计学意义;针对不含乙型流感株B/Victoria的三价流感病毒灭活疫苗,四价流感病毒灭活疫苗抗体保护率的合并RR值为1.28（95% CI：1.08~1.51,P<0.05）,抗体阳转率的合并RR值为1.94（95% CI：1.50~2.50,P<0.05）;针对不含乙型流感株B/Yamagata的三价流感病毒灭活疫苗,四价流感病毒疫苗抗体保护率的合并RR值为1.10（95% CI：1.02~1.18,P<0.05）,抗体阳转率的合并RR值为1.99（95% CI：1.34~2.97,P<0.05）,差异有统计学意义。结论 18~64岁人群中,四价流感病毒灭活疫苗与三价流感病毒灭活疫苗对于相同的疫苗株产生的免疫原性无差异,对于三价流感病毒灭活疫苗中不含的乙型疫苗株能产生良好的免疫效果。     

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.