2009年10月21日《新英格兰医学杂志》（The New England Journal of Medicine，NEJM）在第361卷发表了华兰生物疫苗有限公司生产的甲型H1N1流感病毒裂解疫苗的临床研究报告----《一种新型甲型H1N1流感疫苗在各年龄人群中的观察》[Anovel influenz a a（H1N1）vaccine in various age groups]，研究采用随机、安慰剂对照、双盲实验设计，全面评估了疫苗的安全性和免疫原性。
(1) Sun YZ, Bian C, Xu K, et al. Immune protection induced on day 10 following administration of the 2009 A/H1N1 pandemic influenza vaccine.PLoS One. 2010 Dec 9;5(12):e14270.
Abstract
Background: The 2009 swine-origin influenza virus (S-OIV) H1N1 pandemic has caused more than 18,000 deaths worldwide.Vaccines against the 2009 A/H1N1 influenza virus are useful for preventing infection and controlling the pandemic. The kinetics of the immune response following vaccination with the 2009 A/H1N1 influenza vaccine need further investigation. Methodology/Principal Findings: 58 volunteers were vaccinated with a 2009 A/H1N1 pandemic influenza monovalent split-virus vaccine (15 mg, single-dose). The sera were collected before Day 0 (pre-vaccination) and on Days 3, 5, 10, 14, 21,30, 45 and 60 post vaccination. Specific antibody responses induced by the vaccination were analyzed using hemagglutination inhibition (HI) assay and enzyme-linked immunosorbent assay (ELISA). After administration of the 2009 A/H1N1 influenza vaccine, specific and protective antibody response with a major subtype of IgG was sufficiently developed as early as Day 10 (seroprotection rate: 93%). This specific antibody response could maintain for at least 60 days without significant reduction. Antibody response induced by the 2009 A/H1N1 influenza vaccine could not render protection against seasonal H1N1 influenza (seroconversion rate: 3% on Day 21). However, volunteers with higher pre-existing seasonal influenza antibody levels (pre-vaccination HI titer ≥1:40, Group 1) more easily developed a strong antibody protection effect against the 2009 A/H1N1 influenza vaccine as compared with those showing lower pre-existing seasonal influenza antibody levels (pre-vaccination HI titer ,1:40, Group 2). The titer of the specific antibody against the 2009 A/H1N1 influenza was much higher in Group 1 (geometric mean titer: 146 on Day 21) than that in Group 2 (geometric mean titer: 70 on Day 21). Conclusions/Significance: Recipients could gain sufficient protection as early as 10 days after vaccine administration. The protection could last at least 60 days. Individuals with a stronger pre-existing seasonal influenza antibody response may have a relatively higher potential for developing a stronger humoral immune response after vaccination with the 2009 A/H1N1 pandemic influenza vaccine.
(2) Liang XF, Wang HQ, Wang JZ et al.Safety and immunogenicity of 2009 pandemic influenza A(H1N1)vaccines in China: a multicentre, double-blind,randomised, placebo-controlled trial.Lancet. 2010 May 15;375(9727):1694.
Summary
Background The current influenza pandemic calls for a safe and effective vaccine. We assessed the safety and immunogenicity of eight formulations of 2009 pandemic influenza A H1N1 vaccine produced by ten Chinese manufacturers. Methods In this multicentre, double-blind, randomised trial, 12691 people aged 3 years or older were recruited in ten centres in China. In each centre, participants were stratifi ed by age and randomly assigned by a random number table to receive one of several vaccine formulations or placebo. The study assessed eight formulations: split-virion formulation containing 7.5μg, 15 μg, or 30μg haemagglutinin per dose, with or without aluminium hydroxide adjuvant, and whole-virion formulation containing 5μg or 10μg haemagglutinin per dose, with adjuvant. All formulations were produced from the reassortant strain X-179A (A/California/07/2009-A/PR/8/34). We analysed the safety (adverse events), immunogenicity (geometric mean titre [GMT] of haemagglutination inhibition antibody), and seroprotection (GMT ≥1:40) of the formulations. Analysis was by per protocol. Two sites registered their trial with ClinicalTrials.gov, numbers NCT00956111 and NCT00975572. The other eight studies were registered with the State Food and Drug Administration of China.
Findings 12691 participants received the first dose on day 0, and 12348 participants received the second dose on day 21. The seroprotection rate 21 days after the first dose of vaccine ranged from 69.5% (95% CI 65.9–72.8) for the 7.5μg adjuvant split-virion formulation to 92.8% (91.9–93.6) for the 30μg non-adjuvant split-virion formulation. The seroprotection rate was 86.5% (796 of 920; 84.1–88.7) in recipients of one dose of the 7.5μg non-adjuvant splitvirion vaccine compared with 9.8% (140 of 1432; 8.3–11.4) in recipients of placebo (p<0.0001). One dose of the 7.5μg non-adjuvant split-virion vaccine induced seroprotection in 178 of 232 children (aged 3 years to <12 years; 76.7%, 70.7–82.0), 211 of 218 adolescents (12 years to <18 years; 96.8%, 93.5–98.7), 289 of 323 adults (18–60 years; 89.5%, 85.6–92.6), and 118 of 147 adults older than 60 years (80.3%, 72.9–86.4), meeting the European Union’s licensure criteria for seroprotection in all age-groups. In children, a second dose of the 7.5μg formulation increased the seroprotection rate to 97.7% (215 of 220, 94.8–99.3). Adverse reactions were mostly mild or moderate, and self-limited. Severe adverse effects occurred in 69 (0.6%, 0.5–0.8) recipients of vaccine compared with one recipient (0.1%, 0–0.2) of placebo. The most common severe adverse reaction was fever, which occurred in 25 (0.22%; 0.14–0.33) recipients of vaccine after the first dose and four (0.04%; 0.01–0.09) recipients of vaccine after the second dose compared with no recipients of placebo after either dose. Interpretation One dose of non-adjuvant split-virion vaccine containing 7.5μg haemagglutinin could be promoted as the formulation of choice against 2009 pandemic influenza A H1N1 for people aged 12 years or older. In children (aged <12 years), two 7.5μg doses might be needed. Funding Sinovac Biotech, Hualan Biological Bacterin, China National Biotec Group, Beijing Tiantan Biological Products, Changchun Institute of Biological Products, Changchun Changsheng Life Sciences, Jiangsu Yanshen Biological Technology Stock, Zhejiang Tianyuan Bio-Pharmaceutical, Lanzhou Institute of Biological Products, Shanghai Institute of Biological Products, and Dalian Aleph Biomedical.
(3)Zhu FC, Wang H, Fang HH, et al. A novel infl uenza A (H1N1) vaccine in various age groups. N Engl J Med 2009; published online, Oct 21. DOI:10.1056/ NEJMoa0908535.
Background There is an urgent need for a vaccine that is effective against the 2009 pandemic influenza A (H1N1) virus. Methods A split-virus, inactivated candidate vaccine against the 2009 H1N1 virus was manufactured, and we evaluated its safety and immunogenicity in a randomized clinical trial. Subjects were between 3 and 77 years of age, stratified into four age groups. The immunization schedule consisted of two vaccinations, 21 days apart. Subjects were injected with placebo or with vaccine, with or without alum adjuvant, at doses of 7.5μg, 15μg, or 30μg. Serologic analysis was performed at baseline and on days 21 and 35. Results A total of 2200 subjects received one dose, and 2103 (95.6%) received the second dose, of vaccine or placebo. No severe adverse side effects associated with the vaccine were noted. In the nonadjuvanted-vaccine groups, injection-site or systemic reactions, most mild in nature, were noted in 5.5 to 15.9% of subjects. Among the subjects receiving 15μg of nonadjuvanted vaccine, a hemagglutination-inhibition titer of 1:40 or more was achieved by day 21 in 74.5% of subjects between 3 and 11 years of age, 97.1% of subjects between 12 and 17 years, 97.1% of subjects between 18 and 60 years, and 79.1% of subjects 61 years of age or older; by day 35, the titer had been achieved in 98.1%, 100%, 97.1%, and 93.3% of subjects, respectively. The proportion with a titer of 1:40 or more was generally highest among the subjects receiving 30μg of vaccine, with or without adjuvant. Vaccine without adjuvant was associated with fewer local reactions and greater immune responses than was vaccine with adjuvant. Conclusions These data suggest that a single dose of 15μg of hemagglutinin antigen without alum adjuvant induces a typically protective immune response in the majority of subjects between 12 and 60 years of age. Lesser immune responses were seen after a single dose of vaccine in younger and older subjects. (ClinicalTrials.gov number,NCT00975572.)
(4) Partridge J, Kieny MP; World Health Organization H1N1 influenza vaccine Task Force. Global production of seasonal and pandemic (H1N1) influenza vaccines in 2009–2010 and comparison with previous estimates and global action plan targets. Vaccine. 2010 Jul 5;28(30):4709-12. Epub 2010 May 18.
Abstract Immunization against influenza is considered among the most important interventions in reducing the public health impact of seasonal epidemic and pandemic influenza infections. However, there are marked differences across countries with regards to production, supply and access to influenza vaccines. A global action plan (GAP) to increase supply of pandemic influenza vaccine was developed by the World Health Organization in May 2006 to reduce the anticipated gap between potential vaccine demand and supply during an influenza pandemic. To quantify the increase in global influenza vaccine production capacity and actual production in response to the influenza A(H1N1) 2009 pandemic, 3 years after the development of the GAP, the WHO conducted a survey of vaccine producers from December 2009 through February 2010, and compared the results of this survey with results from surveys conducted in 2006–2007 and May 2009.
(5) Liang XF, Li L, Liu DW, et al. Safety of Influenza A (H1N1) Vaccine in Postmarketing Surveillance in China. N Engl J Med. 2011 Feb 17;364(7):638-47. Epub 2011 Feb 2.
BACKGROUND On September 21, 2009, China began administering vaccines, obtained from 10 different manufacturers, against 2009 pandemic influenza A (H1N1) virus infection in priority populations. We aimed to assess the safety of this vaccination program. METHODS We designed a plan for passive surveillance for adverse events after immunization with the influenza A (H1N1) vaccine. Physicians or vaccination providers were required to report the numbers of vaccinees and all adverse events to their local Center for Disease Control and Prevention (CDC), which then reported the data to the Chinese CDC through the online National Immunization Information System’s National Adverse Event Following Immunization Surveillance System. Data were collected through March 21, 2010, and were verified and analyzed by the Chinese CDC. RESULTS A total of 89.6 million doses of vaccine were administered from September 21, 2009, through March 21, 2010, and 8067 vaccinees reported having an adverse event, for a rate of 90.0 per 1 million doses. The age-specific rates of adverse events ranged from 31.4 per 1 million doses among persons 60 years of age or older to 130.6 per 1 million doses among persons 9 years of age or younger, and the manufacturerspecific rates ranged from 4.6 to 185.4 per 1 million doses. A total of 6552 of the 8067 adverse events (81.2%; rate, 73.1 per 1 million doses) were verified as vaccine reactions; 1083 of the 8067 (13.4%; rate, 12.1 per 1 million doses) were rare and more serious (vs. common, minor events), most of which (1050) were allergic reactions. Eleven cases of the Guillain–Barré syndrome were reported, for a rate of 0.1 per 1 million doses, which is lower than the background rate in China. CONCLUSIONS No pattern of adverse events that would be of concern was observed after the administration of influenza A (H1N1) vaccine, nor was there evidence of an increased risk of the Guillain–Barré syndrome.
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