A single dose of unadjuvanted vaccine with 7.5 micrograms of antigen is effective against the pandemic influenza A(H1N1) virus for most healthy adults, but children younger than 9 years may need two doses for full protection, data from a trio of clinical trials in China, Hungary, and the United States indicate. The findings were published online in the Lancet on Dec. 16.

China Trial Compared Eight Formulations

A team led by Dr. Xiao-Feng Liang of the Chinese Center for Disease Control and Prevention in Beijing analyzed eight formulations of an H1N1 vaccine produced using the same H1N1 strain. The eight included six split-virion formulations with 7.5 micrograms, 15 micrograms, or 30 micrograms hemagglutinin per dose, with or without aluminum hydroxide adjuvant, and two whole-virion formulations with either 5 micrograms or 10 micrograms of antigen per dose, plus adjuvant (Lancet Dec. 16 2009 [Epub doi: 10.1016/S0140-6736(09)62003-1]).

A total of 12,691 individuals aged 3 years and older were randomized to the groups receiving a formulation or placebo. Overall, seroprotection rates for the formulations ranged from 70% for the 7.5-microgram split-virion adjuvanted vaccine to 93% for the 30-microgram unadjuvanted split-virion vaccine.

The 7.5-microgram unadjuvanted vaccine had the highest overall seroprotection rate of 87% at 21 days after vaccination, compared with 9.8% in the placebo group. One dose of 7.5-microgram unadjuvanted split-virion vaccine yielded seroprotection of 77% in children aged 3 to 12 years, 97% in children aged 12 to 18 years, 90% in adults aged 18 to 60 years, and 80% in adults older than 60 years. These rates meet the European Union’s licensing criteria for seroprotection, the researchers noted. In this study, seroprotection was defined as a hemagglutinin inhibition titer of 1:40 or higher.

Serious adverse events were reported in 69 individuals (0.6%) who were vaccinated and 1 individual in the placebo group. The most common adverse event was fever, which was reported in 25 individuals (0.22%) after their first dose of vaccine and in four individuals (0.04%) after a second dose of vaccine.

“Our findings will help to inform the development of an antigen-sparing strategy for mass immunization during the pandemic, when demand for vaccine far exceeds production capacity,” the researchers said.

Hungarian Study: H1N1 Vaccine With Seasonal Flu Vaccine

Dr. Zoltan Vajo of the University of Debrecen, Hungary, and colleagues conducted a prospective, randomized study of the H1N1 vaccine’s effectiveness when given alone or in conjunction with the seasonal flu vaccine. The study enrolled 355 people in two age groups: 203 adults aged 18 to 60 years and 152 adults older than 60 years (Lancet Dec. 16 2009 [Epub doi: 10.1016/S0140-6736(09)62039-0]). The participants in both age groups were randomized into two vaccination groups, one receiving the H1N1 vaccine alone and the other group receiving the H1N1 vaccine plus the seasonal flu vaccine.

The team’s analysis included data from 176 individuals in each vaccination group. The seroprotection rate against the H1N1 virus was slightly higher in the groups that received both the H1N1 and seasonal flu vaccines (77% for adults aged 18 to 60 years and 82% for adults older than 60 years, versus 74% in adults aged 18 to 60 years and 61% in those older than 60 years receiving the H1N1 vaccine alone).

The findings support the safety of a monovalent adjuvanted H1N1 vaccine, whether given alone or in conjunction with the seasonal influenza vaccine, the researchers concluded.

U.S. Study Compared Vaccine in Children and Adults

In this study, Eric Plennevaux, Ph.D., of Sanofi-Pasteur in Lyon, France, and colleagues reviewed data from 410 children and 724 adults in the United States who were randomized to receive the H1N1 vaccine with 7.5, 15, or 30 micrograms of antigen, and 50 children and 95 adults who received a placebo (Lancet Dec. 16 2009 [Epub doi: 10.1016/S0140-6736(09)62026-2]).

Among children aged 6 months to 35 months, 45% of those who received a 7.5-microgram dose and 50% of those who received a 15-microgram dose were seroprotected 21 days after vaccination.

For children aged 3 to 9 years, the day-21 seroprotection rate was 69% after a 7.5-microgram dose and 75% after a 15-microgram dose. In adults aged 18-64 years, seroprotection rates for the 7.5-microgram, 15-microgram, and 30-microgram doses were 95%, 98%, and 100%, respectively. In adults aged 65 years and older, the seroprotection rates for the three doses were 94%, 93%, and 95%, respectively.

No serious vaccine-related adverse event, death, or new onset of illness was reported during the study. Injection-site pain and tenderness were reported in less than half of individuals in each age group.

The results support the current U.S. recommendation for a single dose of H1N1 vaccine for adults of all ages, the researchers wrote. But the seroprotection in children, especially those aged 3 to 9 years, was “insufficiently immunogenic to meet FDA’s criteria, confirming the need for a second vaccination to provide sufficient protection,” the team said.

Expert Perspective

“Critical evaluation of the safety profile of the vaccines manufactured to respond to the 2009 H1N1 pandemic is of the highest priority,” wrote Dr. Dina Pfeifer of the World Health Organization and colleagues in an editorial accompanying the new study reports (Lancet Dec. 16 2009 [Epub doi:10.1016/S0140-6736(09)62133-4]). The commentators noted that worldwide safety evaluations of the H1N1 vaccine are creating the best-documented safety profile of any vaccine in history. They added that the side effects seen so far in H1N1 clinical trials are “within the expected safety profile for common events with influenza vaccines.”

But the three studies were limited by their use of only a hemagglutinin inhibition assay to determine the vaccine’s effectiveness, said Heath Kelly, MBBS, MPH, of the Victorian Infectious Diseases Reference Laboratory in Melbourne and Dr. Ian Barr of the World Health Organization in a second editorial (Lancet Dec. 16 2009 [Epub doi: 10.1016/S0140-6736(09)62132-2]).

In addition, none of the studies included subgroups that are considered to be the highest priority for vaccination, including pregnant women, morbidly obese individuals, and those with chronic medical conditions. More research is needed to confirm the safety and effectiveness of the H1N1 vaccine in these groups, Drs. Kelly and Barr said.

The Chinese study was funded by Sinovac Biotech, Hualan Biological Bacterin, China National Biotech 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. The Hungarian researchers disclose no conflict of interest. The U.S. study was sponsored by Sanofi Pasteur, and senior author Dr. Martine Denis is an employee of that company.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

12月16日，《柳叶刀》(Lancet)在线发表的一篇文章称，中国、匈牙利和美国开展的3项临床试验表明，对于大部分健康成人，含7.5μg抗原的非佐剂疫苗单剂接种可有效预防大流行性甲型流感(H1N1)病毒，但年龄在9岁以下的儿童可能需要接种两剂才能产生充分保护作用。

 

中国试验比较了8种疫苗制剂

 

由中国疾病预防控制中心梁晓峰博士领导的研究小组对8种采用同一H1N1菌株生产的H1N1疫苗制剂进行了分析。这8种制剂包括6种每剂含7.5μg、15μg或30μg血凝素的病毒裂解疫苗，含或不含氢氧化铝佐剂，以及两种每剂含5μg或10μg抗原的全病毒佐剂疫苗(Lancet Dec. 16 2009 [Epub doi: 10.1016/S0140-6736(09)62003-1])。

 

该试验共纳入了12,691例年龄在3岁或3岁以上的受试者，将其随机分配接种一种疫苗制剂或安慰剂。所有疫苗制剂的总血清保护率从7.5μg病毒裂解佐剂疫苗的70%到30μg病毒裂解非佐剂疫苗的93%之间不等。

 

接种后21天，7.5μg非佐剂疫苗的总血清保护率最高，达到了87%，而安慰剂组仅9.8%。在年龄介于3~12岁的儿童中，7.5μg病毒裂解非佐剂疫苗单剂接种后，血清保护率为77%，在12~18岁的青少年中血清保护率达到97%，在18~60岁的成人中达到90%，在60岁以上的老年人中则为80%。研究者指出，以上结果均达到了欧盟有关疫苗血清保护的审批标准。在该试验中，血清保护定义为血凝抑制滴度达到1:40或更高。

 

69例接种了疫苗的受试者(0.6%)和1例安慰剂组受试者报告了严重不良事件。最常见的不良事件是发热，25例受试者(0.22%)在接种第1剂疫苗后出现了发热，4例(0.04%)则在接种第2剂疫苗后出现了发热。

 

研究者指出，“目前流感疫苗的生产能力远不能满足市场对疫苗的需求，该试验结果将有助于在流感大流行时期针对大规模人群接种制定节约抗原的策略。”

 

匈牙利试验：H1N1疫苗与季节性流感疫苗

 

匈牙利德布勒森大学的Zoltan Vajo博士及其同事开展了一项前瞻性随机试验，以评价H1N1疫苗单独接种或与季节性流感疫苗联合接种的有效性。该试验纳入了355例分别处于两个年龄段的受试者：18~60岁203例，60岁以上152例(Lancet Dec. 16 2009 [Epub doi: 10.1016/S0140-6736(09)62039-0])。将这两个年龄组的受试者随机分配到两个疫苗接种组中，一组单独接种H1N1疫苗，另一组则接受H1N1疫苗与季节性流感疫苗联合接种。

 

研究小组对两个疫苗接种组各176例受试者的数据进行了分析。在同时接种了H1N1疫苗和季节性流感疫苗的受试者中，针对H1N1病毒的血清保护率(18~60岁年龄组77%，60岁以上年龄组82%)略高于单独接种H1N1疫苗的受试者(18~60岁年龄组74%，60岁以上年龄组61%)。

 

研究者总结道，该试验结果证实了H1N1单价佐剂疫苗无论单独接种还是与季节性流感疫苗联合接种都是安全的。

 

美国试验比较了儿童和成人的疫苗接种效果

 

该试验将来自美国的410例儿童和724例成人随机分配接种含7.5μg、15μg或30μg抗原的 H1N1疫苗，并将另外50例儿童和95例成人分配至安慰剂组。法国里昂赛诺菲巴斯德公司的Eric Plennevaux博士及其同事对试验数据进行了分析(Lancet Dec. 16 2009 [Epub doi: 10.1016/S0140-6736(09)62026-2])。

 

在年龄介于6个月~35个月的儿童中，接种后21天，7.5μg剂量组45%的受试者以及15μg剂量组50%的受试者获得了血清保护。

 

在年龄介于3~9岁的儿童中，接种后21天，7.5μg剂量组的血清保护率为69%，15μg剂量组则达到75%。在年龄介于18~64岁的成人中，7.5μg、15μg和30μg剂量组的血清保护率分别为95%、98%和100%。在年龄大于65岁的成人中，3个剂量组的血清保护率分别为94%、93%和95%。

 

试验期间，无任何与疫苗相关的严重不良事件、死亡或新发疾病报告。各年龄组不到一半的受试者报告了注射部位疼痛和压痛。

 

研究者称，该试验结果支持了目前美国关于H1N1疫苗单剂接种适用于任何年龄的成人的推荐意见。但对于儿童，尤其是年龄介于3~9岁的儿童，从血清保护率来看，“其免疫原性未能达到FDA的相关要求，这提示需要二次接种以产生充分的保护作用。”

 

专家观点

 

世界卫生组织的Dina Pfeifer博士及其同事在随刊编者按中写道，“对于那些为了应对2009年H1N1大流行而生产的疫苗，严格评价其安全性是重中之重。” (Lancet Dec. 16 2009 [Epub doi:10.1016/S0140-6736(09)62133-4])。评论员指出，目前从各国开展的H1N1疫苗安全性评价结果来看，这是史上最安全的一类疫苗。到目前为止，H1N1疫苗临床试验所发现的副反应均“没有超出可预见的流感疫苗常见不良事件的范畴。”

 

但澳大利亚墨尔本维州传染病参考实验室的Heath Kelly, MBBS, MPH和世界卫生组织的Ian Barr博士在另一篇随刊编者按中称，这3项试验均存在一定的局限性，都只采用了血凝抑制试验来确定疫苗的有效性(Lancet Dec. 16 2009 [Epub doi: 10.1016/S0140-6736(09)62132-2])。

 

Kelly博士和Barr博士还指出，这3项试验均没有针对优先接种人群开展亚组分析，优先接种人群包括孕妇、病态肥胖者以及患有慢性疾病者。尚需开展进一步的研究以确认H1N1疫苗用于这类人群的安全性和有效性。

 

中国试验由中维科生物技术有限公司、华兰生物公司、中国生物技术集团公司、北京天坛生物制品公司、长春生物制品研究所、长春长生生物科技公司、江苏延申生物科技股份有限公司、浙江天元生物药业公司、兰州生物制品研究所、上海生物制品研究所和大连雅立峰生物制药有限公司资助。匈牙利试验的研究者声明无利益冲突。美国试验由赛诺菲巴斯德公司资助，高级作者Martine Denis博士为该公司员工。

 

爱思唯尔  版权所有