Elsevier

The Lancet

Volume 375, Issue 9708, 2–8 January 2010, Pages 56-66
The Lancet

Articles
Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(09)62003-1Get rights and content

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, 12 691 people aged 3 years or older were recruited in ten centres in China. In each centre, participants were stratified 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 7·5 μg, 15 μg, or 30 μg haemagglutinin per dose, with or without aluminium hydroxide adjuvant, and whole-virion formulation containing 5 μg or 10 μg 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

12 691 participants received the first dose on day 0, and 12 348 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 7·5 μg adjuvant split-virion formulation to 92·8% (91·9–93·6) for the 30 μg 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 7·5 μg non-adjuvant split-virion vaccine compared with 9·8% (140 of 1432; 8·3–11·4) in recipients of placebo (p<0·0001). One dose of the 7·5 μg 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 7·5 μg 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 7·5 μg 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 7·5 μg 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.

Introduction

Since the novel swine-origin influenza A H1N1 virus was identified in Mexico and the USA in April, 2009, it has spread throughout the world, prompting WHO to raise the pandemic alert level to phase 6 on June 11, 2009.1, 2, 3 Vaccination is the most effective measure to control the spread of the virus and to reduce associated morbidity and mortality. Existing evidence shows that the currently used trivalent seasonal influenza vaccines are unlikely to provide protection against the new virus.4 The development of new vaccines is therefore urgent, especially in China, where a sixth of the world's population lives.

Clinical trials of vaccines against the 2009 pandemic H1N1 virus are in progress in China, Australia, the USA, and the European Union (EU). These trials recruited fairly small numbers of participants. Data from the USA,5 the UK,6 Australia,7 and China8 suggest that a segment of the population has pre-existing immunity to the pandemic virus, either as a result of past infections or cross-reaction. Therefore, in clinical trials of vaccines for this pandemic, a placebo group is necessary to distinguish between natural and acquired immunity.

We undertook a multicentre, double-blind, randomised, placebo-controlled trial to assess the safety and immunogenicity of eight formulations of 2009 pandemic influenza A H1N1 vaccine produced by ten Chinese manufacturers.

Section snippets

Participants

This multicentre trial was undertaken between July 22, and Sept 18, 2009, in ten centres in China: Beijing, Wuzhou, and Lipu (Guangxi Autonomous Region); Taizhou and Taixing (Jiangsu Province); Changge and Changshe (Henan Province); Chifeng (Inner Mongolia Autonomous Region); Hengdong (Hunan Province); and Hengshui (Hebei Province). Healthy people aged 3 years or older were recruited for the study. Exclusion criteria included fever (axillary temperature >37·0°C); previous infection with 2009

Results

12 691 participants were enrolled in the ten centres (figure 1 and table 1), including 2828 children (aged 3 to <12 years), 2887 adolescents (12 to <18 years), 4710 adults (18–60 years), and 2266 older adults (61–87 years). 596 (4·7%) participants dropped out during the study period (figure 1).

12 691 participants received the first dose on day 0, and 12 348 participants received the second dose on day 21. These participants completed the 3-day safety observation and were included in the safety

Discussion

Our study showed that all formulations of the 2009 pandemic H1N1 vaccine produced by ten Chinese manufacturers were safe and immunogenic. In adolescents (12 to <18 years), adults (18–60 years), and older adults (>60 years), one dose of the non-adjuvant split-virion vaccine containing 7·5 μg haemagglutinin induced nearly the same level of immune response as did formulations containing more antigen. This formulation required the lowest amount of antigen, which is important during a pandemic when

References (19)

There are more references available in the full text version of this article.

Cited by (0)

View full text