Jiang-Ting Chen

Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial

BACKGROUND Avian influenza A virus H5N1 has caused widespread infections that have resulted in severe disease or death in poultry and wild birds as well as human beings. This virus has the potential to emerge as a pandemic threat and H5N1 vaccines are being developed in many countries. Our aim was to assess the safety and immunogenicity of an inactivated adjuvanted whole-virion H5N1 vaccine. METHODS A stratified randomised, placebo-controlled, double-blind phase I clinical trial was done in 120 volunteers aged 18-60 years. Volunteers were assigned to receive two doses of placebo (n=24) or an inactivated whole-virion influenza A (H5N1) vaccine with 1.25 microg (24), 2.5 microg (24), 5 microg (24), or 10 microg (24) haemagglutinin per dose with aluminium hydroxide adjuvant on day 0 and 28. Serum samples were obtained on day 0, 14, 28, 42, and 56 for haemagglutination inhibition and virus neutralisation assays. This trial is registered with the ClinicalTrials.gov registry with the number NCT00356798. FINDINGS All four formulations of vaccines were well tolerated. No serious adverse event was reported and most local and systemic reactions were mild and transient. All formulations induced antibody responses after the first dose; the highest immune response of 78% seropositivity was seen in the 10 mug group after two vaccine doses. Two individuals dropped out: one in the 1.25 microg group (withdrew consent) and one in the 10 microg group (discontinued); one individual was also excluded from the final analysis. INTERPRETATION A two-dose regimen of an adjuvanted 10 microg inactivated whole-virion H5N1 vaccine met all European regulatory requirements for annual licensing of seasonal influenza vaccine. Lower doses of this vaccine could achieve immune responses equivalent to those elicited by adjuvanted or non-adjuvanted split-virion vaccines. The use of a whole virion vaccine could be more adaptable to the antigen-sparing strategy recommended by WHO for protection against an influenza pandemic.

Optimal vaccination strategies for 2009 pandemic H1N1 and seasonal influenza vaccines in humans.

A randomized clinical trial was conducted to assess whether the immunogenicity of seasonal and pandemic (H1N1/09) influenza vaccines is affected by the order of vaccine administration. 151 healthy adult volunteers were randomized into three groups. All groups received one dose (15 μg haemagglutinin) each of a pandemic H1N1 vaccine and a seasonal trivalent vaccine. Group 1 received the pandemic H1N1 vaccine first, followed by the seasonal vaccine 21 days later. Group 2 received vaccinations in vice versa and Group 3 received both vaccines simultaneously. Post-vaccination blood samples were collected to determine the immunogenicity by hemagglutination-inhibition (HI), microneutralization (MN), and B cell ELISPOT assays. All three vaccination strategies were well-tolerated and generated specific immune responses. However, we found a significant difference in magnitude of antibody responses to pandemic H1N1 between the three groups. Pre- or co-vaccination with the seasonal flu vaccine led to a significant reduction by 50% in HI titre to pandemic H1N1 virus after pandemic vaccination. Pre- or co-vaccination of pandemic H1N1 vaccine had no effect on seasonal flu vaccination. MN and ELISPOT assays showed a similar effect. Vaccination with pandemic H1N1 vaccine first is recommended to avoid an associated inhibitory effect by the seasonal trivalent flu vaccine.

A Rapid Immune Response to 2009 Influenza A(H1N1) Vaccines in Adults: A Randomized, Double-Blind, Controlled Trial

A double-blind, randomized, controlled trial involving 706 adults was conducted to evaluate the immunogenicity and safety of different dosages of whole-virion or split-virion H1N1 influenza vaccines with or without aluminum adjuvant. A rapid and strong immune response was induced at day 14 after the first injection. The seroprotection rates ranged from 72.7% (95% confidence interval [CI], 62.7%-81.1%) for 5-microg whole-virion aluminum formulation to 97.0% (95% CI, 90.9%-99.7%) for 30-microg split-virion nonaluminum formulation. All formulations were well tolerated. The incidences of mild, moderate, and severe reactions were 71 (10.1%), 15 (2.1%), and 1 (0.1%) of 706 reactions, respectively. The 15-microg split-virion formulation had the best immunogenicity and safety.

Safety and immunogenicity of adjuvanted inactivated split-virion and whole-virion influenza A (H5N1) vaccines in children: a phase I-II randomized trial.

OBJECTIVE Highly pathogenic avian influenza A virus H5N1 has the potential to cause a pandemic. Many prototype pandemic influenza A (H5N1) vaccines had been developed and well evaluated in adults in recent years. However, data in children are limited. Herein we evaluate the safety and immunogenicity of adjuvanted split-virion and whole-virion H5N1 vaccines in children. METHODS An open-labelled phase I trial was conducted in children aged 3-11 years to receive aluminum-adjuvated, split-virion H5N1 vaccine (5-30 microg) and in children aged 12-17 years to receive aluminum-adjuvated, whole-virion H5N1 vaccine (5-15 microg). Safety of the two formulations was assessed. Then a randomized phase II trial was conducted, in which 141 children aged 3-11 years received the split-virion vaccine (10 or 15 microg) and 280 children aged 12-17 years received the split-virion vaccine (10-30 microg) or the whole-virion vaccine (5 microg). Serum samples were collected for hemagglutination-inhibition (HI) assays. FINDINGS 5-15 microg adjuvated split-virion vaccines were well tolerated in children aged 3-11 years and 5-30 microg adjuvated split-virion vaccines and 5 microg adjuvated whole-virion vaccine were well tolerated in children aged 12-17 years. Most local and systemic reactions were mild or moderate. Before vaccination, all participants were immunologically naïve to H5N1 virus. Immune responses were induced after the first dose and significantly boosted after the second dose. In 3-11 years children, the 10 and 15 microg split-virion vaccine induced similar responses with 55% seroconversion and seroprotection (HI titer >or=1:40) rates. In 12-17 years children, the 30 microg split-virion vaccine induced the highest immune response with 71% seroconversion and seroprotection rates. The 5 microg whole-virion vaccine induced higher response than the 10 microg split-virion vaccine did. INTERPRETATION The aluminum-adjuvanted, split-virion prototype pandemic influenza A (H5N1) vaccine showed good safety and immunogenicity in children and 30 microg dose induced immune response complying with European Union licensure criteria.

Antibody Persistence after 2-Dose Priming and Booster Response to a Third Dose of an Inactivated, Adjuvanted, Whole-Virion H5N1 Vaccine

An inactivated, alum-adjuvanted, whole-virion H5N1 vaccine had been evaluated previously. Hemagglutination inhibition (HI) assays showed that the antibody levels declined significantly, with 4.8%-20.8% and 0%-18.8% of participants retaining seroprotection (HI titer >or=1:40) 6 and 12 months after the second dose, respectively. A third dose of the same vaccine given 12 months after the second dose significantly boosted immune responses. Thirty days after the third dose in the 1.25-, 2.5-, 5-, and 10-microg dose groups, 29.4%, 31.3%, 78.6%, and 90.0% of participants had HI titers >or=1:40, and 52.9%, 81.2%, 92.9%, and 100% of participants had microneutralization titers >or=1:40, respectively. Both the 5-microg and 10-microg doses met European Union criteria.

Immunogenicity, safety, and lot consistency of a novel inactivated enterovirus 71 vaccine in Chinese children aged 6 to 59 months.

ABSTRACT The determination of lot-to-lot consistency in the manufacturing process is a mandatory step in the clinical development of the novel enterovirus 71 (EV71) vaccine. A phase III, randomized, placebo-controlled, double-blind trial assessed the lot consistency, immunogenicity, and safety of the EV71 vaccine in children aged 6 to 59 months. Healthy children (n = 1,400) received one of three lots of the EV71 vaccine containing 400 U of EV71 antigen or a placebo at days 0 and 28. Blood samples were collected before dose 1 and at 28 days after dose 2 (day 56) for an anti-EV71 neutralizing antibody (NTAb) assay. The geometric mean titer (GMT) and the seropositivity rates (with titers of ≥1:8) were compared at day 56. After each dose, the solicited injection site and general adverse events (AEs) were recorded for 7 days, and unsolicited AEs were recorded for 28 days. At day 56, the seropositivity rates ranged from 99.7% to 100% for the vaccine groups. The NTAb GMTs for the vaccine were 140.3 (95% confidence interval [CI], 117.8 to 167.1), 141.5 (95% CI, 118.0 to 169.6), and 146.6 (95% CI, 122.5 to 175.3). The two-sided 95% CI of the log difference in GMTs between the pairs of lots were between −0.176 and 0.176, therefore meeting the predefined equivalence criteria. The percentages of subjects reporting any injection site AEs, general AEs, or serious AEs were similar across the four vaccination groups. In conclusion, the demonstration of consistency between the manufacturing lots confirms for the purposes of clinical development the reliability of the EV71 vaccine production process. (This study has been registered at ClinicalTrials.gov under registration no. NCT01636245.)

Review of 10 years of marketing experience with Chinese domestic inactivated hepatitis A vaccine Healive

In 2002, the first Chinese domestic preservative-free inactivated hepatitis A vaccine, Healive®, was introduced in China. It is highly immunogenic, and provides lasting protection in healthy individuals and generates protective levels of antibodies in other at-risk individuals. Over 10 years since its first licensure, postmarketing surveillance data have confirmed the outstanding safety profile of the vaccine. Comparative clinical trials indicated that Healive® induce equal or similar immunogenicity with other currently available inactivated hepatitis A vaccines and are interchangeable for the course of HAV immunization in Chinese children. The vaccine is effective in curbing outbreaks of hepatitis A due to rapid seroconversion and the long incubation period of the disease. Additional issues surrounding the use of the vaccine are also reviewed.

A serological survey on neutralizing antibody titer of SARS convalescent sera

A seroepidemiologic study was conducted in North China in 2003 to determine the neutralizing antibody titer of severe acute respiratory syndrome (SARS) convalescent sera. A total of 99 SARS convalescent serum samples were collected from patients from the Inner Mongolia Autonomous Region, Hebei Province, and Beijing 35–180 days after the onset of symptoms. The anti‐SARS antibodies were detected by enzyme‐linked immunosorbent assay (ELISA), neutralization assay, and Western blot. Eighty‐seven serum samples were confirmed to be positive for SARS antibodies. The neutralizing antibody titer of the 87 positive sera was analyzed quantitatively by neutralization assay. The geometric mean titer (GMT) of the 87 convalescent sera was 1:61. The Kolmogorov–Smirnov test showed that the neutralizing antibody titers conform to normal distribution, which suggests that the average anti‐SARS antibody level in this study was representative of the convalescent antibody level of the SARS population. This result could be useful for the development and quality control of SARS vaccines. J. Med. Virol. 77:147–150, 2005.

Interchangeability and tolerability of two inactivated hepatitis A vaccines in Chinese children

In China, no data are available to evaluate the interchangeability between Chinese domestic inactivated hepatitis A vaccines (Healive) and imported inactivated hepatitis A vaccines (Havrix). A double-blind, randomized controlled study was to compare interchangeability and safety of Healive and Havrix among Chinese children. Vaccine was administered to 303 healthy children at 0 and 6 months in one of four vaccine regimens: Healive-Healive; Healive-Havrix; Havrix-Healive or Havrix-Havrix. We collected sera samples at 0 (before vaccination), 6 (before second dose) and 7 months (after second dose), and compared groups in terms of proportion of sero-conversions which is defined as ≥ 20 mIU/ml, and geometric mean concentrations (GMCs) of anti-hepatitis A virus (HAV) antibody. Seroconversion rates were 133/133 (100%) for those received one dose of Healive and 105/131 (80.2%) for those received one dose of Havrix at 6 months, respectively (P<0.001), GMCs for Healive and Havrix were 126.1 and 40.9 mIU/ml (P<0.001), respectively. At 7 months, the seroconversion rate was 100% among all groups. The GMC after two doses of Healive was 8905.5 mIU/ml compared with 1900.9 mIU/ml after two doses of Havrix (P<0.001). The GMC in the Healive-Havrix group was 3275.8 mIU/ml compared with 4165.8 mIU/ml in the Havrix-Healive group (P=0.058). There is not different of reported adverse reactions across the groups. The present study indicated that both vaccines can be recommended for interchangeable using of immunization among Chinese healthy children.

Review of 10 years of clinical experience with Chinese domestic trivalent influenza vaccine Anflu

Influenza viruses cause annual winter epidemics globally and influenza vaccination is most effective way to prevent the disease or severe outcomes from the illness, especially in developing countries. However, the majority of the world’s total production capacity of influenza vaccine is concentrated in several large multinational manufacturers. A safe and effective preventive vaccine for the developing countries is urgent. Anflu®, a Chinese domestic preservative-free, split-virus trivalent influenza vaccine (TIV), was introduced by Sinovac Biotech Ltd. in 2006. Until now, 20.6 million doses worldwide of Anflu® were sold. Since 2003, 13 company-sponsored clinical studies investigating the immunogenicity and safety of Anflu® have been completed, in which 6642 subjects participated and were vaccinated by Anflu®. Anflu® was generally well tolerated in all age groups, and highly immunogenic in healthy adults and elderly and exceeded the licensure criteria in Europe. This review presents and discusses the experience with Anflu® during the past decade. A new Chinese domestic, preservative-free, unadjuvanted, inactivated split-virus trivalent influenza vaccine (TIV), Anflu®, was introduced into human clinical trials in 2003 and then licensed in China in 2006. The vaccine contains 15 µg /0.5 ml hemagglutinin from each of the 3 influenza virus strains (including an H1N1 influenza A virus subtype, an H3N2 influenza A virus subtype, and an influenza B virus) that are expected to be circulating in the up-coming influenza season. The clinical data pertaining to Anflu® will be reviewed and compared with other TIVs available at present.