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Long-term seroprotectionBased on five-year follow-up data from a randomized positive-controlled trial among Chinese children (1-8 years old) following a 0, 6 months vaccination schedule, a power-law model accounting for the kinetics of B-cell turnover, as well as a modified power-law model considering a memory-B-cell subpopulation, were fitted to predict the long-term immune responses induced by HAV vaccination (Healive or Havrix). Anti-HAV levels of each individual and seroconversion rates up to 30 years after vaccination were predicted.A total of 375 participants who completed the two-dose vaccination were included in the analysis. Both models predicted that, over a life-long period, participants vaccinated with Healive would have close but slightly higher antibody titers than those of participants vaccinated with Havrix. Additionally, consistent with previous studies, more than 90% of participants were predicted to maintain seroconversion for at least 30 years. Moreover, the modified power-law model predicted that the antibody titers would reach a plateau level after nearly 15 years post-vaccination.Based on the results of our modeling, Healive may adequately induce long-term immune responses following a 0, 6 months vaccination schedule in children

In China, both inactivated hepatitis A (HA) vaccine and live attenuated HA vaccine are available. We conducted a trial to evaluate 5-year immune persistence induced by one dose of inactivated or live attenuated HA vaccines in children. Subjects with no HA vaccination history had randomly received one dose of inactivated or live attenuated HA vaccine at 18–60 months of age. Anti-HAV antibody concentrations were measured before vaccination and at the first, second, and fifth year after vaccination. Suspected cases of hepatitis A were monitored during the study period. A total of 332 subjects were enrolled and 182 provided evaluable serum samples at all planned time points. seropositive rate at 5 y was 85.9% in the inactivated HA vaccine group and 90.7% in the live attenuated HA vaccine group. GMCs were 76.3% mIU/ml (95% CI: 61.7 – 94.4) and 66.8mIU/ml (95% CI: 57.8 – 77.3), respectively. No significant difference in antibody persistence between 2 groups was found. No clinical hepatitis A case was reported. A single dose of an inactivated or live attenuated HA vaccine at 18–60 months of age resulted in high HAV seropositive rate and anti-HAV antibody concentrations that lasted for at least 5 y.

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. Clinical_Trials identifier: NCT01008137. © 2010.

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 μg) and in children aged 12–17 years to receive aluminum-adjuvated, whole-virion H5N1 vaccine (5–15 μg). 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 μg) and 280 children aged 12–17 years received the split-virion vaccine (10–30 μg) or the whole-virion vaccine (5 μg). Serum samples were collected for hemagglutination-inhibition (HI) assays. Findings 5–15 μg adjuvated split-virion vaccines were well tolerated in children aged 3–11 years and 5–30 μg adjuvated split-virion vaccines and 5 μg 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 naive 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 μg split-virion vaccine induced similar responses with 55% seroconversion and seroprotection (HI titer ≥1:40) rates. In 12–17 years children, the 30 μg split-virion vaccine induced the highest immune response with 71% seroconversion and seroprotection rates. The 5 μg whole-virion vaccine induced higher response than the 10 μg 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 μg dose induced immune response complying with European Union licensure criteria. [ClinicalTrials.gov identifiers: NCT00900588 and NCT00900991 ].

Summary 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 μg (24), 2·5 μg (24), 5 μg (24), or 10 μg (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 μg group after two vaccine doses. Two individuals dropped out: one in the 1·25 μg group (withdrew consent) and one in the 10 μg group (discontinued); one individual was also excluded from the final analysis. Interpretation A two-dose regimen of an adjuvanted 10 μg 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.

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.)

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

To evaluate the safety and immunogenicity of split influenza vaccine (Anflu(®)).An open-labeled clinical trial was carried out in adults aged 18 - 60 years and elders aged over 60 years from August to September, 2010 in Shenyang, Liaoning province. One dose of split influenza vaccine was administered and adverse events were observed. Serum samples were obtained prior to vaccination and 21 days post vaccination. A/H1N1, A/H3N2 and B antibodies against influenza virus were measured using micro-hemagglutination inhibition (HI) assay.A total of 130 subjects were recruited and 120 paired serum samples were obtained. The overall rate of adverse events was 2.3% (3/130) and all of them with systemic reaction. No single serious adverse event was reported. 21 days after the vaccination, the sero-conversion rates of A/H1N1, A/H3N2 and B antibodies against influenza virus among adults were 82.5%, 93.7% and 92.1%, respectively. The Geometric Mean Titer (GMT) ratios were 20.2, 32.0 and 11.4, while the sero-protection rates were 92.1%, 98.4% and 98.4%, respectively. The sero-conversion rates of antibodies among elders were 89.5%, 91.2% and 87.7%, with the GMT ratios as 23.9, 39.8 and 15.1, respectively. The sero-protection rates were 93.0%, 94.7% and 96.5%, respectively.All indexes of A/H1N1, A/H3N2 and B antibodies exceeded the licensure criteria established by the EU Committee for Medicinal Products for Human Use, proving the trial vaccine Anflu(®) with good safety and immunogenicity.

To evaluate the safety and immunogenicity of the Bilive(TM) combined hepatitis A and hepatitis B vaccine in healthy children.A total of 116 healthy children aged 1 - 10 years, who, without history of hepatitis A vaccine vaccination and anti-HAV negative, had completed the full immunization of hepatitis B vaccine were recruited in city of Changzhou in Jiangsu province. The Bilive(TM) combined hepatitis A and hepatitis B vaccine was administered according to a two-dose schedule (0, 6 months). The dosage was 250 U for hepatitis A antigen and 5 microg for hepatitis B surface antigen. The potential adverse effects were observed within 72 hours after vaccination. The serum samples were collected for the testing of anti-HAV and anti-HBs at month 1, 6 and 7 after initial dose.The local and systemic adverse reactions after immunization were slight and temporary. The rates of local and systemic adverse reactions were 12.1% (14/116) and 6.0% (7/116). The sero-conversion rates of HAV were from 92.9% (92/99) to 100.0% (101/101) and the geometric mean titers (GMT) ranged from 47.0 mIU/ml to 2762.3 mIU/ml 1, 6, 7 months after initial dose. The sero-protection rate of HBV was 86.1% (87/101) before vaccination and came up to 100.0% (101/101) one month after initial dose, and the GMTs of HBV were from 894.3 mIU/ml to 3314.3 mIU/ml 1, 6, 7 months after initial dose.The Bilive(TM) combined hepatitis A and hepatitis B vaccine has good safety and immunogenicity in healthy children who had preexisting immunity to hepatitis B virus.

Background Avian influenza A virus H5N1 has the potential to cause a pandemic. Adjuvants and whole-virion vaccines are regarded as antigen sparing for pandemic vaccines. Methods A double-blind, randomized trial was performed from 28 August to 22 December 2007 in 402 adults; 301 adults were randomly assigned to receive 2 doses of an inactivated, aluminum-adjuvanted, whole-virion H5N1 vaccine containing 5, 10, or 15 microg of hemagglutinin per dose 28 days apart, and 101 of them received 2 doses of 10 microg of vaccine 14 days apart. The vaccine was manufactured from the recombinant A/Vietman/1194/2004 (NIBRG14) strain. Blood samples were collected for hemagglutination inhibition and microneutralization assays. Results All formulations were well tolerated, with no serious adverse events. Most local and systemic reactions were mild or moderate. Immune responses were induced after 1 dose in all vaccination groups. The highest immune response was seen after 2 doses of 15 microg of vaccine, with 90% and 100% seroconversion rates and 90% and 100% of participants having a titer of > or = 1:40 for hemagglutination inhibition and microneutralization assays, respectively. Both the 10- and 15-microg doses met or exceeded European Union licensure criteria. Generally, higher immune responses were elicited in participants vaccinated 28 days apart than those vaccinated 14 days apart. Cross-reaction assays showed that after 2 doses of 10 microg of vaccine, 98% and 87% of participants had a microneutralization titer of > or = 1:40 against heterologous Indonesia and Anhui strains, respectively. Conclusions The inactivated, aluminum-adjuvanted, whole-virion H5N1 vaccine not only showed good immunogenicity and safety but also elicited significant cross-reactivity against heterologous H5N1 strains in clade 2. Trial registration ClinicalTrials.gov identifier: NCT00535665.

To evaluate the immunogenicity, safety, stability and consistency of three consecutive lots of an inactivated hepatitis A vaccine (Healive).A double-blind, randomized and controlled clinical trial was conducted in healthy volunteers aged from 1 to 8 years. Totally, 400 subjects were enrolled and assigned into four groups, each receiving one of the three lots of Healive or a licensed control vaccine in 0 and 6th month. Safety was assessed through a 30 minutes and three days observation, thereafter. Anti-HAV titers were determined on the 1st, 6th and 7th month after the vaccination.Seroconversion rate of four groups were all 100% by the end of the schedule while GMTs of Healive were 3237.06-3814.14 mIU/ml but were not significantly different. GMT of control vaccine was 1467.49 mIU/ml. Healive and control vaccine were well tolerated with 1%-5% incidence of overall adverse reactions in which most of them were mild and moderate. No severe adverse reaction was reported.The three consecutive lots of Healive were well consistent as indicated by immunogenicity and safety while immunogenicity was better than the vaccine used as control.

Background Emergence of severe acute respiratory syndrome (SARS) from the winter of 2002 to the spring of 2003 has caused a serious threat to public health. Methods To evaluate the safety and immunogenicity of the inactivated SARS coronavirus (SARS-CoV) vaccine, 36 subjects received two doses of 16 SARS-CoV units (SU) or 32 SU inactivated SARS-CoV vaccine, or placebo control. Results On day 42, the seroconversion reached 100% for both vaccine groups. On day 56, 100% of participants in the group receiving 16 SU and 91.1% in the group receiving 32 SU had seroconverted. The geometric mean titre of neutralizing antibody peaked 2 weeks after the second vaccination, but decreased 4 weeks later. Conclusion The inactivated vaccine was safe and well tolerated and can elicit SARS-CoV-specific neutralizing antibodies.

Immunization is considered as the most effective way for the prophylaxis of hepatitis A virus (HAV) infection. This study aimed to evaluate the immunogenicity and safety of three consecutive lots of a new preservative-free inactivated hepatitis A vaccine (Healive) in healthy children. A double-blind, randomized and controlled clinical trial was conducted in healthy volunteers aged from 1 to 8 years. Total 400 subjects were enrolled and assigned into four groups, receiving one of the three lots of Healive or an established control vaccine. The vaccination was two-dose regimen with 6 months apart. Anti-HAV titers were determined at the 1st, 6th and 7th month. The results showed that Healive was highly immunogenic in children with 100% seroconversion rate (SR) and 3237-3814 mIU/ml geometry mean titer (GMT) 1 month after the second dose. The immunogenicity of Healive was statistically higher than that of the control vaccine with respect to GMT and SR (P=0.037 to P0.001). Both Healive and control vaccine were well tolerated with 1-5% incidence of overall adverse reactions (P0.298). Severe adverse reaction was not reported. Both SRs (1, 6 and 7 months) and GMTs (1 and 7 months) in subjects receiving one of the three consecutive lots of Healive had not statistical difference (P=0.114-0.710), suggesting that Healive was well consistent. The immune responses in younger children (1-3 years) and older children (4-8 years) were similar to each other (P=0.187-0.963). The present study indicated that Healive was greatly consistent between production lots, well tolerated and highly immunogenic in children, which made the preservative-free inactivated hepatitis A vaccine well suitable for inclusion in the routine programme of children vaccination.

To study the evidence of severe acute respiratory syndrome (SARS) infection among close contacts to SARS patients and the level of sera IgG antibody in SARS cases.Specific IgG antibody against SARS-CoV in serum samples from contacts to patients, five months before an SARS outbreak in Beijing. Neutralized test, ELISA and immunity adherence test were studied. Samples were collected after clinical onset of patients or close contacts to patients, for 22 - 24 weeks. 19 close contacts and 13 cases were included in the study.In close contacts, all tests were negative on three methods. All SARS cases were positive except one by immunity adherence test. The neutralized antibody levels were from 1:16 to 1:203, with medium level of 1:43.According to our survey, there was no latent infection among close contacts. IgG antibody in sera continued to be at higher levels among SARS cases 22 - 24 weeks after onset.