Safety and immunogenicity of a 2009 influenza A (H1N1) vaccine in hemodialysis patients

A worldwide vaccination campaign against the 2009 pandemic influenza A (H1N1) virus was launched among high-risk subjects, including hemodialysis patients. The long-term immunogenicity of an influenza vaccine has not been investigated in hemodialysis patients. This study aimed to (1) assess the long-term immunogenicity of a monovalent non-adjuvanted influenza A (H1N1) vaccine in hemodialysis patients and (2) determine the safety of this vaccine. We conducted a prospective cohort study of 44 hemodialysis patients and 149 healthy controls in 2010. All of the participants received a single dose of the monovalent non-adjuvanted 2009 influenza A (H1N1) vaccine. The level of antibodies was measured at baseline and at 4 and 24 weeks post-vaccination using a hemagglutination inhibition assay. The outcomes were the percentages of participants who achieved seroconversion and seroprotection (titer ≥1:40) 4 and 24 weeks after vaccination. At 4 weeks post-vaccination, seroconversion was observed in 17 (38.6%) of the hemodialysis patients and 94 (63.1%) of the controls (P = 0.056), and protective titers were obtained in 22 (50%) of the hemodialysis patients and 100 (67.1%) of the controls (P = 0.426). At 24 weeks post-vaccination, immunogenicity decreased in both the hemodialysis patients and the controls, but there were no significant differences between the hemodialysis patients and the controls in the seroconversion rate (27.3% versus 36.9%, P = 0.526) or the seroprotection rate (38.6% versus 48.3%, P = 0.996). No differences in adverse events were observed between the hemodialysis patients and the controls. In summary, the 2009 influenza A (H1N1) vaccine elicits a similar immune response in both hemodialysis patients and healthy controls, but immunity declines 24 weeks after vaccination in both groups. Hemodialysis patients should at least be vaccinated annually against the influenza virus.     

Immune response after one or two doses of pandemic influenza A (H1N1) monovalent,AS03-adjuvanted vaccine in HIV infected adults

Introduction

Continued research is needed to evaluate and improve the immunogenicity of influenza vaccines in HIV infected patients. We aimed to determine the antibody responses after one or two doses of the AS03-adjuvanted pandemic influenza A (H1N1) vaccine in HIV infected patients.

Method

Following the influenza season 2009/2010, 219 HIV infected patients were included and divided into three groups depending on whether they received none (n = 60), one (n = 31) or two (n = 128) doses of pandemic influenza A (H1N1) vaccine. At inclusion, antibody titers for all patients were analyzed and compared to pre-pandemic antibody titers analyzed from serum samples in a local storage facility.

Results

4–9 months after a single immunization, we found a seroprotection rate of 77.4% and seroconversion rate of 67.7%. After two immunizations the rates increased significantly to seroprotection rate of 97.7% and seroconversion rate of 86.7%.

Conclusion

A single dose of AS03-adjuvanted pandemic influenza A (H1N1) vaccine created an adequate immune response in HIV infected patients lasting as long as 4–9 months. Two doses improved the immunogenicity further.     

Immunogenicity, reactogenicity and safety of the human rotavirus vaccine RIX4414 (Rotarix™) oral suspension (liquid formulation) when co-administered with expanded program on immunization (EPI) vaccines in Vietnam and the Philippines in 2006-2007

Evaluation of immunogenicity and safety of a 2-dose liquid formulation of human rotavirus vaccine, RIX4414 following WHO's Expanded Program on Immunization (EPI) schedule (0, 1, and 2 months; Month 0 indicates day of enrolment) in Vietnam and the Philippines. Infants aged 6-10 (mean = 8.7 ± 1.07 weeks Vietnam) and 5-10 weeks (mean = 6.6 ± 1.03 weeks Philippines) received two doses of RIX4414 vaccine (V) and one dose of placebo (PL) or three placebo doses concomitantly with commercially available diphtheria-tetanus-whole-cell pertussis, hepatitis B and oral poliovirus vaccines. The vaccination schedules were: V-V-PL, V-PL-V and PL-PL-PL (Vietnam); PL-V-V, V-PL-V and PL-PL-PL (Philippines). Anti-rotavirus seroconversion rate was assessed pre-vaccination and post-vaccination (ELISA cut-off = 20 U/ml). 375 infants were enrolled in each country. Seroconversion rates at one month post-Dose 2 of RIX4414 were Vietnam 63.3% (95% CI: 54.3-71.6) in V-V-PL group and 81.5% (95% CI: 73.4-88) in V-PL-V group; Philippines 70% (95% CI: 61-78) in PL-V-V group and 59.2% (95% CI: 49.8-68) in V-PL-V group. Frequencies of solicited (8-day post-each dose) and unsolicited symptoms (31-day post-each dose) were similar. Two-doses of rotavirus vaccine administered within the WHO EPI offer flexibility in existing schedule, though both schedules provides good immune responses.     

Influenza A (H1N1) 2009 two-dose immunization of US children: an observer-blinded, randomized, placebo-controlled trial

The goal of this pediatric clinical trial was to assess the safety and immunogenicity of two different doses of a monovalent inactivated pandemic (H1N1) 2009 vaccine in US children aged 6 months to 9 years of age. Randomized, observer-blinded, US multicenter phase 2 study assessing 2 doses of vaccine given 21 days apart in 474 children aged 6-35 months or 3-9 years. Children in each age group were randomly assigned to receive either a pandemic (H1N1) 2009 vaccine containing 7.5 or 15 μg of hemagglutinin (HA) or placebo in a 4:4:1 ratio. Primary outcome was hemagglutination inhibition (HI) antibody responses 21 days following each vaccination. Safety was monitored throughout the study. The first dose of either A H1N1 vaccine formulation was more immunogenic in children older than 3 years than in younger children. 45-50% of children aged 6-35 months and 69-75% of children aged 3-9 year-old attained HI titers of ≥1:40. A second dose of A H1N1 vaccine further increased HI antibody responses with seroprotection and seroconversion rates reaching 90-99% in both age groups. Interestingly, the pandemic (H1N1) 2009 vaccine formulations elicited similar rates of solicited and unsolicited injection site and systemic reactions as the placebo. The data therefore demonstrate the high level immunogenicity in infants and children of an (H1N1) 2009 influenza vaccine displaying a safety and reactogenicity profile similar to placebo.     

Effect of two injections of non-adjuvanted influenza A H1N1pdm2009 vaccine in renal transplant recipients: INSERM C09-32 TRANSFLUVAC trial

Background

Enhancing vaccine immunogenicity in kidney transplant recipients, particularly against influenza, is required since the immunosuppression used to prevent graft rejection limits vaccine immunogenicity. We therefore investigated the immunogenicity and safety of a double dose non-adjuvanted vaccination regimen against influenza H1N1pdm2009 in kidney transplant adult recipients.

Methods

A prospective single-arm study was conducted including 121 renal transplant recipients under triple immunosuppressive regimen. Patients received 2 injections (day 0, day 21) of an inactivated, non-adjuvanted H1N1pdm2009 vaccine. Immunogenicity (hemagglutination-inhibition [HI] antibodies and anti-hemagglutin [HA] specific T cells) was evaluated after one and two injections (day 21, day 42) and at 6 months (day 182).

Results

The seroprotection rate (HI antibody titer ≥ 1/40) was 19% at day 0 (n = 119), 53% at day 21 (n = 118), 60% at day 42 (n = 116) (p = 0.013; day 42 vs. day 21) and 56% at day 182 (n = 113). The seroconversion rate was 24% and 32%, the geometric mean fold rise was 3.7 and 4.6 after the first and second injections, respectively. T-cell immunity to the H1N1pdm2009 vaccine showed a two-fold increase from baseline, though not statistically significant, in H1N1pdm2009-HA-specific CD4+ and CD8+ T cells in 34% and 48% of cases, respectively. No rejection episodes related to vaccination were observed while the donor-specific antibodies and creatinine clearance remained unchanged throughout the study.

Conclusion

Administration of two doses of the non-adjuvanted influenza H1N1pdm2009 vaccine in renal transplant patients is safe and induces a significant seroprotection, not strong enough yet to meet European or US requirements for adults below 60 years, but comparable to seroprotection levels usually observed in the non immunosuppressed elderly population or conferred by a single dose of adjuvanted vaccine in solid organ transplant recipients. These results provide useful indications for future strategies required to improve immunogenicity of vaccines against influenza in transplanted patients.     

Immune response of single dose vaccination against 2009 pandemic influenza A (H1N1) in the Taiwanese elderly

We conducted a multi-center, randomized and laboratory-blinded clinical trial with subgroup analyses, involving adults aged greater than 60 years old (range 61–86 years old), to investigate the immunogenicity and the potential factors affecting the immune response of a monovalent, unadjuvanted, inactivated, split-virus vaccine. A total of 107 subjects were randomized to receive 15 and 30 μg of hemagglutinin antigen in a 1:1 ratio. The immunogenicity was detected through hemagglutination inhibition (HAI) test of serum obtained before and 3 weeks after vaccination. By 3 weeks after vaccination, HAI titer ≧1:40 was observed in 75.5% and 81.1% of participants receiving 15 and 30 μg of hemagglutinin antigen, respectively. Positive seroconversion was observed in 71.7% and 81.1% of recipients of the 15 and the 30 μg, respectively. The GMTs increased by a factor of 10.7 and 17.4 in the groups of 15 and 30 μg, respectively. This study indicated that one dose of 15 μg hemagglutinin antigen without adjuvant induced protective immune response in the majority of elderly. Multivariate logistic regression analyses showed that gender, age and diabetes were statistically significant factors affecting the seroprotection rate (p = 0.04, 0.01 and 0.01, respectively) and seroconversion rate (p = 0.01, 0.01 and 0.01, respectively).     

Dose sparing intradermal trivalent influenza (2010/2011) vaccination overcomes reduced immunogenicity of the 2009 H1N1 strain

Background

We hypothesized that low dose intradermal vaccination of the trivalent influenza vaccine (TIV) delivered by the MicronJet600™ (NanoPass Technologies, Israel) would be non-inferior to the full dose intramuscular and mid dose Intanza^® vaccination in the elderly and the chronically ill adults.

Methods

We performed a prospective randomized trial on elderly and chronically ill adults. Subjects were randomly assigned into 4 groups. Groups ID3 and ID9 received reduced dose ID TIV (3 μg and 9 μg of hemagglutinin (HA) per strain respectively) delivered by MicronJet600™ (NanoPass Technologies, Israel). Group INT9 received reduced dose ID TIV (9 μg) delivered by Becton Dickinson's Soluvia™ device (Intanza^®9, Sanofi-Pasteur, France). Control group IM15 received a full dose IM TIV (15 μg). We measured antibody titers by hemagglutination inhibition (HAI) and microneutralization (MN) assays at baseline and day 21.

Results

Baseline characteristics for all groups were similar (group and sample sizes: ID3 = 63; ID9 = 68; INT9 = 65; and IM15 = 66). At day 21 post vaccination, the GMT ratio and the seroconversion rates difference for all three strains of the ID vaccine groups were non-inferior to the IM vaccine group. The seroconversion rate, seroprotection rate, and the GMT of the H1N1 strains by HAI and MN assays were significantly higher in the ID groups compared with the full dose IM vaccine group. The seroconversion rates of the H3N2 strain by HAI assay were also significantly higher in the ID groups when compared with the full dose IM group. Direct comparison among the three ID groups showed no significant differences. No serious adverse events related to vaccination were reported.

Conclusion

Dose-sparing ID TIV can overcome reduced immunogenicity of the H1N1 strain, and according to some measures, for the H3N2 strain. At risk subjects indicated for the TIV should be considered for intradermal immunization to compensate for reduced immunogenicity.     

Reduced immune response to influenza A (H1N1) 2009 monovalent vaccine in HIV-infected Japanese subjects

We evaluated the immunogenicity and safety of the influenza A (H1N1) 2009 monovalent vaccine in HIV-infected Japanese subjects. A total of 182 HIV-infected and 42 HIV-uninfected subjects were enrolled, and antibody (ab) titers were measured by hemagglutination-inhibition assay at baseline and 32.3 ± 10.4 and 29.7 ± 3.3 days after vaccination, respectively. In the HIV-infected cohort, ab titers ≥1:40 at baseline and post-vaccination were 12.6% and 49.5%, respectively. The seroconversion rate, defined as either an ab titer ≤1:10 before and ≥1:40 after or ≥1:10 before and ≥4-fold increase in ab titer, was only 38.5% in the HIV-infected cohort, whereas the rate was 85.7% in the HIV-uninfected cohort. Multivariate logistic regression analysis showed that the CD4 cell count was the only significant predictor of a positive vaccine response. There were no serious adverse events in any of the subjects receiving the vaccine. Additional study is warranted to identify a more effective method of vaccinating HIV-infected Japanese subjects.     

Safety and immunogenicity of a virus-like particle pandemic influenza A (H1N1) 2009 vaccine in a blinded, randomized, placebo-controlled trial of adults in Mexico

Virus-like particles (VLPs) can be rapidly developed from influenza virus genetic sequences in order to supply vaccine after the onset of a pandemic. The safety and immunogenicity of one or two doses of a recombinant A (H1N1) 2009 influenza VLP vaccine was evaluated in a two-stage, Phase 2, randomized, double-blind, placebo-controlled study conducted in 4563 healthy adults, 18-64 years of age, during the H1N1 2009 pandemic in Mexico. In Part A, 1013 subjects were randomized into four treatment groups (5 μg, 15 μg, or 45 μg hemagglutinin [HA] VLP vaccine or placebo) and vaccinated 21 days apart, with sera collected on Days 1, 14 and 36 for hemagglutination inhibition (HAI) testing. After review of safety and immunogenicity data from Part A, additional subjects were immunized with a single dose of 15 μg VLP vaccine (N = 2537) or placebo (N = 1011) and assessed for safety in Part B. Results showed the H1N1 2009 VLP vaccine was safe and well-tolerated. Systemic solicited events were similar between placebo and VLP vaccinated groups with no vaccine-related serious adverse events. Dose response trends for solicited local adverse events were observed, with higher incidences of local pain, swelling, tenderness, and redness reported in the higher VLP dose groups (15 μg and 45 μg) compared to the placebo and 5 μg VLP groups following both vaccinations. Although the majority of local AEs were mild in severity, a dose trend in events of moderate or greater severity was also noted for these solicited events. The VLP vaccine groups demonstrated robust HAI immune responses after a single vaccination, with high rates of seroprotection (≥40 HAI titer) in 82-92% of all subjects and in 64-85% of subjects who were seronegative at the time of immunization. HAI geometric mean titers (GMTs), geometric mean ratios (GMRs) and seroconversion rates were also all statistically higher in the VLP groups compared to placebo for both post-baseline time points. Based on these data, additional clinical trials are in development to evaluate influenza vaccine candidate antigens manufactured using Spodoptera frugiperda (Sf9)/baculovirus-based VLP technology.     

Safety and immunogenicity of an AS03-adjuvanted A(H1N1)pmd09 vaccine administered simultaneously or sequentially with a seasonal trivalent vaccine in adults 61 years or older: Data from two multicentre randomised trials

During the 2009–2010 Northern Hemisphere influenza season, both seasonal and pandemic influenza vaccines were expected to be administered to elderly people, which is an important target group for influenza vaccination. Two multicentre randomised clinical studies were conducted in participants aged ≥61 years to assess the immunogenicity and reactogenicity following vaccination with two doses of an AS03-adjuvanted A(H1N1)pmd09 vaccine when either sequentially administered (21 days before first dose [N = 73] or 21 days after second dose [N = 72]) or co-administered (first dose [N = 84] or second dose [N = 84]) with a licensed trivalent seasonal influenza vaccine (TIV). Overall, 313 participants from 2 centres in Sweden (ClinicalTrials.gov, NCT00968890) and 6 centres in Germany (NCT00971425) were randomised to one of the four treatment groups. The AS03-adjuvanted A(H1N1)pmd09 vaccine elicited a good immune response against A(H1N1)pmd09-like virus in all treatment groups after the first and second dose, meeting and exceeding the European licensing criteria for pandemic influenza vaccines. After one dose of the AS03-adjuvanted A(H1N1)pmd09 vaccine, haemagglutination inhibition seroconversion rates ranged from 85% (95% confidence interval: 74–93%) to 93% (85–97%), seroprotection rates from 87% (76–94%) to 96% (90–99%) and geometric mean fold rise from 15 (11–19) to 20 (16–25). The haemagglutination inhibition immune responses to the AS03-adjuvanted A(H1N1)pmd09 vaccine seemed lower when TIV was administered 3 weeks before, while immune responses to TIV seemed not affected by either vaccination schedule. Solicited symptoms were more frequently reported following administration of the AS03-adjuvanted A(H1N1)pmd09 vaccine compared to TIV, but these were mainly mild to moderate in intensity and transient in the four treatment groups. These results suggest that sequential or co-administration of the AS03-adjuvanted A(H1N1)pmd09 vaccine and TIV induced a good immune response to both vaccines and had a clinically acceptable safety profile in people aged ≥61 years.     

Unadjuvanted pandemic H1N1 influenza vaccine in HIV-1-infected adults

We evaluated the immune response to a 2009 influenza A (H1N1) unadjuvanted vaccine in HIV-infected patients and assessed the boosting effect of a second dose. HIV-infected adults were enrolled and scheduled to receive the H1N1 unadjuvanted vaccine containing 15 μg of A/California/7/2009 haemagglutinin. Anti-H1N1 antibody titers were measured at enrollment and 4-8 weeks after each vaccination by using haemagglutination inhibition (HI) and virus neutralization (NT) assays. One hundred and four patients were analyzed. Seroconversion, as measured by using HI and NT assays, was observed in 52 (50.0%) patients and 49 (47.1%) patients, respectively, after the first dose. Seroconversion rate evaluated by using NT, but not HI, antibody titers was associated with HIV RNA levels of <400 copies/ml (odds ratio, 3.21; 95% CI, 1.15-8.96). Other parameters, including CD4 cell count, were not associated with seroconversion. In a cohort that received two vaccine doses at a 4-8-week interval (n = 54), the seroconversion rate and geometric mean titer for HI antibodies were 44.4% (95% CI, 30.8-58.1%) and 30.5 (95% CI, 19.9-46.9) after the first dose, respectively, and 48.1% (95% CI, 34.4-61.9%) and 39.0 (95% CI, 26.1-58.2) after the second dose, respectively. Among HIV-infected patients, the seroconversion rate was around 50% after the first dose of unadjuvanted vaccine. A second dose of vaccine had a limited boosting effect on immunity in this patient cohort.     

Immunogenicity and safety of influenza A (H1N1) 2009 monovalent inactivated split vaccine in Korea

In a pandemic, the development of an effective influenza vaccine is the most important subject from the view of public health. This study was performed to evaluate the immunogenicity and safety of inactivated, monovalent H1N1 2009 vaccine (Green Cross Corporation, Yongin, Korea) among healthy adults aged 19-64 years (Group 1) and the elderly aged ≥65 years (Group 2) in a two-dose regimen, 21 days apart. At baseline, 28 of 454 participants (6.1%) had hemagglutination-inhibition titers of ≥1:40 with no significant difference between age groups (p = 0.27). There was an apparent dose-dependent antibody response; participants receiving the dose of 30 μg hemagglutinin (HA) showed higher geometric mean titers (GMTs) than the 15 μg HA group in both age groups. Despite the rates of seroprotection and seroconversion were significantly higher with 30 μg HA formulation than 15 μg HA formula in Group 2, there was no definite difference in Group 1 irrespective of vaccine formula. Significant GMT elevation after the second dose was not noted in either age group, regardless vaccine formulations. No deaths, vaccine-related serious adverse events, or immediate unsolicited adverse reactions occurred during the study periods.     

Safety and immunogenicity of an MF59(®)-adjuvanted A/H5N1 pre-pandemic influenza vaccine in adults and the elderly

Background

The potential consequences of an avian influenza pandemic warrants the development of safe, highly immunogenic pre-pandemic A/H5N1 vaccines with cross-clade protection. In this randomized, controlled study we compared the immunogenicity and safety of an MF59^®-adjuvanted (Novartis Vaccines, Marburg, Germany) A/H5N1 pre-pandemic vaccine with that of a licensed, MF59-adjuvanted, seasonal influenza vaccine.

Methods

Healthy adult (18–60 years, n = 3372) and elderly (≥61 years, n = 275) volunteers received either an initial dose of a licensed, non-adjuvanted, trivalent, seasonal influenza vaccine (Agrippal^®) on Day 1, followed by one dose of MF59-H5N1 study vaccine on Day 22 and a second dose of MF59-H5N1 on Day 43, or alternatively, placebo on Day 1 followed by one dose of MF59-adjuvanted seasonal reference vaccine on Day 22 and a second dose of reference vaccine on Day 43. Homologous and cross-reactive A/H5N1 antibody responses were analysed by haemagglutination inhibition (HI), single radial haemolysis (SRH), and microneutralization (MN) assays three weeks after each vaccination. Vaccine safety was assessed throughout the study.

Results

Analysis by HI assay found that two doses of MF59-H5N1 resulted in a seroconversion rate of 56% and a geometric mean ratio (GMR) of 7.1 in adult subjects. Similar results were observed on analysis by SRH (GMR 4.03; seroconversion 78% and seroprotection 91%) and MN (seroconversion 67%) assays. These data met the European licensure criteria for influenza vaccines. No significant difference in immunogenicity was detected between the adult and elderly populations. Anti-A/H5N1 cross-clade antibodies were detected by SRH, 49% of adult and 32% of elderly subjects achieved seroconversion after the second vaccine dose. Overall, MF59-H5N1 containing 7.5 μg antigen was less reactogenic than the MF59-adjuvanted trivalent seasonal vaccine which contained 15 μg antigen for each component strain.

Conclusions

Two doses of MF59-H5N1 vaccine were well tolerated and induced adequate levels of seroprotection against homologous and cross-clade A/H5N1 virus. These data support the suitability of MF59-adjuvanted A/H5N1 vaccine for pre-pandemic use in adults and the elderly.     

Evaluation of safety and immunogenicity of HNVAC,an MDCK-based H1N1 pandemic influenza vaccine,in Phase I single centre and Phase II/III multi-centre,double-blind,randomized, placebo-controlled,parallel assignment studies

The clinical evaluation of the MDCK-based H1N1 pandemic influenza vaccine HNVAC in adults aged 18–65 years is reported. In the Phase I randomized, double-blind, placebo-controlled, single-centre study, 160 subjects were parallelly assigned 3:1 to vaccine:placebo groups (n = 60:20) with both the aluminium hydroxide adjuvanted and non-adjuvanted vaccine formulations. A single dose of both the formulations containing 15 μg of haemagglutinin protein showed minimal adverse reactions, the most common of which were pain at injection site (11.67%) and fever (10.00%). Both formulations produced 74–81% seroprotection (SRP: titre of ≥40), 67–70% seroconversion (SRC: four-fold increase in titres between days 0 and 21), and a four-fold increase in geometric mean titres (GMT). Aluminium hydroxide did not have a significant effect either on immunogenicity or on reactogenicity. Nevertheless, based on its recognized positive effects on the stability and immunogenicity of many vaccines, and its marginal benefit in both pre-clinical and Phase I studies of HNVAC, alum adjuvanted HNVAC was further tested in a staggered Phase II/III randomized, double-blind, placebo-controlled, multi-centre study of 200 and 195 subjects, respectively, parallelly assigned 4:1 to adjuvanted vaccine and placebo groups. In these studies, the most common adverse reactions were pain at injection site (6.88% and 5.77% in Stage 1 and Stage 2, respectively) and fever (7.50% and 7.05%, respectively), and a single dose resulted in 87–90% SRP, 85–86% SRC, and a nearly six-fold increase in GMT, meeting or exceeding licensing criteria. It is concluded that HNVAC is safe and immunogenic to adults of 18–65 years.     

Safety and immunogenicity of two different doses of a Vero cell-derived, whole virus clade 2 H5N1 (A/Indonesia/05/2005) influenza vaccine

A successful vaccine development strategy for areas with clustered H5N1 events requires conduct of vaccine trials in potentially non-naïve subjects and evaluation of post-vaccination responsiveness. An open-label, randomized, phase I/II study therefore assessed the immunogenicity and safety of two different dose levels of an inactivated, non-adjuvanted, whole virus clade 2.1 (A/Indonesia/05/2005) H5N1 Vero cell-derived influenza vaccine in healthy adults (21-45 years) from a region where the virus has been circulating (Hong Kong) as well as Singapore. Subjects (N = 110) were randomized 1:1 to receive two vaccinations with either 3.75 μg or 7.5 μg H5N1 haemagglutinin antigen 21 days apart. Safety, immunogenicity (microneutralization [MN] and single radial haemolysis [SRH] at baseline and post-vaccination) and cross-reactivity against a heterologous clade 1 strain (A/Vietnam/1203/2004) of the vaccine were assessed. Pre-existing immunity to the vaccine strain was 14% which is higher than previously reported for these regions. Two vaccinations with either vaccine formulation induced high seroprotection rates (MN titre ≥ 1:20) against the vaccine strain A/Indonesia/05/2005: 82.7% and 86.5% in the 3.75 μg and 7.5 μg dose groups. Seroconversion rates and fold increase exceeded the CPMP criterion of >40% and >2.5 for MN and SRH in both dose groups after the second vaccination, while the seroprotection rate in the 7.5 μg dose group determined by SRH was only marginally lower (69.2%) than the CPMP criterion of >70%. Thus, 11 of 12 CHMP criteria were fulfilled. A cross-reactive antibody response against the heterologous A/Vietnam/1203/2004 strain was demonstrated after the second vaccination (>21% by MN and ≥25% by SRH). Persistence of antibodies against the vaccine strain was also demonstrated 6 months after the first vaccination, indicating that a booster vaccination would be effective in those who have received two priming doses. No serious adverse events were reported. The H5N1 influenza vaccine against clade 2.1 strain A/Indonesia/05/2005 was well tolerated and immunogenic after two vaccinations, and induced a cross-neutralizing antibody response, with no dose effect.     

Immunogenicity and safety of intradermal influenza vaccine in children

In order to compare the immunogenicity and safety of different doses of trivalent influenza vaccine (TIV) administered intradermallly (ID) with those evoked by a full dose of intramuscular (IM) virosomal-adjuvanted influenza vaccine (VA-TIV), 112 previously primed healthy children aged ≥3 years were randomised to receive 9 μg or 15 μg of each strain of ID-TIV, or a full IM dose (15 μg of each strain) of VA-TIV. The A/H1N1 and A/H3N2 seroconversion and seroprotection rates were ≥90% and geometric mean titres (GMTs) increased 3.2-14.9 times without any statistically significant between-group differences; however, the seroconversion and seroprotection rates against the B strain were significantly higher in the children receiving either ID-TIV dose (p < 0.05) without any differences between them. GMT against B virus was significantly higher in the children receiving the highest dose (p < 0.05). Local reactions were significantly more common among the children receiving either ID-TIV dose (p < 0.05), but systemic reactions were relatively uncommon in all three groups. Our findings suggest that ID-TIV with 15 μg of each viral antigen can confer a significant better protection against influenza than that obtained with the same dose of IM TIV in already primed children aged ≥3 years with an acceptable safety profile. The lower dose of ID-TIV needs further evaluation to analyze persistence of protection.     

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 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 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 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].     

Long-lasting immunogenicity of a virosomal vaccine in older children and young adults with type I diabetes mellitus

To evaluate the long-lasting immunogenicity and reactogenicity of a virosomal influenza vaccine in subjects with type I diabetes, a trial was conducted during the 2007–2008 influenza season in Milan, Northern Italy. One hundred five subjects aged 9–30 years were randomized to receive by intramuscular injection vaccination by a single dose (0.5 ml) of either a virosomal (Inflexal V^®) (n = 52) or a standard subunit (Influvac^®) (n = 53) vaccine. Serum hemagglutinin inhibition antibody titres were determined against the three recommended influenza-like strains, A/H1N1, A/H3N2 and B, at pre-vaccination, and 1 and 6 months post-vaccination. Geometric mean titres were increased in the two groups 1 and 6 months post-vaccination (P < 0.001). One month post-vaccination both vaccines met the CPMP requirement for immunogenicity with high seroprotection rates (>95%) for strains A/H1N1 and A/H3N2, and a seroprotection of 73% and 70% in the virosomal and subunit vaccine for strain B. Mean fold increase ranged 2.8 (A/H3N2)–6.2 (A/H1N1) in the virosomal group and 2.3 (A/H3N2)–4.8 (A/H1N1) in the subunit group. Immunogenicity declined 6 months post-vaccination in both groups, and the CPMP requirement for immunogenicity was satisfied only in the virosomal group. In subjects without pre-existing antibodies to strain B (titre <10), the virosomal vaccine showed higher immune response than the subunit vaccine 6 months post-vaccination, with a geometric mean titre (95% CI) of 40.2 (30.7–54.6) vs. 21.2 (14.6–30.8). Reactogenicity was similar in the two vaccines. All reactions were transient and not severe. The results indicate that in older children and young adults with type I diabetes influenza vaccination with a virosomal or a standard subunit vaccine is safe and adequately immunogenic against the three influenza vaccine strains. In addition, the virosomal vaccine may show better long-lasting immune response than the standard subunit vaccine, especially in subjects without pre-existing antibodies to influenza strains.     

Immune response to influenza A (H1N1)v monovalent MF59-adjuvanted vaccine in HIV-infected patients

Immunogenicity of influenza A (H1N1)v MF59-adjuvanted vaccine was studied in HIV-infected patients. The vaccine was effective in inducing a protective immune response in patients with a CD4 >200 cells/μL while individuals with CD4 <200 cells/μL showed lower rates of seroconversion and seroprotection. These results underscore the usefulness of immunization against influenza in HIV-infected patients, though a boosting dose of vaccine may be required in seriously immunocompromised patients.     

Safety and immune response after two-dose meningococcal C conjugate immunization in HIV-infected children and adolescents in Rio de Janeiro,Brazil

We aimed to evaluate immunogenicity and adverse events (AEs) after a booster dose of Meningococcal C conjugated (MCC) vaccine in HIV-infected children and adolescents, who had a previous low seroconversion rate after priming with MCC, at a reference HIV-care center in Rio de Janeiro.Methods2–18 years old HIV-infected subjects with CD4+ T-lymphocyte cell (CD4) ≥15%, without active infection or antibiotic use, were enrolled to receive 2 doses of conjugated meningococcal C oligosaccharide-CRM197 12–18 months apart. All patients were evaluated before and 1–2 months after immunization for seroprotection [defined as human serum bactericidal activity (hSBA) titer ≥1:4]. AEs were assessed at 20 min, 3 and 7 days after each dose. Factors independently associated with seroprotection were studied.Results156 subjects were enrolled and 137 received a booster MCC dose. 55% were female, and median age was 12 years. Eight-nine percent were receiving combined antiretroviral therapy (cART) at the booster visit (median duration of 7.7 years), 59.9% had undetectable viral load (VL) at baseline, and 56.2% at the booster visit. Seroprotection was achieved in 78.8% (108/137) subjects, with a significantly higher GMT than after the priming dose (p < 0.01). Mild AEs were experienced after a second MCC dose (38%). In logistic regression, undetectable viral load at entry [odds ratio (OR) = 7.1, 95% confidence interval (95%CI): 2.14–23.37], and probably higher CD4 percent at the booster immunization visit (OR): 1.1, 95%CI: 1.01–1.17 were associated with seroprotection after a booster dose of MCC.ConclusionA booster dose of MCC was safe and induced high seroprotection rate even 12–18 months after priming. MCC should be administered after maximum virologic suppression has been achieved. These results support the recommendation of 2-dose of MCC for primary immunization in HIV-infected children and adolescents with restored immune function.