Safety and immunogenicity of a virus-like particle pandemic influenza A (H1N1) 2009 vaccine: Results from a double-blinded,randomized Phase I clinical trial in healthy Asian volunteers

Methods

A novel, fully bacterially produced recombinant virus-like particle (VLP) based influenza vaccine (gH1-Qbeta) against A/California/07/2009(H1N1) was tested in a double-blind, randomized phase I clinical trial at two clinical sites in Singapore. The trial evaluated the immunogenicity and safety of gH1-Qbeta in the presence or absence of alhydrogel adjuvant. Healthy adult volunteers with no or low pre-existing immunity against A/California/07/2009 (H1N1) were randomized to receive two intramuscular injections 21 days apart, with 100 μg vaccine, containing 42 μg hemagglutinin antigen. Antibody responses were measured before and 21 days after each immunization by hemagglutination inhibition (HAI) assays. The primary endpoint was seroconversion on Day 42, defined as percentage of subjects which reach a HAI titer ≥40 or achieve an at least 4-fold rise in HAI titer (with pre-existing immunity). The co-secondary endpoints were safety and seroconversion on Day 21.

Results

A total of 84 Asian volunteers were enrolled in this study and randomized to receive the adjuvanted (n = 43) or the non-adjuvanted (n = 41) vaccine. Of those, 43 and 37 respectively (95%) completed the study. There were no deaths or serious adverse events reported during this trial. A total of 535 adverse events occurred during treatment with 49.5% local solicited symptoms, of mostly (76.4%) mild severity. The most common treatment-related systemic symptom was fatigue. The non-adjuvanted vaccine met all primary and secondary endpoints and showed seroconversion in 62.2% and 70.3% of participants respectively on Day 21 and Day 42. While the adjuvanted vaccine showed an increased seroconversion from 25.5% (Day 21) to 51.2% (Day 42), it did not meet the immunogenicity endpoint.

Conclusion

In summary, non-adjuvanted gH1-Qbeta showed similar antibody mediated immunogenicity and a comparable safety profile in healthy humans to commercially available vaccines. These results warrant the consideration of this VLP vaccine platform for the vaccination against influenza infection (HSA CTC1300092).     

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.     

Comparable humoral response after two doses of adjuvanted influenza A/H1N1pdm2009 vaccine or natural infection in allogeneic stem cell transplant recipients

Background

The present study evaluated immunogenicity and tolerance of two-dose influenza A/H1N1pdm09 vaccination in allogeneic hematopoietic stem cell transplantation (HSCT) recipients, and compared the vaccine-induced humoral response to that triggered by natural infection in another group of HSCT patients.

Methods

Adult allogeneic HSCT recipients vaccinated with two doses of influenza A/H1N1pdm09 vaccine, separated by 3 weeks, and patients with proven influenza A/H1N1pdm09 infection were included. Antibody responses were measured by hemagglutination-inhibition assay 1) on days 0, 21, 42 and 6 months after the first vaccine injection in vaccinated patients and 2) before pandemic and after influenza A/H1N1pdm09 infection, in patients presented natural infection.

Results

At baseline, 3% of 59 recipients of adjuvanted vaccine and 0% of 20 infected patients were seroprotected (antibody titer ≥ 1/40). Seroprotection rate observed 42 days after vaccination was not different from that observed after natural infection (66% and 60% respectively, p = 0.78). In vaccinated patients, seroprotection rate increased significantly from 54% to 66% between day 21 and 42 (p = 0.015). Moreover, after 6 months, seroprotection rate in 21 vaccinated patients was similar to that observed in 10 infected patients evaluated at least 76 days after infection (D76–217) (60% and 81% respectively, p = 0.2). In multivariate analysis, no immunosuppressive treatment or chronic graft-versus-host disease (GVHD) and longer time between transplantation and vaccination/infection were associated with a stronger humoral response. The adjuvanted vaccine was safe with low rate of GVHD worsening.

Conclusion

In HSCT recipients, two doses of influenza A/H1N1pdm09 adjuvanted vaccine were safe and induced a humoral response comparable to that triggered by natural infection in these patients.     

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.     

Live attenuated H7N7 influenza vaccine primes for a vigorous antibody response to inactivated H7N7 influenza vaccine

Background

H7 influenza viruses have emerged as potential pandemic threat. We evaluated the safety and immunogenicity of two candidate H7 pandemic live attenuated influenza vaccines (pLAIV) and their ability to prime for responses to an unadjuvanted H7 pandemic inactivated influenza vaccine (pIIV).

Methods

Healthy seronegative adults received two doses of A/Netherlands/219/03 (H7N7) or one dose of A/chicken/British Columbia/CN-6/04 (H7N3) pLAIV all given as 10^7.5 50% tissue culture infective doses (TCID₅₀) intranasally. A subset of subjects received one 45 μg dose of H7N7 pIIV containing the A/Mallard/Netherlands/12/2000 HA intramuscularly 18–24 months after pLAIV. Viral shedding was assessed by culture and real-time polymerase chain reaction (rRT-PCR), B cell responses following pLAIV were evaluated by ELISPOT and flow cytometry. Serum antibody was assessed by hemagglutination-inhibition (HAI), microneutralization (MN) and ELISA assays after each vaccine.

Results

Serum HAI or MN responses were not detected in any subject following one or two doses of either H7 pLAIV, although some subjects had detectable H7 specific B cells after vaccination. However, 10/13 subjects primed with two doses of H7N7 pLAIV responded to a subsequent dose of the homologous H7N7 pIIV with high titer HAI and MN antibody that cross-reacted with both North American and Eurasian lineage H7 viruses, including H7N9. In contrast, naïve subjects and recipients of a single dose of the mismatched H7N3 pLAIV did not develop HAI or MN antibody after pIIV.

Conclusions

While pLAIVs did not elicit detectable serum MN or HAI antibody, strain-specific pLAIV priming established long term immune memory that was cross-reactive with other H7 influenza strains. Understanding the mechanisms underlying priming by pLAIV may aid in pandemic vaccine development.     

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.     

Cell culture (Vero cell) derived whole-virus non-adjuvanted H5N1 influenza vaccine induces long-lasting cross-reactive memory immune response: Homologous or heterologous booster response following two dose or single dose priming

Background

Influenza pandemic preparedness involves priming of the population with pre-pandemic vaccines. Such vaccines should be well tolerated and induce a long-lasting immunological memory that can effectively be boosted with a single dose of pandemic vaccine once available. The presented studies assessed different prime-boost regimens with a Vero cell-derived whole virus non-adjuvanted H5N1 vaccine.

Methods

In one study, 281 healthy adult (18–59 years) and 280 elderly (≥60 years) subjects received two vaccinations, 21 days apart, with Vero cell-derived whole virus non-adjuvanted H5N1 vaccine (7.5 μg HA antigen A/Vietnam/1203/2004) followed by a 6, 12–15, or 24 month booster (7.5 or 3.75 μg A/Indonesia/05/2005 or A/Vietnam/1203/2004). In the other study, 230 healthy adults (18–59 years) received single dose priming (7.5 μg A/Vietnam/1203/2004) followed by a 12 month booster (7.5 or 3.75 μg A/Indonesia/05/2005). Antibody responses were assessed by microneutralization (MN) and single radial hemolysis (SRH) assay. Vaccine safety was assessed throughout.

Results

Two dose priming was equally immunogenic in adults and the elderly: >72% of subjects in each population achieved MN titers ≥1:20 after the second vaccination. Booster vaccinations at 6, 12–15, and 24 months induced substantial antibody increases to both strains: after a 7.5 μg A/Indonesia/05/2005 booster, 93–95% of adults and 72–84% of the elderly achieved MN titers ≥ 1:20 against this strain. Homologous and heterologous booster responses were higher in the 7.5 μg dose group than in the 3.75 μg dose group. Booster responses following single dose priming were similar; a 7.5 μg booster dose induced homologous MN titers ≥1:20 in 93% of subjects.

Conclusions

A Vero cell derived whole virus non-adjuvanted H5N1 influenza vaccine is well tolerated and induces long-lasting cross-clade immunological memory that can be effectively boosted 1–2 years after two dose or single dose priming, supporting its suitability for pre-pandemic vaccination.     

Thymosin-alpha 1 (Zadaxin) enhances the immunogenicity of an adjuvated pandemic H1N1v influenza vaccine (Focetria) in hemodialyzed patients: a pilot study

Background

Although influenza vaccination is widely recommended for immunosuppressed people, the same immune dysfunction that can increase the risk of contracting influenza might also compromise vaccine effectiveness, especially during pandemics. Clinical data have highlighted the role of adjuvants in improving vaccine efficacy. As uremic patients are especially vulnerable to infections, it is recommended that they should be vaccinated yearly against influenza. This paper presents the results of a pilot clinical trial, conducted in hemodialyzed patients with an adjuvated pandemic H1N1v influenza vaccine alone and combined with Thymosin-alpha 1.

Methods

Subjects were subdivided into 3 treatment groups receiving: the adjuvated pandemic influenza vaccine (Focetria™) only (first treatment group), and the Vaccine + Thymosin alpha 1 (Zadaxin™) at a dose of 3.2 and 6.4 mg (second and third treatment groups respectively). The immunoresponse was assessed on days 0, 21, 42, 84 and 168 after vaccine administration by means of Hemagglutination Inhibition (HI), Microneutralization (MN) and Single Radial Hemolysis (SRH) assays. The CHMP regards HI as the gold standard test to evaluate the immune response to influenza vaccines before influenza vaccines are licensed. The CHMP criteria are slightly different in adults (18-60-year-old subjects) and the elderly (>60 years old). Indeed, 40% of seroconversion, 70% of subjects seroprotected 21 days after vaccination, and a 2.5-fold increase in GMR (Geometric Mean Ratio) are required in adults, while in the elderly, the corresponding threshold values are: 30%, 60% and a 2-fold increase. All these criteria must be met for the licensing of a pandemic influenza vaccine.Safety evaluation was performed by means of Adverse Event (AE) recording, laboratory assays (hematology and chemistry), electrocardiogram, and assessment of vital signs.

Results

Three populations were considered: Intention-To-Treat (ITT) (94 patients), Per Protocol (PP) (82 patients), and Safety population (99 patients). With regard to the Geometric Mean Titer (GMT) and the Geometric Mean Ratio (GMR) of HI on Day 21 in the ITT population, both “Vaccine + Thymosin alpha 1” groups presented better results than the “Vaccine only” group.A large proportion of ITT patients in the two Vaccine + Thymosin alpha 1 groups achieved seroconversion by Day 21. On Day 42, the decrease in the GMT of HI was greater in the Vaccine + Thymosin alpha 1 groups than in the vaccine only group. Similar results were obtained in the PP population. The CHMP criteria were fully met in the groups treated with Vaccine + Thymosin alpha 1. No AE was found to be related to Thymosin alpha 1 nor to the Focetria vaccine.

Conclusions

Although further studies in larger hemodialyzed populations are necessary, it can be concluded that Thymosin alpha 1 enhanced the immunogenicity of the pandemic influenza vaccine used. Moreover, it proved safe and well tolerated, and did not affect hematology or blood-chemistry values.     

Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE + GLA) adjuvant

Background

Expression of recombinant hemagglutinin (rHA) in insect cells represents a technology with proven efficacy in seasonal influenza and with the potential for a rapid response to the emergence of new, pandemic strains. We evaluated the safety and immunogenicity of rHA vaccine (H5/Indonesia/5/05) produced in SF+ insect cells using a baculovirus expression vector system (BEVS). The rHA vaccine was tested with and without the adjuvant glucopyranosyl lipid A/stable emulsion (GLA/SE).

Methods

Healthy adults 18–49 were randomized to two IM doses on Days 0 and 21 of placebo; unadjuvanted rHA 135 μg or 45 μg, or rHA 45 μg, 15 μg, 7.5 μg or 3.8 μg with GLA/SE. A pioneer group was monitored through Day 42 before randomizing remaining subjects. H5-specific antibody was determined by hemagglutination inhibition (HAI) and microneutralization (MN) on Days 0, 21 and 42.

Results

392 subjects were randomized, of whom 380 (97%) received two doses and 386 (98%) completed 12 months of follow-up. Injection site pain and tenderness were seen in 50–70% of rHA + GLA/SE recipients and 4–9% of rHA alone and placebo recipients, but most complaints were mild to moderate in intensity. After two doses, the proportions of subjects with HAI titers ≥1:40 were 32% and 15% in the unadjuvanted 135 μg and 45 μg groups, and 82%, 75%, 66%, and 72% in those receiving 45 μg, 15 μg, 7.5 μg, or 3.8 μg with GLA/SE. The geometric mean titers (GMTs) of HAI antibody on Day 42 were 128, 95, 69, and 72 in the 45 μg, 15 μg, 7.5 μg, or 3.8 μg with GLA/SE groups, respectively.

Conclusions

rHA GLA/SE was well tolerated and immunogenic in healthy adults, and GLA/SE substantially improved the serum antibody response. rHA expressed using BEVS recombinant DNA platform technology represents a promising strategy for pandemic control.     

Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults

Purpose

To evaluate the safety and immunogenicity of a prototype quadrivalent inactivated influenza vaccine (QIV) containing two influenza B strains, one of each lineage, compared with licensed trivalent inactivated influenza vaccines (TIVs) containing either a Victoria B-lineage strain (2009–2010 TIV) or a Yamagata B-lineage strain (2008–2009 TIV).

Methods

Healthy adults ≥18 years of age were eligible to participate in this phase II, open-label, randomized, controlled, multicenter study conducted in the US. Participants received a single dose of 2009–2010 TIV, 2008–2009 TIV, or QIV. Sera were collected before and 21 days after vaccine administration to test for hemagglutination inhibition (HAI) antibodies to each of the four influenza strains. Immunogenicity endpoints included geometric mean HAI antibody titers (GMTs) and rates of seroprotection (titer ≥1:40) and seroconversion (4-fold rise pre- to post-vaccination). Safety endpoints included frequency of solicited injection-site and systemic reactions occurring within 3 days of vaccination, and unsolicited non-serious adverse events (AEs) and serious AEs (SAEs) within 21 days of vaccination.

Results

One hundred and ninety participants were enrolled to each vaccine group. QIV induced GMTs to each A and B strain that were noninferior to those induced by the 2009–2010 and 2008–2009 TIVs (i.e., lower limit of the two-sided 95% confidence interval of the ratio of GMT_QIV/GMT_TIV > 0.66 for each strain). Rates of seroprotection and seroconversion were similar in all groups. Incidence and severity of solicited injection-site and systemic reactions, AEs, and SAEs were similar among groups.

Conclusion

QIV, containing two B strains (one from each B lineage), was as safe and immunogenic as licensed TIV. QIV has the potential to be a useful alternative to TIV and offer protection against both B lineages.     

The immunogenicity of a novel A (H1N1) vaccine in HIV-infected children

Background

In October 2009, the United Kingdom Department of Health recommended vaccination of high-risk groups, including children with HIV, with a novel, oil-in-water AS03_B adjuvanted Influenza A (H1N1) vaccine (Pandemrix™). There were no published data available regarding the immunogenicity of this vaccine in such children.

Objectives

This study evaluated the immunogenicity of the adjuvanted Influenza A (H1N1) vaccine in HIV-infected children immunised according to national recommendations and assessed the impact of vaccination on individual CD4 counts and HIV viral loads.

Methods

HIV-infected children attending outpatient appointments between 01 November and 31 December 2009 were offered two doses of H1N1 vaccine three weeks apart and a blood test before and 3 weeks after the second dose of vaccine. Serum antibody responses were determined by a haemagglutination inhibition (HAI) assay using standard methods.

Results

Of the 39 children recruited for vaccination, 31 (median age 11.2, range 3.0-17.9 years) received both doses of vaccine and provided pre- and post-vaccination blood samples. Eight children (26%) had baseline HAI titres ≥1:32. After vaccination, 29 children (94%, 95% CI, 78.6-99.2%) had HAI titres ≥1:32 (seroprotection), of whom 27 (87.1%, 95% CI, 70.1-96.4%) had also had a four-fold rise in titres (seroconversion). In the univariate analysis, post-vaccination geometric mean titres (GMTs) were higher among the 21 children receiving highly active anti-retroviral therapy compared with the 10 treatment-naïve children (GMT 406 [95% CI 218-757] vs. 128 [49-336]; P = 0.035), but this was no longer statistically significant when adjusted for prevaccine GMTs. There was no significant impact of vaccination on CD4+ T cell count or HIV viral load.

Conclusion

The AS03_B-adjuvanted pandemic Influenza A (H1N1) vaccine is highly immunogenic and appears to be safe in HIV-infected children.     

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.     

Pre-vaccination immunity and immune responses to a cell culture-derived whole-virus H1N1 vaccine are similar to a seasonal influenza vaccine

Background

Immune responses to novel pandemic influenza vaccines may be influenced by previous exposure to antigenically similar seasonal strains.

Methods

An open-label, randomized, phase I/II study was conducted to assess the immunogenicity and safety of a non-adjuvanted, inactivated whole-virus H1N1 A/California/07/2009 vaccine. 408 subjects were stratified by age (18–59 and >60 years) and randomized 1:1 to receive two vaccinations with either 3.75 or 7.5 μg hemagglutinin antigen 21 days apart. Safety, immunogenicity and the influence of seasonal influenza vaccination and antibody cross-reactivity with a seasonal H1N1 strain was assessed.

Results

A single vaccination with either dose induced substantial increases in H1N1 A/California/07/2009 hemagglutination inhibition (HI) and neutralizing (MN) antibody titers in both adult and elderly subjects. A single 7.5 μg dose induced seroprotection rates of 86.9% in adults and 75.2% in elderly subjects. Two 7.5 μg vaccinations induced seroprotection rates in adult and elderly subjects of 90.9% and 89.1%, respectively. The robust immune response to vaccination was confirmed by analyses of neutralizing antibody titers. Both HI and MN antibodies persisted for ≥6 months post-vaccination. Between 34% and 49% of subjects had seroprotective levels of H1N1 A/California/07/2009 antibodies at baseline. Higher baseline HI titers were associated with receipt of the 2008–09 or 2009–10 seasonal influenza vaccine. High baseline A/California/07/2009 neutralizing antibody titers were also associated with high baseline titers against A/New Caledonia/20/99, a seasonal H1N1 strain which circulated and was included in the seasonal vaccine from 2000–01 to 2006–07. Pre-adsorption with A/H1N1/New Caledonia/20/99 antigen reduced A/H1N1/California/07/2009 baseline titers in 55% of tested sera. The vaccine was well tolerated with low rates of fever.

Conclusions

A whole-virus H1N1 A/California/07/2009 vaccine was safe and well tolerated and a single dose induced substantial immune responses similar to seasonal influenza vaccines, probably due to immunological priming by previous seasonal influenza vaccines or infections.     

A Phase I,randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine

Background

Large-scale outbreaks of enterovirus 71 (EV71) infections have occurred in Asia-Pacific regions. Severe complications include encephalitis and poliomyelitis-like paralysis, cardiopulmonary collapse, and death, necessitating an effective vaccine against EV71.

Methods

In this randomized Phase I study, we evaluated the safety and immunogenicity of an inactivated alum-adjuvanted EV71 whole-virus vaccine produced on Vero cell cultures. Sixty healthy volunteers aged 20–60 years received two doses of vaccine, administered 21 days apart. Each dose contained either 5 μg of EV71 antigen with 150 μg of adjuvant (Group A05) or 10 μg of EV71 antigen with 300 μg of adjuvant (Group B10). Serologic analysis was performed at baseline, day 21, and day 42.

Results

There were no serious adverse events. Mild injection site pain and myalgia were the most common adverse events with either vaccine formulation. The immunogenicity data showed that 90% of vaccine recipients have a 4-fold or greater increase in neutralization antibody titers (NT) after the first dose, without a further increase in NT after the second dose. The seroconversion rates on day 21 and day 42 were 86.7% and 93.1% respectively, in Group A05, and 92.9% and 96.3%, respectively, in Group B10. Thus, 5 μg and 10 μg of the EV71 vaccine can induce a remarkable immune response in healthy adults after only the first vaccination.

Conclusion

The 5 μg and 10 μg adjuvanted EV71 vaccines are generally safe and immunogenic in healthy adults. (ClinicalTrials.gov number, NCT01268787).     

Monovalent H1N1 influenza vaccine safety in pregnant women,risks for acute adverse events

Objective

To assess risks for acute adverse events and pregnancy complications in pregnant women following monovalent 2009 H1N1 inactivated influenza (MIV) vaccination.

Methods

Within the Vaccine Safety Datalink, we compared rates of pre-specified medically attended events (MAE) occurring within 42 days of MIV vaccination to those occurring in matched cohorts that at the same gestational age were either unvaccinated or received seasonal trivalent inactivated influenza (TIV) vaccine. Using generalized estimating equation method, with a Poisson distribution and log link, we calculated adjusted incident rate ratios (AIRR).

Results

Among 9349 women receiving MIV in any trimester, only one MAE occurred 0–3 days following MIV, an allergic reaction. No cases of Guillain–Barré syndrome, Bell's palsy, or transverse myelitis occurred 1–42 days after MIV. Compared to women receiving TIV and to unvaccinated women, risks for acute MAEs were not increased following MIV for any outcome. Hyperemesis was the most common adverse event in the MIV, TIV, and unvaccinated groups, occurring at a rate of about 4% over a 42-day period in all groups. Over a 42-day window, among all groups, incident gestational diabetes occurred at a rate of 3% and thrombocytopenia occurred at a rate of approximately 0.3%. Among women receiving MIV during pregnancy, increased risks for these and other less common obstetric events were not detected.

Conclusion

In this large cohort of pregnant women no acute safety signals were identified within 6 weeks of receipt of MIV.     

Responses after one dose of a monovalent influenza A (H1N1) 2009 inactivated vaccine in Chinese population—A practical observation

Background

The globally large-scale immunization was the most important method of controlling the 2009 pandemic influenza.

Methods

We conducted an observational clinical trial, including 148 adults aged 18-60 years to evaluate the safety and immunogenicity of a licensed 2009 H1N1 influenza vaccine. All subjects received a single 15-μg dose of a monovalent, unadjuvanted inactivated vaccine. Antibody titers were measured by means of hemagglutinin-inhibition assays and neutralization assays based on Real-Time Cell Analyzer (RTCA) instruments at baseline, 7 days and 21 days after vaccination.

Results

Local and systemic reactions were respectively reported by 19.1% and 22.1% of subjects. All adverse events were mild to moderate in intensity, without any deaths or serious events. By day 21 after vaccination, hemagglutinin-inhibition antibody titers of 1:40 or more were achieved in 101 of 123 (82.1%) subjects and the geometric mean titers (GMTs) increased to 1:95.27. For neutralization assays, all subjects could provide the protection against wide influenza virus, with the GMT of 1:525.44. Moreover, the rates of seroconversion, as measured using hemagglutinin-inhibition assays and neutralization assays, were 73.98% and 91.87% of subjects, respectively.

Conclusions

A single 15-μg dose of a monovalent, unadjuvanted inactivated 2009 H1N1 influenza vaccine was well tolerated, and induced a protective immune response in the majority of subjects aged 18-60 years (clinical trials gov number, NCT01055990).     

High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: Safety,immunogenicity and relative efficacy during the 2009–2010 season

Background

High-dose trivalent influenza vaccine was developed to improve antibody responses to influenza vaccine in the elderly and hence potentially impact favorably on influenza-associated morbidity and mortality in this population.

Methods

A phase IIIb, multicenter, randomized, double-blind, controlled trial was conducted to compare High-Dose (HD) trivalent inactivated influenza vaccine (60 μg of hemagglutinin [HA] per strain) to standard dose (SD) vaccine (15 μg of HA per strain) in adults ≥65 years of age. Assessments of safety (serious adverse events [SAE]), immunogenicity (hemagglutination inhibition [HAI] titers) and relative efficacy were performed during the 2009–2010 influenza season, which coincided with the H1N1 pandemic.

Results

A total of 9172 participants were enrolled in 99 research centers in the US (6117 and 3055 randomized to the HD and SD groups, respectively). Within 180 days after vaccination, 6.7% and 6.5% of participants in the HD and SD vaccine groups, respectively, experienced at least one SAE, of which 0.4% and 0.3% had a fatal outcome. A total of 0.5% of participants in both groups discontinued the study due to a SAE. Post-vaccination HAI titers and rate of post-vaccination HAI titer ≥1:40 were significantly higher in the HD group. No cases of influenza caused by viral types/subtypes similar to those in the vaccines were observed. All cases genetically or antigenically characterized were classified as similar to influenza A/California/7/2009 (H1N1), the pandemic strain. The vaccine efficacy of HD vaccine relative to SD vaccine against any influenza viral type/subtype was 12.6% (95% CI −140.5; 65.8) in the intent-to-treat analysis.

Conclusion

High-dose trivalent inactivated influenza vaccine is safe and well tolerated and provides superior immune responses compared to standard dose vaccine. Demonstration of a superior vaccine efficacy requires a separate large randomized, controlled trial.     

Concomitant administration of live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) and measles,mumps, rubella (MMR) vaccine: Randomized study in toddlers in Taiwan

Background

Japanese encephalitis (JE) is the most important cause of viral encephalitis in Asia.

Methods

In this randomized, open-label, multicenter trial in 550 children aged 12 to 18 months in Taiwan, children received one dose of JE-CV and one dose of MMR vaccine. Vaccines were either administered separately 6 weeks apart (Groups ‘JE-CV’ and ‘MMR’, named after which vaccine was given first), or concomitantly (Group ‘Co-Ad’). JE neutralizing antibody titers were assessed using PRNT₅₀. MMR antibody levels were determined by ELISA.

Results

All groups had low seroprotection/seropositivity rates (<10%) before vaccination for all antigens. Forty two days after vaccination, on either Study Day 42 or 84, seroconversion rates for all antigens were high in all groups, irrespective of the order of vaccinations. Seroconversion for JE ranged from 96.9% in Group Co-Ad on D42 to 100% in Group MMR. Non-inferiority was demonstrated for all analyses as the lower bound of the 95% CI of the difference in seroconversion rates between groups was above the pre-defined limit of −10.0%. The immune responses remained high for all antigens and well above the level of protection 12 months after vaccination in all groups. There were no safety concerns.

Conclusions

JE-CV is safe and induces a strong protective immune response which persists over 1 year when co-administered with MMR vaccine.     

Priming by a novel universal influenza vaccine (Multimeric-001)—A gateway for improving immune response in the elderly population

Background

A new vaccine, “Multimeric-001” (M-001) has been recently developed, containing conserved, common linear influenza epitopes that activate both cellular and humoral arms of the immune system against a wide variety of influenza A and B strains. Apart from its direct action, M-001 is an attractive candidate for priming immune responses to seasonal influenza vaccine for the elderly population. The current clinical study was designed to assess M-001's standalone and priming action in participants over 65 years old. Evaluation of standalone action is based on induction of cell mediated immunity (CMI), since M-001 alone does not induce hemagglutinin inhibition (HAI) antibodies.

Methods

This was a two-center, randomized, placebo-controlled study. 120 participants were randomized 1:1:1:1 into four groups to receive either two sequential non-adjuvanted or a single non-adjuvanted or a single adjuvanted intramuscular injection of 500 mcg M-001 (treatment), or one placebo (saline) injection, before receiving the trivalent inactivated influenza vaccine (TIV). Due to visual differences between placebo and treatment the study was partially blinded. HAI was evaluated at baseline and 3 weeks after standard TIV vaccination as a measure of M-001's efficacy. CMI responses were evaluated in a subset (10/group) of the participants. Participants were monitored for safety throughout the study.

Results

Overall the treatment was well-tolerated and safe, though sample sizes allowed only limited statistical analysis. M-001 priming resulted in enhanced seroconversion towards all three TIV strains, compared to priming with placebo. Significant elevation of influenza-specific CMI was observed following immunization with M-001 alone.

Conclusions

The standalone and priming actions of M-001 were demonstrated in elderly participants despite the limitations of small population size and pre-existing HAI antibody titers in some participants. As a standalone vaccine, M-001 induced significant CMI to multiple strains and as a primer, M-001 enhanced HAI responses. Larger scale studies are warranted.

ClinicalTrials.gov registry number

NCT01419925.     

Poor immune response to a standard single dose non-adjuvanted vaccination against 2009 pandemic H1N1 influenza virus A in the adult and elder hemodialysis patients

Background

Hemodialysis patients have higher risk of mortality and morbidity when infected with 2009 pandemic H1N1 (pH1N1/09) virus. Depending on different methodologies and criteria, previous studies reported variable response rates to adjuvanted vaccines against pH1N1/09 virus in hemodialysis patients, however, the efficacy of non-adjuvanted vaccines, which are currently used in many countries such as the USA and Asian areas, has not been comprehensively evaluated in hemodialysis population before.

Methods

We evaluated the efficacy of a standard single15 μg-dose of non-adjuvanted monovalent pH1N1/09 vaccine (AdimFlu-S) in vaccine-naïve 110 hemodialysis and 173 healthy participants. When enrolling, all participants had not any clinical symptom or sign suggesting pH1N1/09 infection since the index case was identified in Taiwan. Sera from all participants were tested by hemagglutination inhibition (HI) and micro-neutralization-ELISA (microNT-ELISA) tests before and 21 days after vaccination. The outcome parameters were seroconversion rate (≥4-fold in HI titer with titer ≥1:40), seroprotection rate (HI titers ≥1:40), seroresponse rate (≥4-fold increase in HI or microNT-ELISA titer), fold of increase in geometric mean (GM) titers, and adverse effects.

Results

In method A analyses, we included all participants’ data in final analyses, and the seroconversion rates and the fold increase of GM titer after vaccination were 25.4% and 1.8 in adult (18–60-year olds) hemodialysis subgroup, and 23.4% and 1.8 in elder (>60-year olds) hemodialysis subgroup based on HI titers, which were all significantly lower than those of the corresponding healthy control subgroups. Similar trends were observed based on microNT-ELISA titers, further validating the results. Multivariable analysis revealed hemoglobin and cholesterol levels were significant predictors for seroresponse in hemodialysis patients, suggesting the possible impacts of nutrition status and anemia. In method B analyses, we excluded participants with pre-vaccination seroprotection (based on HI or microNT-ELISA criteria) in final analyses. The response rates in various subgroups from method B analyses were also similar as those from method A analyses. No severe adverse effect was noted.

Conclusions

According to the European and U.S. criteria, a single 15 μg-dose of non-adjuvanted pH1N1/09 vaccination is safe but ineffective in both adult and elder hemodialysis patients. Further studies using multiple doses or higher antigen amount are warrant to define the most appropriate regimen.