Safety and immune responses following administration of H1N1 live attenuated influenza vaccine in Thais

Background

Emergence and rapid spread of influenza H1N1 virus prompted health authorities to develop a safe and effective influenza vaccine for domestic use. The Thai Government Pharmaceutical Organization (GPO) with technical support from Russia through WHO had prepared a pandemic live attenuated vaccine (PLAIV) using ca-ts attenuated candidate strain A/17/CA/2009/38 (H1N1) for Thais.

Methods

Each participant received two doses of intranasal H1N1 vaccine or placebo 21 days apart. All were followed up at 7, 21, 42 and 60 days after first immunization. Blood was drawn for hemagglutination inhibition (HAI) assay from all participants at days 1, 21, 42, and 60 after first immunization. A subset of 40 participants aged 19–49 years was randomly selected for nasal washing at days 1, 21, 42, and 60 to assess IgA using direct enzyme-linked immunosorbent assay (ELISA) along with serum HAI and microneutralization (MN) assay determination.

Results

A total of 363 subjects aged 12–75 years were randomized into 2 groups (271 vaccinees:92 placebos). Almost all AEs were mild to moderate. Local reactions were stuffy nose (22.3%), runny nose (25.1%), scratchy throat (27.2%) and sore throat (19.3%). Systemic reactions included headache (21.7%), myalgia (13.8%), fatigue (16.8%) and postnasal drip (19.9%). On day 60, HAI seroconversion rates for vaccine:placebo group were 30.3:6.0 for ITT and 29.4:5.1 for PP analysis. Children showed highest seroconversion rate at 44, but it decreased to 39.4 when all 3 assays (HAI, MN assay and ELISA) from subgroup analysis were considered.

Conclusion

The vaccine candidate is safe. The use of more than one assay may be needed for evaluation of immune response because live attenuated vaccines could effectively induce different kinds of responses. Different individuals could also mount different kinds of immune response, even to the same antigen.     

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 randomised, single-blind, dose-range study to assess the immunogenicity and safety of a cell-culture-derived A/H1N1 influenza vaccine in adult and elderly populations

Background

Modern cell-culture production techniques and the use of adjuvants helps to ensure that the global demand for pandemic influenza vaccine can be met. This study aimed to assess the immunogenicty and safety profiles of various cell-culture-derived A/H1N1 pandemic vaccine formulations in healthy adult and elderly subjects.

Methods

Adult (18–60 years) subjects (n = 544) received vaccine either containing 3.75 μg of antigen with half the standard dose of MF59^® (Novartis Vaccines and Diagnostics) adjuvant, 7.5 μg antigen with a full dose of MF59, or a non-adjuvanted vaccine containing 15 μg of antigen. Elderly (≥61 years) subjects (n = 268) received either the 3.75 μg or 7.5 μg adjuvanted formulations. Two priming vaccine doses were administered 3 weeks apart, followed by a single booster dose of seasonal influenza vaccine 1 year later. Immunogenicity was assessed 3 weeks after each vaccination. The safety profile of each formulation was evaluated throughout the study.

Results

A single primary dose of each A/H1N1 vaccine formulation was sufficient to meet all three European (CHMP) licensure criteria for pandemic influenza vaccines in adult subjects. Two licensure criteria were met after one vaccine dose in elderly subjects; two primary doses were required to meet all three criteria in this age group. The highest antibody titres were observed in response to the 7.5 μg vaccine containing a full dose of MF59 adjuvant. All subjects rapidly generated seroprotective antibody titres in response to booster vaccination.

Conclusion

This study identified one 3.75 μg vaccine dose containing half the standard dose of MF59 adjuvant as optimal for adults, two doses were optimal for elderly subjects. The antigen-sparing properties of MF59, and rapid, modern, cell-culture production techniques represent significant steps towards meeting the global demand for influenza vaccine.     

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.     

Safety and immunogenicity of an 8 year interval heterologous prime-boost influenza A/H7N7-H7N9 vaccination

Background

Influenza A/H7N9 viruses are undergoing antigenic drift since their emergence in 2013, and vaccination strategies are needed for pandemic preparedness. Two doses of adjuvanted monovalent inactivated influenza A/H7N9 vaccine (IIV1 A/H7N9) are needed for optimal serological responses. However, administering 2 doses in a pandemic setting might be challenging. We evaluated the immunogenicity of “boosting” with IIV1 A/H7N9 in subjects “primed” 8?years previously with IIV1 A/H7N7.

Dose ranging of adjuvant and antigen in a cell culture H5N1 influenza vaccine: Safety and immunogenicity of a phase 1/2 clinical trial

Background

Dose-sparing strategies and new production technologies will be necessary to produce adequate supplies of vaccines for pandemic influenza. One approach is to include adjuvant, which can reduce the amount of antigen required for immunization and stimulate cross-reactive responses to drifted variants of novel viruses. Dose-sparing studies of adjuvant, itself a finite resource, have not previously been reported for H5N1 vaccine development.

Methodology/principal findings

A total of 753 healthy 18–40-year-old adults were randomized to one of 12 groups (N ∼ 60/group) to receive two intramuscular doses, 21 days apart, of 3.75, 7.5 or 15 μg of cell culture grown influenza A/H5N1 hemagglutinin (A/Indonesia/5/2005 (H5N1)/PR-8-IBCDC-RG2), each dose level formulated with 0%, 25%, 50% or 100% of the MF59 dose contained in licensed influenza vaccine. 752 subjects actually received one dose, and 695 a second dose. Serum hemagglutination inhibition and neutralizing antibody levels, were determined before and 21 days after each dose. Safety and reactogenicity were assessed by self-completed diary cards. Nonadjuvanted H5N1 formulations were poorly immunogenic, but antibody responses were significantly enhanced by all doses of MF59 for each antigen level. The 3.75 μg H5N1 containing 50% MF59 satisfied the European criteria for pandemic vaccine licensure. All formulations were well tolerated, although MF59 dose-dependent increases in the frequency of injection site pain were observed. The frequencies of injection site and systemic reactions were lower after receipt of the second dose of vaccine. No vaccine-related SAE was reported.

Conclusions

Dose-sparing of both antigen and adjuvant is possible without compromising immunogenicity, while improving reactogenicity and is a promising strategy that will expand the availability of vaccines for global control of pandemic influenza.     

Safety and immunogenicity of monovalent H7N9 influenza vaccine with AS03 adjuvant given sequentially or simultaneously with a seasonal influenza vaccine: A randomized clinical trial

BackgroundInfluenza A/H7N9 viruses have pandemic potential.MethodsWe conducted an open-label, randomized, controlled trial of AS03-adjuvanted 2017 inactivated influenza A/H7N9 vaccine (H7N9 IIV) in healthy adults. Group 1 received H7N9 IIV and seasonal quadrivalent influenza vaccine (IIV4) simultaneously, followed by H7N9 IIV three weeks later. Group 2 received IIV4 alone and then two doses of H7N9 IIV at three-week intervals. Group 3 received one dose of IIV4. We used hemagglutination inhibition (HAI) and microneutralization (MN) assays to measure geometric mean titers and seroprotection (≥1:40 titer) to vaccine strains and monitored for safety.ResultsAmong 149 subjects, seroprotection by HAI three weeks after H7N9 IIV dose 2 was 51% (95 %CI 37%-65%) for Group 1 and 40% (95 %CI 25%-56%) for Group 2. Seroprotection by MN at the same timepoint was 84% (95 %CI 72%-93%) for Group 1 and 74% (95 %CI 60%-86%) for Group 2. By 180 days after H7N9 IIV dose 2, seroprotection by HAI or MN was low for Groups 1 and 2. Responses measured by HAI and MN against each IIV4 strain three weeks after IIV4 vaccination were similar in all groups. Solicited local and systemic reactions were similar after a single vaccination, while those receiving simultaneous H7N9 and IIV4 had slightly more reactogenicity. There were no serious adverse events or medically-attended adverse events related to study product receipt.ConclusionsAdjuvanted H7N9 IIV was modestly immunogenic whether administered simultaneously or sequentially with IIV4, though responses declined by 180 days. IIV4 was immunogenic regardless of schedule.Clinical Trials Registration: NCT03318315     

Safety and immunogenicity of a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125) in healthy young adults

Background

The need for worldwide seasonal and pandemic vaccine production has increased interest in the development of innovative technologies for influenza vaccine production. We evaluated a novel influenza vaccine consisting of the globular head of the HA1 domain of the A/Solomon Islands/3/2006 (H1N1) influenza virus (VAX125) genetically fused to the TLR5 ligand, flagellin, and produced in E. coli.

Methods

128 healthy adult subjects 18–49 years old were enrolled in a clinical trial conducted in three stages at a single center. Stage 1 was an open-label, dose escalation study in which the VAX125 vaccine was administered intramuscularly (im) at doses of 0.1 μg, 0.3 μg, 1 μg, 2 μg, 3 μg, 5 μg and 8 μg to groups of 8 subjects each. Stage 2 was a double-blind, placebo-controlled study in which subjects were randomized to receive 1.0 μg and 2.0 μg VAX125 vaccine doses or placebo, with 16 subjects per group. Finally, an additional 24 subjects received a 0.5 μg dose of VAX125 in stage 3, which was a non-randomized, open label study. In all parts subjects were followed for adverse events and sera was tested by hemagglutination-inhibition (HAI) and microneutralization (MN) against egg-grown virus on days 0, 7, 14, and 28. Serum C-reactive protein (CRP), cytokine levels, and anti-flagellin antibody were also assessed.

Results

Vaccine was generally well tolerated and there were no serious adverse events. Pain at the injection site was the most common local adverse event, and was mild or moderate in intensity. Systemic symptoms after vaccination include fatigue and headache, and two subjects, who received either 3 or 8 μg, had moderately severe systemic symptoms accompanied by substantial increases in serum CRP. Serum antibody responses against SI were seen by HAI and MN in most study subjects, with the geometric mean titer of post vaccination antibody increasing in a dose-dependent fashion. Overall, four-fold or greater serum HAI responses were seen in 61 of 96 (64%) subjects who received doses of 0.5 μg or greater, including in 46 of 72 subjects who received doses from 0.5 μg to 2 μg.

Conclusions

The globular head of the influenza HA expressed in a prokaryotic system was able to induce a functional antibody response against native virions. Vigorous responses were seen at relatively low doses of HA antigen suggesting that the addition of flagellin provided a substantial adjuvanting effect. The high levels of immune response at low doses of antigen and the relative ease of production associated with E. coli expression suggests that this approach may represent an effective strategy for enhancing the global influenza vaccine supply.     

Immunologic consequences of chemotherapy for ovarian cancer: Impaired responses to the influenza vaccine

Objectives

To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define the effect on the serologic response to the influenza vaccine.

Methods

Under IRB approved protocols, patients with ovarian cancer were administered seasonal trivalent killed influenza vaccines. Peripheral blood was collected for immunologic assessments. Serum was analyzed for hemagglutination inhibition (HAI) antibody titers. Peripheral blood mononuclear cells were isolated to characterize T and B cell populations and function.

Results

Thirty-one patients were recruited: 13 in remission receiving a dendritic cell vaccine with or without a single dose of low-dose cyclophosphamide, 3 in remission not receiving treatment, and 15 undergoing standard therapy. Significant effects on T cell and B cell subset distributions were seen. Functional effects were also seen. Few patients were able to mount a 4-fold HAI antibody response. A 4-fold response was observed for H1N1 in 20%, for H3N2 in 26%, and for influenza B in 6%. Pre-existing exposure to influenza was predictive of responders.

Conclusions

Despite CDC recommendations that patients undergoing chemotherapy receive influenza vaccine, there is little evidence to support its serologic effectiveness in this population. Patients with ovarian cancer are almost uniformly unable to mount a meaningful antibody response. These findings have serious implications for future resource allocation for both seasonal and novel pandemic influenza outbreak and understanding the immunologic deficits as a result of chemotherapy may improve patient care.     

Antibody persistence and response to 2010-2011 trivalent influenza vaccine one year after a single dose of 2009 AS03-adjuvanted pandemic H1N1 vaccine in children

Background

In 2009, several countries used the ASO3-adjuvanted pandemic A/H1N1 vaccine. We assessed the persistence of antibody and the priming induced by a single paediatric dose of this vaccine in children.

Methods

Children aged 15-120 months vaccinated one year before with the ASO3-adjuvanted monovalent pandemic vaccine were tested for the presence of antibody against 2010-2011 TIV components (A/California/7/2009(H1N1), A/Wisconsin/15/2009 (H3N2 A/Perth/16/2009-like) and B/Brisbane/60/2008) before and 21-28 days after each dose of 2010-2011 TIV. Hemagglutination-inhibition (HAI) assay was used. Children received one or two doses of 2010-2011 TIV at 21-28 days interval in relation with their previous immunization status.

Results

The results of 128 children were included in the ATP analysis. Before the 2010-2011 TIV administration, 46% of children showed sero-protection to the A/California/7/2009(H1N1) strain (HAI titre ≥40) with lower rates of sero-protection to the H3N2A/Perth/16/2009 (37%) and B/Brisbane/60/2008 (19%). After the first dose of 2010-2011 TIV, 98%, 75%, and 57% of vaccinees attained a sero-protective titre to A/California/7/2009(H1N1), A/Perth/16/2009(H3N2), and B/Brisbane/60/2008 strain, respectively. The youngest age group showed significantly lower antibody response to the influenza B component compared to the older age groups after the first dose of vaccine. Among vaccinees who received the second dose of TIV, 96% and 87% had a sero-protective titre to H3N2A/Perth/16/2009 and B/Brisbane/60/2008, respectively. The 2010-2011 TIV was well tolerated.

Conclusions

We found substantial persistence of antibody to the A/California/7/2009 strain one year after a single paediatric dose of AS03-adjuvanted pandemic vaccine and a seroprotective level of antibody to this strain in virtually all children who received one year later a single dose of the 2010-2011 TIV. In contrast, two doses of the 2010-2011 TIV were necessary to induce an adequate immune response to the A/Perth/16/2009(H3N2) and B/Brisbane/60/2008 strains in children previously naïve to seasonal vaccine.     

Inactivated trivalent seasonal influenza vaccine induces limited cross-reactive neutralizing antibody responses against 2009 pandemic and 1934 PR8 H1N1 strains

Background

In June 2009, we conducted a prospective study in Singapore on 51 individuals to determine their serologic responses before and following receipt of the 2009 Southern Hemisphere seasonal influenza vaccine.

Materials and methods

Paired serum samples were obtained before and 3–4 weeks after vaccination. Virus microneutralization assays were performed to quantify antibodies against A/Brisbane/59/2007 vaccine, pandemic H1N1-2009 and A/Puerto Rico/08/34 H1N1 strains.

Results

Post-vaccination, 43%, 12% and 24% of subjects displayed a 4-fold or greater rise in neutralizing antibody titers against the three strains, respectively. There was a positive correlation among individuals who showed increased titers to both pandemic H1N1-2009 and A/Puerto Rico/08/34 (p < 0.001). However, this correlation was not observed for A/Brisbane/59/2007 with either strain. The relative conservation and accessibility of predicted B-cell epitopes may explain the limited cross-reactivity of the antibodies directed against common H1N1 epitopes.

Conclusions

These results suggest that seasonal influenza vaccination confers a certain degree of cross-protection to other H1N1 strains. The correlation in cross-reactive antibody titers to A/Puerto Rico/08/34 and pandemic H1N1-2009 implies that previous exposure to pre-1957 H1N1 strains may confer some protection against the 2009 pandemic strain.     

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.     

Squalene-adjuvanted H7N9 virus vaccine induces robust humoral immune response against H7N9 and H7N7 viruses

Recent cases of avian influenza H7N9 have caused great concerns that virus may become transmittable between humans. It is imperative to develop an effective vaccine to fight against the pandemic potential of this H7N9 influenza virus to protect human from the disease. This study aims to investigate an optimized formulation for the development of H7N9 vaccines. Various doses of H7N9 inactivated whole or split-virus antigens (0.5, 1.5, or 3 μg based on hemagglutinin content) combined with squalene-based adjuvant (AddaVAX), aluminum hydroxide Al(OH)₃ or without adjuvant were evaluated for the efficacy of H7N9 vaccine regiments in mice. With either H7N9 whole or split-virus based vaccines, AddaVAX-adjuvanted formulations were the most immunogenic in eliciting significant humoral immune response against H7N9 virus and exhibited strong cross-reactive response in hemagglutination inhibition (HAI) and viral-neutralization assays against H7N7 virus as well. In contrast, formulations with Al(OH)₃ or without adjuvant were less immunogenic and elicited lower titers of HAI and microneutralization assays against both viruses. Dose-sparing experiments suggested that the formulation with as low as 0.004 μg of split or whole virus vaccine antigens together with 50% AddaVAX provided sufficient sero-protective HAI titers and achieved essential virus-neutralizing antibody titers against H7-subtype influenza viruses in mice. Protection experiments demonstrated that the formulation of 0.004 μg to 0.5 μg of split-virion vaccines with AddaVAX conferred full protection against viral challenge up to 100 LD50 of wild-type H7N9 virus, with 0% survival in placebo group. Taken together, our study demonstrates that squalene-based adjuvant can significantly enhance the protective efficacy of H7N9 virus vaccine and provides a useful strategy to confront the potential pandemic outbreaks of H7N9 virus.     

Safety and immunogenicity of 2010-2011 H1N12009-containing trivalent inactivated influenza vaccine in children 12-59 months of age previously given AS03-adjuvanted H1N12009 pandemic vaccine: a PHAC/CIHR Influenza Research Network (PCIRN) study

Background

Concern arose in 2010 that reactogenicity, particularly febrile seizures, to influenza A/H1N1-containing 2010–2011 trivalent seasonal inactivated influenza vaccine (TIV) could occur in young children who had been previously immunized and/or infected with the pandemic strain. We conducted a pre-season study of 2010–2011 TIV safety and immunogenicity in children 12–59 months of age to inform public health decision making.

Methods

Children immunized with 1 or 2 doses of the pandemic vaccine, with or without the 2009–10 TIV, received 1 or 2 doses of 2010–11 TIV in an observational, multicentre Canadian study. Standard safety monitoring was enhanced by a telephone call at ∼24 h post-TIV when adverse events were expected to peak. Summary safety reports were rapidly reported to public health before the launch of public programs. TIV immunogenicity was assessed day 0, and 21 days after final vaccination. Clinical Trials Registration NCT01180621.

Results

Among 207 children, a general adverse event was reported by 60.9% of children post-dose one and by 58.3% post-dose two. Only severe fever (>38.5 °C) was more common in two-dose compared to one dose recipients (16.7%, n = 4 v. 1.0%, n = 2). At baseline 99.0% of participants had A/H1N1 hemagglutinin inhibition (HAI) titers ≥10, and 85.5% had a protective titer of ≥40 (95% CI 80.0, 90.0). Baseline geometric mean titers (GMT) were higher in recipients of a 2-dose schedule of pandemic vaccine compared to one-dose recipients: 153.1 (95% CI 126.2, 185.7) v. 78.8 ((58.1, 106.8, p < 0.001). At 21 days, all regulatory criteria for influenza vaccine immunogenicity were exceeded for A/H1N1 and H3N2, but responses to the B antigen were poor. No correlations between reactogenicity and either baseline high influenza titers or serologic response to revaccination were evident.

Conclusions

Infants and toddlers who received AS03-adjuvanted A/H1N1 2009 vaccine up to 11 months earlier retained high titers in the subsequent season but re-exposure to A/H1N1 2009 antigen in TIV resulted in no unusual adverse effects and 100% were sero-protected for A/H1N1 after receipt of the 2010–11 TIV.     

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.     

Immunogenicity and safety of inactivated monovalent 2009 H1N1 influenza A vaccine in immunocompromised children and young adults

Background

Influenza vaccination is recommended for immunocompromised patients.

Methods

Children (6 months to 21 years) with cancer, HIV infection, or sickle cell disease (SCD) received 1 or 2 doses of pandemic 2009 H1N1 monovalent influenza vaccine (H1N1 MIV). Safety and tolerability, hemagglutination inhibition (HI) and microneutralization (MN) antibody titers were measured against 2009 H1N1 influenza A virus after each dose. Seroprotection (SP) and seroconversion (SC) rates were determined.

Results

103 participants were enrolled and 99 were evaluable (39 with HIV, 37 with cancer and 23 with SCD). Mean age (±SD) was 7.9 (±5.4) years for cancer participants, 18.0 (±3.5) for HIV, and 13.3 (±4.2) for SCD. 54% were males; 65% black; and 96% had received seasonal influenza vaccine. HIV-infected participants had a median CD4 count of 625 cells/mm³ (range, 140-1260). 46% had an undetectable HIV viral load and 41% were perinatally infected. No participant had vaccine-related serious adverse events. None developed influenza A proven illness during the 6 months after the vaccine. Local injection reactions were reported in 29% and systemic reactions in 42% after the first dose of vaccine. SC and SP were achieved after the last dose in 48% and 52%, respectively, of participants with leukemia or lymphoma, 50% and 75% of participants with solid tumors, 63% and 92% of HIV-infected participants, and 74% and 100% of participants with SCD.

Conclusion

H1N1 MIV was safe and well tolerated. H1N1 MIV resulted in an adequate immune response in children with SCD. It was only modestly immunogenic in cancer or HIV participants.     

The determinants of 2009 pandemic A/H1N1 influenza vaccination: a systematic review

Background

Pandemic A/H1N1 influenza vaccine coverage varied widely across countries. To understand the factors influencing pandemic influenza vaccination and to guide the development of successful vaccination programs for future influenza pandemics, we identified and summarized studies examining the determinants of vaccination during the 2009 influenza pandemic.

Methods

We performed a systematic literature review using the PubMED electronic database from June 2009 to February 2011. We included studies examining an association between a possible predictive variable and actual receipt of the pandemic A/H1N1 influenza vaccine. We excluded studies examining intention or willingness to receive the vaccine.

Results

Twenty-seven studies were identified from twelve countries. Pandemic influenza vaccine coverage varied from 4.8% to 92%. Coverage varied by population sub-group, country, and assessment method used. Most studies used questionnaires to estimate vaccine coverage, however seven (26%) used a vaccination registry. Factors that positively influenced pandemic influenza vaccination were: male sex, younger age, higher education, being a doctor, being in a priority group for which vaccination was recommended, receiving a prior seasonal influenza vaccination, believing the vaccine to be safe and/or effective, and obtaining information from official medical sources.

Conclusions

Vaccine coverage during the pandemic varied widely across countries and population sub-groups. We identified some consistent determinants of this variation that can be targeted to increase vaccination during future influenza pandemics.     

Randomized comparative study of the serum antihemagglutinin and antineuraminidase antibody responses to six licensed trivalent influenza vaccines

Background

Serum antibody to the hemagglutinin (HA) surface protein of influenza virus induced by influenza vaccination is a correlate of protection against influenza. The neuraminidase (NA) protein is also on the surface of the virus; antibody to it has been shown to impair virus release from infected cells and to reduce the intensity of influenza infections in animal models and in humans challenged with infectious virus. Recently we have shown that NA inhibiting antibody can independently contribute to immunity to naturally-occurring influenza immunity in the presence of antibody to the HA.

Purpose

The present study was conducted to evaluate induction of antibody to the NA and the HA by commercially available influenza vaccines.

Methods

Healthy young adults were vaccinated with one of five commercially available trivalent inactivated vaccines or live influenza vaccine. Frequencies of serum antibody and fold geometric mean titer (GMT) increases four weeks later were measured to each of the three vaccine viruses (A/H1N1, A/H3N2, B) in hemagglutination-inhibition (HAI) and neutralization (neut) assays. Frequency and fold GMT increase in neuraminidase-inhibition (NI) antibody titers were measured to the influenza A viruses (A/H1N1, A/H3N2).

Results

No significant reactogenicity occurred among the vaccinated subjects. The Fluvirin inactivated vaccine induced more anti-HA antibody responses and a higher fold GMT increase than the other inactivated vaccines but there were no major differences in response frequencies or fold GMT increase among the inactivated vaccines. Both the frequency of antibody increase and fold GMT increase were significantly lower for live vaccine than for any inactivated vaccine in HAI and neut assays for all three vaccine viruses. Afluria inactivated vaccine induced more N1 antibody and Fluarix induced more N2 antibody than the other vaccines but all inactivated vaccines induced serum NI antibody. The live vaccine failed to elicit any NI responses for the N2 NA of A/H3N2 virus and frequencies were low for the N1 of A/H1N1 virus.

Conclusions

Trivalent inactivated influenza vaccines with similar HA dosage induce similar serum anti-HA antibody responses in healthy adults. Current inactivated vaccines all induce serum anti-NA antibody to the N1 and N2 NA proteins but some are better than others for N1 or N2. The live vaccine, Flumist, was a poor inducer of either anti-HA or anti-NA serum antibody compared to inactivated vaccine in the healthy adults. In view of the capacity for contributing to immunity to influenza in humans, developing guidelines for NA content and induction of NA antibody is desirable.     

A prospective observational safety study on MF59 adjuvanted cell culture-derived vaccine,Celtura during the A/H1N1 (2009) influenza pandemic

Background

The present study was a prospective observational study to evaluate the safety profile of Celtura^®, a monovalent, cell culture-derived, inactivated subunit influenza vaccine prepared from A/California/07/2009(H1N1) with the adjuvant MF59^®. Subjects were enrolled prospectively during the H1N1 2009 influenza pandemic at medical centres in Colombia, Chile, Switzerland, and Germany during the period December 2009 to June 2010.

Methods

Subjects ages 18 and older were followed for the occurrence of adverse events (AEs) for six months after vaccination. Adverse events of special interest (AESIs) were neuritis, convulsion (seizure), anaphylaxis, encephalitis, vasculitis, Guillain-Barre syndrome, demyelinating conditions, Bell's palsy, and laboratory-confirmed vaccination failure.

Results

Overall, 7348 AEs were reported in 2296 of 3989 enrolled subjects (57.6%). Only two AEs were considered related to injection site reactions. No laboratory-confirmed cases of influenza were reported. There were 108 medically confirmed serious adverse events (SAEs) reported among 73 subjects with 6 such SAEs described as possibly or probably related to vaccination. Three fatal cases were reported and assessed as not related to vaccination. Two AESIs classified as convulsion were reported and assessed as not related to vaccination. Both AESIs occurred well outside the pre-specified 7 day risk window representing the likely timeframe of the occurrence of seizure following vaccination.

Conclusions

The results of this study support the overall good safety profile of MF59 adjuvanted cell culture-derived influenza vaccine as administered in adults during the 2009–2010 H1N1 influenza pandemic. No concern is raised regarding the occurrence of AESIs.