Trivalent Subunit Influenza Vaccine Research Articles

Safety and immunogenicity of a novel quadrivalent subunit influenza vaccine in animal models

ABSTRACT Background: Compared with trivalent influenza vaccines, quadrivalent influenza vaccines are expected to provide wider protection against influenza B virus infections. We developed a novel quadrivalent subunit influenza vaccine which was distinct from the influenza vaccines available on the market in production process. In this research, we evaluated the safety and immunogenicity of the quadrivalent subunit influenza vaccine in animal models. Methods: In toxicity assessment, 40 SD rats were randomly assigned to be intramuscularly injected with 1.0 ml of the tested vaccine (33 μg/ml) or 0.9% sodium chloride solution. In irritation assessment, eight rabbits were randomly assigned to receive 0.5 ml of tested vaccine or phosphate buffer solution intramuscularly. Thirty-two guinea pigs were randomly assigned to be intramuscularly injected with high-dose tested vaccine (0.5 ml), low-dose tested vaccine (0.05 ml), ovalbumin, or 0.9% sodium chloride solution, respectively, for sensitization assessment. In immunogenicity assessment, 50 BALB/c mice were equally randomized to receive one dose of tested vaccine, two doses of tested vaccine with an interval of 14 days, 0.5 ml of trivalent subunit influenza vaccine, 0.5 ml of monovalent subunit influenza vaccine, or 0.5 ml of phosphate buffer solution. Orbital blood was collected before and 28 and 42 days after administration of the injections for detecting influenza antibody titers. Results: No abnormal toxicity and irritation in rats and rabbits showed in the gross autopsy and histopathological examinations. The results of sensitization in guinea pigs indicated that no obvious allergic symptoms observed in the high-dose and low-dose vaccine groups within 30 min after twice provocations, and the result of sensitization evaluation was negative. Vaccine induced significant immune responses in mice with 100% seroconversion rates at 28 and 42 days after the first dose. The geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies at day 28 in one-dose quadri–vaccine and two-dose quadri–vaccine groups were comparable to those in the tri–vaccine or mono-vaccine groups for shared influenza strains. However, the GMTs of HI antibodies against H1N1 (P = 0.025) and BV (P = 0.049) at day 42 in one-dose quadri–vaccine group were significantly lower than those in the tri–vaccine or mono-vaccine groups. The GMTs of HI antibodies against H1N1, H3N1, BY, and BV at day 28 and day 42 were comparable between one-dose quadri–vaccine and two-dose quadri–vaccine groups. Conclusions: The quadrivalent subunit influenza vaccine was safe and immunogenic in animal models. One dose of the vaccine could elicit a satisfactory antibody response in mice.

Immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in children and adolescents: A phase III randomized study

ObjectivesTo analyse the immunogenicity and safety of inactivated subunit quadrivalent influenza vaccine (QIV) versus trivalent influenza vaccine (TIV) in children and adolescents 3–17 years of age. MethodsIn this phase III, multicentre, double-blind study, 1200 subjects were randomized to receive QIV (n=402), TIV with the B-strain of the Victoria lineage (n=404), or TIV with the B-strain of the Yamagata lineage (n=394). The primary objective was to demonstrate non-inferiority of QIV to TIV for immunogenicity against shared influenza strains, based on post-vaccination hemagglutinin inhibition (HI) titres. Secondary objectives were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains, and to further characterize the immune response by analysing virus neutralization and neuraminidase inhibition titres. Reactogenicity and safety were also compared post-vaccination. ResultsQIV elicited a non-inferior response for shared strains (upper limits of the 95% confidence intervals for the HI geometric mean ratios (GMRs) of TIV/QIV<1.5) and a superior response for alternate-lineage B-strains (HI GMRs of TIV/QIV<1.0; p<0.0001) versus TIV. Reporting rates of local and systemic adverse reactions were similar between vaccine arms. ConclusionsQIV had comparable immunogenicity to TIV for shared strains and superior immunogenicity to the alternate-lineage B-strains in TIV. Safety and tolerability profiles were comparable.

A phase 1, randomized, observer blind, antigen and adjuvant dosage finding clinical trial to evaluate the safety and immunogenicity of an adjuvanted, trivalent subunit influenza vaccine in adults ≥ 65 years of age

ObjectiveTo assess the safety and immunogenicity of the MF59®-adjuvanted trivalent influenza vaccine (aTIV; Fluad®) compared with modified aTIV formulations. MethodsA total of 196 subjects ≥ 65 years were randomized to receive7different formulations of vaccine containing a range of adjuvant and antigen dosesby single injection, or divided into two injections at a single time point. The primary study objective was to compare the serologic response of different formulations of aTIV containing increased amounts of adjuvant and antigen21 days after vaccination. Subjects were followed for immunogenicity and safety for one year. ResultsThe highest immune response, as measured by hemagglutination inhibition (HI) assay, 3 weeks after vaccination was observed in subjects in Group 6 with GMT 382.2 (95% confidence interval [CI] 237.5 to 615.0), 552.3 (364.8 to 836.1), and 54.1 (36.9 to 79.4) against A/H1N1, A/H3N2, and B respectively. Rates of seroconversion were also generally highest in this treatment group: 75% (95% CI 55.1 to 89.3), 75% (55.1 to 89.3), and 42.9% (24.5 to 62.8), respectively, against A/H1N1, A/H3N2, and B strains. The highest incidence of solicited adverse events (AEs) was reported by subjects who received both the highest dosage of antigen in combination with the highest dosage of adjuvant at the same site: 67.9% and 57.1% in Groups 4 and 6, respectively. The majority of solicited AEs were mild to moderate in severity. The number of unsolicited AEs was similar across the different dosages. ConclusionIn this phase I trial of adults ≥ 65 years of age who received increased adjuvant and antigen dosages relative to the licensed aTIV, increased dosage of MF59 resulted in increased immunogenicity against all 3 components of seasonal influenza vaccine. The increase in immunogenicity was accompanied by an increase in the incidence of local reactogenicity.

A Phase III randomised trial of the immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in adult and elderly subjects, assessing both anti-haemagglutinin and virus neutralisation antibody responses

BackgroundTrivalent influenza vaccines (TIVs) offer substantial protection against matching B-strains, however, protection against alternate-lineage B-strains may be enhanced by adding a second B-strain in quadrivalent influenza vaccines (QIVs). In this Phase III, double-blind, multicentre, randomised study, the immunogenicity and safety of subunit inactivated QIV versus TIV was assessed in adult (aged ≥18 to ≤60 years) and elderly (aged ≥61 years) subjects by analysing a combination of haemagglutinin inhibition (HI) and virus neutralisation (VN). MethodsSubjects (n = 1980) were recruited off season (2015/2016) from 20 centres in five European countries and randomised to receive either QIV (n = 1538), TIV with B-strain of the Victoria lineage (n = 221) or TIV with B-strain of the Yamagata lineage (n = 221). The primary aim was to demonstrate non-inferiority of QIV to TIV for immunogenicity against matched influenza strains based on post-vaccination HI titres. Secondary aims were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains and to characterise the immune response by reverse cumulative distribution (RCD) curves of antibody titres and derived serological parameters for HI and VN. Reactogenicity and occurrence of adverse events were assessed post-vaccination. ResultsQIV elicited a non-inferior immune response for matched strains (upper limit of 95% CI for HI geometric mean ratios [GMRs] <1.5) and a superior response for alternate-lineage B-strains (HI GMRs < 1; p < 0.0001) versus TIV. RCD curves demonstrated that post-vaccination HI and VN titres were higher for QIV versus TIV for both alternate-lineage B-strains. Seroconversion rates and geometric mean fold increases of the VN assay were consistent with the HI assay for all strains in QIV. Reporting rates of local and systemic reactions were similar in both vaccine groups. ConclusionsQIV was non-inferior in immunogenicity to TIV for matched strains and superior to the alternate-lineage B-strains in TIV. Safety and tolerability profiles of QIV and TIV were comparable.

Quantitative profiling reveals minor changes of T cell receptor repertoire in response to subunit inactivated influenza vaccine

Vaccination against influenza is widely used to protect against seasonal flu epidemic although its effectiveness is debated. Here we performed deep quantitative T cell receptor repertoire profiling in peripheral blood of a healthy volunteer in response to trivalent subunit influenza vaccine. We did not observe significant rebuilding of peripheral blood T cell receptors composition in response to vaccination. However, we found several clonotypes in memory T cell fraction that were undetectable before the vaccination and had a maximum concentration at day 45 after vaccine administration. These cells were found in lower concentration in the course of repertoire monitoring for two years period. Our observation suggests a potential for recruitment of only a limited number of new T cells after each seasonal influenza vaccination.

Phase 4, Post-Marketing Safety Surveillance of the MF59-Adjuvanted Influenza Vaccines FLUAD® and VANTAFLU® in South Korean Subjects Aged ≥65 Years.

BackgroudInfluenza vaccination is recommended for adults aged ≥65 years as they are at high risk of significant morbidity and mortality. This open-label, multicenter, post-marketing surveillance study assessed the safety of the MF59-adjuvanted trivalent inactivated subunit influenza vaccine, which is marketed as FLUAD® and VANTAFLU®, in South Korean subjects aged ≥65 years.Materials and MethodsSolicited local and systemic adverse events (AEs) were collected from day 1 to 4 of the study. All unsolicited AEs and serious AEs (SAEs) were recorded from day 1 until study termination (day 29).ResultsOf the 770 subjects enrolled (FLUAD®, n = 389; VANTAFLU®, n = 381), 39% overall experienced any solicited AE. Local AEs were reported by 33% of subjects overall; with the most common events being injection-site pain (30%) and tenderness (27%). Systemic AEs were reported by 19% of subjects overall with the most common events being myalgia (11%) and fatigue (8%).ConclusionThese results show that the MF59-adjuvanted influenza vaccine known as FLUAD® or VANTAFLU® had acceptable safety profiles in older adults (aged ≥65 years) in South Korea.

Long-term stability of influenza vaccine in a dissolving microneedle patch

This study tested the hypothesis that optimized microneedle patch formulations can stabilize trivalent subunit influenza vaccine during long-term storage outside the cold chain and when exposed to potential stresses found during manufacturing and storage. Formulations containing combinations of trehalose/sucrose, sucrose/arginine, and arginine/heptagluconate were successful at retaining most or all vaccine activity during storage at 25°C for up to 24months as determined by ELISA assay. The best formulation of microneedle patches contained arginine/heptagluconate, which showed no significant loss of vaccine activity during the study. To validate these in vitro findings, mice were immunized using trivalent influenza vaccine stored in microneedle patches for more than 1year at 25°C, which elicited antibody titers greater than or equal to fresh liquid vaccine delivered by intradermal injection, indicating the retention of immunogenicity during storage. Finally, influenza vaccine in microneedle patches lost no significant activity during exposure to 60°C for 4months, multiple freeze-thaw cycles, or electron beam irradiation. We conclude that optimally formulated microneedle patches can retain influenza vaccine activity during extended storage outside the cold chain and during other environmental stresses, which suggests the possibility of microneedle patch storage on pharmacy shelves without refrigeration.

Measurement of Cellular Immunity to Influenza Vaccination in Rheumatoid Arthritis; Comparison of Three Assays

Objective: Monitoring of immune responses is essential in the care of immunosuppressed individuals, including rheumatic patients. Evaluation of cellular immunity is essential for confirming virus-specific effector cell functions, but it is poorly standardized, and suffers from technical limitations and inaccurate results. There is, therefore, a need for reliable techniques for assessing cell-mediated immunity. In this study we compared the cell-mediated immunity response to influenza vaccine between a population of rheumatoid arthritis (RA) patients and healthy subjects by three methods. Methods: Trivalent influenza subunit vaccine was administered to 18 RA patients who were taking disease-modifying antirheumatic drugs and to 18 healthy controls. Peripheral blood mononuclear cells (PBMCs) and sera were obtained immediately before and ~28 days after vaccination. Cell-mediated immunity responses to vaccination were evaluated by (1) flow cytometric analysis of IL-2/IFN-γ production in activated CD4/CD8 T-cells, (2) enzyme-linked immunosorbent assay for the analysis of IFN-γ secretion, and (3) Granzyme B activity assay. Humoral response was evaluated by the hemagglutination inhibition assay. Results: Vaccination induced a significant increase in PBMC IFN-γ secretion and Granzyme B activity in the RA patients. Granzyme B activity also significantly increased in the controls, but there was no change in the levels of secreted IFN-γ. No group differences in the frequencies of IFN-γ/IL-2-producing activated CD4/CD8 T-cells were observed by flow cytometry. The geometric mean of hemagglutination inhibition antibody titers increased significantly for the H1N1/H3N2 influenza strains in both groups. Conclusions: Granzyme B activity assay was the only method to detect a significant cell-mediated immunity response in both groups while significant increase in IFN-γ secretion was demonstrated only in RA patients. Flow cytometric analysis failed to show IL-2 and IFN-γ production in both groups. Currently available methods for measuring cellular responsiveness to influenza vaccination are inconsistent and limited in their ability to reflect acquired cellular immunity.

Investigation of clinical characteristics as predictive factors for the humoral immune response to the influenza vaccine in patients with rheumatoid arthritis

The objective of this observational study is to determine characteristics as predictive factors for the humoral immune response to the influenza vaccine in patients with rheumatoid arthritis (RA). Fifty-seven RA patients who visited our department between 2011 and 2012 were recruited for the present study. The anti-influenza antibody titers of a trivalent influenza subunit vaccine (A/California/7/2009 (H1N1)-like strain (A/H1N1 strain), A/Victoria/210/2009 (H3N2)-like strain (A/H3N2 strain), and B/Brisbane/60/2008-like strain (B strain)) were measured at baseline and 4 weeks after the vaccination using the hemagglutination inhibition assay. Associations between the immune response to the influenza vaccine and clinical characteristics such as background, clinical parameters, and "having treatments or not" were examined to determine predictive factors for the immune response to the influenza vaccine. The titers of the three strains were significantly increased in all RA patients after the influenza vaccination. Concerning predictive factors of the immune response, no significant differences were observed in background (age and sex) or clinical parameters (peripheral lymphocyte count, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, matrix metalloproteinase-3, and disease activity score-28). No significant differences were observed in the titers of anti-influenza antibodies between the treatment (methotrexate, prednisolone, salazosulfapyridine, or tacrolimus) and no-treatment groups. In contrast, there was a significant difference in A/H3N2 strain between the patients with biologics and without biologics. The only factor that affected anti-influenza antibody titers was "having biologics or not"; therefore, the immune response to the influenza vaccine may not be predicted from the viewpoints of background and clinical parameters.

Immunodominance of Antigenic Site B over Site A of Hemagglutinin of Recent H3N2 Influenza Viruses

H3N2 influenza viruses have now circulated in the human population for 43 years since the pandemic of 1968, accumulating sequence changes in the hemagglutinin (HA) and neuraminidase (NA) that are believed to be predominantly due to selection for escape from antibodies. Examination of mutations that persist and accumulate led to identification of antigenically significant mutations that are contained in five antigenic sites (A–E) mapped on to the H3 HA. In early H3N2 isolates, antigenic site A appeared to be dominant while in the 1990s site B seemed more important. To obtain experimental evidence for dominance of antigenic sites on modern H3 HAs, we have measured antibodies in plasma of human subjects who received the 2006–07 trivalent subunit influenza vaccine (H3 component A/Wisconsin/67/05) or the 2008–09 formulation (H3 component A/Uruguay/716/07). Plasmas were tested against expressed HA of Wisconsin-like influenza A/Oklahoma/309/06 and site-directed mutants in antigenic site A (NNES121-124ITEG, N126T, N133D, TSSS135-138GSNA, K140I, RSNNS142-146PGSG), and antigenic site B (HL156-157KS, KFK158-160GST, NDQI189-192QEQT, A196V). “Native ELISA” analysis and escape mutant selection with two human monoclonal antibodies demonstrated that antibody E05 binds to antigenic site A and 1_C02 binds to site B. We find that most individuals, after vaccination in seasons 2006–07 and/or 2008–09, showed dominance of antigenic site B recognition over antigenic site A. A minority showed dominance of site A in 2006 but these were reduced in 2008 when the vaccine virus had a site A mutation. A better understanding of immunodominance may allow prediction of future antigenic drift and assist in vaccine strain selection.

Phase III, randomized controlled trial to evaluate lot consistency of a trivalent subunit egg-based influenza vaccine in adults

Vaccination is the most effective preventive strategy to control influenza. The demonstration of lot-to-lot consistency to confirm the reliability of the manufacturing process has become a mandatory step in vaccine development. This phase III, observer-blind, controlled trial assessed lot-to-lot consistency, immunogenicity, and safety of a subunit trivalent influenza vaccine (Agrippal®, Novartis Vaccines and Diagnostics) in healthy adults aged 18–49 years. The immunogenicity and safety profile of Agrippal was compared with a control vaccine (Fluvirin®, Novartis Vaccines and Diagnostics). A total of 1507 subjects were randomized 2:2:2:1 to receive one vaccination of one of the three lots of influenza vaccine or control vaccine. Antibody levels were measured by hemagglutination inhibition assay on days 1 and 22. Adverse reactions were solicited via diary cards for 7 days after vaccination, and unsolicited adverse events were collected throughout the study period. Equivalence of day 22 immune responses to the three lots was shown for each of the three strains. Robust immunogenic responses after one dose were observed for all vaccine groups, and both Center for Biologics Evaluation and Research criteria for licensure of influenza vaccines were met for all three virus strains. Both vaccines exhibited a robust safety profile and were well tolerated, with no differences in local and systemic solicited reactions or in unsolicited adverse events. The demonstration of consistency between manufacturing lots confirms for purposes of clinical development the reliability of the production process. The robust immunogenic responses and favorable safety profiles further support the use of trivalent subunit influenza vaccines Agrippal and Fluvirin for active immunization against influenza.

Superior immunogenicity of seasonal influenza vaccines containing full dose of MF59® adjuvant

Background: MF59-adjuvanted influenza vaccines have superior immunogenicity in older adults compared with non-adjuvanted vaccines. We assessed whether changing formulation (i.e., increasing H3N2 antigen or decreasing the quantity of adjuvant) of the licensed, MF59-adjuvanted trivalent influenza subunit vaccine Fluad® (Novartis Vaccines and Diagnostics) improves the risk-benefit profile in vaccinees aged ≥65 years. Results: A significant dose-response relationship was observed between antibody levels and MF59 dose; full dose formulations elicited the strongest immune responses, meeting immunogenicity licensure criteria by Day 8. Doubling H3N2 antigen content did not increase the response to this antigen. Increased frequency of circulating CD4+ T-cells specific for vaccine antigens were detected by Day 8; magnitude and functional profile of the CD4+ T-cell response was comparable across the different vaccination groups. Mild to moderate solicited local reactions were more common with vaccines formulated with higher doses of MF59®, but there were no MF59- or antigen dose-related increase in the frequency of solicited systemic reactions or unsolicited adverse events and serious adverse events. Methods: We report on 357 subjects who received one of eight intramuscular vaccine formulations. Hemagglutination-inhibiting antibodies were assayed on Days 1, 8 and 22; magnitude and functional profile of CD4+ T-cell responses to vaccine antigens were assessed in subsets. Solicited adverse reactions were reported via diary cards for seven days after vaccination and spontaneous adverse events were monitored throughout the study. Conclusion: This study confirms that the current formulation is the optimal one for MF59-adjuvanted influenza vaccine for use in older adults.

Trivalent inactivated subunit influenza vaccine Influvac®: 30-year experience of safety and immunogenicity

Background/objectivesBetween 1982 and 2011, 84 clinical studies were performed by the manufacturers of Influvac®, including the annual update studies required for licensing in Europe. This paper presents data from a 30-year evaluation of clinical experience with Influvac®. Subjects and methodsIn all, 8776 subjects were vaccinated with Influvac®, including healthy adults, healthy elderly subjects, adult and elderly at-risk subjects, and healthy and at-risk children. All subjects received the trivalent inactivated subunit influenza vaccine Influvac® (Abbott, Weesp, The Netherlands). Subjects recorded solicited local and systemic reactions for 3–7days after vaccination. Inconvenience was scored in some studies. Unsolicited reports of adverse events were collected up to 21days after vaccination. Haemagglutination inhibition (HI) antibody titres were determined before and up to 45weeks after vaccination with Influvac®. The immunogenicity of Influvac® was assessed using the criteria of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency. Post marketing surveillance data were also analyzed. ResultsTreatment-emergent adverse events up to 21days after vaccination were reported by 583 of 4746 subjects (12.3%), most commonly headache. Overall, 2318 of 6825 subjects (34.0%) recorded local reactions (most commonly tenderness and pain on slightest pressure) and 1229 of 6825 subjects (18.2%) recorded systemic reactions (most commonly headache and fatigue). All local and systemic reactions were mild or moderate and resolved in 1–2days. Most subjects in each population group reported inconvenience as none-to-mild. Post marketing surveillance data collected from 1982 to 2012 indicated an overall reporting rate of 24.5 events/million doses. The age-specific CHMP serological criteria for immunogenicity were generally met in all the adult and elderly populations and the HI antibody titres and derived serological parameters in children were similar to those in adults. The CHMP requirement for immunogenicity for annual re-licensing for both healthy adults and elderly subjects was consistently met over the 30-year period. One study in elderly subjects demonstrated that HI antibody titres were maintained at relatively high levels for at least 6months, providing coverage throughout the influenza season, but by 1year after vaccination antibody titres had declined to low enough levels to necessitate revaccination. ConclusionsThis review of the 30-year clinical experience with Influvac® found that the overall benefit-to-risk ratio is positive for all age groups from 6months upwards. The currently available evidence from the many clinical trials that have been performed confirms that Influvac® remains an effective and safe vaccine for preventing seasonal influenza.

The observation of humoral responses after influenza vaccination in patients with rheumatoid arthritis treated with Japanese oriental (kampo) medicine: an observational study.

Objective. The efficacy of influenza vaccination in patients treated with Japanese Oriental (Kampo) Medicine is unknown. The objectives of this study were to observe the efficacy of influenza vaccination in RA patients treated with Kampo. Methods. Trivalent influenza subunit vaccine was administered to 45 RA patients who had received Kampo. They were divided into 2 groups: RA patients treated without MTX (“without MTX group”) and treated with MTX (“with MTX group”). Antibody titers were measured before and 4 weeks after vaccination using hemagglutination inhibition assay. Results. Geometric mean titers (GMTs) of anti-influenza antibodies significantly increased for all influenza strains. Response to the influenza vaccination in RA patients treated with Kampo was not lower than that of healthy subjects and the response in the “with MTX group” had a tendency to be higher than that in RA patients treated with MTX in the previous study. There was no significant difference in the GMT after 4 weeks between the “with MTX group” and the “without MTX group.” A decreased efficacy in both seroprotection and seroconversion was not found in the “with MTX group.” Conclusion. These observations may open the way for further clinical trials to establish the efficacy for the influenza vaccination in RA patients treated with Kampo.

Patients with humoral primary immunodeficiency do not develop protective anti-influenza antibody titers after vaccination with trivalent subunit influenza vaccine

Yearly influenza vaccination is recommended for patients with humoral primary immunodeficiency (hPID). However, humoral responses following vaccination can be expected to be reduced in these patients. The efficacy of influenza vaccination in patients with hPID, anti-influenza antibody responses was assessed in 26 patients with hPID and 26 matched healthy controls (HC) using hemagglutination inhibition assay. Following vaccination, geometric mean titers (GMT) significantly increased for all influenza strains in the HC group, but only for A/H1N1 in the patient group. Fold increase in anti-influenza titer and seroprotection rates were lower for patients than for HC for A/H3N2 and A/H1N1, leading to postvaccination titer > or =40 in only 29% and 83% vs. 77% and 100%, respectively. Previous vaccination in patients and treatment with IVIg did not result in a higher rate of postvaccination titer > or =40. In conclusion, patients with hPID show hardly any humoral response following influenza vaccination.

A novel mammalian cell-culture technique for consistent production of a well-tolerated and immunogenic trivalent subunit influenza vaccine

Conventional influenza vaccine production methods have limitations due to their reliance on chicken eggs. We evaluated whether a mammalian cell-culture system could reliably produce an influenza vaccine with favourable tolerability and immunogenicity profiles. Adult subjects ( n = 1200; 18–60 years of age) were randomized (2:2:2:1) to receive either one of three lots of a cell-culture-derived influenza vaccine (CCIV) or an egg-based trivalent inactivated influenza vaccine (TIV). Safety and reactogenicity were assessed using solicited indicators for 7 days post-vaccination, all other adverse events (AEs) were recorded for 21 days post-vaccination, and all serious AEs and AEs necessitating a physician's visit, and/or resulting in subject's withdrawal from the study, were collected for up to 6 months post-vaccination. Antibody titres were measured by haemagglutination inhibition (HI) assay using egg-based viral antigens. All three lots of CCIV had similar safety and tolerability profiles, analogous to those of the TIV. Lot-to-lot consistency was statistically demonstrated through bioequivalence for immunogenicity. Antibody titres assessed at 6 months demonstrated good persistence. This Phase III trial is the first to demonstrate lot-to-lot bioequivalence of a CCIV and persistence of immunogenicity in comparison with a TIV.

Cross-reactive antibodies in middle-aged and elderly volunteers after MF59-adjuvanted subunit trivalent influenza vaccine against B viruses of the B/Victoria or B/Yamagata lineages

This study evaluated whether MF59-adjuvanted subunit trivalent influenza vaccine for the 2003/04 winter season (A/Moscow/10/99, H3N2; A/New Caledonia/20/99, H1N1; B/Hong Kong/330/01) would confer protection against mismatched and frequently co-circulating variants of influenza B/Victoria- and B/Yamagata-like virus strains. Haemagglutination inhibiting (HI) antibodies were measured in middle-aged and elderly volunteers against the homologous B/Victoria-like vaccine strain (B/Hong Kong/330/01) and against mismatched B/Victoria-like (B/Malaysia/2506/04) and B/Yamagata-like (B/Singapore/379/99 and B/Shanghai/361/02) strains. Immunization induced significant increases in the amounts of HI antibodies against all influenza B strains under investigation. However, the responses against the heterologous B/Shanghai/361/02 virus did not reach the desirable values of seroprotection. An age-dependent decline of the responses was found for B/Victoria-like antigens, but not for B/Yamagata-like strains. Although further studies are needed, our data support the recommendation of including influenza B viruses of the B/Victoria and B/Yamagata lineages in the future influenza vaccine preparations.

Trivalent inactivated subunit influenza vaccine Influvac ®: 25-Year experience of safety and immunogenicity

Between 1982 and 2006, 76 clinical studies (including the annual update studies required for licensing in Europe) were performed with the trivalent inactivated subunit influenza vaccine Influvac ®. In all, 6415 subjects were vaccinated, of whom 5034 were eligible for safety evaluation and 4534 for efficacy evaluation. Treatment-emergent adverse events occurred in 13.7% of subjects. Transient mild-to-moderate local and systemic reactions occurred in up to half of subjects. Post-marketing surveillance confirmed the well-established safety profile reported for inactivated influenza vaccines. All three serological criteria for immunogenicity of the Committee for Medicinal Products for Human Use (CHMP) were met for all three virus strain (sub)types in healthy adults, elderly (over 60 years), nursing home residents, and those at high risk of influenza-related complications. In an additional trial in children aged 3–12 years, all three CHMP criteria for adults were met for all three virus strains. Influvac ® is thus immunogenic and safe, and is a suitable vaccine to combat the annually recurring medical and economic burden of influenza epidemics.

Immune Responses of Mice to Influenza Subunit Vaccine in Combination with CIA07 as an Adjuvant

CIA07 is an immunostimulatory agent composed of E. coli DNA fragments and modified LPS lacking the lipid A moiety. In this study, we investigated whether CIA07 promotes immune responses as an adjuvant to the influenza subunit vaccine. Balb/c mice were immunized intramuscularly once or twice at a 4-week interval with the trivalent influenza subunit vaccine antigen alone or in combination with CIA07 as adjuvant. Antigen-specific serum antibody titers and hemagglutination-inhibition (HI) antibody titers were assessed. At 4 weeks after each immunization, the antigen-specific total serum IgG antibody titer in mice receiving CIA07 was 2 to 3 times higher than that in animals administered antigen alone (P<0.05). The CIA07-treated group additionally displayed higher HI antibody titers against each of the 3 vaccine strains, compared to the antigen group. Animals receiving antigen alone displayed barely detectable antigen-specific serum IgG2a antibody titers. In contrast, coadministration of CIA07 with antigen led to significantly enhanced IgG2a antibody responses, suggesting that CIA07 stimulates a Th1-type immune response. Moreover, the CIA07-treated group displayed a marked increase in the number of interferon gamma-producing CD8(+) T cells in splenocytes. These data collectively demonstrate that CIA07 has the ability to induce both Th1-type cellular and Th2-type humoral immune responses to the influenza subunit vaccine, and support its potential as an effective adjuvant to the influenza vaccine.

Immunogenicity of Influenza Vaccination in Patients with Non-Hodgkin Lymphoma: Final Report after Two Epidemic Seasons.

Vaccination against influenza is recommended for immunocompromised individuals. However, there is little information concerning the efficacy of vaccination in patients (pts) with non-Hodgkin lymphoma (NHL). The purpose of this study was to assess humoral response to standard intramuscular trivalent subunit influenza vaccine in pts with NHL as compared to healthy subjects. In two consecutive epidemic seasons, 2003/2004 and 2004/2005, 163 pts and 92 healthy controls were vaccinated. Antibody titers to hemagglutinin (HA) and neuraminidase (NA) were measured in serum samples collected before vaccination, and 1 and 6 months apart. Changes in the hemagglutination inhibition (HAI) and neuraminidase inhibition (NII) antibody titers were assessed by comparing geometric mean titers and mean fold increases to baseline values and by comparing changes in the HA seroconversion and seroprotection rates. Pts who received influenza vaccine during 2003/2004 season had after one month increases in the geometric mean titers by a factor of 8,64–26,60 for HI and 6,93–12,66 for NI, as compared with respective increases by a factor of 9,12–24,41 and 4,83–10,31 for the healthy controls. At one month after vaccination seroprotection and seroresponse rates were similar in the two groups, ranging from 68,42 to 84,21 % and 71,93 to 94,74 % in NHL and 66,67–82,22 % and 62,22–86,67 % in controls, respectively. After six months, seroprotection and seroresponse rates had decreased in NHL group to 31,91–38,30% and 46,81–72,34%, respectively. Pts who received influenza vaccine during 2004/2005 season had after 1 month increases in the geometric mean titers by a factor of 38,76–41,49 for HI and 26,59–30,31 for NI, as compared with respective increases by a factor of 81,19–104,32 and 52,16–54,52 for the healthy controls. Seroprotection and seroresponse rates were lower in the former group, ranging from 62,11 to 65,26 % and 74,47 to 77,66 %, respectively. After six months, these parameters had decreased to 24,72–31,46% and 57,30–59,55%, respectively. In both studied seasons, pts achieved titres of functional antibodies greater than the protective threshold, irrespective of the previous chemotherapy administration. The results of this study indicate that standard influenza vaccination induces sufficient immune responses in pts with NHL. Previous chemotherapy adminstration seems to have no impact on the efficacy of vaccination.