Michele Pellegrini

Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant.

Background: Children have high morbidity and hospitalization rates from seasonal influenza. Meta-analyses suggest that conventional inactivated influenza vaccines are of low efficacy in young children, making vaccines that induce greater and broader immune protection in this vulnerable population a medical priority. Adjuvanted influenza vaccines may offer a solution. Subjects and Methods: Unprimed healthy children (6 to <36 months) were enrolled in an observer-blinded study and randomly assigned to receive 2 doses of MF59-adjuvanted vaccine (Sub/MF59, n = 130) or nonadjuvanted split vaccine (split, n = 139); subgroups of these (n = 43 and 46, respectively) received a booster dose 1 year later. Safety and clinical tolerability were assessed after each dose. Hemagglutination inhibition antibody titers were measured against influenza A and B strains included in the formulation of the vaccines and against mismatched strains. Results: Clinical tolerability and safety were generally comparable between vaccine groups, though some transient, mild solicited reactions were more frequent in the Sub/MF59 group. Postvaccination hemagglutination inhibition antibody titers to all 3 vaccine strains were significantly higher with Sub/MF59 than with split vaccine (all comparisons P < 0.001) after each of the 3 vaccine doses. In addition, Sub/MF59 induced significantly higher cross-reactivity against A/H3N2 and A/H1N1 mismatched strains. Conclusion: MF59-adjuvanted influenza vaccine was well tolerated in healthy young children after each of 3 doses and induced greater, longer-lasting, and broader immune responses than a nonadjuvanted split vaccine. The enhanced immunogenicity of the adjuvanted vaccine was most evident in very young children and for the B vaccine strain.

MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database.

BACKGROUND Adding adjuvants such as MF59((R)) to influenza vaccines can enhance the immune response. This analysis evaluated the safety profile of MF59-adjuvanted [(+)MF59] compared with non-adjuvanted [(-)MF59] vaccines in a large clinical database. METHODS Safety data were pooled from 64 clinical trials involving (+)MF59 seasonal and pandemic influenza vaccines. Safety outcomes were analysed in the overall population and in subjects aged > or =65 years, in all clinical trials and in controlled trials only. FINDINGS Data from 20,447 (+)MF59 and 7526 (-)MF59 subjects were analysed. Overall, (+)MF59 subjects had lower risks than (-)MF59 subjects of experiencing any unsolicited adverse event (AE) (26.8% vs 39.2%; adjusted risk ratio [ARR] 0.65; 95% CI 0.60-0.70), cardiovascular AEs (1.9% vs 5.6%; ARR 0.44; 95% CI 0.35-0.55), new onset chronic diseases (1.3% vs 1.9%; ARR 0.71; 95% CI 0.57-0.87) and death (0.8% vs 1.2%; ARR 0.67; 95% CI 0.51-0.87). Few AEs of potential autoimmune origin were reported: 0.71 and 0.67 per 1000 with (+)MF59 and (-)MF59, respectively. As expected, (+)MF59 subjects had a higher risk of solicited local or systemic reactions within 3 days of vaccination (58.5% vs 46.9%, weighted RR 1.34; 95% CI 1.28-1.40). Safety outcomes were consistent between total and elderly populations, and between all trials and controlled trials, although statistical significance was lost for some of the outcomes in the subgroups. INTERPRETATION This large-scale analysis supports the good safety profile of (+)MF59 seasonal and pandemic influenza vaccines and suggests a clinical benefit over (-)MF59 influenza vaccines.

MF59®-adjuvanted influenza vaccine (FLUAD®) in children: Safety and immunogenicity following a second year seasonal vaccination

After priming with two intramuscular doses of MF59-adjuvanted (Sub/MF59) or split influenza vaccines during the 2006/07 season, 89 healthy children received a third booster dose of the respective vaccine (2007/08 Northern Hemisphere formulation) approximately 1 year later, and were followed up for 6 months post-third injection. Immunogenicity was evaluated on 81 of them by a hemagglutination inhibition (HI) assay before and 3 weeks after vaccination. The Sub/MF59 influenza vaccine was safe and well tolerated following the booster vaccination. Pre-booster HI antibody titers were consistently higher in the Sub/MF59 group than in the comparator group, confirming significantly longer persistence of antibodies after priming with Sub/MF59 vaccine. Post-booster immune responses were significantly higher in the Sub/MF59 group compared with the split group, especially vs. the influenza B strain, which is epidemiologically relevant in the pediatric population. Altogether, these data further support the potential use of MF59-adjuvanted influenza vaccine as a safe and highly immunogenic influenza vaccine for young children.

MF59 -adjuvanted vaccines for seasonal and pandemic influenza prophylaxis

Abstract  Influenza is a major cause of worldwide morbidity and mortality through frequent seasonal epidemics and infrequent pandemics. Morbidity and mortality rates from seasonal influenza are highest in the most frail, such as the elderly, those with underlying chronic conditions and very young children. Antigenic mismatch between strains recommended for vaccine formulation and circulating viruses can further reduce vaccine efficacy in these populations. Seasonal influenza vaccines with enhanced, cross‐reactive immunogenicity are needed to address these problems and can confer a better immune protection, particularly in seasons were antigenic mismatch occurs. A related issue for vaccine development is the growing threat of pandemic influenza caused by H5N1 avian strains. Vaccines against strains with pandemic potential offer the best approach for reducing the potential impact of a pandemic. However, current non‐adjuvanted pre‐pandemic vaccines offer suboptimal immunogenicity against H5N1. For both seasonal and pre‐pandemic vaccines, the addition of adjuvants may be the best approach for providing enhanced cross‐reactive immunogenicity. MF59®, the first oil‐in‐water emulsion licensed as an adjuvant for human use, can enhance vaccine immune responses through multiple mechanisms. A trivalent MF59‐adjuvanted seasonal influenza vaccine (Fluad®) has shown to induce significantly higher immune responses to influenza vaccination in the elderly, compared with non‐adjuvanted vaccines, and to provide cross‐reactive immunity against divergent influenza strains. Similar results have been generated with a MF59‐adjuvanted H5N1 pre‐pandemic vaccine, which showed higher and broader immunogenicity compared with non‐adjuvanted pre‐pandemic vaccines.

Safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents: an integrated analysis.

We reviewed the safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents (aged 6 months-18 years) in an integrated analysis of all pediatric trials evaluating MF59-containing influenza vaccines completed to date (5 trials). In the MF59-adjuvanted group (n=1181) versus the non-adjuvanted group (n=545) there was no increase in the incidence of unsolicited adverse events and serious adverse events. As expected, solicited local or systemic reactions occurred more frequently in MF59-adjuvanted subjects; however, a majority of reactions were mild and transient. These data support the safety of MF59-adjuvanted influenza vaccines in the pediatric population.

Short‐Term Immunogenicity and Safety of an Accelerated Pre‐Exposure Prophylaxis Regimen With Japanese Encephalitis Vaccine in Combination With a Rabies Vaccine: A Phase III, Multicenter, Observer‐Blind Study

BACKGROUND The current Japanese encephalitis (JE) vaccination regimen requires two doses and 4 weeks to complete, which may not always be feasible for travelers on short notice. One of the primary endpoints of this phase III study was to demonstrate noninferiority of immune responses to a JE vaccine following an accelerated 1-week JE vaccination regimen administered concomitantly with a rabies vaccine as compared to a standard 4-week JE regimen alone. In addition, the immunogenicity of concomitant administration of JE and rabies vaccines following standard regimens was evaluated, as well as the tolerability and safety profile of each regimen under study. METHODS Healthy adults aged 18 to ≤65 years were randomized to regimens with an accelerated or standard schedule: JE+rabies-standard (n = 167), JE+rabies-accelerated (n = 217) or JE-standard (n = 56). Immunogenicity against JE antigen was assessed by a 50% plaque reduction neutralization test (PRNT50 ) titer of ≥1 : 10, measured 28 days after last active vaccine (LAV) administration. Solicited reactions were collected 7 days after each vaccination; spontaneously reported adverse events (AEs) and serious AEs were monitored up to day 57. This paper reports results until day 57. RESULTS Noninferiority of immune responses was established for JE+rabies-accelerated compared to the JE-standard regimen 28 days after LAV administration. Overall, 99% and 100% of subjects in the JE+rabies-accelerated and JE-standard groups, respectively, achieved PRNT50 titers of ≥1 : 10 at 28 days after LAV administration. No impact of concomitant rabies vaccination was observed either on immune responses or on the safety profile of the JE vaccine. CONCLUSIONS This was the first randomized, controlled trial that demonstrated the strong short-term immunogenicity of a new, accelerated, 1-week JE-regimen, which was noninferior to that of the standard regimen, with a satisfactory tolerability and safety profile and no impact of concomitant rabies vaccination. This accelerated regimen, if licensed, could potentially be a valid alternative for individuals requiring a primary series of JE vaccination and rabies pre-exposure prophylaxis on short notice.

Safety and immunogenicity of an MF59™-adjuvanted subunit influenza vaccine in elderly Chinese subjects

BackgroundThe safety and immunogenicity of an MF59™-adjuvanted subunit influenza vaccine (Sub/MF59™; FLUAD®, Novartis Vaccines) was evaluated among elderly Chinese subjects (≥ 60 years of age). After a preliminary Phase I, open-label study (n = 25) to assess safety 1–14 days post-vaccination, a comparative observer-blind, randomised, controlled clinical trial (n = 600) was performed to assess safety and immunogenicity versus a non-adjuvanted subunit influenza vaccine (Subunit; Agrippal®, Novartis Vaccines). Subjects were randomised (2:1) to receive Sub/MF59™ or Subunit.ResultsBoth vaccines were well tolerated, with no vaccine-related serious adverse events reported during the Phase I trial. During the observer-blind study, local and systemic reactions were generally similar for both vaccines 1–22 days post-vaccination; however, injection-site induration was more frequent among the Subunit group (P < 0.05), and mild pain at the injection site and fever were more frequent among Sub/MF59™ recipients (P ≤ 0.005). Both vaccines induced a significant (P < 0.001) increase in geometric mean titres (GMTs) for the three strains tested, versus baseline; GMTs against A/H1N1, A/H3N2 and B were significantly higher in the Sub/MF59™ group (P = 0.034, P < 0.001 and P = 0.005, respectively). GMT ratios against A/H1N1, A/H3N2 and B were also significantly higher in the Sub/MF59™ group (P = 0.038, P < 0.001 and P = 0.006, respectively). Similarly, the percentage of subjects achieving seroprotection or seroconversion on Day 22 was greater for Sub/MF59™ recipients, reaching significance for A/H3N2 (P < 0.001).ConclusionMF59™-adjuvanted subunit influenza vaccine is well tolerated by elderly Chinese subjects and induces a higher level of immunogenicity than a non-adjuvanted subunit influenza vaccine in this population that is at high risk of influenza-related complications.Clinical trial registryhttp://www.clinicaltrials.gov, NCT00310648

One-year immunogenicity kinetics and safety of a purified chick embryo cell rabies vaccine and an inactivated Vero cell-derived Japanese encephalitis vaccine administered concomitantly according to a new, 1-week, accelerated primary series.

BACKGROUND Conventional rabies pre-exposure prophylaxis (PrEP) and Japanese encephalitis (JE) primary series vaccination regimens each require up to 4 weeks to complete and, thus, may not be feasible for individuals who need these immunizations on short notice. This Phase 3b, randomized, controlled, observer-blind study evaluated the immunogenicity and safety of concomitant administration of a purified chick embryo cell culture rabies vaccine and an inactivated, adsorbed JE vaccine according to an accelerated (1 week) regimen when compared with the conventional regimens (4 weeks). This report describes the kinetics of immune responses up to 1 year after vaccination. METHODS A total of 661 healthy adults (18 to ≤65 years) were randomized into the following accelerated or conventional vaccine regimens: Rabies + JE-Conventional, Rabies + JE-Accelerated, Rabies-Conventional and JE-Conventional. Immunogenicity was assessed by virus neutralization tests. Safety and tolerability were also evaluated. RESULTS Irrespective of rabies vaccination regimen, ≥97% of subjects had adequate levels of rabies virus neutralizing antibody (RVNA) concentrations (≥0.5 IU/ml) up to Day 57, with percentages of subjects with RVNA concentrations ≥0.5 IU/ml at Day 366 ranging between 68% in the Rabies + JE-Accelerated group and 80% of subjects in the Rabies-Conventional group. The Rabies + JE-Accelerated group revealed high JE neutralizing antibody titers at all-time points. At Day 366, the percentage of subjects with antibody titers indicative of seroprotection (PRNT50 titers ≥1:10) remained high across JE vaccine groups (86-94%). CONCLUSIONS The accelerated PrEP rabies and JE vaccination regimens, once licensed, could represent a valid alternative in the short-term to currently recommended conventional regimens. The concomitant administration of these two vaccines does not compromise immune responses to any of the vaccine antigens particularly when aiming for short-term protection. Further evidence will clarify the need for and timing to administration of rabies vaccine booster doses in subjects primed with an accelerated PrEP regimen. (NCT01662440).

Safety and immunogenicity profiles of an adjuvanted seasonal influenza vaccine in Guatemalan children.

INTRODUCTION The efficacy of non-adjuvanted seasonal influenza vaccine in young children is considered to be suboptimal. This study compared the safety and immunogenicity profiles of MF59-adjuvanted, trivalent, influenza vaccine (ATIV) and non-adjuvanted, trivalent, influenza vaccine (TIV) in Guatemalan children (N = 360) between 6 and < 60 months of age. METHODOLOGY Children received two doses of ATIV or TIV administered four weeks apart. Solicited adverse reactions were recorded for seven days after each vaccination. Serious adverse events were recorded throughout the entire study period. Antibody responses were assessed by hemagglutination inhibition (HI) assay at baseline, four weeks after administration of the first vaccine dose, and three weeks after administration of the second dose. RESULTS Both ATIV and TIV were well tolerated, with similar rates of solicited reactions and adverse events observed in response to both vaccines. MF59-adjuvanted vaccine induced considerably higher antibody titers than did TIV. After two doses, the B strain-specific antibody response to TIV was insufficient to meet the Center for Biologics Evaluation and Research (CBER) licensure criterion for seroprotection, whereas responses to the MF59-adjuvanted vaccine met the seroprotection criterion against all three strains. Cross-reactive antibody responses to MF59-adjuvanted vaccine met the CBER seroprotection criterion against all three strains after two doses; B strain-specific heterologous responses to non-adjuvanted TIV were inadequate. CONCLUSIONS The MF59-adjuvanted seasonal influenza vaccine was well-tolerated and highly immunogenic in children 6 to < 60 months of age, inducing seroprotective antibody titers against both the vaccine strains and antigenically distinct heterologous strains.

Immunogenicity, Safety, and Tolerability of Two Trivalent Subunit Inactivated Influenza Vaccines: A Phase III, Observer-Blind, Randomized, Controlled Multicenter Study

The objective of this study was to evaluate and compare the immunogenicity, safety, and tolerability of two influenza subunit vaccines, a primarily European-marketed trivalent vaccine (Agrippal®, Novartis Vaccines), and a predominantly U.S.-marketed control trivalent vaccine (Fluvirin®, Novartis Vaccines), in subjects aged 3-64 y. The immunogenicity of both vaccines was evaluated according to the Center for Biologics Evaluation and Research (CBER) criteria. This clinical trial was performed between April and December 2007 in Argentina. A total of 1893 subjects were stratified into three age groups (3-8 y, 9-17 y, and 18-64 y), and randomized in a 2:1 ratio to receive either Agrippal or Fluvirin. Adolescents and adults received one dose of vaccine intramuscularly, whereas children aged 3-8 years received two vaccine doses, administered 4 wk apart. Antibody levels were measured by means of hemagglutination inhibition assay before vaccination (baseline); 21 d after the first vaccination (adults and adolescents); and, for children aged 3-8 y, 28 d after the first vaccination and 21 d after the second vaccine dose. Adverse reactions were solicited via diary cards for 7 d after each vaccination, and unsolicited adverse events were reported throughout the study period. Both vaccines were safe and well-tolerated, and elicited robust immunogenic responses in all age groups, meeting both CBER licensure criteria for all three viral strains after completion of the age-recommended vaccination schedule. These findings support the use of the trivalent subunit influenza vaccines Agrippal and Fluvirin for universal vaccination campaigns on an annual basis. ClinicalTrials.gov: NCT00464672.