Non-adjuvanted Influenza Vaccine Research Articles

A 1-year follow-on study from a randomised, head-to-head, multicentre, open-label study of two pandemic influenza vaccines in children

Pandemic influenza A H1N1 infections occurred worldwide from 2009. Children were particularly vulnerable. Novel vaccines were used during the pandemic. To assess the persistence of antibody to H1N1 influenza 1 year after children aged 6 months to 12 years had been immunised with two doses of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine; and also to assess the immunogenicity and reactogenicity in this population of a single dose of 2010-11 trivalent seasonal influenza vaccine. Multicentre, open-label, follow-on from randomised, head-to-head trial. Five UK sites (Southampton, Oxford, Bristol, London and Exeter). Children who completed last year's head-to-head randomised study were invited to participate. Children who had subsequently received a further dose of H1N1 vaccine, or who had already received a dose of 2010-11 trivalent seasonal influenza vaccine, were excluded. In the previous study, children were randomised (in a 1 : 1 ratio) to receive two doses, 21 days apart, of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine. In this follow-on study, a blood sample was taken to assess the persistence of antibody 1 year later, followed by administration of one 0.5 ml-dose of trivalent seasonal influenza vaccine. A second blood sample was taken 3 weeks later. Comparison between vaccines of the percentage of participants with a microneutralisation (MN) titre ≥ 1 : 40 and a haemagglutination titre ≥ 1 : 32, 1 year after vaccination. Immunogenicity of the trivalent seasonal influenza vaccine was assessed 3 weeks after vaccination by both the MN and the haemagglutination inhibition (HI) titres. Reactogenicity data were recorded for 7 days after vaccination. A total of 323 children were enrolled and 318 were included in the analysis of the persistence of antibody. One year after receipt of whole-virion vaccine, the MN titre was ≥ 1 : 40 in 32.4% of those vaccinated when < 3 years old and in 65.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1 : 32 in 63.2% and 79.1% of children in the respective age groups. One year after receipt of the adjuvanted vaccine, the MN titre was ≥ 1 : 40 in 100% of those vaccinated when < 3 years old and in 96.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1 : 32 in 98.4% and 96.9% of children in the respective age groups. Three hundred and two children were given trivalent seasonal influenza vaccination. Three weeks later, sera were obtained from 282 children; 100% had an MN titre ≥ 1 : 40 and HI titre ≥ 1 : 32. Trivalent seasonal influenza vaccine was well tolerated, although in children < 5 years old, fever ≥ 38 °C was reported in 13.6% of those who had previously received whole-virion vaccine, and in 18.3% of those who had received adjuvanted vaccine. Nearly all children who received two doses of AS03B-adjuvanted split-virion pandemic H1N1 influenza vaccine had titres of antibody deemed protective (HI titre ≥ 1 : 32, MN titre ≥ 1 : 40) 1 year later. Children who received two doses of whole-virion vaccine had lower titres, although many were above the putative protective thresholds. One year after either pandemic vaccine, the 2010-11 trivalent seasonal influenza vaccine produced a marked serological response to the H1N1 component of the vaccine and was well tolerated. We propose to investigate whether or not previous receipt of monovalent influenza vaccines affected serological response to the H3N2 and B components of the 2010-11 seasonal influenza vaccine, using stored sera. ClinicalTrials.gov NCT01239537. The National Institute for Health Research Health Technology Assessment programme.

Strong serological responses and HIV RNA increase following AS03‐adjuvanted pandemic immunization in HIV‐infected patients

We aimed to determine the antibody responses and effect on viral load of the AS03-adjuvanted pandemic H1N1 vaccine in HIV-infected patients. A total of 121 HIV-infected patients and 138 healthy subjects were enrolled in a prospective, open-label study. Healthy subjects received one dose and HIV-infected patients two doses of the AS03-adjuvanted split influenza A/09/H1N1 vaccine (Pandemrix®; GlaxoSmithKline, Brentford, United Kingdom.) at an interval of 3-4 weeks. The study was extended in 2010/2011 for 66 patients. Geometric mean titres (GMTs), seroprotection rates (post-vaccination titre ≥ 1:40) and HIV-1 RNA levels were measured before and 4 weeks after immunization. After two immunizations, the seroprotection rate (94.2 vs. 87%, respectively) and GMT (376 vs. 340, respectively) in HIV-infected patients were as high as in healthy subjects after one dose, regardless of CD4 cell count. Four weeks after immunization, HIV RNA was detected in plasma samples from 40 of 68 (58.0%) previously aviraemic patients [median 152 HIV-1 RNA copies/mL; interquartile range (IQR) 87-509 copies/mL]. Subsequent measures indicated that HIV RNA levels had again declined to <20 copies/mL in most patients (27 of 34; 79.4%). Following (nonadjuvanted) influenza immunization in 2010/2011, HIV RNA levels only slightly increased (median final level 28 copies/mL) in three of 66 (4.5%) previously aviraemic patients, including two of 25 (8%) patients in whom an increase had been elicited by AS03-adjuvanted vaccine the year before. Most HIV-infected patients developed seroprotection after two doses of AS03-adjuvanted pandemic vaccine. A transient effect on HIV RNA levels was observed in previously aviraemic patients. A booster dose of the nonadjuvanted influenza vaccine containing the A/09/H1N1 strain the following year did not reproduce this finding, indicating a non-antigen-specific adjuvant effect.

Non-adjuvanted 2009 influenza A (H1N1)v vaccine in pregnant women: The results of a French prospective descriptive study

In 2009, during the influenza A (H1N1)v pandemic, the French Health authorities recommended influenza immunisation for pregnant women because of the higher risk of serious influenza outcomes in that population. Thus, the non-adjuvanted inactivated influenza vaccine Panenza(®) was administered to French women from the second trimester of pregnancy. Several studies suggest that inactivated seasonal influenza vaccines are safe during pregnancy but there are few data about the effects of new A (H1N1)vaccines (new antigen) on pregnant women. The aim of the present prospective study was to describe pregnancy outcomes among women vaccinated with non-adjuvanted influenza vaccines in South Western France. the study ran from November 2009 to February 2010 and included, on a voluntary basis, pregnant women who were vaccinated against A (H1N1) influenza in vaccination clinics or maternity wards. 569 pregnant women were monitored until delivery. Compared with the general population, the risks of maternal conditions, malformations and neonatal conditions were not statistically different. This study does not reveal any sign of safety concerns regarding the effects of the vaccine on pregnancy outcomes.

Long-Term Immunogenicity after One and Two Doses of a Monovalent MF59-Adjuvanted A/H1N1 Influenza Virus Vaccine Coadministered with the Seasonal 2009-2010 Nonadjuvanted Influenza Virus Vaccine in HIV-Infected Children, Adolescents, and Young Adults in a Randomized Controlled Trial

Few data are available on the safety and long-term immunogenicity of A/H1N1 pandemic influenza vaccines for HIV-infected pediatric patients. We performed a randomized controlled trial to evaluate the safety and long-term immunogenicity of 1 versus 2 doses of the 2009 monovalent pandemic influenza A/H1N1 MF59-adjuvanted vaccine (PV) coadministered with the seasonal 2009-2010 trivalent nonadjuvanted influenza vaccine (SV) to HIV-infected children, adolescents, and young adults. A total of 66 HIV-infected patients aged 9 to 26 years were randomized to receive one (group 1) or two (group 2) doses of PV coadministered with 1 dose of SV. The main outcome was the seroconversion rate for PV at 1 month. Secondary outcomes were the geometric mean titer ratios and the seroprotection rates at 1 month for all vaccines, seroconversion rates at 1 month for SV, and longitudinal changes of antibody titers (ABTs) at 1, 2, 6, and 12 months for all vaccines. Groups 1 and 2 had similar CD4 counts and HIV RNA levels during the study. The seroconversion rate for PV was 100% at 1 month in both groups. ABTs for PV were high during the first 6 months and declined below seroprotection levels thereafter. Longitudinal changes in ABTs were similar in groups 1 and 2 for both PV and SV. The side effects of vaccination were mild and mostly local. In HIV-infected children, adolescents, and young adults, the immune response triggered by a single dose of PV was similar to that obtained with a double dose and was associated with long-term antibody response.

Intranasal Immunization of Ferrets with Commercial Trivalent Influenza Vaccines Formulated in a Nanoemulsion-Based Adjuvant

NB-1008 is a surfactant-stabilized soybean oil-in-water nanoemulsion (NE) adjuvant with influenza virus antigen incorporated into the NE by simple mixing. Intranasal administration of the antigen with NE adjuvant efficiently produces both mucosal and serum antibody responses as well as a robust cellular Th1 immune response. To demonstrate the adjuvant effect of the W(80)5EC NE, a killed commercial influenza vaccine for intramuscular administration (Fluzone or Fluvirin) was mixed with the W(80)5EC NE adjuvant and administered intranasally to naïve ferrets. After a single intranasal immunization, the adjuvanted influenza vaccine elicited elevated serum hemagglutination inhibition (HAI) geometric mean titers (GMTs) ranging from 196 to 905 for the three hemagglutinin (HA) antigens present in the vaccine, which are approximately 19- to 90-fold higher titers at 1/50 the standard intramuscular commercial nonadjuvanted influenza vaccine dose. Seroconversion rates of 67% to 100% were achieved against each of the three viral strains present. The adjuvanted nasal influenza vaccine also produced significant cross immunity to five other H3N2 influenza virus strains not present in the vaccine and produced sterile immunity after challenge with homologous live virus. No safety issues were observed in 249 ferrets receiving the adjuvanted influenza vaccine. These findings demonstrate the ability of W(80)5EC NE to adjuvant nasally administered influenza vaccine and provide a basis for studying the intranasal W(80)5EC-adjuvanted influenza vaccine in humans.

Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy

A potential association between the new onset of narcolepsy accompanied by cataplexy - a putative autoimmune disorder, and vaccination with an AS03-adjuvanted A(H1N1) pandemic influenza vaccine is under investigation. We sought cases of narcolepsy from the pharmacovigilance database of a pandemic vaccine adjuvanted with another emulsion adjuvant, MF59(®), and a pooled clinical trials database of MF59-adjuvanted and non-adjuvanted influenza vaccine recipients. Using 6 narrowly restrictive and 24 broad sleep disturbance-related MedDRA preferred search terms (PT), we analysed spontaneous adverse events (AEs) reports received through July 31, 2010 and adjudicated suspected cases with onset 1 week-3 months after vaccination, against standardized clinical criteria defining narcolepsy. A pooled clinical trials database of 115 trials comprising 79,004 subjects receiving various MF59-adjuvanted and non-adjuvanted influenza vaccines in controlled and uncontrolled trials was analysed for cases with a narrow PT that had onset 1 week after vaccination. Five thousand three hundred and five spontaneous AE reports were received from an estimated 23.26 million MF59-adjuvanted pandemic vaccine doses that had been administered. No case meeting the clinical definition of narcolepsy was discovered. In the pooled database of controlled clinical trials, no cases were discovered using the narrow PT, and rates and adjusted odds ratio for broad search terms for all temporal windows showed no significant difference between subjects receiving MF59-adjuvanted or non-adjuvanted vaccine. No case of narcolepsy and no evidence of an increased risk of sleep-related AEs were discovered in recipients of MF59-adjuvanted A(H1N1) pandemic and other MF59-adjuvanted influenza vaccine.

Immunogenicity Is Not Improved by Increased Antigen Dose or Booster Dosing of Seasonal Influenza Vaccine in a Randomized Trial of HIV Infected Adults

IntroductionThe risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy.MethodsA randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity.Results297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ≥40 = 31–58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related.ConclusionEven with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population.Trial RegistrationClinicalTrials.gov NCT00764998

Intranasal DNA Vaccination Induces Potent Mucosal and Systemic Immune Responses and Cross-protective Immunity Against Influenza Viruses

The induction of potent virus-specific immune responses at mucosal surfaces where virus transmission occurs is a major challenge for vaccination strategies. In the case of influenza vaccination, this has been achieved only by intranasal delivery of live-attenuated vaccines that otherwise pose safety problems. Here, we demonstrate that potent mucosal and systemic immune responses, both cellular and humoral, are induced by intranasal immunization using formulated DNA. We show that formulation with the DNA carrier polyethylenimine (PEI) improved by a 1,000-fold the efficiency of gene transfer in the respiratory track following intranasal administration of luciferase-coding DNA. Using PEI formulation, intranasal vaccination with DNA-encoding hemagglutinin (HA) from influenza A H5N1 or (H1N1)2009 viruses induced high levels of HA-specific immunoglobulin A (IgA) antibodies that were detected in bronchoalveolar lavages (BALs) and the serum. No mucosal responses could be detected after parenteral or intranasal immunization with naked-DNA. Furthermore, intranasal DNA vaccination with HA from a given H5N1 virus elicited full protection against the parental strain and partial cross-protection against a distinct highly pathogenic H5N1 strain that could be improved by adding neuraminidase (NA) DNA plasmids. Our observations warrant further investigation of intranasal DNA as an effective vaccination route.

Vaccination against the 2009 pandemic influenza A (H1N1) among healthcare workers in the major teaching hospital of Sicily (Italy)

The aim of the study was to investigate factors involved in vaccination acceptance among healthcare workers (HCWs) and adverse reactions rates associated with pandemic influenza vaccination. The study was carried out in the major teaching hospital of Sicily from November 2009 to February 2010 on 2267 HCWs. A total of 407 (18%) HCWs were vaccinated against the 2009 pandemic influenza A (H1N1). A logistic regression analysis indicates an increased risk of non-vaccination against pandemic influenza in females (OR=1.6; 95% CI=1.3–2.1) compared to males, in nurses/technicians/administrative workers (OR=1.7; 95% CI=1.3–2.2) compared to doctors/biologists, and in HCWs who were non-vaccinated against seasonal influenza in 2008–2009 (OR=4.9; 95% CI=3.7–6.5) compared to vaccinated HCWs. Overall, 302 (74.2%) out of 407 questionnaires distributed to vaccinated HCWs were returned within the observation period. One hundred fifty-two workers (50.3%) experienced at least one adverse reaction (30.1%, local reactions; 6.6% systemic reactions and 13.6% both of them). The most frequent side effect of vaccination was pain at the injection site (43.4%). Twelve (3.9%) out of 302 HCWs stated they experienced influenza-like illness episodes during the follow-up period. The use of an adjuvanted vaccine against pandemic influenza A (H1N1) appears to be an effective and safe preventive strategy, showing a prevalence of both local and systemic adverse reactions not very different from that seen after vaccination with non-adjuvanted seasonal influenza vaccine. Despite this finding, vaccination coverage among HCWs remains very low, suggesting the need to implement educational campaigns directed to groups with lower coverage rates.

Safety and immunogenicity of a trivalent single dose seasonal influenza vaccine containing pandemic A(H1N1) antigen in younger and elderly subjects: A phase III open-label single-arm study

BackgroundDuring the pandemic of the 2009 A(H1N1) influenza virus strain, 20–40% of the population in some areas were infected. Infection with A(H1N1) may be mild, with an average case fatality rate below 0.25%, but severe disease is not limited to patients with underlying medical conditions. Since A(H1N1) is expected to continue to circulate it is included in the seasonal influenza vaccines for the 2010–2011 winter season. We investigated the immunogenicity and safety of a preservative-free non-adjuvanted seasonal trivalent influenza vaccine. MethodsWe conducted a single center single-arm study involving 142 subjects (77 adults of 18–60 years and 65 subjects 61 years and above) to test the immunogenicity, safety, and tolerability of a trivalent split influenza vaccine. The vaccine contained 15μg of hemagglutinin of each of the virus strains recommended for the 2010–2011 northern hemisphere winter season (A/California/7/2009 (H1N1)-like strain; A/Perth/16/2009 (H3N2)-like strain; B/Brisbane/60/2008-like strain) in a non-adjuvanted preservative-free formulation. Antibody response to each antigen was measured by hemagglutination inhibition (HI) 21 days after immunization. Subject diary cards and additional telephone interviews were used to assess the safety profile. ResultsBy day 21 after the vaccination, seroconversion, or a 4-fold antibody increase in HI antibody titers, was detectable against A(H1N1) in 84% and 75% of younger and older adults, against A(H3N2) in 80% and 57%, and against the B influenza strain in 61% and 33%. HI antibody titers of 40 or more were observed against A(H1N1) in 99% and 90% of younger and older adults, against A(H3N2) in 100% and 90%, and against the B influenza strain in 91% and 78%. Pre-vaccination antibody titers were protective against A(H1N1), A(H3N2), and B in 26%, 44% and 33%, respectively of the adults below 61 years and in 27%, 54% and 44% of the subjects of 61 years and above. Local and systemic reactions were more common in younger than in older subjects and the most frequently reported reactions were pain at the injection site (36%), myalgia (24%), and fatigue (15%). Five percent elderly subjects and 1% of younger subjects had mild or moderate unsolicited adverse events such as prolonged ecchymosis or night sweats that resolved within 7 days after vaccination. ConclusionsThis single dose trivalent seasonal influenza vaccine generated protective antibodies to all three viral strains and had an acceptable safety profile in both younger and older adults (ClinicalTrials.gov identifier: NCT01147081).

Safety Review: Squalene and Thimerosal in Vaccines

Few studies show the reluctance of the people to get vaccinated against A (H1N1) influenza for fear of side effects of squalene (MF59, AS03, AF03) and thimerosal. The aim of this paper is to assess the safety in using these adjuvants and preservative reviewing data of clinical trials relative to wich formulation includes these compounds. In the current state of knowledge, these vaccines have proved to be effective even though they more frequently give local adverse events than non-adjuvanted influenza vaccines. Systemic side effects are generally not serious. In the studies, adjuvanted vaccines do not increase neither the risk of Guillain Barre syndrome nor auto-immune diseases. There is no convincing evidence that exposure to thimerosal in vaccines had any deletorious effect on physiological outcome.

Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03B/oil-in-water emulsion-adjuvanted (AS03B) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age

To evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children aged 6 months to 12 years. Multicentre, randomised, head-to-head, open-label trial. Five UK sites (Oxford, Bristol, Southampton, Exeter and London). Children aged 6 months to < 13 years, for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures, were eligible for inclusion. A tocopherol/oil-in-water emulsion-adjuvanted (AS03(B)) egg culture-derived split-virion H1N1 vaccine and a non-adjuvanted cell culture-derived whole-virion vaccine, given as a two-dose schedule, 21 days apart, were compared. Participants were grouped into those aged 6 months to < 3 years (younger group) and 3 years to < 13 years of age (older group) and were randomised by study investigators (1 : 1 ratio) to receive one of the two vaccines. Vaccines were administered by intramuscular injection (deltoid or anterior-lateral thigh, depending on age and muscle bulk). Local reactions and systemic symptoms were collected for 1 week post immunisation, and serum was collected at baseline and after the second dose. To assess safety and tolerability, parents or guardians recorded the following information in diary cards from days 0-7 post vaccination: axillary temperature, injection site reactions, solicited and unsolicited systemic symptoms, and medications. Comparison between vaccines of the percentage of participants demonstrating seroconversion by microneutralisation assay. Among 937 children receiving vaccine, per-protocol seroconversion rates were higher after the AS03(B)-adjuvanted vaccine than after the whole-virion vaccine (98.2% vs 80.1% in children < 3 years, 99.1% vs 95.9% among those aged 3-12 years), as were severe local reactions (3.6% vs 0.0% in those under 5 years, 7.8% vs 1.1% in those aged 5-12 years), irritability in children < 5 years (46.7% vs 32.0%), and muscle pain in older children (28.9% vs 13.2%). The second dose of the adjuvanted vaccine was more reactogenic than the first, especially for fever > 38.0°C in those under 5 years of age (8.9% vs 22.4%). The adjuvanted vaccine, although reactogenic, was more immunogenic, especially in younger children, indicating the potential for improved immunogenicity of influenza vaccines in this age group. ISRCTN89141709.

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.

Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study

Objectives To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United...

Influenza vaccine administration in rheumatoid arthritis patients under treatment with TNFα blockers: Safety and immunogenicity

Twenty-eight patients with low-moderate, stable rheumatoid arthritis (RA), under treatment with tumor necrosis factor (TNF) alpha blockers, were immunized at least once with non-adjuvanted trivalent influenza vaccine during three consecutive influenza seasons. Antibodies toward A influenza antigens significantly increased and reached protective levels, still detectable 6 months after vaccination, both in RA patients and healthy controls. Response to B antigen instead was only observed from the second year for healthy controls and in the third year for patients. No significant difference in disease activity and anti-nuclear antibodies was observed as a consequence of vaccine administration, whereas T regulatory cells showed a significant increase 30 days after immunization in RA patients. This study confirms safety of influenza vaccine administration in RA patients treated with TNFalpha blockers. The cohort follow-up revealed the overcoming of poor B vaccine antigen immunogenicity via repeated vaccinations. Finally, protective antibody response was still observed 6 months after vaccination.

Humoral and cellular immune responses to split-virion H5N1 influenza vaccine in young and elderly adults

We evaluated the humoral and cellular immunogenicity of adjuvanted and non-adjuvanted H5N1 influenza vaccine in two groups of 300 adults: aged 18–60 and >60 years in a randomized, open-label, uncontrolled phase 2 trial. Participants received two injections (D0, D21) of 7.5μg hemagglutinin without adjuvant or 30μg with aluminum hydroxide adjuvant. Antibody responses and cytokine secretion were assessed before and after vaccination. Excluding the 6/300 non-elderly and 47/300 elderly participants with pre-existing antibodies, geometric mean titers (dil−1) on D42 were higher with 30μg+Ad and were comparable between age groups. Participants with pre-existing antibodies responded strongly to the first vaccination (GMTs in the range 147–228 on D21). Vaccination increased both Th1 and Th2 T-cell responses. The predominantly Th1 profile observed before vaccination was unaffected by vaccination. H5N1 influenza vaccine is no less immunogenic in elderly adults than in younger adults and, due to a higher proportion non-naïve elderly, immunogenicity was higher in this latter group.

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

BackgroundAdding adjuvants such as MF59® 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. MethodsSafety 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 ≥65 years, in all clinical trials and in controlled trials only. FindingsData 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. InterpretationThis large-scale analysis supports the good safety profile of (+)MF59 seasonal and pandemic influenza vaccines and suggests a clinical benefit over (−)MF59 influenza vaccines.

Cross-Reactive Antibody Responses to the 2009 Pandemic H1N1 Influenza Virus

A new pandemic influenza A (H1N1) virus has emerged, causing illness globally, primarily in younger age groups. To assess the level of preexisting immunity in humans and to evaluate seasonal vaccine strategies, we measured the antibody response to the pandemic virus resulting from previous influenza infection or vaccination in different age groups. Using a microneutralization assay, we measured cross-reactive antibodies to pandemic H1N1 virus (2009 H1N1) in stored serum samples from persons who either donated blood or were vaccinated with recent seasonal or 1976 swine influenza vaccines. A total of 4 of 107 persons (4%) who were born after 1980 had preexisting cross-reactive antibody titers of 40 or more against 2009 H1N1, whereas 39 of 115 persons (34%) born before 1950 had titers of 80 or more. Vaccination with seasonal trivalent inactivated influenza vaccines resulted in an increase in the level of cross-reactive antibody to 2009 H1N1 by a factor of four or more in none of 55 children between the ages of 6 months and 9 years, in 12 to 22% of 231 adults between the ages of 18 and 64 years, and in 5% or less of 113 adults 60 years of age or older. Seasonal vaccines that were formulated with adjuvant did not further enhance cross-reactive antibody responses. Vaccination with the A/New Jersey/1976 swine influenza vaccine substantially boosted cross-reactive antibodies to 2009 H1N1 in adults. Vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1 in any age group. Persons under the age of 30 years had little evidence of cross-reactive antibodies to the pandemic virus. However, a proportion of older adults had preexisting cross-reactive antibodies.

Adjuvant is necessary for a robust immune response to a single dose of H1N1 pandemic flu vaccine in mice

Pandemic H1N1 influenza vaccine antigens are currently being manufactured. The MF59 adjuvant has an established safety profile in humans and a proven ability to increase responses to some influenza vaccines in humans. To inform initial decisions on the use of these vaccine components to protect human populations, we have immunized mice with MF59-adjuvanted or non-adjuvanted pandemic influenza vaccine. Immunizing unprimed mice with a single dose of MF59-adjuvanted vaccine elicits functional antibody titers equivalent to those associated with protection of humans from seasonal influenza. Without adjuvant, two doses are required for a robust antibody response. Unadjuvanted vaccines with 0.5 and 1 microgram of antigen elicit equivalent titers. These data support including MF59 in pandemic flu vaccines to rapidly protect young adults and children, who may have little or no previous exposure to influenza infection or immunization.

MF59 Emulsion Is an Effective Delivery System for a Synthetic TLR4 Agonist (E6020)

The effectiveness of vaccines depends on the age and immunocompetence of the vaccinee. Conventional non-adjuvanted influenza vaccines are suboptimal in the elderly and vaccines with improved ability to prevent influenza are required. The TLR4 agonist E6020, either given alone or co-delivered with MF59, was evaluated and compared to MF59 and the TLR9 agonist CpG. Its ability to enhance antibody titres and to modulate the quality of the immune response to a subunit influenza vaccine was investigated. Mice were immunized with either antigens alone, with MF59 or with the TLR agonists alone, or with a combination thereof. Serum samples were assayed for IgG antibody titres and hemagglutination inhibition (HI) titres. Th1/Th2 type responses were determined by titrating IgG subclasses in serum samples and by T-cell cytokine responses in splenocytes. MF59 was the best single adjuvant inducing HI and T-cell responses in comparison to all alternatives. The co-delivery of E6020 or CpG with MF59 did not further increase antibody titres however shifted towards a more Th1 based immune response. Combining adjuvants like E6020 and MF59 allowed a finer tuning of the immune response towards a particular Th bias, thus have significant implications for the development of improved influenza vaccines.