Victoria Landolfi

Efficacy of high-dose versus standard-dose influenza vaccine in older adults.

BACKGROUND As compared with a standard-dose vaccine, a high-dose, trivalent, inactivated influenza vaccine (IIV3-HD) improves antibody responses to influenza among adults 65 years of age or older. This study evaluated whether IIV3-HD also improves protection against laboratory-confirmed influenza illness. METHODS We conducted a phase IIIb-IV, multicenter, randomized, double-blind, active-controlled trial to compare IIV3-HD (60 μg of hemagglutinin per strain) with standard-dose trivalent, inactivated influenza vaccine (IIV3-SD [15 μg of hemagglutinin per strain]) in adults 65 years of age or older. Assessments of relative efficacy, effectiveness, safety (serious adverse events), and immunogenicity (hemagglutination-inhibition [HAI] titers) were performed during the 2011-2012 (year 1) and the 2012-2013 (year 2) northern-hemisphere influenza seasons. RESULTS A total of 31,989 participants were enrolled from 126 research centers in the United States and Canada (15,991 were randomly assigned to receive IIV3-HD, and 15,998 to receive IIV3-SD). In the intention-to-treat analysis, 228 participants in the IIV3-HD group (1.4%) and 301 participants in the IIV3-SD group (1.9%) had laboratory-confirmed influenza caused by any viral type or subtype associated with a protocol-defined influenza-like illness (relative efficacy, 24.2%; 95% confidence interval [CI], 9.7 to 36.5). At least one serious adverse event during the safety surveillance period was reported by 1323 (8.3%) of the participants in the IIV3-HD group, as compared with 1442 (9.0%) of the participants in the IIV3-SD group (relative risk, 0.92; 95% CI, 0.85 to 0.99). After vaccination, HAI titers and seroprotection rates (the percentage of participants with HAI titers ≥ 1:40) were significantly higher in the IIV3-HD group. Conclusions: Among persons 65 years of age or older, IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did IIV3-SD. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01427309.).

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

BACKGROUND High-dose trivalent influenza vaccine was developed to improve antibody responses to influenza vaccine in the elderly and hence potentially impact favorably on influenza-associated morbidity and mortality in this population. METHODS A phase IIIb, multicenter, randomized, double-blind, controlled trial was conducted to compare High-Dose (HD) trivalent inactivated influenza vaccine (60μg of hemagglutinin [HA] per strain) to standard dose (SD) vaccine (15μg of HA per strain) in adults ≥65 years of age. Assessments of safety (serious adverse events [SAE]), immunogenicity (hemagglutination inhibition [HAI] titers) and relative efficacy were performed during the 2009-2010 influenza season, which coincided with the H1N1 pandemic. RESULTS A total of 9172 participants were enrolled in 99 research centers in the US (6117 and 3055 randomized to the HD and SD groups, respectively). Within 180 days after vaccination, 6.7% and 6.5% of participants in the HD and SD vaccine groups, respectively, experienced at least one SAE, of which 0.4% and 0.3% had a fatal outcome. A total of 0.5% of participants in both groups discontinued the study due to a SAE. Post-vaccination HAI titers and rate of post-vaccination HAI titer ≥1:40 were significantly higher in the HD group. No cases of influenza caused by viral types/subtypes similar to those in the vaccines were observed. All cases genetically or antigenically characterized were classified as similar to influenza A/California/7/2009 (H1N1), the pandemic strain. The vaccine efficacy of HD vaccine relative to SD vaccine against any influenza viral type/subtype was 12.6% (95% CI -140.5; 65.8) in the intent-to-treat analysis. CONCLUSION High-dose trivalent inactivated influenza vaccine is safe and well tolerated and provides superior immune responses compared to standard dose vaccine. Demonstration of a superior vaccine efficacy requires a separate large randomized, controlled trial.

Immunogenicity and safety of Fluzone(®) intradermal and high-dose influenza vaccines in older adults ≥65 years of age: a randomized, controlled, phase II trial.

We conducted a randomized, controlled, multicenter, phase II study to evaluate the immunogenicity and safety of an investigational intradermal (ID) trivalent influenza vaccine (TIV) and a high-dose (HD) intramuscular (IM) TIV in older adults (≥65 years of age). Older adult subjects were immunized with ID vaccine containing either 15μg hemagglutinin (HA)/strain (n=636) or 21μg HA/strain (n=634), with HD IM vaccine containing 60μg HA/strain (n=320), or with standard-dose (SD) IM vaccine (Fluzone(®); 15μg HA/strain; n=319). For comparison, younger adults (18-49 years of age) were immunized with SD IM vaccine. In older adults, post-vaccination geometric mean titers induced by the ID vaccines were superior to those induced by the SD IM vaccine for the A/H1N1 and A/H3N2 strains and non-inferior for the B strain. Seroconversion rates induced by the ID vaccines were superior to those induced by the SD IM vaccine in older adults for the A/H1N1 and B strains and non-inferior for the A/H3N2 strain. Results did not differ significantly for the two ID vaccine dosages. Post-vaccination geometric mean titers, seroconversion rates, and most seroprotection rates were significantly higher in HD vaccine recipients than in older adult recipients of the SD IM or ID vaccines and, for most measures, were comparable to those of younger adult SD IM vaccine recipients. Injection-site reactions, but not systemic reactions or unsolicited adverse events, were more common with the ID vaccines than with the IM vaccines. No treatment-related serious adverse events were reported. This study demonstrated that: (1) the ID and HD vaccines were well-tolerated and more immunogenic than the SD IM vaccine in older adults; (2) the HD vaccine was more immunogenic than the ID vaccines in older adults; and (3) the HD vaccine in older adults and the SD IM vaccine in younger adults elicited comparable antibody responses (ClinicalTrials.gov identifier no.: NCT00551031).

Prevention of serious events in adults 65 years of age or older: A comparison between high-dose and standard-dose inactivated influenza vaccines

BACKGROUND A recent study showed that a high-dose inactivated influenza vaccine (IIV-HD) was 24.2% more efficacious than a standard-dose inactivated influenza vaccine (IIV-SD) in preventing laboratory-confirmed symptomatic influenza in adults ≥65 years. Here we evaluate the effectiveness of IIV-HD compared to IIV-SD in preventing serious illnesses considered potential sequelae or complications of influenza infection. METHODS The original study was a double-blind, randomized, active-controlled, multicenter trial. Participants were adults ≥65 years randomized to receive IIV-HD or IIV-SD, and followed for 6-8 months post-vaccination for the occurrence of influenza and serious adverse events (SAEs). SAEs were events: leading to death or hospitalization (or its prolongation); considered life-threatening or medically important; or resulting in disability. For the present analysis, reported SAEs were classified as possibly related to influenza by three blinded physicians and rates per 1000 participant-seasons were calculated. Relative vaccine effectiveness (rVE) was estimated as (1-Rate Ratio)×100. RESULTS 31,989 participants were enrolled, with 15,991 and 15,998 randomized to receive IIV-HD and IIV-SD, respectively. IIV-HD was significantly more effective than IIV-SD in preventing SAEs possibly related to influenza overall (rVE, 17.7%; 95% confidence interval [CI], 6.6-27.4%) and serious pneumonia (rVE, 39.8%; 95% CI, 19.3-55.1%). Borderline significance was observed for the efficacy of IIV-HD relative to IIV-SD for the prevention of all-cause hospitalizations (rVE, 6.9%; 95% CI, 0.5-12.8%). CONCLUSIONS Compared to IIV-SD, IIV-HD reduced the risk of SAEs possibly related to influenza. The observed relative effectiveness against serious pneumonia is particularly noteworthy considering the burden of influenza and pneumonia in older adults.

Efficacy and immunogenicity of high-dose influenza vaccine in older adults by age, comorbidities, and frailty.

BACKGROUND A randomized trial demonstrated that a high-dose inactivated influenza vaccine (IIV-HD) was 24.2% more efficacious than a standard-dose vaccine (IIV-SD) against laboratory-confirmed influenza illness in adults ≥65 years. To evaluate the consistency of IIV-HD benefits, supplemental analyses explored efficacy and immunogenicity by baseline characteristics of special interest. METHODS Double-blind, randomized, active-controlled, multicenter trial. Adults ≥65 years were randomized 1:1 to receive IIV-HD or IIV-SD and followed for 6-8 months postvaccination for the occurrence of influenza. One third of participants were randomly selected to provide sera for measurement of hemagglutination inhibition antibody (HAI) titers. Efficacy (IIV-HD vs. IIV-SD) against laboratory-confirmed, protocol-defined influenza-like illness (PD-ILI) and HAI geometric mean titer (GMT) ratios (IIV-HD/IIV-SD) were evaluated by age, and number of high-risk comorbid and frailty conditions. RESULTS Efficacy (95% confidence intervals) of IIV-HD relative to IIV-SD against laboratory-confirmed PD-ILI was 19.7% (0.4%; 35.4%) for participants 65-74 years, 32.4% (8.1%; 50.6%) for those ≥75 years, 22.1% (3.9%; 37.0%) for participants with ≥1 high-risk comorbidity, 23.6% (-3.2%; 43.6%) for those with ≥2 high-risk comorbidities, 27.5% (0.4%; 47.4%) for persons with 1 frailty condition, 23.9% (-9.0%; 47.2%) for those with 2 frailty conditions, and 16.0% (-16.3%; 39.4%) for those with ≥3 frailty conditions. There was no evidence of vaccine efficacy heterogeneity within age, comorbidity, and frailty strata (P-values 0.351, 0.875, and 0.838, respectively). HAI GMT ratios were significantly higher among IIV-HD recipients for all strains and across all subgroups. CONCLUSIONS Estimates of relative efficacy consistently favored IIV-HD over IIV-SD. There was no significant evidence that baseline age, comorbidity, or frailty modified the efficacy of IIV-HD relative to IIV-SD. IIV-HD significantly improved HAI responses for all strains and in all subgroups. IIV-HD is likely to provide benefits beyond IIV-SD for adults ≥65 years, irrespective of age and presence of comorbid or frailty conditions.

Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial

ABSTRACT Although a number of studies have investigated and quantified immune correlates of protection against influenza in adults and children, data on immune protection in the elderly are sparse. A recent vaccine efficacy trial comparing standard-dose with high-dose inactivated influenza vaccine in persons 65 years of age and older provided the opportunity to examine the relationship between values of three immunologic assays and protection against community-acquired A/H3N2 influenza illness. The high-dose vaccine induced significantly higher antibody titers than the standard-dose vaccine for all assays. For the hemagglutination inhibition assay, a titer of 40 was found to correspond with 50% protection when the assay virus was antigenically well matched to the circulating virus—the same titer as is generally recognized for 50% protection in younger adults. A dramatically higher titer was required for 50% protection when the assay virus was a poor match to the circulating virus. With the well-matched virus, some protection was seen at the lowest titers; with the poorly matched virus, high levels of protection were not achieved even at the highest titers. Strong associations were also seen between virus neutralization test titers and protection, but reliable estimates for 50% protection were not obtained. An association was seen between titers of an enzyme-linked lectin assay for antineuraminidase N2 antibodies and protection; in particular, the proportion of treatment effect explained by assay titer in models that included both this assay and one of the other assays was consistently higher than in models that included either assay alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01427309.)

Safety and immunogenicity of a quadrivalent intradermal influenza vaccine in adults

BACKGROUND An intradermal (ID) trivalent split-virion influenza vaccine (IIV3-ID) (Fluzone(®) Intradermal, Sanofi Pasteur, Swiftwater, PA) has been available in the US since the 2011/2012 influenza season for adults aged 18-64 years. This study examined whether adding a second B-lineage strain affects immunogenicity and safety. METHODS This randomized, double-blind, multicentre trial evaluated the immunogenicity and safety of an intradermal quadrivalent split-virion influenza vaccine (IIV4-ID) in adults 18-64 years of age in the US during the 2012-2013 influenza season. Participants were randomized 2:1:1 to receive a single injection of IIV4-ID, licensed IIV3-ID, or an investigational IIV3-ID containing the alternate B-lineage strain. Haemagglutination inhibition antibody titres were assessed in two-thirds of participants before vaccination and 28 days after vaccination. RESULTS 1672 participants were vaccinated with IIV4-ID, 837 with licensed IIV3-ID, and 846 with an investigational IIV3-ID. For all four vaccine strains, antibody responses to IIV4-ID were statistically non-inferior to the response to the IIV3-ID vaccines containing the matched strains. For both B strains, post-vaccination antibody responses to IIV4-ID were statistically superior to the responses to IIV3-ID lacking the corresponding B strain. Adverse events were similar for IIV4-ID and IIV3-ID. The most commonly reported solicited reactions were pain, pruritus, myalgia, headache, and malaise; and most were grade 1 or 2 and appeared and resolved within 3 days of vaccination. IIV4-ID was statistically non-inferior to the two pooled IIV3-ID vaccines for the proportions of participants with at least one grade 2 or 3 systemic reaction. CONCLUSIONS Antibody responses to the IIV4-ID were non-inferior to IIV3-ID for the A and matched B strains and superior for the unmatched B strains. IIV4-ID was well tolerated without any safety concerns. IIV4-ID may help address an unmet need due to mismatched B strains in previous influenza vaccines.

Effect of Previous-Year Vaccination on the Efficacy, Immunogenicity, and Safety of High-Dose Inactivated Influenza Vaccine in Older Adults

High-dose inactivated split-virus influenza vaccine showed higher immunogenicity and relative efficacy compared with standard-dose inactivated split-virus influenza vaccine, irrespective of type of vaccine used the preceding year. The safety profile was also unaffected by previous-year vaccine.

Safety and immunogenicity of revaccination with reduced dose intradermal and standard dose intramuscular influenza vaccines in adults 18–64 years of age

BACKGROUND This clinical trial examined the safety and immunogenicity of annual revaccination with Fluzone(®) Intradermal (Sanofi Pasteur, Swiftwater, PA) vaccine compared to a standard intramuscular (IM) split-virion trivalent influenza vaccine (Fluzone(®), Sanofi Pasteur). METHODS This phase II, active-controlled, multi-centre, open-label trial was conducted in 2009 and 2010, and enrolled 1250 adults 18-64 years of age who were randomly selected from participants in a phase III influenza vaccine trial the previous year (NCT00772109). Subjects who had previously received the ID vaccine were randomized 2:1 to be revaccinated with the ID or IM vaccine and those who previously received the IM vaccine were randomized 1:1. Solicited reactions were recorded on the day of vaccination and continuing for the next 7 days, non-serious adverse events for 28 days, and serious adverse events for 6 months after vaccination. Hemagglutination inhibition antibody titres were assessed pre-vaccination and at day 28. RESULTS Reactions were well-tolerated and resolved in the first 7 days, but erythema, induration, swelling, pruritus and ecchymosis were reported by more subjects receiving the ID vaccine than the IM vaccine. Compared to receipt of IM vaccine in the previous year, ID vaccine in the previous year led to statistically higher rates of erythema, swelling and induration after IM vaccine in the second year. Injection-site pain and systemic reactions did not differ between ID and IM vaccines. No treatment-related serious adverse events were reported. Geometric mean antibody titres, seroprotection rates, and seroconversion rates were non-inferior for the ID and IM vaccines for all three viral strains. CONCLUSIONS The ID vaccine was as immunogenic as the IM vaccine, and raised no safety concerns. It can be used interchangeably with the IM vaccine for annual revaccination in adults 18-64 years of age in consecutive years without safety concerns.

Safety and immunogenicity of high-dose trivalent inactivated influenza vaccine in adults 50-64 years of age.

BACKGROUND Individuals 50-64 years of age have reduced immune responses to influenza vaccines. The current study examined whether a high-dose inactivated trivalent influenza vaccine (IIV3-HD) might improve immune responses over a standard-dose inactivated influenza vaccine (IIV3-SD) in this age group. METHODS This was a multicenter, observer-blinded, randomized, active-controlled phase II trial. Adults 50-64 years of age were randomized 1:1 to receive IIV3-HD or IIV3-SD. Hemagglutination inhibition titers were measured before and 28 days after vaccination. Reactogenicity was recorded for 7 days after vaccination and adverse events for 28 days. RESULTS 148 participants received IIV3-HD and 152 received IIV3-SD. For all vaccine strains, day 28 geometric mean hemagglutination inhibition titers were significantly higher in the IIV3-HD group than in the IIV3-SD group (geometric mean titer ratio [95% confidence interval (CI)]=1.43 [1.04-1.97] for A/H1N1, 1.65 [1.21-2.25] for A/H3N2, and 1.60 [1.23-2.08] for B). Seroconversion rates were significantly higher in the IIV3-HD group than in the IIV3-SD group for strains A/H3N2 and B but not A/H1N1 (difference [95% CI]=13.5% [4.76-22.0] for A/H3N2, 23.1% [11.7-33.6] for B, and -0.2% [-9.66 to 9.18] for A/H1N1). The post-vaccination seroprotection rate was significantly higher in the IIV3-HD group than in the IIV3-SD group for strain B but not for strains A/H1N1 or A/H3N2 (difference=9.1% [2.95-15.7] for B, 2.0% [-0.907 to 5.68] for A/H1N1, and 0.6% [-3.14 to 4.43] for A/H3N2). Reactogenicity was higher in the IIV3-HD group than in the IIV3-SD group, but reactions were mostly of low intensity, transient, and self-limited. Rates of unsolicited adverse events were similar between groups. No serious AEs, AEs leading to early withdrawal, or deaths were reported. CONCLUSIONS The study suggests that in adults 50-64 years of age, IIV3-HD may improve immunogenicity compared to IIV3-SD while maintaining an acceptable safety profile.