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The virosomal influenza vaccine Invivac®: Immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad®) in elderly subjects
Vaccine 24 (2006) 6629–6631
Short communication
The virosomal influenza vaccine Invivac®: Immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad®) in elderly subjects I.A. de Bruijn ∗ , J. Nauta, L. Gerez, A.M. Palache Solvay Pharmaceuticals B.V., PO Box 900, 1380 DA Weesp, The Netherlands Available online 5 June 2006
Abstract Several approaches are currently being pursued in order to improve the efficacy of influenza vaccines in elderly individuals and others who have impaired immune responses to conventional influenza vaccines. There are two influenza vaccines available for elderly subjects: Fluad® (Chiron) and Invivac® (Solvay Pharmaceuticals). The present clinical study was a randomized, endpoint-blind, parallel group study in elderly subjects aged 61 years and older to investigate the safety and immunogenicity of these vaccines as compared to a standard influenza vaccine Invivac® (Solvay Pharmaceuticals). The three vaccines had similar immunogenicity results, whereas the tolerability profile of Invivac was better as compared to Fluad. © 2006 Elsevier Ltd. All rights reserved. Keywords: Influenza; Influenza vaccine; Elderly; Improved immunogenicity; Tolerability; Virosomal; Adjuvant
1. Introduction Current available influenza vaccines are safe and effective in preventing influenza. Nevertheless, there is a need for influenza vaccines with improved efficacy particularly in the elderly. Several approaches are currently being pursued in order to improve the efficacy of influenza vaccines in elderly individuals and others who have impaired immune responses to conventional influenza vaccines. The present clinical study assessed the immunogenicity and tolerability of two commercially available vaccines for elderly subjects as compared to a standard influenza vaccine.
2. Methods We carried out a randomized, endpoint-blind, parallel group study in elderly subjects. Subjects were 61 years of age or older and had not been vaccinated with influenza vaccine within 6 months of the study. Exclusion criteria were ∗
Corresponding author. Tel.: +31 294 477634; fax: +31 294 410571. E-mail address: [email protected] (I.A. de Bruijn).
0264-410X/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2006.05.035
allergy to any constituent of the vaccines, presenting with fever, having an auto-immune disease or using immunosuppressive medication or having had a serious adverse reaction to previous influenza vaccination. 2.1. Study objectives and outline Primary objective: to show that in elderly a virosomal influenza vaccine is not inferior to a standard inactivated influenza vaccine regarding immunogenicity. Secondary objectives: to investigate whether in elderly the virosomal vaccine is not inferior to an adjuvanted influenza vaccine regarding immunogenicity and to assess whether the virosomal vaccine meets the European CHMP requirement for immunogenicity in elderly. Safety objectives: to collect data on the safety and the tolerability of the virosomal vaccine in elderly subjects; and to investigate whether the virosomal vaccine is superior to an adjuvanted vaccine with respect to local reactogenicity. Assessments were made at two visits: screening and baseline assessments (Visit 1) and follow up assessments 3 weeks later (Visit 2). Immunogenicity was assessed by HI titer in pre- and post-vaccination serum. Safety was assessed by monitoring adverse events throughout the
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Table 1 Geometric mean titer ratio’s Strain
A (H3N2)-like (N = 125)
A (H1N1)-like (N = 121)
B-like (N = 126)
Invivac to Influvac Geometric mean ratio 95% confidence interval
1.11 (0.907, 1.366)
0.88 (0.668, 1.152)
0.94 (0.712, 1.237)
Invivac to Fluad Geometric mean ratio 95% confidence interval
0.89 (0.742, 1.072)
1.11 (0.837, 1.466)
0.90 (0.698, 1.172)
study and recording local and systemic reactogenicity during 3 days after vaccination. 2.2. Vaccines The subjects received a single 0.5 mL dose of the 2004/2005 season’s: virosomal influenza vaccine Invivac® (Solvay Pharmaceuticals B.V., The Netherlands), adjuvanted vaccine Fluad® (Chiron, Italy), or subunit vaccine Influvac® (Solvay Pharmaceuticals B.V., The Netherlands). 2.3. Number of subjects Planned: 360 subjects (120 subjects per group). Consented and randomized: 386 subjects (129, 127 and 130 in the Influvac, Invivac and Fluad groups, respectively). Safety sample: 386 subjects. Efficacy sample: 372 subjects (125, 121 and 126, respectively).
Table 2 Reactogenicity
N Local reactions (%) Subjects reporting at least one reaction Most frequently reported: pain Systemic reactions (%) Subjects reporting at least one reaction Most frequently reported: headache
Influvac
Invivac
Fluad
129
127
130
18.8
21.3
46.2
13
37
21.9
18.9
31.5
11
14
18
9
70.3, respectively, for Influvac, Invivac and Fluad; about 50% of subjects was aged over 70 years. 3.1. Immunogenicity
2.4. Efficacy and safety Efficacy: The primary efficacy variable was the geometric mean HI titer 3 weeks after vaccination. Safety: spontaneously reported treatment emergent adverse events (TEAEs) were monitored throughout the study. Tolerability, including local and systemic reactions, was recorded by the subjects on a questionnaire during the first 72 h after vaccination. 2.5. Statistical methods Efficacy: Immunogenicity was assessed using the CHMP criteria for influenza vaccines. Non-inferiority was analyzed by calculating, per viral strain, the lower limit of the twosided 95% confidence interval (CI) for the ratio of the Day 22 geometric mean titers (Invivac/comparator). Safety: The superiority of Invivac over Fluad with respect to local reactogenicity was analyzed by comparing the number of local reactions per subject between the Invivac and Fluad groups using Wilcoxon’s rank-sum test at the two-sided 0.05 significance level.
3. Results The demographic characteristics were comparable between the three groups, mean ages were 70.5, 69.8 and
Pre-vaccination titers were similar between the three vaccination groups for all three strains. For all three vaccines, the CHMP criteria for immunogenicity were fulfilled. Seroprotection rates exceeded 90% for almost all strains (data not shown). Analysis of the post-vaccination geometric mean ratios (GMRs) for Invivac to Influvac and Invivac to Fluad is summarized in Table 1. For all three strains the lower limit of the CI fell above the pre-defined non-inferiority margin of 0.25. It can thus be concluded that, in the elderly, the immunogenicity of Invivac is neither inferior to that of Influvac, nor to that of Fluad. 3.2. Tolerability and safety No deaths occurred during the study. One subject (Fluad) experienced four serious adverse events (arthralgia, sepsis, joint abscess and psoas abscess), all were judged as not related to the study vaccine and the subject recovered completely. Number of subjects who experienced at least one TEAE were: Influvac 11 (8.5%), Invivac 8 (6.3%) and Fluad 18 (13.8%). The most frequently reported TEAEs were: arthralgia (Influvac: 1.6%; Invivac: 0.8%; Fluad: 0.8%) and injection site erythema (Influvac: 0.0%; Invivac: 0.8%; Fluad: 2.3%). Local and systemic reactions are shown in Table 2. For Influvac and Invivac these reactions lasted mostly 1–2 days, whereas for Fluad a significant amount of reactions lasted 3 days. Eight
I.A. de Bruijn et al. / Vaccine 24 (2006) 6629–6631
subjects (Invivac: one subject (0.8%) and Fluad: seven subjects (5.4%)) had injection site reactions still present after 3 days post-vaccination. On comparison of the mean number of local reactions per subject between Invivac and Fluad (0.3 and 1.1, respectively), a statistically significantly lower number of local reactions was observed following vaccination with Invivac compared with Fluad (p < 0.001).
4. Conclusions • In elderly subjects, the virosomal influenza vaccine Invivac is not inferior to the conventional influenza vaccine Influvac or to the adjuvanted influenza vaccine Fluad with respect to the immunogenicity of the HA of the three viral strains contained in the vaccines.
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• All vaccines met all three CHMP criteria for immunogenicity in the elderly, for all three strains. • Invivac was safe and well tolerated in elderly subjects. The safety and tolerability of Invivac was similar to the standard influenza vaccine Influvac. • Subjects vaccinated with the adjuvanted influenza vaccine Fluad reported on average significantly more local reactions per subject than subjects vaccinated with Invivac or Influvac. • Local reactions after vaccination with Fluad lasted somewhat longer than with Invivac or Influvac. It can be concluded that in elderly subjects, Invivac has a similar immunogenicity to the standard as well as to the adjuvanted influenza vaccine, but has a better tolerability profile as compared to the adjuvanted vaccine Fluad.
Short communication
The virosomal influenza vaccine Invivac®: Immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad®) in elderly subjects I.A. de Bruijn ∗ , J. Nauta, L. Gerez, A.M. Palache Solvay Pharmaceuticals B.V., PO Box 900, 1380 DA Weesp, The Netherlands Available online 5 June 2006
Abstract Several approaches are currently being pursued in order to improve the efficacy of influenza vaccines in elderly individuals and others who have impaired immune responses to conventional influenza vaccines. There are two influenza vaccines available for elderly subjects: Fluad® (Chiron) and Invivac® (Solvay Pharmaceuticals). The present clinical study was a randomized, endpoint-blind, parallel group study in elderly subjects aged 61 years and older to investigate the safety and immunogenicity of these vaccines as compared to a standard influenza vaccine Invivac® (Solvay Pharmaceuticals). The three vaccines had similar immunogenicity results, whereas the tolerability profile of Invivac was better as compared to Fluad. © 2006 Elsevier Ltd. All rights reserved. Keywords: Influenza; Influenza vaccine; Elderly; Improved immunogenicity; Tolerability; Virosomal; Adjuvant
1. Introduction Current available influenza vaccines are safe and effective in preventing influenza. Nevertheless, there is a need for influenza vaccines with improved efficacy particularly in the elderly. Several approaches are currently being pursued in order to improve the efficacy of influenza vaccines in elderly individuals and others who have impaired immune responses to conventional influenza vaccines. The present clinical study assessed the immunogenicity and tolerability of two commercially available vaccines for elderly subjects as compared to a standard influenza vaccine.
2. Methods We carried out a randomized, endpoint-blind, parallel group study in elderly subjects. Subjects were 61 years of age or older and had not been vaccinated with influenza vaccine within 6 months of the study. Exclusion criteria were ∗
Corresponding author. Tel.: +31 294 477634; fax: +31 294 410571. E-mail address: [email protected] (I.A. de Bruijn).
0264-410X/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2006.05.035
allergy to any constituent of the vaccines, presenting with fever, having an auto-immune disease or using immunosuppressive medication or having had a serious adverse reaction to previous influenza vaccination. 2.1. Study objectives and outline Primary objective: to show that in elderly a virosomal influenza vaccine is not inferior to a standard inactivated influenza vaccine regarding immunogenicity. Secondary objectives: to investigate whether in elderly the virosomal vaccine is not inferior to an adjuvanted influenza vaccine regarding immunogenicity and to assess whether the virosomal vaccine meets the European CHMP requirement for immunogenicity in elderly. Safety objectives: to collect data on the safety and the tolerability of the virosomal vaccine in elderly subjects; and to investigate whether the virosomal vaccine is superior to an adjuvanted vaccine with respect to local reactogenicity. Assessments were made at two visits: screening and baseline assessments (Visit 1) and follow up assessments 3 weeks later (Visit 2). Immunogenicity was assessed by HI titer in pre- and post-vaccination serum. Safety was assessed by monitoring adverse events throughout the
6630
I.A. de Bruijn et al. / Vaccine 24 (2006) 6629–6631
Table 1 Geometric mean titer ratio’s Strain
A (H3N2)-like (N = 125)
A (H1N1)-like (N = 121)
B-like (N = 126)
Invivac to Influvac Geometric mean ratio 95% confidence interval
1.11 (0.907, 1.366)
0.88 (0.668, 1.152)
0.94 (0.712, 1.237)
Invivac to Fluad Geometric mean ratio 95% confidence interval
0.89 (0.742, 1.072)
1.11 (0.837, 1.466)
0.90 (0.698, 1.172)
study and recording local and systemic reactogenicity during 3 days after vaccination. 2.2. Vaccines The subjects received a single 0.5 mL dose of the 2004/2005 season’s: virosomal influenza vaccine Invivac® (Solvay Pharmaceuticals B.V., The Netherlands), adjuvanted vaccine Fluad® (Chiron, Italy), or subunit vaccine Influvac® (Solvay Pharmaceuticals B.V., The Netherlands). 2.3. Number of subjects Planned: 360 subjects (120 subjects per group). Consented and randomized: 386 subjects (129, 127 and 130 in the Influvac, Invivac and Fluad groups, respectively). Safety sample: 386 subjects. Efficacy sample: 372 subjects (125, 121 and 126, respectively).
Table 2 Reactogenicity
N Local reactions (%) Subjects reporting at least one reaction Most frequently reported: pain Systemic reactions (%) Subjects reporting at least one reaction Most frequently reported: headache
Influvac
Invivac
Fluad
129
127
130
18.8
21.3
46.2
13
37
21.9
18.9
31.5
11
14
18
9
70.3, respectively, for Influvac, Invivac and Fluad; about 50% of subjects was aged over 70 years. 3.1. Immunogenicity
2.4. Efficacy and safety Efficacy: The primary efficacy variable was the geometric mean HI titer 3 weeks after vaccination. Safety: spontaneously reported treatment emergent adverse events (TEAEs) were monitored throughout the study. Tolerability, including local and systemic reactions, was recorded by the subjects on a questionnaire during the first 72 h after vaccination. 2.5. Statistical methods Efficacy: Immunogenicity was assessed using the CHMP criteria for influenza vaccines. Non-inferiority was analyzed by calculating, per viral strain, the lower limit of the twosided 95% confidence interval (CI) for the ratio of the Day 22 geometric mean titers (Invivac/comparator). Safety: The superiority of Invivac over Fluad with respect to local reactogenicity was analyzed by comparing the number of local reactions per subject between the Invivac and Fluad groups using Wilcoxon’s rank-sum test at the two-sided 0.05 significance level.
3. Results The demographic characteristics were comparable between the three groups, mean ages were 70.5, 69.8 and
Pre-vaccination titers were similar between the three vaccination groups for all three strains. For all three vaccines, the CHMP criteria for immunogenicity were fulfilled. Seroprotection rates exceeded 90% for almost all strains (data not shown). Analysis of the post-vaccination geometric mean ratios (GMRs) for Invivac to Influvac and Invivac to Fluad is summarized in Table 1. For all three strains the lower limit of the CI fell above the pre-defined non-inferiority margin of 0.25. It can thus be concluded that, in the elderly, the immunogenicity of Invivac is neither inferior to that of Influvac, nor to that of Fluad. 3.2. Tolerability and safety No deaths occurred during the study. One subject (Fluad) experienced four serious adverse events (arthralgia, sepsis, joint abscess and psoas abscess), all were judged as not related to the study vaccine and the subject recovered completely. Number of subjects who experienced at least one TEAE were: Influvac 11 (8.5%), Invivac 8 (6.3%) and Fluad 18 (13.8%). The most frequently reported TEAEs were: arthralgia (Influvac: 1.6%; Invivac: 0.8%; Fluad: 0.8%) and injection site erythema (Influvac: 0.0%; Invivac: 0.8%; Fluad: 2.3%). Local and systemic reactions are shown in Table 2. For Influvac and Invivac these reactions lasted mostly 1–2 days, whereas for Fluad a significant amount of reactions lasted 3 days. Eight
I.A. de Bruijn et al. / Vaccine 24 (2006) 6629–6631
subjects (Invivac: one subject (0.8%) and Fluad: seven subjects (5.4%)) had injection site reactions still present after 3 days post-vaccination. On comparison of the mean number of local reactions per subject between Invivac and Fluad (0.3 and 1.1, respectively), a statistically significantly lower number of local reactions was observed following vaccination with Invivac compared with Fluad (p < 0.001).
4. Conclusions • In elderly subjects, the virosomal influenza vaccine Invivac is not inferior to the conventional influenza vaccine Influvac or to the adjuvanted influenza vaccine Fluad with respect to the immunogenicity of the HA of the three viral strains contained in the vaccines.
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• All vaccines met all three CHMP criteria for immunogenicity in the elderly, for all three strains. • Invivac was safe and well tolerated in elderly subjects. The safety and tolerability of Invivac was similar to the standard influenza vaccine Influvac. • Subjects vaccinated with the adjuvanted influenza vaccine Fluad reported on average significantly more local reactions per subject than subjects vaccinated with Invivac or Influvac. • Local reactions after vaccination with Fluad lasted somewhat longer than with Invivac or Influvac. It can be concluded that in elderly subjects, Invivac has a similar immunogenicity to the standard as well as to the adjuvanted influenza vaccine, but has a better tolerability profile as compared to the adjuvanted vaccine Fluad.