Abstract
Immunogenicity and safety of a booster dose of an MF59-adjuvanted H5N1 vaccine containing 7.5 μg A/turkey/Turkey/1/2005-like (clade 2.2) H5N1 hemagglutinin, given approximately 18 months after primary vaccination with a heterologous strain, were evaluated. The booster vaccine was well tolerated and induced a robust, cross-reactive immune response.
Immunization against pandemic virus strains, such as H5N1, is a keystone of pandemic preparedness plans (5, 7, 12). In addition, due to the need to rapidly produce many doses, vaccine hemagglutinin (HA) content may be a limiting factor, which may be countered by the inclusion of an adjuvant, such as MF59. Considering the unpredictable emergence and rapid spread of pandemic influenza together with the time needed to produce and distribute a pandemic influenza vaccine, proactive prepandemic vaccination presents a valuable opportunity to reduce the impact of pandemic influenza disease. In addition to having an excellent safety profile, a prepandemic vaccine should offer broad, robust immunity that can be easily boosted with a flexible dosing schedule (5).
(This work was presented in part at Influenza Vaccines for the World [IVW 2009], 27 to 30 April 2009, Cannes, France.)
An H5N1 vaccine containing the MF59 adjuvant (Aflunov; Novartis Vaccines and Diagnostics) was developed and administered to healthy volunteers in a clinical trial setting. The present study was an extension of a trial (NCT00311480) in which 486 subjects over 18 years of age received two primary doses of the MF59-adjuvanted H5N1 vaccine, formulated with 7.5 μg or 15 μg HA per dose of the A/Vietnam/1194/2004 (clade 1), at an interval of 3 weeks; a subset of 223 subjects received a homologous booster dose at 6 months (2). Those who did not receive the booster dose at 6 months were eligible for inclusion in this extension study (NCT 00561184), which evaluated the safety and immunogenicity of one 0.5-ml dose of MF59-adjuvanted H5N1 vaccine, containing 7.5 μg of HA from the A/turkey/Turkey/1/2005-like strain (clade 2), approximately 18 months after primary vaccination. The inclusion and exclusion criteria and laboratory and safety surveillance methods used in this extension study were similar to those of the initial study (2). There was no statistical null hypothesis for the immunogenicity assessments, which were based on European Committee for Medicinal Products for Human Use (CHMP) criteria (4), and the calculations of all statistical parameters and confidence intervals are descriptive.
Following completion of the primary vaccination course in the initial study using the MF59-adjuvanted H5N1 vaccine formulated with A/Vietnam/1194/2004 (clade 1), all CHMP criteria were met (2). Following the primary course, hemagglutination inhibition (HI) antibody for the priming strain, A/Vietnam/1194/2004 (clade 1), declined to low levels by the time of the booster dose (Table 1). Antibody levels increased 1 week following the booster vaccination for both the booster (A/turkey/Turkey/1/2005-like [clade 2.2]) and heterologous priming (A/Vietnam/1194/2004 [clade 1]) strains and remained high 3 weeks postbooster (Table 1). The CHMP criterion for the seroprotection rate by HI was met 3 weeks following the booster vaccination for the A/turkey/Turkey/1/2005-like (clade 2.2) and A/Vietnam/1194/2004 (clade 1) strains in elderly subjects and for the A/Vietnam/1194/2004 (clade 1) strain in nonelderly subjects. The seroprotection rates 3 weeks after booster vaccination were comparable to those reached after completion of the primary vaccination course (2). The CHMP criterion for the seroconversion rate by HI was met for both strains 1 week after the booster dose in the nonelderly subjects. Seroconversion rate criteria were met for both strains for elderly and nonelderly subjects 3 weeks after the booster dose. Immunogenicity, when measured using the SRH and MN assays, showed similar trends (data not shown). Overall, the results from this study compare favorably with those in other clinical trials, with similar immune responses after primary vaccination and booster doses (6, 9). These results suggest that subjects were effectively primed, which facilitated a rapid immune response to the heterologous A/turkey/Turkey/1/2005-like (clade 2.2) strain after a single dose.
TABLE 1.
Hemagglutination inhibition response by MF59-adjuvanted H5N1 subunit influenza vaccine formulation and age cohorta
| Time | Parameter | Value for age cohortb |
|||
|---|---|---|---|---|---|
| Nonelderly |
Elderly |
||||
| Strain H5N1 A/turkey/Turkey (clade 2.2) | Strain H5N1 A/Vietnam (clade 1) | Strain H5N1 A/turkey/Turkey (clade 2.2) | Strain H5N1 A/Vietnam (clade 1) | ||
| Prebooster | GMT | 5 (5-5) | 6.35 (4.78-8.44) | 14 (5.79-33) | 20 (6.75-59) |
| Seroprotection rate, % | 0 (0-12) | 7 (1-23) | 29 (10-56) | 29 (10-56) | |
| 1 week after booster | GMT | 37 (19-70) | 103 (53-201) | 35 (13-95) | 59 (20-173) |
| GMR | 7.35 (3.86-14) | 16 (8.17-32) | 2.56 (1.25-5.24) | 2.95 (1.26-6.87) | |
| Seroprotection rate, % | 55 (36-74) | 69 (49-85) | 53 (28-77) | 65 (38-86) | |
| Seroconversion rate, % | 55 (36-74) | 66 (46-82) | 29 (10-56) | 35 (14-62) | |
| 3 weeks after booster | GMT | 72 (34-151) | 156 (73-336) | 102 (38-277) | 181 (67-490) |
| GMR | 14 (6.82-30) | 25 (11-53) | 7.38 (2.74-20) | 9.04 (2.97-28) | |
| Seroprotection rate, % | 62 (42-79) | 76 (56-90) | 76 (50-93) | 82 (57-96) | |
| Seroconversion rate, % | 62 (42-79) | 76 (56-90) | 59 (33-82) | 53 (28-77) | |
Primary vaccination with H5N1 A/Vietnam, 7.5 or 15 μg on study days 1 and 22; booster with H5N1 A/turkey/Turkey, 7.5 or 15 μg on study day 382. GMT, geometric mean titer; GMR, geometric mean ratio. Two-sided 95% confidence intervals are shown in parentheses. CHMP criteria: nonelderly, GMR > 2.5; seroprotection ≥ 70%; seroconversion ≥ 40%; elderly, GMR > 2.0; seroprotection ≥ 60%; seroconversion ≥ 30%.
Nonelderly cohort (n = 29), 18 to 60 years of age; elderly cohort (n = 17), >60 years of age.
The incidence of solicited reactions reported within 7 days of booster administration was 72% (22/29) in nonelderly subjects and 39% (7/18) in elderly subjects. The most frequently reported local reactions for all subjects were pain and induration (Fig. 1). The most frequently reported solicited systemic reactions were myalgia and headache for nonelderly subjects and myalgia and fatigue for elderly subjects (Fig. 1). No subject reported fever. All reactions were transient (≤2 days) and were considered mild to moderate in intensity. No unsolicited AEs and SAEs were considered to be vaccine related. The incidence of AEs compares favorably with the results from the initial study (2). Overall, the safety assessments confirmed that the A/turkey/Turkey/1/2005-like (clade 2.2) booster was well tolerated when administered after primary vaccination with A/Vietnam/1194/2004 (clade 1), supporting the safety profile of MF59-adjuvanted vaccines (8, 10).
FIG. 1.
Reported incidences of local and systemic reactions for nonelderly adults (18 to 60 years of age; white bars) and elderly adults (>60 years of age; black bars).
Several studies have demonstrated that the inclusion of MF59 in a seasonal or pandemic influenza vaccine increases both the homologous and heterologous immune responses (1, 3, 9-11) even at low antigen doses. The findings from this extension study provide further support for both the immunopotentiating capabilities of MF59 and the potential for adoption of antigen-sparing strategies in a prepandemic context. This study further illustrates how prepandemic vaccination may prime a population, providing initial protection against an influenza pandemic that can be boosted with a different strain. This prime-boost strategy is likely to be the most effective way to protect populations against future influenza pandemics.
Acknowledgments
A. Banzhoff had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. R. Gasparini was the principal investigator. All authors participated in the analysis and interpretation of the data and/or were involved in drafting and revising the manuscript for important intellectual content.
Novartis Vaccines and Diagnostics sponsored this study.
E. Fragapane and A. Banzhoff are employees of Novartis Vaccines and Diagnostics, the sponsor of the study; R. Gasparini has no conflict of interest; F. Schioppa received funding from Novartis Vaccines and Diagnostics to perform the study; E. Montomoli received funding from Novartis Vaccines and Diagnostics to perform single radial hemolysis analysis; F. Laghi-Pasini has received a travel grant from Novartis Vaccines and Diagnostics.
Footnotes
Published ahead of print on 1 September 2010.
REFERENCES
- 1.Atmar, R. L., W. A. Keitel, S. M. Patel, et al. 2006. Safety and immunogenicity of nonadjuvanted and MF59-adjuvanted influenza A/H9N2 vaccine preparations. Clin. Infect. Dis. 43:1135-1142. [DOI] [PubMed] [Google Scholar]
- 2.Banzhoff, A., R. Gasparini, F. Laghi-Pasini, et al. 2009. Pre-pandemic influenza immunization: MF59-adjuvanted H5N1 vaccine induces immunogenic memory and heterotypic antibody response in non-elderly and elderly adults. PLoS One 4:e4384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Banzhoff, A., M. Pellegrini, G. Del Giudice, E. Fragapane, N. Groth, and A. Podda, 2008. MF59-adjuvanted vaccines for seasonal and pandemic influenza prophylaxis. Influenza Other Respir. Viruses 2:243-249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Committee for Proprietary Medicinal Products. 1997. Note for guidance on harmonization of requirements for influenza vaccines CPMP/BWP/214/96. European Agency for the Evaluation of Medicinal Products, London, United Kingdom.
- 5.Jennings, L. C., A. S. Monto, P. K. Chan, T. D. Szucs, and K. G. Nicholson. 2008. Stockpiling prepandemic influenza vaccines: a new cornerstone of pandemic preparedness plans. Lancet Infect. Dis. 8:650-658. [DOI] [PubMed] [Google Scholar]
- 6.Lin, J. T., C. G. Li, X. Wang, et al. 2009. Antibody persistence after 2-dose priming and booster response to a third dose of an inactivated, adjuvanted, whole-virion H5N1 vaccine. J. Infect. Dis. 199:184-187. [DOI] [PubMed] [Google Scholar]
- 7.Monto, A. S. 2009. The risk of seasonal and pandemic influenza: prospects for control. Clin. Infect. Dis. 48(Suppl. 1):S20-S25. [DOI] [PubMed] [Google Scholar]
- 8.Nicholson, K. G., A. E. Colegate, A. Podda, et al. 2001. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 357:1937-1943. [DOI] [PubMed] [Google Scholar]
- 9.Nolan, T., P. C. Richmond, M. V. Skeljo, et al. 2008. Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults. Vaccine 26:4160-4167. [DOI] [PubMed] [Google Scholar]
- 10.Stephenson, I., R. Bugarini, K. G. Nicholson, et al. 2005. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J. Infect. Dis. 191:1210-1215. [DOI] [PubMed] [Google Scholar]
- 11.Stephenson, I., K. G. Nicholson, A. Colegate, et al. 2003. Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 A/Duck/Singapore/97 vaccine in a primed human population. Vaccine 21:1687-1693. [DOI] [PubMed] [Google Scholar]
- 12.World Health Organization. Accessed 17 March 2008. Responding to the avian influenza pandemic threat: recommended strategic actions. http://www.who.int/csr/resouces/publications/influenza/WHO_CDS_CSR_GIP-05_8-EN.pdf. World Health Organization, Geneva, Switzerland.