BACKGROUND: Two phylogenetic lineages of influenza B virus coexist and circulate in the human population (B/Yamagata and B/Victoria) but only one B-strain is included in each seasonal vaccine. Mismatch regularly occurs between the recommended and circulating B-strain. Inclusion of both lineages in vaccines may offer better protection against influenza. METHODS: This study (NCT00714285) assessed the immunogenicity and safety of two candidate quadrivalent influenza vaccines (QIV) containing two A- and two B-strains (one from each lineage) in adults (18-60 years). Subjects were randomized and stratified by age to receive either QIV (non-adjuvanted or low-dose adjuvanted [LD QIV-AS]) or trivalent influenza vaccine (TIV, non-adjuvanted or low-dose adjuvanted [LD TIV-AS]), N = 105 in all treatment groups. The study evaluated the statistical non-inferiority of the immunological response elicited by QIV and LD QIV-AS versus TIV and LD TIV-AS and the statistical superiority of the response elicited by the quadrivalent vaccines against the B-strain (B/Jiangsu) not included in the TIV. RESULTS: Pre-defined non-inferiority and superiority criteria were reached for both QIVs compared to the TIVs. On Day 21 in all vaccine groups SCRs were ≥54.8%, SPRs ≥88.5% and SCFs ≥5.4 for the A strains and B strain included in all vaccines (B/Malaysia). This fulfilled the European (CHMP) and the US (CBER) licensing criteria for the assessment of influenza vaccines in adults (CHMP criteria: SCR > 40%, SPR > 70%, SCF > 2; CBER criteria: LL of 95% CI for SPR ≥ 70% or SCR ≥ 40%). Only the QIVs met the CHMP and CBER criteria for the B/Jiangsu strain. In the QIV and LD-QIV-AS groups, the SCFs were 9.1 and 8.1, respectively and the SPRs were 98.1% and 95.2%, whereas for the TIV and LD-TIV-AS groups, the SCFs were 2.3 and 2.5, respectively, and the SPRs were 75.0% and 63.8%, with the LLs of the 95% CI <70% for SPR and <40% for SCR. CONCLUSIONS: Addition of a fourth strain did not impact the immune response elicited by the three original strains contained in the TIV. A clear immunological benefit was seen with the QIV formulation for the second B-strain, indicating that quadrivalent vaccines could provide broader protection against influenza. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00714285.

The Vaccination and Travel Medicine Center Poliklinika 2 Bratří Štefanu 895 Hradec Králové 500 03 Czech Republic

Zobrazit více v PubMed

Stöhr K. Influenza–WHO cares. Lancet Infect Dis. 2002;2:517. doi: 10.1016/S1473-3099(02)00366-3. PubMed DOI

Barr IG, Komadina N, Durrant C, Sjogren H, Hurt AC, Shaw RP. Circulation and antigenic drift in human influenza B viruses in SE Asia and Oceania since 2000. Commun Dis Intell. 2006;30:350–357. PubMed

Rota PA, Wallis TR, Harmon MW, Rota JS, Kendal AP, Nerome K. Cocirculation of two distinct evolutionary lineages of influenza type B virus since 1983. Virology. 1990;175:59–68. doi: 10.1016/0042-6822(90)90186-U. PubMed DOI

Li WC, Shih SR, Huang YC, Chen GW, Chang SC, Hsiao MJ, Tsao KC, Lin TY. Clinical and genetic characterization of severe influenza B-associated diseases during an outbreak in Taiwan. J Clin Virol. 2008;42:45–51. doi: 10.1016/j.jcv.2007.11.026. PubMed DOI

McCullers JA, Saito T, Iverson AR. Multiple Genotypes of Influenza B Virus Circulated between 1979 and 2003. J Virol. 2004;78:12817–12828. doi: 10.1128/JVI.78.23.12817-12828.2004. PubMed DOI PMC

Belshe RB. The need for quadrivalent vaccine against seasonal influenza. Vaccine. 2010;28:D45–D53. PubMed

Couch RB. Background and Presentation of Possible Vaccine Options. Vaccines and Related Biological Products Advisory Committee (VRBPAC), Food and Drug Administration, Topic 4: Influenza Type B Strain - Discussion on Circulating Lineages. 2007. http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4282S2-00-index.htm.

Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality Associated With Influenza and Respiratory Syncytial Virus in the United States. JAMA. 2003;289:179–186. doi: 10.1001/jama.289.2.179. PubMed DOI

World Health Organization. Recommended viruses for influenza vaccines for use in the 2010–2011 Northern Hemisphere influenza season. http://www.who.int/influenza/vaccines/virus/recommendations/201002_Recommendation.pdf. PubMed

US Centers for Disease Control and Prevention (CDC) Seasonal influenza activity surveillance reports: 1999–2000 to 2010–2011 seasons. http://www.cdc.gov/flu/weekly/pastreports.htm. PubMed

Ambrose CS, Levin MJ. The rationale for quadrivalent influenza vaccines. Hum Vaccin Immunother. 2012;8:1–8. doi: 10.4161/hv.8.1.19091. PubMed DOI PMC

Jefferson T, Di PC, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2010;7:CD001269. doi: 10.1002/14651858.CD001269.pub4. PubMed DOI

Belshe RB, Coelingh K, Ambrose CS, Woo JC, Wu X. Efficacy of live attenuated influenza vaccine in children against influenza B viruses by lineage and antigenic similarity. Vaccine. 2010;28:2149–2156. doi: 10.1016/j.vaccine.2009.11.068. PubMed DOI

Jackson L, Gaglani M, Keyserling H, Balser J, Bouveret N, Fries L, Treanor J. Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons. BMC Infect Dis. 2010;10:71. doi: 10.1186/1471-2334-10-71. PubMed DOI PMC

Beran J, Wertzova V, Honegr K, Kaliskova E, Havlickova M, Havlik J, Jirincova H, Van BP, Jain V, Innis B, Devaster JM. Challenge of conducting a placebo-controlled randomized efficacy study for influenza vaccine in a season with low attack rate and a mismatched vaccine B strain: a concrete example. BMC Infect Dis. 2009;9:2. doi: 10.1186/1471-2334-9-2. PubMed DOI PMC

Heckler R, Baillot A, Engelmann H, Neumeier E, Windorfer A. Cross-protection against homologous drift variants of influenza A and B after vaccination with split vaccine. Intervirology. 2007;50:58–62. doi: 10.1159/000096314. PubMed DOI

Levandowski RA, Regnery HL, Staton E, Burgess BG, Williams MS, Groothuis JR. Antibody responses to influenza B viruses in immunologically unprimed children. Pediatrics. 1991;88:1031–1036. PubMed

Englund JA, Walter EB, Gbadebo A, Monto AS, Zhu Y, Neuzil KM. Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers. Pediatrics. 2006;118:e579–e585. doi: 10.1542/peds.2006-0201. PubMed DOI

. World Health Organization (WHO). Recommended composition of influenza virus vaccines for use in the 2012–2013 northern hemisphere influenza season. http://www.who.int/influenza/vaccines/virus/recommendations/201202_recommendation.pdf.

Garçon N, Chomez P, Van Mechelen M. GlaxoSmithKline Adjuvant Systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines. 2007;6:723–739. doi: 10.1586/14760584.6.5.723. PubMed DOI

Leroux-Roels I, Borkowski A, Vanwolleghem T, Drame M, Clement F, Hons E, Devaster JM, Leroux-Roels G. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet. 2007;370:580–589. doi: 10.1016/S0140-6736(07)61297-5. PubMed DOI

World Health Organization (WHO) Recommended composition of influenza virus vaccine for use in the 2007–2008 influenza season. http://www.who.int/wer/2007/wer8209.pdf. PubMed

Hehme NW, Künzel W, Petschke F, Türk G, Raderecht C, Van Hoecke C, Sänger R. Ten Years of Experience with the Trivalent Split-Influenza Vaccine, Fluarix(TM) Clin Drug Investig. 2002;22:751–769. doi: 10.2165/00044011-200222110-00004. DOI

Center for Biologics Evaluation and Research (CBER). Guidance for Industry: Clinical data needed to support the licensure of seasonal inactivated influenza vaccines. Food and Drug Administration (FDA) http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm091990.pdf.

Committee for Proprietary Medicinal Products (CPMP) Note for guidance on harmonisation of requirements for influenza vaccines. The European Agency for the Evaluation of Medicinal Products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003945.pdf.

Hehme N, Engelmann H, Kuenzel W, Neumeier E, Saenger R. Immunogenicity of a monovalent, aluminum-adjuvanted influenza whole virus vaccine for pandemic use. Virus Res. 2004;103:163–171. doi: 10.1016/j.virusres.2004.02.029. PubMed DOI

Rowe T, Abernathy RA, Hu-Primmer J, Thompson WW, Lu X, Lim W, Fukuda K, Cox NJ, Katz JM. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol. 1999;37:937–943. PubMed PMC

Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am J Hyg. 1938;27:493–497.

Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, Singleton JA, Iskander JK, Wortley PM, Shay DK, Bresee JS, Cox NJ. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 2010;59:1–62. PubMed

Camilloni B, Neri M, Lepri E, Iorio AM. Cross-reactive antibodies in middle-aged and elderly volunteers after MF59-adjuvanted subunit trivalent influenza vaccine against B viruses of the B/Victoria or B/Yamagata lineages. Vaccine. 2009;27:4099–4103. doi: 10.1016/j.vaccine.2009.04.078. PubMed DOI

Block SL, Falloon J, Hirschfield JA, Krilov LR, Dubovsky F, Yi T, Belshe RB. Immunogenicity and safety of a quadrivalent live attenuated influenza vaccine in children. Pediatr Infect Dis J. 2012;31:745–751. doi: 10.1097/INF.0b013e31825687b0. PubMed DOI

Block SL, Yi T, Sheldon E, Dubovsky F, Falloon J. A randomized, double-blind noninferiority study of quadrivalent live attenuated influenza vaccine in adults. Vaccine. 2011;29:9391–9397. doi: 10.1016/j.vaccine.2011.09.109. PubMed DOI

Belongia EA, Kieke BA, Donahue JG, Coleman LA, Irving SA, Meece JK, Vandermause M, Lindstrom S, Gargiullo P, Shay DK. Influenza vaccine effectiveness in Wisconsin during the 2007–08 season: comparison of interim and final results. Vaccine. 2011;29:6558–6563. doi: 10.1016/j.vaccine.2011.07.002. PubMed DOI

Frey S, Vesikari T, Szymczakiewicz-Multanowska A, Lattanzi M, Izu A, Groth N, Holmes S. Clinical Efficacy of Cell Culture−Derived and Egg-Derived Inactivated Subunit Influenza Vaccines in Healthy Adults. Clin Infect Dis. 2010;51:997–1004. doi: 10.1086/656578. PubMed DOI

Monto AS, Ohmit SE, Petrie JG, Johnson E, Truscon R, Teich E, Rotthoff J, Boulton M, Victor JC. Comparative Efficacy of Inactivated and Live Attenuated Influenza Vaccines. N Engl J Med. 2009;361:1260–1267. doi: 10.1056/NEJMoa0808652. PubMed DOI

Reed C, Meltzer MI, Finelli L, Fiore A. Public health impact of including two lineages of influenza B in a quadrivalent seasonal influenza vaccine. Vaccine. 2012;30:1993–1998. doi: 10.1016/j.vaccine.2011.12.098. PubMed DOI

Lee BY, Bartsch SM, Willig AM. The economic value of a quadrivalent versus trivalent influenza vaccine. Vaccine. 2012;30:7443–7446. doi: 10.1016/j.vaccine.2012.10.025. PubMed DOI PMC

Roman F, Vaman T, Gerlach B, Markendorf A, Gillard P, Devaster JM. Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: preliminary report of an observer-blind, randomised trial. Vaccine. 2010;28:1740–1745. doi: 10.1016/j.vaccine.2009.12.014. PubMed DOI

Curran MP, Leroux-Roels I. Inactivated split-virion seasonal influenza vaccine (Fluarix): a review of its use in the prevention of seasonal influenza in adults and the elderly. Drugs. 2010;70:1519–1543. doi: 10.2165/11205020-000000000-00000. PubMed DOI

Madhun AS, Akselsen PE, Sjursen H, Pedersen G, Svindland S, Nøstbakken JK, Nilsen M, Mohn K, Jul-Larsen A, Smith I, Major D, Wood J, Cox RJ. An adjuvanted pandemic influenza H1N1 vaccine provides early and long term protection in health care workers. Vaccine. 2010;29:266–273. doi: 10.1016/j.vaccine.2010.10.038. PubMed DOI

Roman F, Vaman T, Kafeja F, Hanon E, Van Damme P. AS03(A)-Adjuvanted influenza A (H1N1) 2009 vaccine for adults up to 85 years of age. Clin Infect Dis. 2010;51:668–677. doi: 10.1086/655830. PubMed DOI

Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, Groth N, Stephenson I. Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N Engl J Med. 2009;361:2424–2435. doi: 10.1056/NEJMoa0907650. PubMed DOI

Liang XF, Wang HQ, Wang JZ, Fang HH, Wu J, Zhu FC, Li RC, Xia SL, Zhao YL, Li FJ, Yan SH, Yin WD, An K, Feng DJ, Cui XL, Qi FC, Ju CJ, Zhang YH, Guo ZJ, Chen PY, Chen Z, Yan KM, Wang Y. Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2010;375:56–66. doi: 10.1016/S0140-6736(09)62003-1. PubMed DOI

Wu J, Li W, Wang HQ, Chen JT, Lv M, Zhou JC, Liang XF, Fang HH, Liu Y, Liu LY, Wang X, Zhang WL, Zhang XM, Song LF, Qiu YZ, Li CG, Wang JZ, Wang Y, Yin WD. A rapid immune response to 2009 influenza A(H1N1) vaccines in adults: a randomized, double-blind, controlled trial. J Infect Dis. 2010;202:675–680. doi: 10.1086/655226. PubMed DOI

Langley JM, Frenette L, Ferguson L, Riff D, Sheldon E, Risi G, Johnson C, Li P, Kenney R, Innis B, Fries L. Safety and cross-reactive immunogenicity of candidate AS03-adjuvanted prepandemic H5N1 influenza vaccines: a randomized controlled phase 1/2 trial in adults. J Infect Dis. 2010;201:1644–1653. doi: 10.1086/652701. PubMed DOI

Monto AS, Hornbuckle K, Ohmit SE. Influenza vaccine effectiveness among elderly nursing home residents: a cohort study. Am J Epidemiol. 2001;154:155–160. doi: 10.1093/aje/154.2.155. PubMed DOI

Zobrazit více v PubMed

ClinicalTrials.gov
NCT00714285