New Developments in Seasonal Vaccines

What is it?
Quadrivalent vaccines (QIV) provide coverage against two influenza A virus strains and two influenza B virus strains; the traditional trivalent vaccines (TIV) provide coverage against two influenza virus strains and only one influenza B virus strain.

The rationale
Two influenza B lineages (Yamagata and Victoria) have been co-circulating since the 1980s (Chen 2008), although the prevalence of the two strains varies each year. Vaccination against one lineage of influenza B virus offers poor cross protection against infection by the other lineage. Thus vaccine effectiveness is markedly reduced when there is a mismatch between the vaccine coverage and the circulating lineage of influenza B. This discordance is important, because, as noted above, trivalent vaccines provide coverage against only one of the two influenza B lineages.

Influenza B Virus Disease Burden
On average, influenza B accounts for about one quarter of total influenza activity each season, but its activity can vary and can range from 1% to 60% of the total seasonal influenza activity. (Ambrose 2012). In addition, it causes epidemics every 2 to 4 years. (Belshe 2010).

Although influenza B infects patients of all ages, it causes a disproportionately higher amount of disease relative to influenza A in children and young adults. Overall, influenza B was responsible for 34% of reported pediatric influenza deaths (Ambrose 2012).

Influenza B infection is also prominent in older adults causing nursing home outbreaks. (Camilloni 2010)

Safety
Quadrivalent influenza vaccines are made in the same way as the trivalent influenza vaccines. Studies have shown (Beran 2013, Block 2013, Greenberg 2013 inter alia) that QIV vaccines have a safety profile similar to TIV vaccines, with similar—mostly mild—side effects.

Cost and benefit
The QIV is more costly than the TIV and the formulation of a quadrivalent vaccine represents an increased cost to the manufacturers, and to the healthcare system. Modeling studies have suggested that the use of a quadrivalent vaccine would have had a beneficial public health impact in the years 1999 to 2009 (Reed 2012 ) and may also have been associated with substantial savings of healthcare costs, including those incurred by third-party payers (Lee 2012, 2013).

 

Recent QIV Literature

Jain VK. et al. Time to Change Dosing of Inactivated Quadrivalent Influenza Vaccine in Young Children: Evidence From a Phase III, Randomized, Controlled Trial. J Pediatric Infect Dis Soc. 2017 Jan 6. pii: piw068.
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Jamotte A. et al. Public health impact and economic benefits of quadrivalent influenza vaccine in Latin America. Hum Vaccin Immunother. 2017 Jan 24:1-12.
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QIV Literature
2012 - January 2017

Ambrose, C.S. and Levin, M.J. The rationale for quadrivalent influenza vaccines. Human Vaccines & Immunotherapeutics 8:1, 81–88; January 2012
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Baden, L.R. For an influenza vaccine, are two Bs better than one? (Editorial). N Engl J Med 2013
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Barr, I.G. and Jelley, L.L. The Coming Era of Quadrivalent Human Influenza Vaccines Who will Benefit? Drugs 2012; 72 (17): 2177-2185
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Bart S. et al. Immunogenicity and safety of a cell culture-based quadrivalent influenza vaccine in adults: a Phase III, double-blind, multicenter, randomized, non-inferiority study. Hum Vaccin Immunother. 2016 Jun 20:0.
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Baxter D. Evaluating the case for trivalent or quadrivalent influenza vaccines. Hum Vaccin Immunother. 2016 Jul 19:1-6.
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Bekkat-Berkani R. et al. Evidence update: GlaxoSmithKline's inactivated quadrivalent influenza vaccines. Expert Rev Vaccines. 2015 Dec 5:1-14.
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Belshe, R.B. The need for quadrivalent vaccine against seasonal influenza. Vaccine 28S (2010) D45–D53
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Beran J. et al. Immunogenicity and safety of quadrivalent versus trivalent inactivated influenza vaccine: a randomized, controlled trial in adults. BMC Infect Dis. 2013 May 20;13:224.
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Block S.L. et al. Immunogenicity and safety of a quadrivalent live attenuated influenza vaccine in children. Pediatr Infect Dis J. 2012 Jul;31(7):745-51.
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Brogan AJ. et al. Cost-effectiveness of seasonal quadrivalent versus trivalent influenza vaccination in the United States: A dynamic transmission modeling approach. Hum Vaccin Immunother. 2016 Oct 26:0.
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Cadorna-Carlos JB. et al. Safety, immunogenicity, and lot-to-lot consistency of a quadrivalent inactivated influenza vaccine in children, adolescents, and adults: A randomized, controlled, phase III trial. Vaccine. 2015 May 15;33(21):2485-92.
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Camilloni, B. et al. An influenza B outbreak during the 2007/2008 winter among appropriately immunized elderly people living in a nursing home.Vaccine 28:7536-7541) Vaccine. 2010 Nov 3;28(47):7536-41.
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Chen R. and Holmes E.C. The evolutionary dynamics of human influenza B virus. J Mol Evol. 2008 Jun;66(6):655-63.
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Chit A, Roiz J, Aballea S. An Assessment of the Expected Cost-Effectiveness of Quadrivalent Influenza Vaccines in Ontario, Canada Using a Static Model. PLoS One. 2015 Jul 29;10(7):e0133606.
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Crépey P. et al. Retrospective public health impact of a quadrivalent influenza vaccine in the United States. Influenza Other Respir Viruses. 2015 Aug;9 Suppl 1:39-46.
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Dolin, R. The Quadrivalent Approach to Influenza J Infect Dis. (2013) 208 (4): 539-540.
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Domachowske, J.B. et al. A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3-17 years. J Infect Dis. 2013 Jun 15;207(12):1878-87.
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Gorse GJ. et al. Safety and immunogenicity of a quadrivalent intradermal influenza vaccine in adults. Vaccine. 2015 Jan 19. pii: S0264-410X(15)00044-4.
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Graaf H, Faust SN. Fluarix quadrivalent vaccine for influenza. Expert Rev Vaccines. 2015 Jun 22:1-9.
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Greenberg, D.P. et al. Safety and Immunogenicity of an Inactivated Quadrivalent Influenza Vaccine in Children 6 Months through 8 Years of Age.Pediatr Infect Dis J. 2014 Jan 17. [Epub ahead of print]
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Greenberg, D.P. et al. Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults. Vaccine. 2013 Jan 21;31(5):770-6.
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Hartvickson R. et al. Non-inferiority of mammalian cell-derived quadrivalent subunit influenza virus vaccines compared to trivalent subunit influenza virus in healthy children: a phase III randomized, multicenter, double-blind, clinical trial. Int J Infect Dis. 2015 Nov 13. pii: S1201-9712(15)00264-7.
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Jain VK. et al. A historically-controlled Phase III study in adults to characterize the acceptability of a process change for manufacturing inactivated quadrivalent influenza vaccine. BMC Infect Dis. 2014 Mar 10;14(1):133.
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Jain, V.K. et al. Vaccine for prevention of mild and moderate-to-severe influenza in children. N Engl J Med 2013
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Jain VK. et al. Time to Change Dosing of Inactivated Quadrivalent Influenza Vaccine in Young Children: Evidence From a Phase III, Randomized, Controlled Trial. J Pediatric Infect Dis Soc. 2017 Jan 6. pii: piw068.
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Jamotte A. et al. Public health impact and economic benefits of quadrivalent influenza vaccine in Latin America. Hum Vaccin Immunother. 2017 Jan 24:1-12.
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Jamotte A. et al. Impact of quadrivalent influenza vaccine on public health and influenza-related costs in Australia. BMC Public Health. 2016 Jul 22;16:630.
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Kieninger, D. et al. Immunogenicity, reactogenicity and safety of an inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine: a phase III, randomized trial in adults aged =18 years.BMC Infect Dis. 2013 Jul 24;13(1):343.
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Kittikraisak W. et al. Assessment of potential public health impact of a quadrivalent inactivated influenza vaccine in Thailand. Influenza Other Respir Viruses. 2015 Nov 21.
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Langley, J.M. et al. Immunogenicity and Safety of an Inactivated Quadrivalent Influenza Vaccine Candidate: A Phase III Randomized Controlled Trial in Children J Infect Dis. J Infect Dis. (2013) 208 (4): 544-553.
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Lee, B.Y., Bartscha, S.M., Willig, A.M. The economic value of a quadrivalent versus trivalent influenza vaccine. Vaccine 30 (2012) 7443– 7446
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Lee, B.Y., Bartsch, S.M., Willig, A.M. Corrigendum to “The economic value of a quadrivalent versus trivalent influenza vaccine” [Vaccine 30 (2012) 7443–7446] Vaccine 31 (2013) 2477– 2479
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McKeage, K. Inactivated quadrivalent split-virus seasonal influenza vaccine (Fluarix® quadrivalent): a review of its use in the prevention of disease caused by influenza A and B. Drugs. 2013 Sep;73(14):1587-94.
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McNaughton R. et al. Safety of Intranasal Quadrivalent Live Attenuated Influenza Vaccine (QLAIV) in Children and Adolescents: A Pilot Prospective Cohort Study in England. Drug Saf. 2016 Jan 21.
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Meier G. et al. Cost-effectiveness analysis of quadrivalent influenza vaccination in at-risk adults and the elderly: an updated analysis in the UK. J Med Econ. 2015 Jun 1:1-16.
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Milne GJ. et al. Trivalent and quadrivalent influenza vaccination effectiveness in Australia and South Africa: results from a modelling study. Influenza Other Respir Viruses. 2015 Dec 12.

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Moa AM. et al. Immunogenicity and safety of inactivated quadrivalent influenza vaccine in adults: A systematic review and meta-analysis of randomised controlled trials. Vaccine. 2016 Jul 29;34(35):4092-102.
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Pépin, S. et al. Safety and immunogenicity of a quadrivalent inactivated influenza vaccine in adults. Vaccine. 2013 Nov 12;31(47):5572-8.
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Quinn E, Jit M, Newall AT. Key issues and challenges in estimating the impact and cost-effectiveness of quadrivalent influenza vaccination. Expert Rev Pharmacoecon Outcomes Res. 2014 Jun;14(3):425-35.
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Reed, C. et al. Public health impact of including two lineages of influenza B in a quadrivalent seasonal influenza vaccine. Vaccine 2012;30:1993-8.

Regan AK, Tracey L, Gibbs R. Post-marketing surveillance of adverse events following immunization with inactivated quadrivalent and trivalent influenza vaccine in health care providers in Western Australia. Vaccine. 2015 Oct 21. pii: S0264-410X(15)01416-4.
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Rodriguez Weber MA. et al. Immunogenicity and safety of inactivated quadrivalent and trivalent influenza vaccines in children 18-47 months of age. Pediatr Infect Dis J. 2014 Dec;33(12):1262-9.
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Robertson CA. Fluzone® Intradermal Quadrivalent Influenza Vaccine. Expert Rev Vaccines. 2016 Oct;15(10):1245-53.
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Sheldon, E.A. et al. Immunogenicity of a quadrivalent Ann Arbor strain live attenuated influenza vaccine delivered using a blow-fill-seal device in adults: a randomized, active-controlled study. Influenza Other Respir Viruses. 2013 Nov;7(6):1142-50.
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Thommes EW. et al. Cost-effectiveness evaluation of quadrivalent influenza vaccines for seasonal influenza prevention: a dynamic modeling study of Canada and the United Kingdom. BMC Infect Dis. 2015 Oct 27;15:465.
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Tinoco, J.C. et al. Immunogenicity, reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged ≥18 years: A phase III, randomized trial. Vaccine. 2014 Jan 28. pii: S0264-410X(14)00054-1.
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Toback, S.L. et al. Quadrivalent Ann Arbor strain live-attenuated influenza vaccine. Expert Rev Vaccines. 2012 Nov;11(11):1293-303.
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Tsurudome Y. et al. Immunogenicity and safety of an inactivated quadrivalent influenza vaccine in healthy adults: a phase II, open-label, uncontrolled trial in Japan. Microbiol Immunol. 2015 Oct;59(10):597-604.
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Tsurudome Y. et al. Immunogenicity and safety of an inactivated quadrivalent influenza vaccine in healthy adults: a phase II, open-label, uncontrolled trial in Japan. Microbiol Immunol. 2015 Aug 14.
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Yang MC, Tan EC, Su JJ. Cost-Effectiveness Analysis of Quadrivalent versus Trivalent Influenza Vaccine in Taiwan: A Lifetime Multi-Cohort Model. Hum Vaccin Immunother. 2016 Sep 13:0.
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You J, Ming WK, Chan P. Cost-effectiveness analysis of quadrivalent influenza vaccine versus trivalent influenza vaccine for elderly in Hong Kong. BMC Infect Dis. 2014 Nov 25;14(1):618.
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Van Bellinghen LA, Meier G, Van Vlaenderen I. The Potential Cost-Effectiveness of Quadrivalent versus Trivalent Influenza Vaccine in Elderly People and Clinical Risk Groups in the UK: A Lifetime Multi-Cohort Model. PLoS One. 2014 Jun 6;9(6):e98437.
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Zhao B. et al. Epidemiological study of influenza B in Shanghai during the 2009-2014 seasons: implications for influenza vaccination strategy. Clin Microbiol Infect. 2015 Apr 13. pii: S1198-743X(15)00373-0.
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