Influenza Virus Vaccine 2013-2014 Strain Selection

1. Influenza Virus Vaccine2013-2014 Strain Selection Vaccines and Related Biological Products Advisory Committee (2/27/2013) Jerry P. Weir, Ph.D., Director Division of Viral Products/OVRR/CBER/FDA

2. Purpose of Today’s VRBPAC Committee Discussion • Review influenza surveillance and epidemiology data, antigenic characteristics of recent virus isolates, serological responses to current vaccines, and the availability of candidate vaccine strains and reagents • Make recommendations for the strains of influenza A (H1N1 and H3N2) and B viruses to be included in 2013-2014 influenza vaccines licensed for use in the United States

3. Types of Analyses Used forVaccine Strain Selection • Epidemiology of circulating strains (CDC) • Surveillance data from U.S. and around the world • Antigenic relationships among contemporary viruses and candidate vaccine strains (CDC/DOD/CBER) • Hemagglutination inhibition (HI) tests using post-infection ferret sera • HI tests using panels of sera from humans receiving recent TIV • Virus neutralization tests • Antigenic cartography • Phylogenetic analyses of HA and NA genes • Vaccine effectiveness

4. Key Challenges for Vaccine Strain Selection • Vaccine effectiveness depends on match between the hemagglutinin (HA) of the vaccine and the HA of circulating strains of virus • Antigenic drift of HA continuous for influenza A and B • Antibody to HA correlated with vaccine efficacy • Timelines for influenza vaccine production are relatively fixed • Strain selection in February necessary for availability of vaccine for subsequent northern hemisphere winter (influenza season) • Manufacturers typically begin production of one monovalent before strain selection recommendations are made (at risk) • Availability of reference strains suitable for vaccine manufacture • Vaccine production depends on growth properties of strains used for manufacture • Strain-specific reagents needed for potency determination (inactivated vaccines)

5. Development of Quadrivalent Seasonal Influenza Vaccines • Two antigenically distinct lineages of influenza B co-circulate • Represented by B/Victoria/2/87 and B/Yamagata/16/88 • Both trivalent and quadrivalent influenza vaccines likely to be produced (different manufacturers) and available for use • Process for selecting appropriate B strains for inclusion in trivalent and quadrivalent vaccines should follow the current process of strain selection • WHO and VRBPAC review and make recommendations for each formulation – trivalent and quadrivalent • All trivalent vaccines should contain same B vaccine strain • Decision regarding inclusion of a 2nd B strain should be data driven

6. Review of the 2012-2013 Seasonal Influenza Vaccine Strain Composition • VRBPAC strain selection – 2/28/2012 • Committee recommended the following strains for inclusion in U.S. 2012-2013 trivalent influenza vaccines • A/California/7/2009 (H1N1)-like virus • No change from the 2011-2012 vaccine recommendation • A/Victoria/361/2011 (H3N2)-like virus • Change from the A/Perth/16/2009 2011-2012 vaccine recommendation • B/Wisconsin/1/2010-like virus (B/Yamagata lineage) • Change from the B/Brisbane/60/2008 (B/Victoria) 2011-2012 vaccine recommendation • For manufacturers producing a quadrivalent influenza vaccine, the Committee recommended a second B strain • B/Brisbane/60/2008 (B/Victoria), previously recommended for TIV in 2011-2012

7. Recent Influenza Vaccine Approvals • FluMist Quadrivalent • MedImmune, LLC • February 29, 2012 • First licensed quadrivalent vaccine to prevent seasonal influenza • For use in persons ages 2 years through 49 years • Contains four strains of the influenza virus, two influenza A strains (H1N1 and H3N2) and two influenza B strains (Yamagata and Victoria lineages) • Flucelvax • Novartis Vaccines and Diagnostics, Inc. • November 20, 2012 • Trivalent vaccine • First licensed seasonal influenza vaccine manufactured using cell culture technology (MDCK) • For use in persons ages 18 years and older

8. Recent Influenza Vaccine Approvals – Cont. • Fluarix Quadrivalent • GlaxoSmithKline Biologicals • December 14, 2012 • First licensed quadrivalent inactivated influenza vaccine to prevent seasonal influenza • For use in persons ages 3 years and older • Contains four strains of the influenza virus, two influenza A strains (H1N1 and H3N2) and two influenza B strains (Yamagata and Victoria lineages) • Flublok • Protein Sciences Corporation • January 16, 2013 • Trivalent vaccine • First licensed influenza vaccine manufactured using an insect virus (baculovirus) expression system and recombinant DNA technology • For use in persons ages 18 through 49

9. Recent Influenza Vaccine IssuesDiscussed by VRBPAC • Licensure Pathways for Pandemic Influenza Vaccines (Feb 29, 2012) • Discussed various approaches for licensing pandemic influenza vaccines, including adjuvanted pandemic influenza vaccines, using • Safety and immunogenicity data obtained from clinical trials with the candidate pandemic vaccine • clinical endpoint efficacy data accrued with a U.S.-licensed unadjuvanted seasonal vaccine, made by the same manufacturer and process, to infer effectiveness of an adjuvanted pandemic influenza A subtype vaccine

10. Recent Influenza Vaccine IssuesDiscussed by VRBPAC – Continued • September 19, 2012 • Consideration of the Appropriateness of Cell Lines Derived from Human Tumors for Vaccine Manufacture • Previous VRBPAC discussions had focused on the use of tumorigenic cell lines for vaccine production • Use of Madin-Darby canine kidney (MDCK) cells for the production of inactivated influenza virus vaccines discussed at VRBPAC in 2005 • Use of non-tumorigenic MDCK cells for the manufacture of a live, attenuated influenza virus vaccine discussed at VRBPAC in 2008 • Committee concluded that the risk-mitigation strategies are the same for vaccines generated using human tumor-derived cell lines as for other cell substrates • The committee encouraged the use of new virus-detection technologies (e.g., as massively parallel sequencing) in the characterization of human tumor-derived cell substrates as well as for other cell substrates

11. Recent Influenza Vaccine IssuesDiscussed by VRBPAC – Continued • November 14, 2012 • Safety and Immunogenicity of an Influenza A (H5N1) Virus Monovalent Vaccine (Q-Pan) Manufactured by GlaxoSmithKline • Q-Pan H5N1 contains AS03, an adjuvant system containing α-tocopherol and squalene in an oil in water emulsion • Committee voted that the safety and immunogenicity data support licensure of Q-Pan H5N1 via the accelerated approval regulations for the proposed indication (i.e., active immunization for the prevention of disease in persons 18 years of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine) • The committee discussed approaches to verify and describe the clinical benefit of Q-Pan H5N1 as required under the Accelerated Approval regulations (21 CFR 601.41), including 1) the use of data derived from an efficacy study conducted by GSK with seasonal unadjuvanted influenza virus vaccine made by the same process or 2) confirmation of the clinical benefit of Q-Pan H5N1 by conducting an effectiveness study during an H5N1 pandemic

12. Recent CBER Workshops Relatedto Influenza Vaccines • June 19-20, 2012 • Universal Influenza Vaccines Meeting, co-sponsored by NIAID and CBER • Goals of a universal influenza vaccine discussed (e.g., subtype specific vaccines, pandemic influenza vaccines, etc.) • Obstacles to universal influenza vaccine development identified • Difficulties in translating laboratory findings to clinical trials discussed • Translational needs and infrastructure needs identified

13. WHO Recommendations for Influenza Vaccine CompositionNorthern Hemisphere: 2013-2014 • Recommended that the following viruses be used for influenza vaccines in the 2013-2014 influenza season (NH winter): • an A/California/7/2009 (H1N1) pdm09 - like virus • A(H3N2) virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011 • B/Massachusetts/2/2012-like virus (B/Yamagata lineage) • It is recommended that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Brisbane/60/2008-like virus (B/Victoria/2/87 lineage vaccine virus) • As in previous years, national or regional control authorities approve the composition and formulation of vaccines used in each country

14. Committee Discussion • Which influenza strains should be recommended for the antigenic composition of the 2013-2014 influenza virus vaccine in the U.S.? • Data to be considered includes: • the epidemiology of circulating influenza viruses • the antigenic characteristics of influenza virus strains currently circulating in human populations • the serologic responses to circulating influenza viruses of persons immunized with current influenza virus vaccines • manufacturing considerations including the availability of suitable vaccine candidate strains

15. Options for Strain Composition for 2013-2014 Trivalent Influenza Vaccines • Influenza A (H1N1) • Retain current vaccine strain A/California/7/2009 (H1N1)-like virus • Replace current vaccine strain with an alternative candidate vaccine virus • Influenza A (H3N2) • Replace current vaccine strain A/Victoria/361/2011 (H3N2) - like virus with an A(H3N2) virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011 • Retain the current vaccine strain • Replace current vaccine strain with an alternative candidate vaccine virus • Influenza B • Replace current vaccine strain with a B/Massachusetts/2/2012-like virus (B/Yamagata lineage) • Retain current B/Wisconsin/1/2010 - like virus (B/Yamagata lineage) • Replace current vaccine strain with an alternative candidate vaccine virus from the B/Victoria lineage

16. Options for Strain Selection for the 2nd Influenza B Strain in a Quadrivalent Influenza Vaccine • Influenza B • Include recent vaccine strain B/Brisbane/60/2008-like virus (B/Victoria lineage) • Include an alternative candidate vaccine virus of the B/Victoria lineage