Vaccine Information: FLUZONE QUADRIVALENT SOUTHERN HEMISPHERE (Page 3 of 6)

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluzone Quadrivalent has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. Vaccination of female rabbits with Fluzone Quadrivalent revealed no evidence of impaired female fertility [see Animal Data (8.1)].

14 CLINICAL STUDIES

The effectiveness of Fluzone Quadrivalent was demonstrated based on clinical endpoint efficacy data for Fluzone (trivalent influenza vaccine) and on an evaluation of serum HI antibody responses to Fluzone Quadrivalent. Fluzone Quadrivalent, an inactivated influenza vaccine that contains the hemagglutinins of two influenza A subtype viruses and two influenza type B viruses, is manufactured according to the same process as Fluzone.

Fluzone Quadrivalent Southern Hemisphere and Fluzone Quadrivalent are manufactured using the same process. Data in this section were obtained in studies with Fluzone Quadrivalent.

14.1 Efficacy of Fluzone (Trivalent Influenza Vaccine) in Children 6 through 24 Months of Age

A randomized, double-blind, placebo-controlled study was conducted at a single US center during the 1999-2000 (Year 1) and 2000-2001 (Year 2) influenza seasons. The intent-to-treat analysis set included a total of 786 children 6 through 24 months of age. Participants received two 0.25 mL doses of either Fluzone (N=525) or a placebo (N=261). Among all randomized participants in both years, the mean age was 13.8 months; 52.5% were male, 50.8% were Caucasian, 42.0% were Black, and 7.2% were of other racial groups. Cases of influenza were identified through active and passive surveillance for influenza-like illness or acute otitis media and confirmed by culture. Influenza-like illness was defined as fever with signs or symptoms of an upper respiratory infection. Vaccine efficacy against all influenza viral types and subtypes was a secondary endpoint and is presented in Table 8.

Table 8: Estimated Efficacy of Fluzone (Trivalent Influenza Vaccine) Against Culture- Confirmed Influenza in Children Aged 6 through 24 Months during the 1999-2000 and 2000-2001 Influenza Seasons – Intent-to-Treat Analysis Set *

	Fluzone †				Placebo ‡				Fluzone vs. Placebo
Year	n §	N ¶	Rate(n/N)#	(95% CI)	n §	N ¶	Rate(n/N)#	(95% CI)	Relative Risk(95% CI)	Percent Relative Reduction Þ (95% CI)
* The intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinated † Fluzone (0.25 mL): 1999-2000 formulation containing A/Beijing/262/95 (H1N1), A/Sydney/15/97 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage) and 2000-2001 formulation containing A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage) ‡ Placebo: 0.4% NaCl § n is the number of participants with culture-confirmed influenza for the given year of study as listed in the first column ¶ N is the number of participants randomly assigned to receive Fluzone or placebo for the given year of study as listed in the column headers (intent-to-treat analysis set) # Rate (%) = (n/N) * 100 Þ Relative reduction in vaccine efficacy was defined as (1-relative risk) × 100 ß Includes all culture confirmed influenza cases throughout the study duration for Year 1 (12 months of follow-up) à Includes all culture-confirmed influenza cases throughout the study duration for Year 2 (6 months of follow-up)
Year 1ß	15	273	5.5	(3.1; 8.9)	22	138	15.9	(10.3; 23.1)	0.34 (0.18; 0.64)	66 (36; 82)
(1999-2000)
Year 2à	9	252	3.6	(1.6; 6.7)	4	123	3.3	(0.9; 8.1)	1.10 (0.34; 3.50)	-10 (-250; 66)
(2000-2001)

14.2 Efficacy of Fluzone (Trivalent Influenza Vaccine) in Adults

A randomized, double-blind, placebo-controlled study was conducted in a single US center during the 2007-2008 influenza season. Participants received one dose of either Fluzone vaccine (N=813), an active comparator (N=814), or placebo (N=325). The intent-to-treat analysis set included 1138 healthy adults who received Fluzone or placebo. Participants were 18 through 49 years of age (mean age was 23.3 years); 63.3% were female, 83.1% were Caucasian, and 16.9% were of other racial/ethnic groups. Cases of influenza were identified through active and passive surveillance and confirmed by cell culture and/or real-time polymerase chain reaction (PCR).

Influenza-like illness was defined as an illness with at least 1 respiratory symptom (cough or nasal congestion) and at least 1 constitutional symptom (fever or feverishness, chills, or body aches). Vaccine efficacy of Fluzone against all influenza viral types and subtypes is presented in Table 9.

Table 9: Estimated Efficacy of Fluzone (Trivalent Influenza Vaccine) Against Influenza in Adults Aged 18 through 49 Years during the 2007-2008 Influenza Season – Intent-to-Treat Analysis Set *^, †

Laboratory- Confirmed Symptomatic Influenza	Fluzone ‡(N=813)§			Placebo ¶(N=325)§			Fluzone vs. Placebo
	n #	Rate(%)Þ	(95% CI)	n #	Rate(%)Þ	(95% CI)	Relative Risk(95% CI)	Percent Relative Reduction ß(95% CI)
* NCT00538512 † The intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinated ‡ Fluzone: 2007-2008 formulation containing A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (Victoria lineage) § N is the number of participants randomly assigned to receive Fluzone or placebo ¶ Placebo: 0.9% NaCl # n is the number of participants satisfying the criteria listed in the first column Þ Rate (%) = (n/N) * 100 ß Relative reduction in vaccine efficacy was defined as (1 — relative risk) × 100
Positive culture	21	2.6	(1.6; 3.9)	31	9.5	(6.6; 13.3)	0.27 (0.16; 0.46)	73 (54; 84)
Positive PCR	28	3.4	(2.3; 4.9)	35	10.8	(7.6; 14.7)	0.32 (0.20; 0.52)	68 (48; 80)
Positive culture, positive PCR, or both	28	3.4	(2.3; 4.9)	35	10.8	(7.6; 14.7)	0.32 (0.20; 0.52)	68 (48; 80)