Fluvirin (Influenza Virus Vaccine) - Description and Clinical Pharmacology

DESCRIPTION

FLUVIRIN^® is a trivalent, sub-unit (purified surface antigen) influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens' eggs inoculated with a specific type of influenza virus suspension containing neomycin and polymyxin. Each of the influenza virus strains is harvested and clarified separately by centrifugation and filtration prior to inactivation with betapropiolactone. The inactivated virus is concentrated and purified by zonal centrifugation. The surface antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle by further centrifugation in the presence of nonylphenol ethoxylate, a process which removes most of the internal proteins. The nonylphenol ethoxylate is removed from the surface antigen preparation.

FLUVIRIN^® is a homogenized, sterile, slightly opalescent suspension in a phosphate buffered saline. FLUVIRIN^® has been standardized according to USPHS requirements for the 2009-2010 influenza season and is formulated to contain 45 mcg hemagglutinin (HA) per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the following 3 viruses: A/Brisbane/59/2007, IVR-148 (H1N1); A/Uruguay/716/2007, NYMC X-175C (H3N2) (an A/Brisbane/10/2007-like virus); and B/Brisbane/60/2008.

The 0.5-mL prefilled syringe presentation is formulated without preservative. However, thimerosal, a mercury derivative used during manufacturing, is removed by subsequent purification steps to a trace amount (≤ 1 mcg mercury per 0.5-mL dose).

The 5-mL multidose vial formulation contains thimerosal, a mercury derivative, added as a preservative. Each 0.5-mL dose from the multidose vial contains 25 mcg mercury.

Each dose from the multidose vial or from the prefilled syringe may also contain residual amounts of egg proteins (≤ 1 mcg ovalbumin), polymyxin (≤ 3.75 mcg), neomycin (≤ 2.5 mcg), betapropiolactone (not more than 0.5 mcg) and nonylphenol ethoxylate (not more than 0.015% w/v).

The multidose vial stopper and the syringe stopper/plunger do not contain latex.

CLINICAL PHARMACOLOGY

Mechanism of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. In some human studies, antibody titer of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects [see REFERENCES (15.1, 15.2)].

Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of strains (i.e., typically two type A and one type B), representing the influenza viruses likely to be circulating in the United States in the upcoming winter.

Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year [see REFERENCES].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

FLUVIRIN^® has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

CLINICAL STUDIES

Between 1982 and 1991, twelve clinical studies were conducted in healthy adult and geriatric subjects and one in children between 4 and 12 years of age who were considered to be "at risk". Since 1991 an annual clinical study has been conducted in the UK in healthy adults aged 18 years or older. FLUVIRIN^® was also used as a control in a US clinical trial in adults (18-49 years of age). In all the trials, blood samples were taken prior to vaccination and approximately three weeks after vaccination to assess the immunogenic response to vaccination by measurement of anti-HA antibodies.

Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6-48 months). Of these, 285 healthy subjects plus 41 "at risk" pediatric subjects, received FLUVIRIN^®.

FLUVIRIN^® should only be used for the immunization of persons aged 4 years and over.

Immunogenicity in Adults (18 to 64 years of age)

Tables 4 and 5 show the immunogenicity data for the adult age group. The seven clinical studies presented enrolled a total of 774 adult subjects. In the adult group, for all antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria was met: the proportion of subjects with seroconversion (post-vaccination titer ≥1:40 from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase from pre-vaccination titer ≥1:10) in antibody titer was greater than 40%; the geometric mean titer (GMT) increase was >2.5; the proportion of subjects with a post-vaccination hemagglutination inhibition (HI) antibody titer ≥1:40 was greater than 70%.

TABLE 4 Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer ≥1:40 for Adult Subjects

∞ Seroconversion: proportion of subjects with either a post-vaccination HI titer ≥1:40 from a pre-vaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer ≥1:10 in antibody titer.
¥ HI titer ≥1:40: proportion of subjects with a post-vaccination titer ≥ 1:40.
φ 95% CI: 95% confidence interval
Year/Strain	No. of	Seroconversion †ž			HI titer ≥1:40 ¥
	subjects	N	%	95% CI φ	n	%	95% CI φ
1998-1999
A/H1N1		48	73	(62, 83)	50	76	(65, 86)
A/H3N2	66	43	65	(54, 77)	47	71	(60, 82)
B		42	64	(52, 75)	62	94	(88, 100)
1999-2000
A/H1N1		45	59	(48, 70)	50	66	(55, 76)
A/H3N2	76	51	67	(57, 78)	66	87	(79, 94)
B		53	70	(59, 80)	75	99	(96, 100)
2000-2001
A/H1N1		41	55	(44, 67)	41	55	(44, 67)
A/H3N2	74	45	61	(50, 72)	52	84	(75, 92)
B		50	68	(57, 78)	73	99	(96, 100)
2001-2002
A/H1N1		44	59	(48, 70)	48	64	(53, 75)
A/H3N2	75	46	61	(50, 72)	68	91	(84, 97)
B		42	56	(45, 67)	66	88	(81, 95)
2002-2003
A/H1N1		62	58	(49, 68)	73	69	(60, 78)
A/H3N2	106	72	68	(59, 77)	93	88	(81, 94)
B		78	74	(65, 82)	101	95	(91, 99)
2004-2005
A/H1N1		52	70	(59, 80)	66	89	(80, 95)
A/H3N2	74	60	81	(70, 89)	73	99	(93, 100)
B		57	77	(66, 86)	69	93	(85, 98)
2005-2006
A/H1N1		191	63	(57, 68)	296	98	(95, 99)
A/H3N2	303	273	90	(86, 93)	294	97	(94, 99)
B		213	70	(65, 75)	263	87	(82, 90)

TABLE 5 Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers, Pre- and Post-Immunization, for Adult Subjects

* 95% CI: 95% confidence interval
Year/Strain	No. of	Geometric Mean Titer (GMT)
	subjects	Pre-vaccination	Post-vaccination	Fold Increase	(95% CI)*
1998-1999
A/H1N1		7.26	160.87	22.16	(14.25, 34.46)
/H3N2	66	8.23	87.02	10.57	(6.91, 16.16)
B		20.97	231.07	110.2	(6.90, 17.59)
1999-2000
A/H1N1		7.43	58.95	7.93	(5.73, 10.97)
A/H3N2	76	15.29	122.83	8.03	(5.80, 11.13)
B		25.70	254.76	9.91	(6.97, 14.10)
2000-2001
A/H1N1		5.42	33.80	6.24	(4.49, 8.69)
A/H3N2	74	15.98	126.01	7.89	(5.61, 11.09)
B		26.24	308.25	11.75	(7.73, 17.85)
2001-2002
A/H1N1		7.76	54.78	7.06	(5.24, 9.52)
A/H3N2	75	23.67	153.81	6.50	(4.78, 8.84)
B		19.91	107.53	5.40	(3.95, 7.38)
2002-2003
A/H1N1		7.78	60.39	7.77	(5.81, 10.39)
A/H3N2	106	23.32	292.03	12.52	(8.77, 17.87)
B		30.20	314.11	10.40	(7.54, 14.34)
2004-2005
A/H1N1		13	159	12	(8.39, 17)
A/H3N2	74	37	658	18	(12, 26)
B		15	156	11	(7.87, 14)
2005-2006
A/H1N1		29	232	8	(6.68, 9.59)
A/H3N2	303	14	221	15	(14, 17)
B		13	83	6.5	(5.73, 7.37)

Immunogenicity in Geriatric Subjects (65 years of age and older)

Tables 6 and 7 show the immunogenicity of FLUVIRIN^® in the geriatric age group. The six clinical studies presented enrolled a total of 296 geriatric subjects. For each of the influenza antigens, the percentage of subjects who achieved seroconversion and the percentage of subjects who achieved HI titers of ≥1:40 are shown, as well as the fold increase in GMT.

For all antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria was met: the proportion of subjects with seroconversion (post-vaccination titer ≥1:40 from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase from pre-vaccination titer ≥1:10) in antibody titer was greater than 30%; the geometric mean titer (GMT) increase was >2.0; the proportion of subjects with a post-vaccination hemagglutination inhibition (HI) antibody titer ≥1:40 was greater than 60%. The pre-specified efficacy criteria were met in each study, although a relatively lower immunogenicity of A/H1N1 strain was seen in the last four studies (the same strain was in each of the formulations).

TABLE 6 Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer ≥1:40 for Geriatric Subjects

∞ Seroconversion: proportion of subjects with either a post-vaccination HI titer ≥1:40 from a pre-vaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer ≥1:10 in antibody titer
¥ HI titer ≥1:40: proportion of subjects with a post-vaccination titer ≥1:40
φ 95% CI: 95% confidence interval
Year/Strain	No. of	Seroconversion †ž			HI titer ≥1:40 ¥
	subjects	N	%	95% CI φ	N	%	95% CI φ
1998-1999
A/H1N1		33	79	(66, 91)	38	90	(82, 99)
A/H3N2	42	33	79	(66, 91)	36	86	(75, 96)
B		13	31	(17, 45)	42	100	(100, 100)
1999-2000
A/H1N1		10	29	(14, 45)	23	68	(52, 83)
A/H3N2	34	18	53	(36, 70)	31	91	(82, 100)
B		9	26	(12, 41)	32	94	(86, 100)
2000-2001
A/H1N1		5	14	(3, 26)	10	29	(14, 44)
A/H3N2	35	22	63	(47, 79)	31	89	(78, 99)
B		13	37	(21, 53)	33	94	(87, 100)
2001-2002
A/H1N1		5	14	(3, 26)	14	40	(24, 56)
A/H3N2	35	15	43	(26, 59)	33	94	(87, 100)
B		6	17	(5, 30)	32	91	(82, 100)
2002-2003
A/H1N1		24	27	(18, 36)	52	58	(48, 69)
A/H3N2	89	42	47	(37, 58)	85	96	(91, 100)
B		41	46	(36, 56)	86	97	(93, 100)
2004-2005
A/H1N1		17	28	(17, 41)	46	75	(63, 86)
A/H3N2	61	29	48	(35, 61)	60	98	(91, 100)
B		38	62	(49, 74)	51	84	(72, 92)

TABLE 7 Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers, Pre- and Post-Immunization, for Geriatric Subjects

* 95% CI: 95% confidence interval
Year/Strain	No. of	Geometric Mean Titer (GMT)
	subjects	Pre-vaccination	Post-vaccination	Fold Increase	(95% CI)*
1998-1999
A/H1N1		13.92	176.65	12.69	(8.24, 19.56)
A/H3N2	42	10.69	124.92	11.69	(7.02, 19.46)
B		114.1	273.56	2.40	(1.82, 3.17)
1999-2000
A/H1N1		15.82	50.58	3.20	(2.13, 4.80)
A/H3N2	34	28.00	133.19	4.76	(2.92, 7.76)
B		57.16	127.86	2.24	(1.56, 3.20)
2000-2001
A/H1N1		6.66	18.85	2.83	(1.91, 4.18)
A/H3N2	35	25.87	140.68	5.44	(3.72, 7.96)
B		61.24	191.23	3.12	(2.13, 4.59)
2001-2002
A/H1N1		12.69	26.65	2.10	(1.55, 2.84)
A/H3N2	35	47.33	114.26	2.41	(1.73, 3.38)
B		45.49	91.89	2.02	(1.47, 2.78)
2002-2003
A/H1N1		13.29	31.92	2.40	(1.90, 3.03)
A/H3N2	89	65.86	272.79	4.14	(3.09, 5.55)
B		74.87	288.57	3.85	(2.89, 5.13)
2004-2005
A/H1N1		21	64	3.13	(2.33, 4.2)
A/H3N2	61	72	320	4.43	(3.13, 6.27)
B		20	114	5.69	(4.39, 7.38)

Immunogenicity in Pediatric Subjects

A small-scale study, was conducted in 1987 to evaluate safety and immunogenicity of FLUVIRIN^® in 38 "at risk" children, with diabetes and/or asthma, or lymphoid leukemia. Thirty-eight participants aged between 4 and 12 years of age were assessed. Ten subjects had diabetes, 21 had asthma, two had both diabetes and asthma, and one had lymphoid leukemia. There were four healthy control subjects. All participants received a single 0.5-mL dose of FLUVIRIN^®.

Immunogenicity results were obtained for 19 of the 38 subjects enrolled in the study. The point estimate of the percentage of subjects achieving a titer of ≥ 1:40 was 84% for the A/H1N1 strain 79% for the B strain, and 53% for the A/H3N2 strain. The GMT fold increases were 5.8 for the A/H1N1 strain, 40 for the B strain and 17.7 for the A/H3N2 strain.

Three clinical studies were carried out between 1995 and 2004 in a total of 520 pediatric subjects (age range 6-47 months). Of these, 285 healthy subjects plus 41 "at risk" pediatric subjects, received FLUVIRIN^®.

In a 1995/1996 clinical study, 41 subjects (aged 6-36 months) at increased risk for influenza-related complications received two 0.25-mL doses of FLUVIRIN^®. At least 49% of subjects showed a ≥4-fold increase in HI antibody titer to all three strains. HI antibody titers of 1:40 or greater were seen in at least 71% of the subjects for all three influenza strains, with increases in geometric mean titer of 6.0-fold or greater to all three strains.

Two clinical studies (1999-2000 and 2004) indicated a lower immunogenicity profile for FLUVIRIN^® compared with two commercial split vaccines; in a study in the age group 6-48 months the comparator was a US licensed vaccine, Fluzone^®, and in another study in the age group 6-36 months the comparator was a non-US licensed inactivated influenza vaccine. Despite the small sample size (a total of 285 healthy subjects received FLUVIRIN^® in these two clinical studies) the lower immunogenicity profile of FLUVIRIN^® was greatest versus the comparator vaccines in children <36months but was also evident in those 36-48 months of age, though the differences were less.

FLUVIRIN^® should only be used for the immunization of persons aged 4 years and over.