Protective efficacy of live-attenuated influenza vaccine (multivalent, Ann Arbor strain): a literature review addressing interference

Figures & data

Figure 1. Vaccine virus replication in ferret nasal wash samples (study 1).

Vaccine virus present in nasal wash samples after dose 1 (day 0) and dose 2 (day 28) was detected and quantitated by inoculation of decimal dilutions of samples into Madin–Darby canine kidney cells. The amount of vaccine virus present was expressed as log₁₀ median TCID₅₀ per ml.

TCID₅₀: Median tissue culture infectious dose.

Figure 2. Vaccine virus replication in ferret nasal wash samples (study 2).

Vaccine virus present in nasal wash samples after dose 1 (day 0) and dose 2 (day 28) was detected and quantitated by inoculation of decimal dilutions of samples into Madin–Darby canine kidney cells. The amount of vaccine virus present was expressed as log₁₀ median TCID₅₀ per ml.

TCID₅₀: Median tissue culture infectious dose.

Figure 3. Although high rates of seroconversion following live-attenuated influenza vaccine are associated with high efficacy, high efficacy is observed with low rates of seroconversion.

Serum antibody was measured before and after vaccination using HAI assays, and seroconversion was defined as a fourfold or greater rise in HAI antibody titers. HAI data are for all subjects, regardless of baseline serostatus. Efficacy indicates protection of vaccine recipients against wild-type influenza strains that were matched to the live-attenuated influenza vaccine strains. Error bars represent the 95% CI.

HAI: Hemagglutination inhibition.

Table 1. Ferret hemagglutination inhibition titers and seroconversion rates at day 14 after vaccination with trivalent or quadrivalent live-attenuated influenza vaccine formulations.

Vaccine	HAI mean titer (log2) ± SD^† (% seroconversion)
	H1N1	H3N2	B/Florida/7/2004	B/Malaysia
Quadrivalent 1 B/Malaysia/2506/04 B/Florida/7/2004	6.6 ± 1.3 (100)	3.5 ± 1.7 (100)	4.2 ± 0.8 (100)	3.5 ± 1.1 (100)
Trivalent B/Malaysia/2506/04	6.4 ± 0.9 (100)	3.4 ± 1.8 (100)	BLD	5.0 ± 0.7 (100)
Trivalent B/Florida/07/2004	7.8 ± 0.8 (100)	5.6 ± 0.5 (100)	4.8 ± 0.8 (100)	BLD

^†Limit of detection = 1.0 log₂ HAI.

BLD: Below limit of detection; HAI: Hemagglutination inhibition; SD: Standard deviation.

Table 2. Ferret hemagglutination inhibition titers and seroconversion rates at day 14 after vaccination with trivalent or quadrivalent live-attenuated influenza vaccine formulations.

Vaccine	HAI mean titer (log2) ± SD^† (% seroconversion)
	H1N1	H3N2	B/Florida/4/06	B/Malaysia/2505/04
Quadrivalent 2 B/Malaysia/2506/04 B/Florida/4/06	4.7 ± 1.3 (100)	2.4 ± 1.2 (0)	6.8 ± 0.6 (100)	4.3 ± 0.6 (100)
Trivalent B/Malaysia/2506/04	5.0 ± 0.8 (100)	2.1 ± 1.6 (0)	BLD	5.8 ± 0.6 (100)
Trivalent B/Florida/04/2006	5.4 ± 1.2 (100)	2.2 ± 1.4 (0)	6.5 ± 0.9 (100)	BLD

^†Limit of detection = 1.0 log₂ HAI.

BLD: Below limit of detection; HAI: Hemagglutination inhibition; SD: Standard deviation.

Table 3. Studies comparing responses to monovalent and multivalent live-attenuated influenza vaccine.

Study (year)	Strains in vaccine	Potency^† (log10 TCID50)	Study population, age	Proportion of vaccinees shedding designated vaccine strain n/N (%)				Proportion of vaccinees developing ≥fourfold rise in serum antibody n/N (%)			Evidence for interference	Ref.
				H1N1	H3N2	B		H1N1	H3N2	B
Gruber et al. (1993)	Study 1 A/H1 A/H3 B A/H1, A/H3, B	6.0 6.0 4.0 6.0, 6.0, 4.0 (Low B)	Children, 6–24 months	5/8 (63) 9/10 (90)	11/12 (92) 10/10 (100)	7/8 (88) 3/11 (27)		5/8 (63) 8/10 (80)	11/12 (92) 10/10 (100)	0/8 (0) 2/11 (18)	Shedding data indicate that A strains interfered with B strain only when potency of B strains was 100-fold lower in trivalent vaccine than potency of A strains. Antibody responses were comparable in monovalent and trivalent formulations	[7]
	Study 2 A/H1 A/H3 B A/H1, A/H3, B	6.0 6.0 6.0 6.0, 6.0, 6.0 (High B)	Children, 6–24 months	5/8 (63) 24/25 (96)	11/12 (92) 24/24 (100)	10/11 (91) 21/26 (81)		5/8 (63) 18/25 (74)	11/12 (92) 24/24 (100)	0/8 (0) 5/26 (19)
Gruber et al. (1996)	A/H1N1 A/H3N2 A/H1, A/H3	6.2 6.2 6.2, 6.2	Children, 6–18 months	7/44 (16) NR	16/45 (36) NR			30/36 (83) 10/32 (31)	31/31 (100) 32/32 (100)		Antibody responses to A/H1N1 were lower in bivalent formulation compared with monovalent formulation	[14]
Keitel et al. (1993)^‡	Study 1 B A/H1, A/H3 A/H1, A/H3, B	7.1 7.1, 7.1 7.1, 7.1, 7.1	Adults, 18–40 years	7/9 (78) 6/11 (55)	0/9 (0) 1/11 (9)	10/10 (100) 10/11 (91)		8/9 (89) 7/11 (64)	2/9 (22) 2/11 (18)	4/9 (44) 2/11 (18)	Shedding data indicate interference with the B strain in study 2, but not in study 1. Antibody responses to B strain were lower in trivalent formulations	[15]
	Study 2 B A/H1, A/H3 A/H1, A/H3, B	7.1 7.1, 7.1 7.1, 7.1, 7.1	Adults, 18–40 years	8/9 (89) 4/10 (40)	6/9 (67) 1/10 (10)	10/10 (100) 5/10 (50)		9/9 (100) 7/10 (70)	4/9 (44) 3/10 (30)	6/10 (60) 0/10 (0)
Atmar et al. (1995)	A/H1 A/H3 B A/H1, A/H3, B	7.1 7.1 7.1 7.1	Adults, 18–40 years	ND	ND	ND		35/80 (44) 36/80 (45)	22/80 (28) 15/80 (19)	21/80 (26) 24/80 (30)	Antibody responses to all strains were comparable in monovalent and trivalent formulations	[13]
Potter et al. (1983)	A/H1 A/H3 A/H1, A/H3	8.0 8.0 8.0, 8.0	Adults	ND	ND	ND		10/30 (33) 13/40 (33)	17/27 (63) 14/40 (35)		Antibody responses to A/H3N2 were lower in bivalent formulation compared with monovalent formulation	[10]

^†Potency expressed in terms of log₁₀ TCID₅₀.

^‡Two doses of vaccine were administered in each study; data presented here are for the first dose only.

A/H1N1 LAIV strains used were A/Kawasaki/9/86 [7,13–15] and A/USSR/77 [10]. A/H3N2 LAIV strains used were A/Los Angeles/2/87 [7,13–15], A/Bethesda/1/85 [13], and A/Victoria/3/75 [10]. B LAIV strains used were B/Ann Arbor/1/86 [7,15] and B/Yamagata/17/88 [13].

ND: Not done; n/N: Number shedding/number of vaccine recipients; NR: Not reported; TCID₅₀: Median tissue culture infectious dose.

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