Immunogenicity and safety of seasonal influenza vaccines in children under 3 years of age

Figures & data

Figure 1. Daily UK national health service 111 calls flagged for flu or cold for children younger than 1 year (left) and children aged 1–4 years (right) [7].

Figure 2. Flowchart of eligible studies.

Table 1. Studies categorized by vaccine type (TIV, QIV, TIV vs QIV).

Study #	Vaccines	Strains in vaccines	Age	Sample size	Administration	Ref
TIV
1	(V) IIV3 – Vaxigrip, Influvac, Agrippal, Fluarix(C) None	A/H1N1/California/7/2009A/H3N2/Victoria/361/2011B/Wisconsin/1/2010	6–35 months*data for dose 2 were not categorized by age	n = 436	2 doses, 28 days apart	[49]
2	(V) CAIV-T (C) Sterile saline	Year 1:A/H1N1/NewCaledonia/20/99A/H3N2/Sydney/05/97B/Yamanashi/166/98Year 2:A/H1N1/NewCaledonia/20/99A/H3N2/Panama/2007/99B/Yamanashi/166/98	12–36 months	n(V) = 1900n(C) = 1274Groups: (year1/year2) 1: (V)/(V) 2: (V)/(C) 3: (C)/(V) 4: (C)/(C)	Year 1:2 doses, 28 days apartYear 2:1 dose of either (V) or (C) irrelevant of which group they belonged to in year1	[28]
3	(V) IIV3-MF59 – Fluad(C) IIV3 – Vaxigrip*(C) non-adjuvant	A/H1N1/New Caledonia/20/99, A/H3N2/Wisconsin/67/2005, B/Victoria/Malaysia/2506/2004*Year 2 – A/H1N1/Solomon Islands/3/2006	6–35 months	Year 1: n = 281n(V) = 130n(C) = 139Year 2: n = 89n(V) = 43n(C) = 46	Year 1 = > 2 doses 4 weeks apartYear 2 = > third dose of respective vaccine 1 year later	[39]
4	(V-0.25) IIV3 – TF-0.25 mL(V-0.5) IIV3 – TF-0.5 mL(C) IIV3 – Vaxigrip	A/H1N1/Brisbane/59/2007, A/H3N2/Uruguay/716/2007, B/Yamagata/Florida/4/2006*(V) vaccines were TF (thimerosal-free)	6–35 months	n = 374n (V-0.25) = 141n (V-0.5) = 146n (C) = 37	Primed children-> get 1 dose day 0Unprimed -> get 2 doses day 0 and 28–35	[41]
5	(aTIV) IIV3 – Fluad includes MF59 adjuvant(TIV) IIV3 – AgrippalS1(C) meningococcal C conjugate vaccine, tickborne encephalitis vaccine	Season 2007/8: A/H1N1/Solomon Islands/3/2006, A/H3N2/Wisconsin/67/2005, B/Victoria/Malaysia/2506/2004Season 2008/9: A/H1N1/Brisbane/59/2007, A/H3N3/Brisbane/10/2007, B/Yamagata/Florida/4/2006	6–35 monthsand 6–23 months	* Germany; n (2007/08) = 654n (2008/09) = 2104 Finland; n = 1949	2 doses 28 days apart	[30]
6	(Vd) IIV3 – TIV-AS03d(Vc) IIV3 – TIV-AS03c(B) booster non-adjuvant TIV Fluarix	(V) – A/H1N1/pdm09, A/H3N2/Uruguay/7/16/2007, B/Victoria/Brisbane/60/2008+ oil-in-water adjuvant α-tocopherol and squalene; 1.48 mg/1.337 mg in AS03d – 2.97 mg/2.675 mg in AS03c – 5.93 mg/5.35 mg in AS03b(B) – A/H1N1/pdm09, A/H3N2/Victoria/210/2009, B/Victoria/Brisbane/60/2008	6–35 months	n = 40n(Vc) = 20n(Vd) = 20	(Vd) – 2 doses, 21 days apart(Vc) – 1 dose	[40]
7	(V) – IIV3 Vaxigrip(C) – Inactivated poliovirus vaccine	A/H1N1/Brisbane/59/2007, A/H3N2/Brisbane/10/2007, B/Yamagata/Florida/04/2006	6–35 months	Year 2:n(V) = 1818n(C) = 1835Year 3:n(V) = 1702n(C) = 1625	2 doses 1 month apart*this is year 2 and 3 continuation of study 42	[31]
8	(V) – IIV3 Vaxigrip(C) – Inactivated poliovirus vaccine	A/H1N1/Brisbane/59/2007, A/H3N2/Brisbane/10/2007, B/Yamagata/Florida/04/2007	6–35 months	n(V) = 1017n(C) = 1001	2 doses 1 month apart	[32]
9	(V) CAIV-T(C) Placebo	Year 1: A/H1N1/New Caledonia/20/99,A/H3N2/Sydney/05/97, B/Yamanashi/166/98Year 2: A/H1N1/New Caledonia/20/99,A/H3N2/Panama/2007/99, B/Victoria/504/2000	6–35 months	Year 1:n(V) = 951n(C) = 665Year 2:n(V) = 640n(C) = 450	Year 1: 2 doses, 35 ± 7 days apart Year 2: 1 dose, according to the group in year 1	[29]
QIV
10	(V) IIV4 – Fluzone Quadrivalent*half dose 0.25 mL, full dose 0.5 mL(C) None	A/H1N1/California/07/2009, A/H3N2/Hong Kong/4801/2014, B/Victoria/Brisbane/60/2008, B/Yamagata/Phuket/3073/2013	6–35 months	n = 1950n (half) = 949n (full) = 9921460 participants in immunogenicity subset	2 doses (28 days apart) -> 1 year later antigen challenge	[43]
11	IIV4 – Vaxigrip Tetra	A/H1N1/Victoria/2570/2019, A/H3N2/Hong Kong/2671/2019, B/Victoria/Washington/02/2019, B/Yamagata/Phuket/3073/2013	6–35 months	n = 79	Primed children-> 1 dose day 0Unprimed -> 2 doses, 28 days apart	[50]
12	(V) – IIV4 (Afluria)(C) – IIV4 (Fluzone)	A/H1N1/California/7/2009, A/H3N2/Hong Kong/4801/2014, B/Victoria/Brisbane/60/2008, B/Yamagata/Phuket/3073/2013	6–35 months	n(V) = 586n (C) = 193	Primed children-> get 1 doseUnprimed -> 2 doses 28 days apart	[44]
13	(V) – IIV4 (Fluarix)(C) – Hepatitis A vaccine, Varicella vaccine, Pneumococcal conjugate vaccine	*Results were given as IIV4 but many combinations were given of the following list (each IIV4 had A/H1N1 + A/H3N2 + B/Victoria + B/Yamagata linages):A/H1N1 – California/7/2009 or Christchurch/16/2010A/H3N2 – Victoria/361/2011 or Texas/50/2012B/Victoria/Brisbane/60/2008B/Yamagata – Brisbane/3/2007 or Hubei-Wujiagang/158/2009 or Massachusetts/2/2012	6–35 months	n = 12,018n(V) = 6006n(C) = 6012	Primed children-> get 1 dose day 0Unprimed -> 2 doses day 0 and 28	[34]
14	(V) – IIV4 Influvac Tetra(C) – pneumococcal 13-valent conjugate vaccine, meningococcal group C conjugate vaccine, hepatitis A vaccine, tickborne encephalitis vaccine, or varicella vaccine	*Reference is WHO (on study breakdown)Season 2017/18 NH:A/H1N1/Michigan/45/2015, A/H3N2/Hong Kong/480/2014, B/Victoria/Brisbane/60/2008, B/Yamagata/Phuket/3073/2013Season 2018/19 NH:A/H1N1/Michigan/45/2015, A/H3N2/Singapore/INFIMH-16-0019/2016, B/Victoria/Colorado/06/2017, B/Yamagata/Phuket/3073/2013Season 2019 SH:A/H1N1/Michigan/45/2015, A/H3N2/Switzerland/8060/2017, B/Victoria/Colorado/06/2017, B/Yamagata/Phuket/3073/2013	6–35 months	n = 2000n (V) = 1005n (C) = 995	2 doses 28–33 days apart3 influenza seasons 2017/18, 2018/19, 2019	[35]
15	(V) – IIV4 Vaxigrip Tetra(C) – Placebo, saline	A/H1N1/California/7/2009, A/H3N2/Victoria/361/2011, B/Victoria/Brisbane/60/2008, B/Yamagata/Massachusetts/2/2012	6–35 months	n = 5436	2 doses 28 days apart	[36]
16	(V) – IIV4 GSK**	A/H1N1//California/7/2009A/H3N2/Victoria/210/2009B/Yamagata/Brisbane/3/2007B/Victoria/Brisbane/60/2008	6–35 months	n = 301	Primed children-> get 1 dose day 0Unprimed -> get 2 doses day 0 and 28	[42]
17	(V) – IIV4(C) – hepatitis A vaccine, varicella vaccine, pneumococcal conjugate vaccine	Cohort # (C#)A/H1N1:C1+ C2 -> /California/7/2009C3+ C4+ C5 -> /Christchurch/16/2010A/H3N2:C1+ C2 -> /Victoria/210/2009C3+ C4 -> /Victoria/361/2011C5 -> /Texas/50/2012B/Victoria:C1+ C2+ C3+ C4+ C5 -> /Brisbane/60/2008B/Yamagata:C1 -> /Brisbane/3/2007C2+ C3+ C4 -> /Hubei-Wujiagana/158/2009C5 -> /Massachusetts/2/2012	6–35 months	n = 12,018C1 n = 1777C2 n = 2526C3 n = 1564C4 n = 1501C5 n = 4650C1 – EuropeC2,4,5 – Asia Pacific and Central AmericaC3 – Lebanon and Turkey	Primed children-> get 1 dose day 0Unprimed -> get 2 doses day 0 and 28	[37]
TIV vs QIV
18	(V) IIV4 – NBP607-QIV (C) IIV3 – AgrippalS1*this was the comparator	A/H1N1/Christchurch/16/2010A/H3N2/Texas/50/2012B/Yamagata/Massachusetts/2/2012	6–35 months	n = 454n (V) = 366n (C) = 88	Primed children-> get 1 dose day 0Unprimed -> get 2 doses day 0 and 28–35	[45]
19	(V) IIV4(C) IIV3 – TIV-Vic/Yam	TIV-Vic; A/H1N1/Michigan/45/2015, A/H3N2/Hong Kong/4801/2014, B/Victoria/Brisbane/60/2008TIV-Yam; A/H1N1/Michigan/45/2015, A/H3N2/Hong Kong/4801/2014, B/Yamagata/Phuket/3073/2013	6–35 months	n = 2320n (V) = 1160n (C-Vic) = 580n (C-Yam) = 580	2 doses 28 days apart	[48]
20	(IIV3-1) TIV-Vic(IIV3-2) TIV-Yam(IIV4)(C) PlaceboIIV3-1/2 ***	IIV3-1;A/H1N1/California/7/2009, A/H3N2/Texas/50/2012, B/Victoria/Brisbane/60/2008IIV3-2;A/H1N1/California/7/2009, A/H3N2/Texas/50/2012, B/Yamagata/Massachusetts/02/2012	6–35 months	n = 5806n (IIV4) = 2721n (placebo) = 2715n (IIV3-1) = 183n (IIV3-2) = 186	2 doses 28 days apart	[33]
21	(V) – IIV4 (GSK)(C) – IIV3 (Sanofi Pasteur)	A/H1N1/California/7/2009, A/H3N2/Texas/50/2012, B/Yamagata/Massachusetts/2/2012	6–35 months	n(V) = 158n(C) = 156	Primed children-> get 1 dose day 0Unprimed -> get 2 doses day 0 and 28	[46]
22	(IIV3) (LAIV4)	Not mentioned *2015-16 vaxigrip (99.8%), influvac (0.2%), fluarix (0% −2)2016–17 influvac (99.8%), vaxigrip (0.2%)2017–18 influvac (88.4%), agrippal (11.6%)	< 2 years old	n(2015–16) = 60,088n(2016–17) = 60,860n(2017–18) = 60,345	LAIV4 one doseIIV3 – 2 doses, 28 days apart	[38]
23	(V4) – IIV4 GSK(V3) – IIV3 GSK	A/H1N1//California/7/2009, A/H3N2/Victoria/361/2011, B/Victoria/Brisbane/60/2008, B/Yamagata/Hubei-Wujiagang/158/2009	6–35 months	n(V4) = 299n(V3) = 302	Primed children-> get 1 dose day 0Unprimed -> get 2 doses day 0 and 28	[47]

The study number in the reference column can be used to cross-reference the study in tables #

*no age distinction for sample size.

**included TIV but not in the relevant age group. ***IIV3-1/2 is the administration of a combination of TIV-Vic and TIV-Yam.

Abbreviations: (V), test vaccine/(C), comparator vaccine/IIV3, Inactive Influenza Vaccine 3 (trivalent)/IIV4, Inactive Influenza Vaccines 4 (quadrivalent)/CAIV-T, cold-adapted influenza vaccine trivalent/LAIV4, live attenuated influenza vaccine 4 (quadrivalent)/nTIVs, non-adjuvanted TIVs/TF, thimerosal-free/TIV-Yam, trivalent influenza vaccine containing B/Yamagata strains/TIV-Vic, trivalent influenza vaccine containing B/Victoria strains.

Table 2. Efficacy, immunogenicity, and safety of different vaccine types in children aged 6–35 months.

Study number	Vaccine Type	Overall efficacy of the vaccine	Immunogenic responses to vaccines	Reactogenicity and effects of the vaccine on safety	Ref
TIV
1	IIV3	–	–	Low and comparable values when comparing the 1^st and 2^nd dose	[49]
2	CAIV-T	Similar VE for all three strains and comparable VE between antigenically-matching and mismatched strains. High VE maintained for a year.	SCR and GMFI rates were elevated and higher in seronegative patients.	High rates of mild systemic S.AE after the first dose and second year vaccination.	[28]
3	IIV3s; MF59-TIV and nTIV	–	MF59-TIV elicited higher immunogenic responses than nTIV. SPR rates were not attained for mismatched-strains influenza B.	Similar and low reactogenicity between MF59-TIV and nTIV.	[39]
4	IIV3s; TF-0.25, TF-0.5, IIV3	–	Higher dose increased immunogenicity. CHMP, EMA, and CBER criteria were met for SCR and SPR.	No statistically significant values.	[41]
5	IIV3s; MF59-TIV and nTIV	MF59-TIV has high efficacy levels against all influenza strains, more prominently vaccine-matched strains. nTIV levels were not as elevated as MF59-TIV and were almost null for the 6–23 months old group.	SPR of MF59-TIV higher than nTIV and maintained until day 181 against homologous and heterologous A/B strains. Titers after one dose of MF59-TIV exceeded two nTIV doses.	Non-inferiority of MF59-TIV to nTIV, both are safe.	[30]
6	IIV3s; TIV-AS03d, AS03c, nTIV	–	Titers after TIV-AS03c at day 42 were attained at day 21 after TIV-AS03d administration. TIV-AS03d maintained seropositivity at 6 months.	AS03-adjuvanted vaccines are more reactogenic than non-adjuvanted vaccines but are still relatively safe for use.	[40]
7	IIV3	VE was not significant in children (6–35 months old).	–	–	[31]
8	IIV3	VE was not significant against A/H3N2 strains in children (6–35 months old).	–	–	[32]
9	CAIV-T	High efficacy was demonstrated by CAIV-T vaccines in all cohorts.	–	CAIV-T is safe for the 6–35 months old age group.	[29]
QIV
10	IIV4 (half and full doses)	–	High SCR, GMT, and GMFI rates in both groups with no statistically significant difference between them (noninferiority of the full dose compared to the half dose).	Values are comparable between half and full doses. All S.AEs were resolved within 3 days and no SAE was related to the vaccine.	[43]
11	IIV4	–	–	S.AEs were mild and resolved within 7 days. U.AEs and SAEs were not related to the vaccine. Overall safe for children 6–35 months of age.	[50]
12	IIV4s	–	Both vaccines elicited strong responses against all strains (non-inferiority was demonstrated between them).	Both vaccines are well tolerated with mild-moderate S.AEs and SAEs were not related to the vaccine.	[44]
13	IIV4	High efficacy demonstrated in all groups, but it is higher in the 18–35 months old group.	Immunogenic against all strains and elicited responses were higher in 18–35 months old than in 6–17 months old.	No significant different between IIV4 and NIV.	[34]
14	IIV4	VE high against vaccine-matched and mismatched strains in all three seasons. Demonstrated persistence over the surveillance period. VE was higher in Northern Hemisphere than Southern Hemisphere.	Primary vaccination elicited broad response indicated by increased titers against all strains and >65% seroconversion. Long-term protection exhibited for up to 12 months post-vaccination. Revaccination group elicited strong responses against all strains. Visit 4 pre-revaccination titer slightly higher for A compared to B strains but still low overall. Visit 5 28 days post-revaccination titer was much higher than visit 4 for all strains.	IIV4 is safe in both the short-term and the long-term.	[35]
15	IIV4	VE was high against all influenza strains. Two doses of IIV4 demonstrated protection in children under 35 months old.	–	–	[36]
16	IIV4	–	HI titers achieved CBER criteria against the relevant strains except for SPR against A/H3N2.	IIV4 deemed safe for children 6–35 months old.	[42]
17	IIV4	The higher VE reported in the Northern hemisphere was 20% higher than the highest reported in the Subtropical countries.	–	–	[37]
TIV vs QIV
18	IIV4 and IIV3	–	CHMP criteria was met against A/H1N1, A/H3N2, and B/Yamagata lineages for both IIV3 and IIV4 vaccines (not against B/Victoria since the vaccine did not contain it). SCR and SPR values were lower for IIV3 but GMT values were higher compared to IIV4.	No significant differences between the two vaccines and all AEs were mild and uncommon.	[45]
19	IIV4 and IIV3s (TIV-Yam and TIV-Vic or combination of TIV-Yam/Vic)	–	IIV4 provided protection against both A strains and B/Yamagata but not B/Victoria. Combined IIV3s elicited high responses against A strains and the individual IIV3s elicited high responses against vaccine-matching strains but not mis-matching strains. Immunogenicity against B strains is lower than that against A strains.	No significant difference between IIV4 and IIV3s. All AEs were of low frequency and SAEs were not related to the vaccines.	[48]
20	IIV4 and IIV3s (TIV-Yam and TIV-Vic or combination of TIV-Yam/Vic)	Only IIV4 was tested for efficacy and produced higher VE against antigenically matching strains compared to any influenza strains.	IIV4 demonstrated non-inferiority compared to IIV3-1/2 (combined) against A strains and against B/Yamagata compared to TIV-Yam but not against B/Victoria compared to TIV-Vic. When comparing IIV4 with IIV3s containing alternating B-lineages, superiority was observed.	No significant difference between the groups, except a higher frequency of local S.AE after IIV4.	[33]
21	IIV4 and IIV3	–	IIV4 and IIV3 elicited significant immunogenic responses comparable against A/H1N1, A/H3N2, and B/Yamagata but IIV4 elicited higher responses against B/Victoria. CBER criteria for SCR was met by IIV4.	Both IIV4 and IIV3 are tolerable and have similar reactogenicity profiles.	[46]
22	LAIV4 and IIV3	2015–16; IIV3 provided better protection against A than LAIV4 and weaker than LAIV4 in B strains. 2016–17; neither as effective against A/H3N2. 2017–18; neither protected against A and IIV3 did not protect against B, while LAIV4 was highly effective.	–	–	[38]
23	IIV4 and IIV3	–	Non-inferiority was demonstrated by IIV4 compared to IIV3 against shared strains (A/H1N1, A/H3N2 and B/Yamagata) but superiority of IIV4 was observed against B/Victoria.	IIV4 and IIV3 have similar reactogenicity profiles. S.AEs were mild-moderated and infrequent. All SAEs, MAEs, and U.AEs were resolved by the end of the study.	[47]

Abbreviations: (V), test vaccine/(C), comparator vaccine/VE, vaccine efficacy/GMT, geometric mean titer/SCR, seroconversion rate/SPR, seroprotection rate/IIV3, Inactive Influenza Vaccine 3 (trivalent)/IIV4, Inactive Influenza Vaccines 4 (quadrivalent)/CAIV-T, cold-adapted influenza vaccine trivalent/LAIV4, live attenuated influenza vaccine 4 (quadrivalent)/nTIVs, non-adjuvanted TIVs/TF, thimerosal-free/TIV-Yam, trivalent influenza vaccine containing B/Yamagata strains/TIV-Vic, trivalent influenza vaccine containing B/Victoria strains.

Table 3. Summary of the efficacy, immunogenicity, and reactogenicity of different vaccine types in children aged 6–35 months.

.

Key for colors; Green – positive outcome (high for efficacy and immunogenicity/low for safety), Yellow – not positive nor negative outcome (moderate for efficacy and immunogenicity/tolerable for safety), Red – negative outcome (low for efficacy and immunogenicity/high for safety), Grey – nonsignificant values.

Efficacy and Immunogenicity; High – provides good protection, Moderate – provides protection but not effectively, Low – does not provide protection, Not significant – no significant data reported in the study. Safety; High – Not safe/severe and common adverse reactions, Tolerable – Common but not severe adverse reactions, Low – Uncommon and not severe adverse reactions.Abbreviations: IIV3, Inactive Influenza Vaccine 3 (trivalent)/IIV4, Inactive Influenza Vaccines 4 (quadrivalent)/CAIV-T, cold-adapted influenza vaccine trivalent/LAIV4, live attenuated influenza vaccine 4 (quadrivalent)/nTIVs, non-adjuvanted TIVs/TF, thimerosal-free/TIV-Yam, trivalent influenza vaccine containing B/Yamagata strains/TIV-Vic, trivalent influenza vaccine containing B/Victoria strains.

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