Table 2.
Nine RCTs conducted in children (6 months to 17 years)
| Author, year | Study period and countr(ies) | Treatment arms brand name (manufacturer) HA/strain (dosing) | Mean age (SD) | Age range | Sex (overall % female) | Vaccination history (overall % previously immunised) | ITT sample size | Outcome | Author reported conclusions |
| Trivalent and quadrivalent influenza vaccines (TIV/QIV) | |||||||||
| Della Cioppa, 201110 |
October 2008–March 2009 Belgium |
NR—TIV, 7.5 µg/strain (2×0.25 mL dose) |
20.0 months (7.0) | 6 to <36 months | 43.5 | NR | 25 | Local and systemic reactogenicity AEs |
Reactogenicity of the 7.5 µg TIV/QIV formulations was slightly lower than for the corresponding 15 µg formulations. The majority of unsolicited AEs were mild or moderate in severity and none of the SAEs was considered to be related to the study vaccine. |
| Agrippal—TIV, 15 µg/strain (2×0.5 mL dose) |
15.0 months (8.8) | 6 to <36 months | 43.5 | NR | 22 | ||||
| NR—QIV, 7.5 µg/strain (2×0.25 mL dose) |
18.0 months (8.9) | 6 to <36 months | 43.5 | NR | 25 | ||||
| NR—QIV, 15 µg/strain (2×0.5 mL dose) |
15.2 months (7.8) | 6 to <36 months | 43.5 | NR | 28 | ||||
| Vaxigrip (Sanofi Pasteur), 7.5 µg/strain (2×0.25 mL dose) |
16.1 months (8.5) | 6 to <36 months | 43.5 | NR | 26 | ||||
| Skowronski, 201111 |
September 2008–December 2008 Canada |
Vaxigrip (Sanofi-Pasteur), 15 µg/strain (2×0.5 mL dose) |
13.2 months (5.1) | 6–23 months | 53.2 | 0 | 124 | Local and systemic reactogenicity AEs |
Local reactions generally were less common in infants than toddlers and more common with full doses versus half doses, but none of these differences were significant. One serious AE was reported: a toddler in the half dose group was hospitalised with pneumonia 28 days after the first vaccination. The event was deemed unlikely related to the vaccine. Compared with 0.25 mL half-dosing, administration of 2 full 0.5 mL doses of trivalent inactivated influenza vaccine can increase antibody response without increasing reactogenicity in previously unimmunised infants aged 6 to 11 months. |
| Vaxigrip (Sanofi-Pasteur), 15 µg/strain (2×0.25 mL dose) |
12.8 months (5.0) | 6–23 months | 53.2 | 0 | 128 | ||||
| Langley, 201212 | November 2008–August 2009 Canada |
Fluviral F1 (Sanofi-Pasteur), 7.5 µg/strain (1×0.25 mL dose) |
18.2 months (9.06) | 6–35 months | 47.9 | 42.6 | 164 | Local and Systemic reactogenicity AEs |
Fluviral F1 group had 1 case of pneumonia resolved. Fluviral F2 group had 1 case of bronchial hyper-reactivity in resolving stage. The 0.5 mL dose of the study vaccine, when administered to children aged 6–35 months, resulted in a modest but not statistically significant improvement in immunogenicity with clinically similar safety and reactogenicity compared with the 0.25 mL dose. |
| Fluviral F2 (Sanofi-Pasteur), 15 µg/strain (1×0.5 mL dose) |
17.5 months (8.27) | 6–35 months | 47.9 | 42.6 | 167 | ||||
| Vaxigrip (Sanofi-Pasteur), 7.5 µg/strain (1×0.25 mL dose) |
17.0 months (8.33) | 6–35 months | 47.9 | 42.6 | 43 | ||||
| Pavia-Ruz, 201313 |
October 2008–March 2009 Hong Kong, Mexico, Taiwan, Thailand and the USA |
Fluarix (GSK), 15 µg/strain (1×0.5 mL dose) |
21.2 months (8.37) | 6–35 months | 51 | 30.1 | 1018 | Local and systemic reactogenicity AEs |
The reactogenicity and safety profile of the study vaccine did not appear to be affected by doubling the dose. One participant in the Flu-15 μg group had two SAEs, (apnea and cyanosis) which were considered by the investigator to be possibly related to vaccination. The subject was hospitalised and the events resolved on the same day as they occurred. |
| Fluarix (GSK), 7.5 µg/strain (1×0.25 mL dose) |
21.2 months (8.03) | 6–35 months | 51 | 30.1 | 1018 | ||||
| Fluzone (Sanofi-Pasteur), 7.5 µg/strain (1×0.25 mL dose) |
21.1 months (8.20) | 6–35 months | 51 | 30.1 | 1031 | ||||
| Halasa, 201514 |
2010–2012 USA |
Fluzone (Sanofi Pasteur), 7.5 µg/strain (1×0.25 mL dose) |
13.5 | 6–35 months, 12–35 months | 52 | 13.2 | 80 | Local and systemic reactogenicity | No significant differences between the full-dose or half-dose groups for either the fully primed or naive cohorts for systemic reactions or local reactions when both seasons were combined. The only significant difference in the 2011–2012 season was that 8 of 48 (16.7%) participants in the half-dose group compared with 32 of 96 (33.3%) in the full-dose group had increased redness at the injection site (p<0.05). No significant differences between the groups in AE, SAE or onset of chronic medical conditions between the dose groups in either the naive or fully primed cohorts, and none of the SAEs were deemed related to the vaccine. |
| Fluzone (Sanofi Pasteur), 15 µg/strain (1×0.5 mL dose) |
14.5 | 163 | |||||||
| Phung, 201626 | September 2010–January 2011 Finland |
FLUAD (NR), NR (1×0.5 mL dose) |
68.7 months (18) | 6–35 months | 55.8 | 85.7 | 60 | Local and systemic reactogenicity AEs |
Trial protocol with no author conclusions. |
| FLUAD (NR), NR (1×0.25 mL dose) |
60.4 months (23.2) | 6–35 months | 55.8 | 85.7 | 75 | ||||
| Agrippal S1 (NR), NR (1×0.5 mL dose) |
68 months (17.1) | 6–35 months | 55.8 | 85.7 | 51 | ||||
| Agrippal S1 (NR), NR (1×0.25 mL dose) |
32.4 months (1.9) | 6–35 months | 55.8 | 85.7 | 11 | ||||
| Jain, 201716 |
2014–2015 Influenza Season USA and New Mexico |
Flulaval (GSK), 15 µg/strain (1×0.5 mL dose) |
19.7 months (8.7) | 6–35 months | 46.9 | 57.5 | 1013 | Local and systemic reactogenicity AEs |
None of the febrile seizures or the SAEs were considered by the investigator to be related to vaccination. Double-dose vaccines may improve protection against influenza B in some young children and simplifies annual influenza vaccination by allowing the same vaccine dose to be used for all eligible children and adults. |
| Fluzone (Sanofi Pasteur), 7.5 µg/strain (1×0.25 mL dose) |
19.9 months (8.9) | 6–35 months | 46.9 | 57.5 | 1028 | ||||
| Ojeda, 201917 |
December 2017–January 2018 Mexico |
Vaxigrip Tetra (Sanofi Pasteur) PFS 15 µg/strain (1×0.5 mL dose) |
NR (6 months to 17 years) |
6 months to 17 years | 46.4 | NR | 149 | Local and systemic reactogenicity AEs |
Solicited systemic reactions were reported in more infants aged 6–35 months in the MDV group than in the PFS group, however, this was not clinically significant. AE not considered related to a study vaccine. There were no differences in reactogenicity or safety between the two vaccine formats. These results showed that the MDV format of QIV was as safe and immunogenic as the PFS format in infants, children, and adolescents. These findings support the use of MDV QIV as a resource-saving alternative for seasonal influenza vaccination. |
| Vaxigrip Tetra (Sanofi Pasteur) MDV 15 µg/strain (1×0.5 mL dose) |
NR (6 months to 17 years) |
6 months to 17 years | 46.4 | NR | 153 | ||||
| Robertson, 201918 | September 2016–March 2017 USA |
Fluzone (Sanofi Pasteur) 15 µg/strain (1×0.5 mL dose) |
20.5 months (8.55) | 6–35 months | 49.7 | 47.25 | 992 | Local and systemic reactogenicity AEs |
No significant differences between full-dose and half-dose groups. AE leading to study discontinuation/SAE not considered vaccine-related. A full-dose vaccine was immunogenic and had a safety profile comparable to that of a half dose, with no new safety concerns observed. |
| Fluzone (Sanofi Pasteur) 7.5 µg/strain (1×0.25 dose) |
20.4 months (8.75) | 6–35 months | 49.7 | 47.25 | 949 | ||||
AE, adverse events; HA, haemagglutinin; ID, intradermal; IM, intramuscular; ITT, intention to treat; MDV, multidose vials; NR, not reported; PFS, prefilled dose; RCT, randomised controlled trial; SAEs, serious adverse events.