VaxigripTetra® (Sanofi Pasteur, Lyon, France) is a quadrivalent split-virion inactivated influenza vaccine (IIV4) containing two B-lineage strains approved in the European Union and Taiwan in 2016 for individuals ≥ 3 years of age. Here, we describe an observer-blind, randomized, controlled, multicenter trial study evaluating the immunogenicity and safety of the Northern Hemisphere 2015–2016 formulations of IIV4 and the licensed split-virion trivalent inactivated influenza vaccine (IIV3) in the Republic of Korea (ClinicalTrials.gov no. NCT02550197). The study included 300 Korean adults 18–60 years of age randomized 2:1 to receive a single injection of IIV4 or IIV3. For each of the four vaccine strains in IIV4, 21 days after vaccination, geometric mean post-/pre-vaccination ratios of hemagglutination inhibition titers were ≥ 3.97. Seroconversion/significant increases rates were ≥ 40% for all but the A/H1N1 strain, for which the rate was 39.7%. Results were similar for the three strains in IIV3. For the additional B-lineage strain not in IIV3 (Victoria), hemagglutination inhibition antibody titers were higher for IIV4 than for IIV3. Solicited reactions and adverse events were similar between IIV4 and IIV3, and no serious adverse events or new safety signals were detected. These results confirm the robust immunogenicity and acceptable safety of IIV4 in adults 18–60 years of age and show that including a second B-lineage strain should provide broader protection against B-strain influenza without affecting vaccine safety or the immunogenicity of other three vaccine strains.

Vaccination against influenza during pregnancy provides direct protection to pregnant women and indirect protection to their infants. Trivalent inactivated influenza vaccines (IIV3s) are safe and effective during pregnancy, but quadrivalent inactivated influenza vaccines (IIV4s) have not been evaluated in pregnant women and their infants. Here, we report the results of a randomized phase IV study to evaluate the immunogenicity and safety of IIV4 vs. IIV3 in pregnant women. Participants aged ≥18 years at weeks 20 to 32 of gestation were randomly assigned in a 2:1 ratio to receive a single dose of IIV4 (n = 230) or IIV3 (n = 116). Between baseline and 21 days after vaccination, hemagglutination inhibition (HAI) antibody titers increased in both groups by similar magnitudes for the two influenza A strains and single B strain common to IIV4 and IIV3. For the additional B strain in IIV4, HAI titers were higher in IIV4 recipients than IIV3 recipients (post-/prevaccination geometric mean titer ratio, 6.3 [95% CI: 5.1 − 7.7] vs. 3.4 [95% CI: 2.7 − 4.3]). At delivery, in both groups, HAI antibody titers for all strains were 1.5 − 1.9-fold higher in umbilical cord blood than in maternal blood, confirming active transplacental antibody transfer. Rates of solicited and unsolicited vaccine-related adverse events in mothers were similar between the two groups. Live births were reported for all participants and there were no vaccine-related adverse events in newborns. These results suggest IIV4 is as safe and immunogenic as IIV3 in pregnant women, and that maternal immunization with IIV4 should protect newborns against influenza via passively acquired antibodies.

A split-virion trivalent inactivated influenza vaccine produced according to the Chinese pharmacopeia (Shz-IIV3) has been commercially available in China since 2014. Here, we describe the results of a phase IV open-label trial to describe the immunogenicity and safety of the 2014–2015 Northern Hemisphere formulation of Shz-IIV3 in individuals ≥ 6 months of age. Subjects 6–35 months of age received 2 half-doses of Shz-IIV3 (0.25 ml) 28 d apart, and subjects ≥ 3 y of age received a single full dose (0.5 ml). The study included 602 subjects. Except for the A (H3N2) strain in subjects 3–17 years, geometric mean hemagglutination inhibition titer ratios were ≥ 10 and rates of seroconversion/significant increase in titer were ≥ 78% in all age groups. For the H3N2 strain in subjects 3–17 years, the geometric mean titer ratio was 3.8 and the rate of seroconversion/significant increase was 56%. Post-vaccination seroprotection rates were ≥ 88% for all strains in all age groups. The most common solicited reactions were injection-site pain/tenderness and fever, most of which were grade 1 and resolved within 3 d. Vaccine-related unsolicited adverse events were reported only by subjects 6–23 months, most of which were mild abnormal crying and irritability. No vaccine-related serious adverse events and no deaths were reported. No new safety signals or unexpected safety events occurred, although an immediate anaphylactic skin reaction occurred in one subject. This study confirmed that the 2014–2015 Northern Hemisphere formulation of Shz-IIV3 was well tolerated and highly immunogenic in subjects ≥ 6 months of age.

A quadrivalent, split-virion influenza vaccine (Shz QIV), containing two influenza A strains, and both B lineages strains, has been developed in China. We report the safety and immunogenicity of Shz QIV in two studies: a single-center, phase I, open-label, safety trial (n = 101) and a multicenter, phase III, observer-blind, randomized, safety and immunogenicity trial (n = 7,106) comparing Shz QIV with two trivalent influenza vaccines (Shz TIVs; one containing a B/Victoria-like strain and the other a B/Yamagata-like strain). Participants received one dose of Shz QIV (0.5 mL), except children aged 6 months to 8 years who received one or two doses (0.25 mL or 0.5 mL) depending on previous influenza vaccination. The Shz TIV groups received one or two (0.25 mL) doses depending on previous influenza vaccination (ages 6–35 months) or a single (0.5 mL) dose (ages ≥3 years). Immunogenicity was assessed at baseline and 28 days after the last dose, with safety assessed through to 6 months. The primary objective was to demonstrate the non-inferiority of antibody responses to Shz QIV (0.25 mL and 0.5 mL) versus Shz TIVs for each strain in ages 6–35 months and ≥3 years. Overall, Shz QIV was well tolerated, and showed similar safety to the Shz TIVs. Shz QIV (0.5 mL) induced non-inferior antibody responses to all antigens versus Shz TIV, with superiority demonstrated to the non-corresponding B strain in each TIV. Shz QIV (0.25 mL) non-inferiority in those aged 6–35 months was demonstrated for both A strains and the B/Yamagata-like strain, but not the B/Victoria-like strain. In summary, Shz QIV (0.5 mL) is immunogenic and has a good safety profile. WHO Universal Trial Numbers (UTNs) U1111-1174-4615 and U1111-1174-4698 ClinicalTrials.gov NCT04210349 and NCT03430089

Seasonal influenza vaccine formulations must be updated annually to correspond to the influenza viruses in circulation. This was an uncontrolled, open-label, multi-center phase IV study conducted in Belgium to comply with interim European Medicines Agency (EMA) guidelines for rapidly evaluating the safety of newly formulated seasonal influenza vaccines. Adult volunteers received one dose of the 2014-2015 Northern Hemisphere formulation of licensed intradermal trivalent influenza vaccine at either the standard dose (9µg hemagglutinin/strain for 18−59 year-olds) or the high dose (15µg hemagglutinin/strain for ≥ 60 year-olds). Vaccinees recorded their solicited reactions and unsolicited adverse events for 7 d after vaccination. Solicited reaction frequencies were compared to historical reference values obtained from previous clinical trials to determine if the new formulations were excessively reactogenic or allergenic. A total of 210 participants (105 per age group) were included and vaccinated in October 2014. In both groups, pain, erythema, and pruritus were the most common solicited injection site reactions, and headache and myalgia were the most common solicited systemic reactions. Although the frequencies of shivering in 18−59 year-olds and malaise in ≥ 60 year-olds were higher than historical reference values, they were not considered indicative of excessive reactogenicity because almost all of these reactions were mild. The study design was endorsed by the EMA and permitted the reactogenicity of both vaccine formulations to be assessed within one month by collecting adverse events for 7 d. Both formulations exhibited acceptable safety profiles although this should be confirmed through forthcoming enhanced post-marketing safety surveillance systems.