Immunogenicity and safety of an inactivated quadrivalent influenza vaccine: a randomized, double-blind, controlled phase III clinical trial in children aged 6–35 months in China

Abstract

Mismatch between circulating influenza B viruses and vaccine strains occurs frequently. In a randomized, double-blind, controlled phase III clinical study, healthy children aged 6-35 months were randomized into three groups at a ratio of 2:1:1, received two doses of quadrivalent influenza vaccines (QIVs) or licensed trivalent influenza vaccines (TIVs). The primary objective was to evaluate the non-inferiority immunogenicity of QIV compared with the two TIVs, containing B/Victoria or B/Yamagata strain. Safety information was collected for 28 days after each vaccination. Serious adverse events (SAEs) were monitored for 6 months after the second vaccination. A total of 2146 subjects (QIV: 1069, TIV-Vic: 540, TIV-Yam: 537) were enrolled in this study. QIV was found non-inferior to TIVs for shared strains (A/ H1N1 and A/H3N2) and corresponding BY strain based on hemagglutination inhibition (HI) antibodies 28 days after the second dose of vaccination. The resulted geometric mean titer (GMT) ratios (QIV/TIV) were 0.98 (0.89, 1.07) for H1N1, 0.95 (0.85, 1.05) for H3N2 and 0.89 (0.81, 0.98) for BY. And the seroconversion rate differences (QIV-TIV) were −0.46% (−3.24%, 2.31%) for H1N1, −1.95% (−5.54%, 1.65%) for H3N2 and −3.58% (−8.11%, 0.95%) for BY. The BV strain in QIV did not reach the noninferiority criteria, with GMT of 1:52.25 (vs. 1:61.02 of TIV-Vic) and seroconversion rate of 59.49% (vs. 66.85% of TIV-Vic). No increased safety concerns occurred in QIV group. Candidate QIV can provide good protection for children aged 6 to 35 months, and its immunogenicity and safety were proved. Clinical Trials Registration: ClinicalTrials.gov number: NCT03859141.

Immunological non-inferiority and safety of a quadrivalent inactivated influenza vaccine versus two trivalent inactivated influenza vaccines in China: Results from two studies

“…In addition, Shz QIV (0.5 mL) induced superior antibody responses to all corresponding strains compared with Shz QIV (0.25 mL), suggesting that Shz QIV (0.5 mL) may be a better option in children aged 6–35 months. The findings for the 0.25 mL dose are similar to those previously observed in China with the currently approved QIV (Sinovac Biotech, Beijing); 20 in 2,320 children aged 6–35 months, QIV (0.25 mL) was non-inferior to TIVs for the influenza A strains and the B/Yamagata lineage strain, but non-inferiority was not shown for the B/Victoria lineage strain. The safety, immunogenicity and efficacy of QIV inactivated influenza vaccine, Vaxigrip Tetra®, has been previously confirmed for the 0.5 mL dose in participants aged 6–35 months worldwide, 21 and our safety and immunogenicity findings with Shz QIV, which is based on Vaxigrip Tetra®, in Chinese participants are in line with those observations.…”

Advances in Development and Application of Influenza Vaccines

“…The IIV4 mainly include vaccines for influenza A(H3N2), A(H1N1) subtype, and Victoria and Yamagata strains of influenza B virus. The positive seroconversion rate of hemagglutination inhibition (HI) as a measure of the presence of antibodies in the serum of the vaccinated individual that can neutralize influenza virus, average increase rate in Geometric Mean Titers (GMT) of HI, and serum antibody protection rate of the vaccines after immunization all meet the expectations, suggesting that the vaccines have high immunogenicity (73,74,79,80).…”

“…Such a vaccine formulation can concentrate and increase the levels of active antigenic proteins in a given volume of the vaccine, which can stimulate maximum antibody production effects while greatly reduces the unnecessary side effects potentially caused by other components of the virion particle. Therefore, split influenza vaccines are safer than inactivated whole influenza vaccines (73,74). Currently, the vaccines of this type that have been approved for marketing in China include the trivalent inactivated influenza vaccine (IIV3), and the quadrivalent inactivated influenza vaccine (IIV4) (44).…”

Opposing Effects of Prior Infection versus Prior Vaccination on Vaccine Immunogenicity against Influenza A(H3N2) Viruses

“…However, poor vaccination responses were not associated with high pre-vaccination antibody titers in the present study. Recent clinical trials demonstrate that inactivated influenza vaccines are immunogenic and effective in previously-naïve infants [ 64 , 65 , 66 , 67 ], indicating that these vaccines can prime naïve B cells. However, memory B cells are intrinsically programed to out-compete naïve B cells upon B cell receptor engagement [ 68 , 69 , 70 ], and it has been proposed that this could account for the observation that antibody responses to A(H1N1pdm09) vaccines were highly focused on epitopes shared with previously encountered A(H1N1) viruses in selected age groups [ 41 , 71 , 72 , 73 ].…”