Enhanced passive safety surveillance of a quadrivalent inactivated split virion influenza vaccine in Finland during the influenza season 2020/21.

BACKGROUND: The European Medicines Agency (EMA) requires enhanced safety surveillance to be conducted for annual seasonal influenza vaccines with the aim of rapidly detecting any potential new safety concerns before the peak immunisation period of the vaccine in any given year. The aim of this study was to detect any clinically significant change in the frequency or severity of expected reactogenicity of the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunisation in Finland for the 2020/21 season. The primary objective was to investigate the frequency of suspected adverse drug reactions (ADRs) occurring within 7 days following vaccination. METHODS: Enhanced passive safety surveillance of individuals vaccinated with IIV4 was conducted from October 9, 2020 to November 30, 2020 across seven sites in Finland. The vaccinee reporting rate and ADR reporting rate were calculated and compared with known or expected safety data in order to identify any clinically significant changes. RESULTS: Data were collected from 1008 individuals with 29 vaccinees reporting 82 suspected ADRs. Of these, 28 people reported 79 suspected ADRs within 7 days following vaccination, corresponding to a vaccinee reporting rate of 2.78% (95% CI: 1.85, 3.99) (ADR reporting rate, 7.84% [95% CI: 6.25, 9.67%]). The most frequently reported ADRs were injection site reactions (vaccination site pain, vaccination site erythema and vaccination site swelling) (n = 46, 2.28%), myalgia (n = 9, 0.89%) and headache (n = 8, 0.79%). No serious suspected adverse events were reported at any point post-vaccination and ADR reporting rates were in general lower compared to those reported for IIV4 in the 2019/20 surveillance study. CONCLUSION: No clinically significant changes in what is known or expected for IIV4 were reported for the 2020/21 season which supports the safety profile of this vaccine and will help maintain public confidence in influenza vaccination.

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.

BACKGROUND: We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. METHODS: This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. FINDINGS: Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11 815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36 725) in the high-dose group. INTERPRETATION: Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1-2, dose-ranging study.

BACKGROUND: CoV2 preS dTM is a stabilised pre-fusion spike protein vaccine produced in a baculovirus expression system being developed against SARS-CoV-2. We present interim safety and immunogenicity results of the first-in-human study of the CoV2 preS dTM vaccine with two different adjuvant formulations. METHODS: This phase 1-2, randomised, double-blind study is being done in healthy, SARS-CoV-2-seronegative adults in ten clinical research centres in the USA. Participants were stratified by age (18-49 years and ≥50 years) and randomly assigned using an interactive response technology system with block randomisation (blocks of varying size) to receive one dose (on day 1) or two doses (on days 1 and 22) of placebo or candidate vaccine, containing low-dose (effective dose 1·3 µg) or high-dose (2·6 µg) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline) or unadjuvanted high-dose antigen (18-49 years only). Primary endpoints were safety, assessed up to day 43, and immunogenicity, measured as SARS-C0V-2 neutralising antibodies (geometric mean titres), assessed on days 1, 22, and 36 serum samples. Safety was assessed according to treatment received in the safety analysis set, which included all randomly assigned participants who received at least one dose. Neutralising antibody titres were assessed in the per-protocol analysis set for immunogenicity, which included participants who received at least one dose, met all inclusion and exclusion criteria, had no protocol deviation, had negative results in the neutralisation test at baseline, and had at least one valid post-dose serology sample. This planned interim analysis reports data up to 43 days after the first vaccination; participants in the trial will be followed up for 12 months after the last study injection. This trial is registered with ClinicalTrials.gov, NCT04537208, and is ongoing. FINDINGS: Between Sept 3 and Sept 29, 2020, 441 individuals (299 aged 18-49 years and 142 aged ≥50 years) were randomly assigned to one of the 11 treatment groups. The interim safety analyses included 439 (>99%) of 441 randomly assigned participants (299 aged 18-49 years and 140 aged ≥50 years). Neutralising antibody titres were analysed in 326 (74%) of 441 participants (235 [79%] of 299 aged 18-49 years and 91 [64%] of 142 aged ≥50 years). There were no vaccine-related unsolicited immediate adverse events, serious adverse events, medically attended adverse events classified as severe, or adverse events of special interest. Among all study participants, solicited local and systemic reactions of any grade after two vaccine doses were reported in 81% (95% CI 61-93; 21 of 26) of participants in the low-dose plus AF03 group, 93% (84-97; 74 of 80) in the low-dose plus AS03 group, 89% (70-98; 23 of 26) in the high-dose plus AF03 group, 95% (88-99; 81 of 85) in the high-dose plus AS03 group, 29% (10-56; five of 17) in the unadjuvanted high-dose group, and 21% (8-40; six of 29) in the placebo group. A single vaccine dose did not generate neutralising antibody titres above placebo levels in any group at days 22 or 36. Among participants aged 18-49 years, neutralising antibody titres after two vaccine doses were 13·1 (95% CI 6·40-26·9) in the low-dose plus AF03 group, 20·5 (13·1-32·1) in the low-dose plus AS03 group, 43·2 (20·6-90·4) in the high-dose plus AF03 group, 75·1 (50·5-112·0) in the high-dose plus AS03 group, 5·00 (not calculated) in the unadjuvanted high-dose group, and 5·00 (not calculated) in the placebo group. Among participants aged 50 years or older, neutralising antibody titres after two vaccine doses were 8·62 (1·90-39·0) in the low-dose plus AF03 group, 12·9 (7·09-23·4) in the low-dose plus AS03 group, 12·3 (4·35-35·0) in the high-dose plus AF03 group, 52·3 (25·3-108·0) in the high-dose plus AS03 group, and 5·00 (not calculated) in the placebo group. INTERPRETATION: The lower than expected immune responses, especially in the older age groups, and the high reactogenicity after dose two were probably due to higher than anticipated host-cell protein content and lower than planned antigen doses in the formulations tested, which was discovered during characterisation studies on the final bulk drug substance. Further development of the AS03-adjuvanted candidate vaccine will focus on identifying the optimal antigen formulation and dose. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Enhanced passive safety surveillance of the quadrivalent inactivated split-virion influenza vaccine (IIV4) in Finland during the 2019/20 influenza season.

BACKGROUND AND AIMS: The Enhanced Passive Safety Surveillance is a requirement of the European Medicines Agency (EMA) for seasonal influenza vaccines, aiming to rapidly detect any significant change in frequency or severity of expected reactogenicity or allergic events prior to widespread use of a vaccine in any particular year. The aim of this surveillance was to assess the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunization in Finland, as per the national immunization program for 2019/20. The primary objective was to investigate the suspected adverse drug reactions (ADR) occurring within 7 days following vaccination. METHODS: Passive surveillance of individuals vaccinated with IIV4 was conducted within the first 4 to 6 weeks of the influenza season in Finland. Potential ADRs were reported via phone or posted adverse event forms. The vaccinee reporting rate and ADR reporting rate were calculated and compared with the known or expected safety data in order to identify any change which was clinically significant. RESULTS: Data were collected from 939 individuals, with 56 reports received for 163 suspected ADRs. Of these, 38 individuals reported 117 suspected ADRs within 7 days following vaccination, corresponding to an ADR reporting rate of 12.46% (95% CI: 10.41, 14.74%); vaccination-site pain, vaccination-site reaction, and pyrexia were the most frequently reported ADRs. The 18-to-65 years of age category had an ADR reporting rate of 12.56%, the over-65 years of age category had an ADR reporting rate of 16.22%, and no ADRs were reported for individuals aged 6 months to 18 years. No serious suspected ADRs were reported at any time post-vaccination, and the ADR rates were comparable to those reported for IIV4 in the 2018/19 seasonal assessment. The frequency of suspected ADRs was generally aligned with those reported in the Summary of Product Characteristics (SmPC), with the exception of asthenia, somnolence, and erythema, which were slightly higher. No reporting pattern by type, frequency, or severity was identified for the suspected ADRs. CONCLUSIONS: No clinically significant changes in what is known or expected for IIV4 was reported for the 2019/20 season, which supports the overall safety profile.

Enhanced passive safety surveillance of a trivalent and a quadrivalent influenza vaccine in Denmark and Finland during the 2018/2019 season.

The European Medicines Agency requires Enhanced Passive Safety Surveillance (EPSS) for all seasonal influenza vaccines. Here, we report the EPSS results for the trivalent inactivated influenza vaccine (IIV3; Vaxigrip®) and the quadrivalent inactivated influenza vaccine (IIV4; VaxigripTetraTM) during the 2018/19 influenza season in Denmark and Finland. The primary objective was to estimate the rates of suspected adverse reactions (ARs) occurring within 7 days following routine vaccination. Between October and November 2018, 1000 safety report cards (SRCs) for IIV3 were distributed in Denmark, and 996 SRCs for IIV4 were distributed in Finland. Participants were instructed to report any ARs by telephone or e-mail using the information provided on the SRC. All participants vaccinated with IIV3 were aged ≥18 years. Most participants vaccinated with IIV4 (95.5%) were aged 18 - 65 years, 2.2% were aged 6 months to 17 years, and 2.3% were aged >65 years. Fifty-five ARs were reported by 12 participants (1.2%) vaccinated with IIV3 and 162 ARs were reported by 53 participants (5.3%) vaccinated with IIV4. The most frequent ARs were vaccination site pain and fever for IIV3, and vaccination site pain, vaccination site inflammation, myalgia, and headache for IIV4. The 2018/19 AR rates for IIV3 were comparable to 2017/18 rates. The 2018/19 AR rates for IIV4 were higher than those in 2017/18 but were still lower than the expected AR rates listed in the IIV4 Summary of Product Characteristics. In conclusion, the 2018/19 EPSS showed no clinically significant change from the expected safety profiles of IIV3 and IIV4 vaccines.

Safety of a quadrivalent influenza vaccine in Vietnamese healthy subjects aged 6 months and older.

Quadrivalent influenza vaccines (QIVs) provide protection against the two influenza A viruses (H1N1 and H3N2) and both co-circulating influenza B lineages. QIVs have been found safe, immunogenic, and efficacious in several phase III clinical trials. Here we assess the safety of QIV after vaccination in Vietnamese infants, children, and adults. Participants (n = 228) were asked to report any solicited adverse events (AEs) occurring within 7 days, unsolicited non-serious AEs occurring within 28 days post-vaccination, and serious adverse events (SAEs) at any time during the study. The study was completed by 224 participants (97.4%). Thirty-one children (39.7%) aged 6 - 35 months, 32 children (40.0%) aged 3 - 8 years, 2 participants (9.0%) aged 9 - 17 years, 5 participants (17.9%) aged 18 - 60 years, and 3 participants (15.0%) aged ≥60 years reported ≥1 solicited reaction within 7 days following vaccination. The most frequent-solicited AEs were injection-site tenderness or pain, appetite loss, fever, and abnormal crying in 6 - 35 month-olds, and fever, headache, and myalgia in other age groups. No severe-unsolicited AEs or vaccine-related SAEs were reported. These results suggest that QIV is well tolerated across age groups in Vietnam, and can be safely used to protect the Vietnamese population against influenza and its potentially serious complications.

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in pregnant women: a randomized, observer-blind trial.

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-/pre-vaccination 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.

Immunogenicity and safety of a multi-dose quadrivalent inactivated influenza vaccine in individuals aged 6 months to 17 years: a randomized phase III trial.

Annual vaccination is the most effective way to prevent seasonal influenza. Influenza vaccines in multi-dose vial (MDV) formats can facilitate timely vaccination of large populations by reducing per-dose costs and cold storage requirements compared to single-dose pre-filled syringe (PFS) formats. MDV vaccines require thiomersal or another preservative to prevent microbial contamination. We conducted a randomized, open-label trial in 302 healthy subjects aged 6 months to 17 years to evaluate the immunogenicity and safety of a quadrivalent influenza vaccine (QIV) in a thiomersal-containing MDV format compared to the licensed thiomersal-free PFS format. Subjects were randomly assigned in a 1:1 ratio to receive the MDV (n = 153) or PFS (n = 149) format. Post-vaccination hemagglutination inhibition titers for all four vaccine strains were ≥4.9-fold higher than baseline titers with no difference in magnitude between the MDV and PFS groups. Seroconversion rates per strain were also comparable between the two groups. 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.

Enhanced passive safety surveillance of three marketed influenza vaccines in the UK and the Republic of Ireland during the 2017/18 season.

Safety surveillance is required for each season's influenza vaccines to rapidly detect and evaluate potential new safety concerns before the peak period of immunization. Here we report the results of an enhanced passive safety surveillance for a trivalent split-virion inactivated influenza vaccine (IIV3; Vaxigrip®), an intradermal version of this vaccine (IIV3-ID; Intanza® 15 µg), and a recently licensed quadrivalent version (IIV4; VaxigripTetraTM) during the 2017/18 influenza season in the UK and Republic of Ireland. The primary objective was to determine the rates of adverse reactions (ARs) occurring within 7 days following routine vaccination. Between September and November 2017, 979 safety report cards were distributed to vaccinees receiving IIV3-ID, 1005 to those receiving IIV3, and 957 to those receiving IIV4. At least one AR was reported by 28 participants (2.9%) vaccinated with IIV3-ID, 14 participants (1.4%) vaccinated with IIV3, and 20 participants (2.1%) vaccinated with IIV4. The most frequent ARs were injection-site reactions and headache. One participant vaccinated with IIV3-ID reported two suspected serious ARs (dyskinesia and a shock symptom), although these could not be confirmed as vaccine-related. Rates of ARs for IIV3 and IIV3-ID for 2017/18 did not differ from the 2016/17 rates. For IIV4, in its first season since licensure, AR frequencies were similar to those in the Summary of Product Characteristics. In conclusion, no change was found compared to the known or expected AR rates for IIV3, IIV3-ID, or IIV4 during the 2017/18 season.

Report from enhanced safety surveillance of two influenza vaccines (Vaxigrip and Intanza 15 µg) in two European countries during influenza season 2016/17 and comparison with 2015/16 season.

Passive enhanced safety surveillance (ESS) was implemented in the United Kingdom and in the Republic of Ireland for Vaxigrip and Intanza 15 µg influenza vaccines during the 2016/17 influenza season. Lessons learned during 2015/16 ESS implementation were integrated and applied towards the current ESS. The primary objective was to estimate the reporting rates of suspected adverse reactions (ARs) occurring within 7 days of vaccination with Vaxigrip or Intanza 15 µg. For Vaxigrip (N = 962), 17 vaccinees (1.8%) reported 59 suspected ARs (6.1%) within 7 days of vaccination. For Intanza 15 µg (N = 1000), 21 vaccinees (2.1%) reported 101 (10.1%) suspected ARs within 7 days of vaccination. No obvious pattern in the type of suspected ARs or their frequency was observed for either vaccine. None of the frequencies of suspected ARs were above the 2015/16 ESS frequencies for Vaxigrip, whereas for Intanza 15 µg only one AR (oropharyngeal pain) crossed the historical threshold. There was no change in reactogenicity and data was consistent with the safety profiles of the two vaccines. The passive ESS experience gained from season to season will help to contribute to a sustainable safety surveillance system of seasonal influenza vaccines early in the season.

Passive enhanced safety surveillance for Vaxigrip and Intanza 15 µg in the United Kingdom and Finland during the northern hemisphere influenza season 2015/16.

Enhanced safety surveillance (ESS) was conducted in the United Kingdom and Finland for Vaxigrip and Intanza 15 µg to comply with the European Medicines Agency interim guidance aimed to detect any potential increase in reactogenicity in near real time following the annual update of the influenza vaccine strain composition. This pilot passive ESS was established to strengthen safety monitoring by facilitating spontaneous vaccinee reports and estimating near real-time vaccinee exposure. The primary objective was to estimate the reporting rates of suspected adverse reactions (ARs) occurring within 7 days post vaccination during the northern hemisphere 2015/16 influenza season. Among the Vaxigrip vaccinees (n = 1,012), 32 (3.2%) reported a total of 122 suspected ARs, including 110 suspected ARs that occurred within 7 days post vaccination. Among the Intanza 15 µg vaccinees (n = 1,017), 31 (3.0%) reported a total of 114 suspected ARs, including 99 that occurred within 7 days post-vaccination. These results were consistent with the known safety profile of the two vaccines and did not show any change in reactogenicity or safety concerns. This passive ESS showed improved data reporting and demonstrated its suitability to health authorities' requirements; further fine tuning of the methodology is under discussion between all stakeholders.