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Summary: Background: In a parallel-group, international, phase 3 study (ClinicalTrials.gov NCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03). Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18–55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18–55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18–55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety. Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18–55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58–29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71–46.95) (anti-B.1.351); and for BiV, 14.39 (11.39–18.28) (anti-D614G) and 34.18 (25.84–45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified. Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).

Narcolepsy type 1 (NT1), characterized by the loss of hypocretin/orexin (HCRT) production in the lateral hypothalamus, has been linked to Pandemrix vaccination during the 2009 H1N1 pandemic, especially in children and adolescents. It is still unknown why this vaccination increased the risk of developing NT1. This study investigated the effects of Pandemrix vaccination during adolescence on Hcrt mRNA expression in mice. Mice received a primary vaccination (50 µL i.m.) during prepubescence and a booster vaccination during peri-adolescence. Hcrt expression was measured at three-time points after the vaccinations. Control groups included both a saline group and an undisturbed group of mice. Hcrt expression was decreased after both Pandemrix and saline injections, but 21 days after the second injection, the saline group no longer showed decreased Hcrt expression, while the Pandemrix group still exhibited a significant reduction of about 60% compared to the undisturbed control group. This finding suggests that Pandemrix vaccination during adolescence influences Hcrt expression in mice into early adulthood. The Hcrt mRNA level did not reach the low levels known to induce NT1 symptoms, instead, our finding supports the multiple-hit hypothesis of NT1 that states that several insults to the HCRT system may be needed to induce NT1 and that Pandemrix could be one such insult., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The study aimed at identifying biomarkers of immune response elicited by non-adjuvanted-(NAV) and adjuvanted-(AV) H1N1(pdm09) vaccines. The results showed that despite both vaccines elicited similar levels of anti-H1N1 antibodies at day30 after vaccination, higher reactivity was observed in AV at day180. While AV induced early changes in cell-surface molecules on monocytes, CD4 + , CD8 + T-cells and B-cells, NAV triggered minor changes, starting later on at day3. Furthermore, AV induced a late and persistent increase in TLR gene expression after day3, except for tlr4 , while NAV displayed earlier but transient tlr3/4/7/9 up-regulation. Contrasting with NAV, prominent chemokine gene expression ( cxcl8,cxcl9,ccl5 ) and a broad spectrum up-regulation of plasmatic biomarkers (CXCL8,IL-6,IL-1β,IL-12,IL-10) was evident in AV, which showed a major involvement of TNF and IL-10. Similarly, AV induced a robust IL-10-modulated proinflammatory storm, with early and persistent involvement of TNF-α/IL-12/IFN-γ axis derived from NK-cells, CD4 + and CD8 + T-cells along with promiscuous production of IL-4/IL-5/IL-13. Conversely, NAV promotes a concise and restricted intracytoplasmic chemokine/cytokine response, essentially mediated by TNF-α and IL-4, with late IL-10 production by CD8 + T-cells. Systems biology approach underscored that AV guided the formation of an imbricate network characterized by a progressive increase in the number of neighborhood connections amongst innate and adaptive immunity. In AV, the early cross-talk between innate and adaptive immunity, followed by the triad NK/CD4 + /CD8 + T-cells at day3, sponsored a later/robust biomarker network. These findings indicate the relevance of adjuvanted vaccination to orchestrate broad, balanced and multifactorial cellular immune events that lead ultimately to a stronger H1N1 humoral immunity. [ABSTRACT FROM AUTHOR]

Background H7 influenza strains can cause severe and often fatal human infections, especially in the elderly. This phase II, observer-blind, randomized trial ( www.ClinicalTrials.gov : NCT01949090 ) assessed the immunogenicity and safety of a novel AS03-adjuvanted H7N1 vaccine that may serve as a model H7-subtype vaccine. Methods 360 adults ≥65 years of age in stable health received either 1 of 4 adjuvanted A/mallard/Netherlands/12/2000 split virion vaccine formulations (3.75 μg or 7.5 μg hemagglutinin adjuvanted with either AS03 A or AS03 B ) or saline placebo, given as a 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays for the per-protocol cohort, comprising 332 participants at 21 days post-each dose, 332 at month 6, and 309 at month 12 (HI assay only). Safety was assessed up to month 12 for all participants who had received ≥1 dose (360 participants). Results For H7N1 HI antibody assessment at day 42 (21 days post-dose 2), seroprotection rates (SPR) in the vaccinated groups were 69.6%–88.7%, seroconversion rates (SCR) 69.6%–88.5%, mean geometric increase (MGI) 11.0–18.9, and HI geometric mean titers (GMTs) 55.0–104.8. These parameters declined by month 6 and month 12. Microneutralization GMTs were 46.2–74.7 in the vaccinated groups at day 42, while vaccine response rate (VRR; proportion with ≥4-fold increase in MN titer) was 46.4%–81.5%. For the cross-reactive H7N9 strain, at day 42, HI GMT were 64.3–201.3, SPR 78.6%–96.3%, SCR 79.3%–96.3%, and MGI 14.1–37.7; MN GMTs were 44.0–85.6, and VRR 46.4–85.2%. The most frequent solicited symptom was injection site pain (41.7%–65.0% of vaccine recipients). In total, 40 participants reported 67 serious adverse events; none were considered causally related to vaccination. Conclusions In adults aged ≥65 years, the adjuvanted H7N1 vaccine was immunogenic after 2 doses, and had an acceptable safety profile. www.ClinicalTrials.gov : NCT01949090 . [ABSTRACT FROM AUTHOR]

Background H7 influenza strains have pandemic potential. AS03-adjuvanted H7N1 A/mallard/Netherlands/12/2000 split-virion vaccine formulations were evaluated as model H7-subtype vaccine and tested after H7N9 emerged in China, and caused severe human disease with high mortality. Methods In this phase I/II, observer-blind, randomized trial in US and Canada, 420 healthy adults (21–64 years) were randomized to receive 1 of 4 H7N1 vaccine formulations (3.75 or 7.5 μg hemagglutinin adjuvanted with either AS03 A or AS03 B ), 15 μg unadjuvanted H7N1 hemagglutinin, or saline placebo, given as 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays, at day 42 (21 days post-dose 2), month 6, and month 12 (HI only) for the per-protocol cohorts (398, 379 and 368 participants, respectively). Safety is reported up to month 12. Results Beneficial AS03 adjuvant effect was demonstrated. Committee for Medical Products for Human Use, and Center for Biologics Evaluation and Research (CBER) criteria were met for all adjuvanted formulations at day 42 (H7N1 HI assay); seroprotection (SPR) and seroconversion rates (SCR) were 88.5–94.8%, mean geometric increase (MGI) 19.2–34.9, and geometric mean titers (GMT) 98.3–180.7. Unadjuvanted H7N1 vaccine did not meet CBER criteria. In adjuvanted groups, antibody titers decreased over time; month 12 SPRs and GMTs were low (2.0–18.8% and 8.1–12.2). MN antibodies showed similar kinetics, with titers persisting at higher range than HI at month 6. All adjuvanted groups showed cross-reactivity against H7N9, with HI responses similar to H7N1. The most frequent solicited symptom in adjuvanted groups was injection site pain (71.2–86.7%); grade 3 solicited symptoms were infrequent. Nine participants reported 17 serious adverse events; none were considered causally related to vaccination. Conclusions Adjuvanted H7N1 vaccine formulations had an acceptable safety profile and induced an antibody response after 2 doses with cross-reactivity to H7N9. ClinicalTrials.gov: NCT01934127 [ABSTRACT FROM AUTHOR]

Background: In a parallel-group, international, phase 3 study (ClinicalTrials.govNCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03)., Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18-55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18-55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18-55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety., Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18-55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58-29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71-46.95) (anti-B.1.351); and for BiV, 14.39 (11.39-18.28) (anti-D614G) and 34.18 (25.84-45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified., Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine., Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA)., Competing Interests: GdB, JW, AP, MSR, HA, MIB, RMCa, RF, BF, JG, M-HG, SG, OH, RM, JP, NR, RMCh and SSr are Sanofi employees. GdB, AP, MIB, BF, OH, NR, RMCh and SSr hold stock or stock options in Sanofi. SSa was a Sanofi employee at the time of study conduct and held shares and/or stock options in the company at the time of study conduct. GdB, SSr, RMCh, and SSa are inventors on a pending patent application filed by Sanofi and GSK for the development of the CoV-2 dTM vaccine. MAC, LS and MK are employed by GSK and hold restricted shares in the GSK group of companies. FTDS was employed by GSK and held restricted shares in the GSK group of companies, at the time of the study. FMT declares trial fees paid to their institution by Sanofi; honoraria received from GSK group of companies, Pfizer Inc., Sanofi, MSD, Moderna, Biofabri, AstraZeneca, Novavax, Janssen; meeting and/or travel fees received from Pfizer Inc, MSD, GSK and Sanofi; data safety monitoring board or advisory board participation for Pfizer and Biofabri; being a member of ETAGE–WHO Europe, coordinator of the Spanish Pediatric Critical Trials Network and coordinator of the WHO Collaborating Centre for Vaccines Safety of Santiago de Compostela; and payments made to their institution for their role as principal investigator in randomized controlled trials for Ablynx, Abbot, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Janssen, Medimmune, Novavax, Novartis and GSK. DMRM declares that her institution received funding from Sanofi. AF receives research funding, paid to his employers, from Sanofi both for work related to this study and other unrelated vaccine trials and from GSK for other unrelated studies. He receives research funding from other vaccine manufacturers relating to trials and studies and undertakes paid consultancy related to a number of developmental antimicrobial drugs and vaccines. OL declares that their institution received funding for conducting the trial. NLM received travel support from Sanofi and chaired a Scientific Advisory Board for them, unrelated to current study. LDS received a research grant from Sanofi. SD, SA, DB, AB, DD, PG, JAH, CR and AW declare no conflicts of interest., (© 2023 The Author(s).)

Design Children with HIV are especially susceptible to complications from influenza infection, and effective vaccines are central to reducing disease burden in this population. We undertook a prospective, observational study to investigate the safety and immunogenicity of the inactivated split-virion AS03-adjuvanted pandemic H1 N1(2009) vaccine in children with HIV. Setting National referral centre for Paediatric HIV in Ireland. Sample Twenty four children with HIV were recruited consecutively and received two doses of the vaccine. The serological response was measured before each vaccine dose (Day 0 and Day 28) and 2 months after the booster dose. Antibody titres were measured using a haemagglutination inhibition ( HAI) assay. Seroprotection was defined as a HAI titre ≥ 1:40; seroconversion was defined as a ≥ fourfold increase in antibody titre and a postvaccination titre ≥ 1:40. Main outcome measures The seroconversion rates after prime and booster doses were 75% and 71%, respectively. HIV virological suppression at the time of immunization was associated with a significantly increased seroconversion rate ( P = 0·009), magnitude of serological response ( P = 0·02) and presence of seroprotective HAI titres ( P = 0·017) two months after the booster dose. No other factor was significantly associated with the seroconversion/seroprotection rate. No serious adverse effects were reported. Vaccination had no impact on HIV disease progression. The AS03-adjuvanted pandemic H1 N1 vaccine appears to be safe and immunogenic among HIV-infected children. A robust serological response appears to be optimized by adherence to a HAART regimen delivering virological suppression. [ABSTRACT FROM AUTHOR]

Abstract: Vaccines with acceptable efficacy profile against the H1N1 A/California/7/2009 virus are needed for use in children. The two studies presented here evaluated the immunogenicity and the reactogenicity/safety of A/H1N1/2009 vaccines containing either 3.75μg haemagglutinin antigen (HA) and AS03A-adjuvant (3.75μg HA/AS03A study) (N =210 [53, 57 and 100 in the 3–5, 6–9 and 10–17 years age strata, respectively]) or 1.9μg HA and AS03B-adjuvant (1.9μg HA/AS03B study) (N =244 [61, 65 and 118 in the 3–5, 6–9 and 10–17 years age strata, respectively]), given as two-dose series. Although the haemagglutination inhibition antibody titres were higher in the 3.75μg HA/AS03A study, both vaccine dosages were highly immunogenic and exceeded regulatory acceptance criteria after the first and the second doses. Seroprotection rates reached 100% and seroconversion rates ranged from 98.2% to 99.1% after each dose of both vaccine dosages. Geometric mean titres increased from 456.5 to 1538.5 and from 297.9 to 1106.7 between the first and the second doses in the 3.75μg HA/AS03A study and the 1.9μg HA/AS03B study, respectively. Despite an observed slight increase of the reactogenicity following the second dose in the 3.75μg HA/AS03A study, the vaccines safety profiles were considered clinically acceptable. In conclusion, both dosages of the AS03-adjuvanted A/H1N1/2009 pandemic influenza vaccines were highly immunogenic and well-tolerated in children and adolescents. [Copyright &y& Elsevier]

We investigated the role of AS03 A (here AS03), an α-tocopherol oil-in-water emulsion-based adjuvant system, on the long-term persistence of humoral and cell-mediated immune responses to A(H1N1)pdm09 influenza vaccines. In two studies, a total of 261 healthy adults (≤60 years old) were randomized to receive two doses of AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin (HA) or nonadjuvanted vaccine containing 15 μg of hemagglutinin (in study A) or 3.75 μg of hemagglutinin (in study B) 21 days apart. Hemagglutination inhibition (HI) antibody, memory B-cell, and CD4 + /CD8 + T-cell responses were characterized up to 1 year following dose 1. We also assessed the effects of age and seasonal influenza vaccination history. AS03-adjuvanted (3.75 μg HA) vaccine and nonadjuvanted vaccine at 15 μg but not at 3.75 μg HA elicited HI antibody responses persisting at levels that continued to meet European licensure criteria through month 12. At month 12, the geometric mean titer for AS03-adjuvanted vaccine was similar to that for nonadjuvanted (15-μg) vaccine in study A (1:86 and 1:88, respectively) and higher than that for nonadjuvanted (3.75-μg) vaccine in study B (1:77 and 1:35, respectively). A(H1N1)pdm09-specific CD4 + T-cell and B-cell responses were stronger in AS03-adjuvanted groups and persisted only in these groups for 12 months at levels exceeding prevaccination frequencies. Advancing age and a seasonal vaccination history tended to reduce HI antibody and memory B-cell responses and, albeit less consistently, CD4 + T-cell responses. Thus, AS03 seemed to enhance the persistence of humoral and cell-mediated responses to A(H1N1)pdm09 vaccine, allowing for antigen sparing and mitigating potential negative effects of age and previous seasonal vaccination. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00968539 and NCT00989287.)., (Copyright © 2017 van der Most et al.)

In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.