TY - JOUR
T1 - Reactogenicity, safety, and immunogenicity of chimeric haemagglutinin influenza split-virion vaccines, adjuvanted with AS01 or AS03 or non-adjuvanted
T2 - a phase 1–2 randomised controlled trial
AU - Folschweiller, Nicolas
AU - Vanden Abeele, Carline
AU - Chu, Laurence
AU - Van Damme, Pierre
AU - García-Sastre, Adolfo
AU - Krammer, Florian
AU - Nachbagauer, Raffael
AU - Palese, Peter
AU - Solórzano, Alicia
AU - Bi, Dan
AU - David, Marie Pierre
AU - Friel, Damien
AU - Innis, Bruce L.
AU - Koch, Juliane
AU - Mallett, Corey P.
AU - Rouxel, Ronan Nicolas
AU - Salaun, Bruno
AU - Vantomme, Valerie
AU - Verheust, Céline
AU - Struyf, Frank
N1 - Funding Information:
GSK Biologicals funded this study and was involved in all stages of study conduct, including data analysis, and took charge of all costs associated with the development and publication of this manuscript. Basic research leading to this trial was supported by the Center for Research on Influenza Pathogenesis, a National Institute of Allergy and Infectious Diseases (NIAID)-funded Center of Excellence for Influenza Research and Surveillance (contract HHSN272201400008C), and the Center for Research on Influenza Pathogenesis and Transmission, a NIAID-funded Center of Excellence for Influenza Research and Response (contract 75N93021C00014), and by the NIAID grants P01 AI097092, U19 AI109946, R01 AI128821. During the drafting and review phase of this manuscript, investigators from the Icahn School of Medicine at Mount Sinai were supported by the NIAID Collaborative Influenza Vaccine Innovation Centers (contract 75N93019C00051), NIAID-funded Center of Excellence for Influenza Research and Response (contract 75N93021C00014; PP), and NIAID grants P01 AI097092-07 and R01 AI145870-03 (PP). Fluarix quadrivalent is a trademark owned by or licensed to the GSK group of companies. We thank patients, clinical teams, and investigators involved in the clinical trial. We thank Randy A Albrecht, Badiaa Bouzya, Brigitte Cheuvart, Veronika Chromikova, Flavia Cisternino, Muriel Debois, Jeanne-Marie Devaster, Walthere Dewe, Fabienne Douaud, Loic Francois, Rong Hai, Gwenny Honee, Catherine Luke, Domenica Majorino, Pascale Paindavoine, Stephanie Ravault, Luis Romano, Daniel Stadlbauer, Weina Sun, Olivier Van Der Meeren, Brenda Williams, and the Independent Data Monitoring Committee for their contribution to the studies, as well as Ulrike Krause and Clarisse Lorin for their critical review of the manuscript. We also thank Business and Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Mary L Greenacre (An Sgriobhadair, Haydon Bridge, UK, on behalf of GSK) provided medical writing support. Bruno Dumont and Aurélie Roth (Business and Decision Life Sciences, on behalf of GSK) coordinated the manuscript development and editorial support.
Funding Information:
GSK Biologicals funded this study and was involved in all stages of study conduct, including data analysis, and took charge of all costs associated with the development and publication of this manuscript. Basic research leading to this trial was supported by the Center for Research on Influenza Pathogenesis, a National Institute of Allergy and Infectious Diseases (NIAID)-funded Center of Excellence for Influenza Research and Surveillance (contract HHSN272201400008C), and the Center for Research on Influenza Pathogenesis and Transmission, a NIAID-funded Center of Excellence for Influenza Research and Response (contract 75N93021C00014), and by the NIAID grants P01 AI097092, U19 AI109946, R01 AI128821. During the drafting and review phase of this manuscript, investigators from the Icahn School of Medicine at Mount Sinai were supported by the NIAID Collaborative Influenza Vaccine Innovation Centers (contract 75N93019C00051), NIAID-funded Center of Excellence for Influenza Research and Response (contract 75N93021C00014; PP), and NIAID grants P01 AI097092-07 and R01 AI145870-03 (PP). Fluarix quadrivalent is a trademark owned by or licensed to the GSK group of companies. We thank patients, clinical teams, and investigators involved in the clinical trial. We thank Randy A Albrecht, Badiaa Bouzya, Brigitte Cheuvart, Veronika Chromikova, Flavia Cisternino, Muriel Debois, Jeanne-Marie Devaster, Walthere Dewe, Fabienne Douaud, Loic Francois, Rong Hai, Gwenny Honee, Catherine Luke, Domenica Majorino, Pascale Paindavoine, Stephanie Ravault, Luis Romano, Daniel Stadlbauer, Weina Sun, Olivier Van Der Meeren, Brenda Williams, and the Independent Data Monitoring Committee for their contribution to the studies, as well as Ulrike Krause and Clarisse Lorin for their critical review of the manuscript. We also thank Business and Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Mary L Greenacre (An Sgriobhadair, Haydon Bridge, UK, on behalf of GSK) provided medical writing support. Bruno Dumont and Aurélie Roth (Business and Decision Life Sciences, on behalf of GSK) coordinated the manuscript development and editorial support.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/7
Y1 - 2022/7
N2 - Background: One strategy to develop a universal influenza virus vaccine is to redirect the immune system to the highly conserved haemagglutinin stalk domain by sequentially administering vaccines expressing chimeric (c) haemagglutinins with a conserved stalk domain and divergent head domain, to which humans are naive. We aimed to assess the reactogenicity, safety, and immunogenicity of adjuvanted and unadjuvanted investigational supra-seasonal universal influenza virus vaccines (SUIVs) in healthy young adults. Methods: In this observer-masked, randomised, controlled, phase 1–2 trial, we recruited adults aged 18–39 years with no clinically significant conditions from six centres in Belgium and the USA. Participants were randomly assigned to ten equally sized groups via an online system with the MATerial Excellence programme. Vaccines contained heterosubtypic group 1 H8, H5, or H11 haemagglutinin heads, an H1 haemagglutinin stalk, and an N1 neuraminidase (cH8/1N1, cH5/1N1, and cH11/1N1; haemagglutinin dose 15 μg/0·5 mL), administered on days 1 and 57, with a month 14 booster. SUIVs were evaluated in the sequences: cH8/1N1–placebo–cH5/1N1, cH5/1N1–placebo–cH8/1N1, or cH8/1N1–cH5/1N1–cH11/1N1, adjuvanted with either AS03 or AS01, or not adjuvanted. The last group received inactivated quadrivalent influenza vaccine (IIV4)–placebo–IIV4. Primary outcomes were safety (analysed in the exposed population) and immunogenicity in terms of the anti-H1 stalk humoral response at 28 days after vaccination (analysed in the per-protocol population, defined as participants who received the study vaccines according to the protocol). This trial is registered with ClinicalTrials.gov, NCT03275389. Findings: Between Sept 25, 2017, and March 26, 2020, 507 eligible participants were enrolled. 468 (92%) participants received at least one dose of study vaccine (exposed population), of whom 244 (52%) were included in the per-protocol population at final analysis at month 26. The safety profiles of all chimeric vaccines were clinically acceptable, with no safety concerns identified. Injection-site pain was the most common adverse event, occurring in 84–96% of participants receiving an adjuvanted SUIV or non-adjuvanted IIV4 and in 40–50% of participants receiving a non-adjuvanted SUIV. Spontaneously reported adverse events up to 28 days after vaccination occurred in 36–60% of participants, with no trends observed for any group. 17 participants had a serious adverse event, none of which were considered to be causally related to the vaccine. Anti-H1 stalk antibody titres were highest in AS03-adjuvanted groups, followed by AS01-adjuvanted and non-adjuvanted groups, and were higher after cH8/1N1 than after cH5/1N1 and after a two-dose primary schedule than after a one-dose schedule. Geometric mean concentrations by ELISA ranged from 21 938·1 ELISA units/mL (95% CI 18 037·8–26 681·8) in the IIV4–placebo–IIV4 group to 116 596·8 ELISA units/mL (93 869·6–144 826·6) in the AS03-adjuvanted cH8/1N1–cH5/1N1–cH11/1N1 group 28 days after the first dose and from 15 105·9 ELISA units/mL (12 007·7–19 003·6) in the non-adjuvanted cH5/1N1–placebo–cH8/1N1 group to 74 639·7 ELISA units/mL (59 986·3–92 872·6) in the AS03-adjuvanted cH8/1N1–cH5/1N1–cH11/1N1 group 28 days after the second dose. Interpretation: The stalk domain seems to be a rational target for development of a universal influenza virus vaccine via administration of chimeric haemagglutinins with head domains to which humans are naive. Funding: GlaxoSmithKline Biologicals.
AB - Background: One strategy to develop a universal influenza virus vaccine is to redirect the immune system to the highly conserved haemagglutinin stalk domain by sequentially administering vaccines expressing chimeric (c) haemagglutinins with a conserved stalk domain and divergent head domain, to which humans are naive. We aimed to assess the reactogenicity, safety, and immunogenicity of adjuvanted and unadjuvanted investigational supra-seasonal universal influenza virus vaccines (SUIVs) in healthy young adults. Methods: In this observer-masked, randomised, controlled, phase 1–2 trial, we recruited adults aged 18–39 years with no clinically significant conditions from six centres in Belgium and the USA. Participants were randomly assigned to ten equally sized groups via an online system with the MATerial Excellence programme. Vaccines contained heterosubtypic group 1 H8, H5, or H11 haemagglutinin heads, an H1 haemagglutinin stalk, and an N1 neuraminidase (cH8/1N1, cH5/1N1, and cH11/1N1; haemagglutinin dose 15 μg/0·5 mL), administered on days 1 and 57, with a month 14 booster. SUIVs were evaluated in the sequences: cH8/1N1–placebo–cH5/1N1, cH5/1N1–placebo–cH8/1N1, or cH8/1N1–cH5/1N1–cH11/1N1, adjuvanted with either AS03 or AS01, or not adjuvanted. The last group received inactivated quadrivalent influenza vaccine (IIV4)–placebo–IIV4. Primary outcomes were safety (analysed in the exposed population) and immunogenicity in terms of the anti-H1 stalk humoral response at 28 days after vaccination (analysed in the per-protocol population, defined as participants who received the study vaccines according to the protocol). This trial is registered with ClinicalTrials.gov, NCT03275389. Findings: Between Sept 25, 2017, and March 26, 2020, 507 eligible participants were enrolled. 468 (92%) participants received at least one dose of study vaccine (exposed population), of whom 244 (52%) were included in the per-protocol population at final analysis at month 26. The safety profiles of all chimeric vaccines were clinically acceptable, with no safety concerns identified. Injection-site pain was the most common adverse event, occurring in 84–96% of participants receiving an adjuvanted SUIV or non-adjuvanted IIV4 and in 40–50% of participants receiving a non-adjuvanted SUIV. Spontaneously reported adverse events up to 28 days after vaccination occurred in 36–60% of participants, with no trends observed for any group. 17 participants had a serious adverse event, none of which were considered to be causally related to the vaccine. Anti-H1 stalk antibody titres were highest in AS03-adjuvanted groups, followed by AS01-adjuvanted and non-adjuvanted groups, and were higher after cH8/1N1 than after cH5/1N1 and after a two-dose primary schedule than after a one-dose schedule. Geometric mean concentrations by ELISA ranged from 21 938·1 ELISA units/mL (95% CI 18 037·8–26 681·8) in the IIV4–placebo–IIV4 group to 116 596·8 ELISA units/mL (93 869·6–144 826·6) in the AS03-adjuvanted cH8/1N1–cH5/1N1–cH11/1N1 group 28 days after the first dose and from 15 105·9 ELISA units/mL (12 007·7–19 003·6) in the non-adjuvanted cH5/1N1–placebo–cH8/1N1 group to 74 639·7 ELISA units/mL (59 986·3–92 872·6) in the AS03-adjuvanted cH8/1N1–cH5/1N1–cH11/1N1 group 28 days after the second dose. Interpretation: The stalk domain seems to be a rational target for development of a universal influenza virus vaccine via administration of chimeric haemagglutinins with head domains to which humans are naive. Funding: GlaxoSmithKline Biologicals.
UR - http://www.scopus.com/inward/record.url?scp=85132517301&partnerID=8YFLogxK
U2 - 10.1016/S1473-3099(22)00024-X
DO - 10.1016/S1473-3099(22)00024-X
M3 - Article
C2 - 35461522
AN - SCOPUS:85132517301
SN - 1473-3099
VL - 22
SP - 1062
EP - 1075
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 7
ER -