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Clinical Trial
. 2022 Jul;22(7):1062-1075.
doi: 10.1016/S1473-3099(22)00024-X. Epub 2022 Apr 21.

Reactogenicity, safety, and immunogenicity of chimeric haemagglutinin influenza split-virion vaccines, adjuvanted with AS01 or AS03 or non-adjuvanted: a phase 1-2 randomised controlled trial

Nicolas Folschweiller  1 , Carline Vanden Abeele  2 , Laurence Chu  3 , Pierre Van Damme  4 , Adolfo García-Sastre  5 , Florian Krammer  6 , Raffael Nachbagauer  7 , Peter Palese  8 , Alicia Solórzano  9 , Dan Bi  2 , Marie-Pierre David  2 , Damien Friel  2 , Bruce L Innis  10 , Juliane Koch  11 , Corey P Mallett  12 , Ronan Nicolas Rouxel  13 , Bruno Salaun  14 , Valerie Vantomme  2 , Céline Verheust  2 , Frank Struyf  15
Affiliations
Clinical Trial

Reactogenicity, safety, and immunogenicity of chimeric haemagglutinin influenza split-virion vaccines, adjuvanted with AS01 or AS03 or non-adjuvanted: a phase 1-2 randomised controlled trial

Nicolas Folschweiller et al. Lancet Infect Dis. 2022 Jul.

Erratum in

Abstract

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.

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Conflict of interest statement

Declaration of interests AG-S, FK, RN, PP, and AS report study funding from the GSK group of companies made to the Icahn School of Medicine at Mount Sinai (New York, NY, USA). AG-S and PP also report study funding from the US National Institutes of Health and National Institute of Allergy and Infectious Diseases made to the Icahn School of Medicine at Mount Sinai. AG-S, FK, RN, PP, BLI, and CPM are named as inventors on a patent family regarding influenza virus vaccine constructs filed by the Icahn School of Medicine at Mount Sinai and the GSK group of companies, not licensed at the time of writing. AG-S is named as inventor of a patent owned by Mount Sinai on plasmid-based rescue technologies to generate recombinant influenza viruses, with royalties paid to Medimmune, now acquired by AstraZeneca. AG-S and PP are named as inventors on live attenuated NS1 mutant influenza viruses licensed to Vivaldi, with no royalties to date. RN is named as inventor on patents for influenza virus vaccines filed by Mount Sinai, the University of Pennsylvania (Philadelphia, PA), and Moderna. AG-S reports consulting fees from Avimex, 7Hills, Esperovax, Pfizer, Applied Biological Laboratories, and Farmak, outside of the submitted work. AG-S reports stock ownership from Vivaldi Biosciences, Pagoda, Contrafect, Vaxalto, and Accurius, outside the submitted work. AG-S reports research funding from The Bill & Melinda Gates Foundation, US Department of Defense, Defense Advanced Research Projects Agency, the National Institutes of Health, Pfizer, Pharmamar, Blade Therapeutics, Avimex, Accurius, Dynavax, Kenall Manufacturing, ImmunityBio, Nanocomposix, and Merck, outside the submitted work, paid to the Icahn School of Medicine at Mount Sinai. FK reports consulting fees from Avimex, Goldman Sachs, Pfizer, Seqirus, and Third Rock Ventures, outside the submitted work. FK also reports that royalty payments were made by the GSK group of companies to the Icahn School of Medicine at Mount Sinai. RN is currently an employee of Moderna and received stock and stock option grants from Moderna. RN also reports consulting fees from Guidepoint and ExpertConnect, outside the submitted work. PP reports consulting fees from Avimex, outside the submitted work. CVA, DB, M-PD, DF, CPM, BS, VV, and CV are employed by the GSK group of companies. NF, BLI, JK, RNR, and FS were employed by the GSK group of companies at the time the study was performed. NF, DB, M-PD, DF, BS, CPM, VV, CV, and FS hold shares in the GSK group of companies. NF is currently an employee of Takeda Pharmaceuticals International. BLI is currently an employee of PATH. FS is currently an employee of Janssen, Pharmaceutical Companies of Johnson & Johnson. PVD reports grants from the University of Antwerp (Antwerp, Belgium) from the GSK group of companies, Pfizer, Sanofi, Merck, Takeda, Baxter, CanSino China, Themis, Osivax, Johnson & Johnson, Abbott, The Bill & Melinda Gates Foundation, PATH, the Flemish Government, and the EU, outside the submitted work. PVD also reports participating on data and safety monitoring boards for Janssen Vaccines and Virometrix, outside the submitted work. These authors declare no other financial and non-financial relationships and activities. LC declares no competing interests.

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