First-in-human use of a modular capsid virus-like vaccine platform: An open-label, non-randomised, phase 1 clinical trial of the SARS-CoV-2 vaccine ABNCoV2

Merel J Smit; Adam F Sander; Maud B P A Ariaans; Cyrielle Fougeroux; Constanze Heinzel; Rolf Fendel; Meral Esen; Peter G Kremsner; Rob Ter Heine; Heiman F Wertheim; Manja Idorn; Søren Riis Paludan; Alexander P Underwood; Alekxander Binderup; Santseharay Ramirez; Jens Bukh; Max Soegaard; Sayit M Erdogan; Tobias Gustavsson; Stine Clemmensen; Thor G Theander; Ali Salanti; Mette Hamborg; Willem A de Jongh; Matthew B B McCall; Morten A Nielsen; Benjamin G Mordmüller; COUGH-1 trial study group; Robert Dagil; Louise Goksøyr; Thomas Morgan Hulen; Christoph Mikkel Janitzek Brygger; Paul Karim Khalifé; Elena Ethel Vidal-Calvo

doi:10.1016/S2666-5247(22)00337-8

First-in-human use of a modular capsid virus-like vaccine platform: An open-label, non-randomised, phase 1 clinical trial of the SARS-CoV-2 vaccine ABNCoV2

Merel J Smit, Adam F Sander, Maud B P A Ariaans, Cyrielle Fougeroux, Constanze Heinzel, Rolf Fendel, Meral Esen, Peter G Kremsner, Rob Ter Heine, Heiman F Wertheim, Manja Idorn, Søren Riis Paludan, Alexander P Underwood, Alekxander Binderup, Santseharay Ramirez, Jens Bukh, Max Soegaard, Sayit M Erdogan, Tobias Gustavsson, Stine ClemmensenThor G Theander, Ali Salanti, Mette Hamborg, Willem A de Jongh, Matthew B B McCall, Morten A Nielsen, Benjamin G Mordmüller, COUGH-1 trial study group, Robert Dagil, Louise Goksøyr, Thomas Morgan Hulen, Christoph Mikkel Janitzek Brygger, Paul Karim Khalifé, Elena Ethel Vidal-Calvo

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

BACKGROUND: Capsid virus-like particles (cVLP) have proven safe and immunogenic and can be a versatile platform to counter pandemics. We aimed to clinically test a modular cVLP COVID-19 vaccine in individuals who were naive to SARS-CoV-2.

METHODS: In this phase 1, single-centre, dose-escalation, adjuvant-selection, open-label clinical trial, we recruited participants at the Radboud University Medical Center in Nijmegen, Netherlands, and sequentially assigned them to seven groups. Eligible participants were healthy, aged 18-55 years, and tested negative for SARS-CoV-2 and anti-SARS-CoV-2 antibodies. Participants were vaccinated intramuscularly on days 0 and 28 with 6 μg, 12 μg, 25 μg, 50 μg, or 70 μg of the cVLP-based COVID-19 vaccine (ABNCoV2). A subgroup received MF59-adjuvanted ABNCoV2. Follow-up was for 24 weeks after second vaccination. The primary objectives were to assess the safety and tolerability of ABNCoV2 and to identify a dose that optimises the tolerability-immunogenicity ratio 14 days after the first vaccination. The primary safety endpoint was the number of related grade 3 adverse events and serious adverse events in the intention-to-treat population. The primary immunogenicity endpoint was the concentration of ABNCoV2-specific antibodies. The trial is registered with ClinicalTrials.gov, NCT04839146.

FINDINGS: 45 participants (six to nine per group) were enrolled between March 15 and July 15, 2021. Participants had a total of 249 at least possibly related solicited adverse events (185 grade 1, 63 grade 2, and one grade 3) within a week after vaccination. Two serious adverse events occurred; one was classified as a possible adverse reaction. Antibody titres were dose-dependent with levels plateauing at a vaccination dose of 25-70 μg ABNCoV2. After second vaccination, live virus neutralisation activity against major SARS-CoV-2 variants was high but was lower with an omicron (BA.1) variant. Vaccine-specific IFNγ+ CD4+ T cells were induced.

INTERPRETATION: Immunisation with ABNCoV2 was well tolerated, safe, and resulted in a functional immune response. The data support the need for additional clinical development of ABNCoV2 as a second-generation SARS-CoV-2 vaccine. The modular cVLP platform will accelerate vaccine development, beyond SARS-CoV-2.

FUNDING: EU, Carlsberg Foundation, and the Novo Nordisk Foundation.

Original language	English
Journal	The Lancet Microbe
Volume	4
Issue number	3
Pages (from-to)	e140-e148
ISSN	2666-5247
DOIs	https://doi.org/10.1016/S2666-5247(22)00337-8
Publication status	Published - 2023

Bibliographical note

Keywords

Humans
COVID-19 Vaccines
Viral Vaccines/adverse effects
COVID-19
SARS-CoV-2
Capsid
Adjuvants, Immunologic
Capsid Proteins

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Smit, M. J., Sander, A. F., Ariaans, M. B. P. A., Fougeroux, C., Heinzel, C., Fendel, R., Esen, M., Kremsner, P. G., Ter Heine, R., Wertheim, H. F., Idorn, M., Paludan, S. R., Underwood, A. P., Binderup, A., Ramirez, S., Bukh, J., Soegaard, M., Erdogan, S. M., Gustavsson, T., ... Vidal-Calvo, E. E. (2023). First-in-human use of a modular capsid virus-like vaccine platform: An open-label, non-randomised, phase 1 clinical trial of the SARS-CoV-2 vaccine ABNCoV2. The Lancet Microbe, 4(3), e140-e148. https://doi.org/10.1016/S2666-5247(22)00337-8

First-in-human use of a modular capsid virus-like vaccine platform : An open-label, non-randomised, phase 1 clinical trial of the SARS-CoV-2 vaccine ABNCoV2. / Smit, Merel J; Sander, Adam F; Ariaans, Maud B P A; Fougeroux, Cyrielle; Heinzel, Constanze; Fendel, Rolf; Esen, Meral; Kremsner, Peter G; Ter Heine, Rob; Wertheim, Heiman F; Idorn, Manja; Paludan, Søren Riis; Underwood, Alexander P; Binderup, Alekxander; Ramirez, Santseharay ; Bukh, Jens; Soegaard, Max; Erdogan, Sayit M ; Gustavsson, Tobias; Clemmensen, Stine; Theander, Thor G ; Salanti, Ali; Hamborg, Mette; de Jongh, Willem A; McCall, Matthew B B; Nielsen, Morten A; Mordmüller, Benjamin G; COUGH-1 trial study group ; Dagil, Robert; Goksøyr, Louise; Hulen, Thomas Morgan; Brygger, Christoph Mikkel Janitzek; Khalifé, Paul Karim; Vidal-Calvo, Elena Ethel.

In: The Lancet Microbe, Vol. 4, No. 3, 2023, p. e140-e148.

Research output: Contribution to journal › Journal article › Research › peer-review

Smit, MJ, Sander, AF, Ariaans, MBPA, Fougeroux, C, Heinzel, C, Fendel, R, Esen, M, Kremsner, PG, Ter Heine, R, Wertheim, HF, Idorn, M, Paludan, SR, Underwood, AP, Binderup, A, Ramirez, S , Bukh, J, Soegaard, M, Erdogan, SM , Gustavsson, T, Clemmensen, S, Theander, TG , Salanti, A, Hamborg, M, de Jongh, WA, McCall, MBB, Nielsen, MA, Mordmüller, BG, COUGH-1 trial study group, Dagil, R, Goksøyr, L, Hulen, TM, Brygger, CMJ, Khalifé, PK & Vidal-Calvo, EE 2023, 'First-in-human use of a modular capsid virus-like vaccine platform: An open-label, non-randomised, phase 1 clinical trial of the SARS-CoV-2 vaccine ABNCoV2', The Lancet Microbe, vol. 4, no. 3, pp. e140-e148. https://doi.org/10.1016/S2666-5247(22)00337-8

Smit, Merel J ; Sander, Adam F ; Ariaans, Maud B P A ; Fougeroux, Cyrielle ; Heinzel, Constanze ; Fendel, Rolf ; Esen, Meral ; Kremsner, Peter G ; Ter Heine, Rob ; Wertheim, Heiman F ; Idorn, Manja ; Paludan, Søren Riis ; Underwood, Alexander P ; Binderup, Alekxander ; Ramirez, Santseharay ; Bukh, Jens ; Soegaard, Max ; Erdogan, Sayit M ; Gustavsson, Tobias ; Clemmensen, Stine ; Theander, Thor G ; Salanti, Ali ; Hamborg, Mette ; de Jongh, Willem A ; McCall, Matthew B B ; Nielsen, Morten A ; Mordmüller, Benjamin G ; COUGH-1 trial study group ; Dagil, Robert ; Goksøyr, Louise ; Hulen, Thomas Morgan ; Brygger, Christoph Mikkel Janitzek ; Khalifé, Paul Karim ; Vidal-Calvo, Elena Ethel. / First-in-human use of a modular capsid virus-like vaccine platform : An open-label, non-randomised, phase 1 clinical trial of the SARS-CoV-2 vaccine ABNCoV2. In: The Lancet Microbe. 2023 ; Vol. 4, No. 3. pp. e140-e148.

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abstract = "BACKGROUND: Capsid virus-like particles (cVLP) have proven safe and immunogenic and can be a versatile platform to counter pandemics. We aimed to clinically test a modular cVLP COVID-19 vaccine in individuals who were naive to SARS-CoV-2.METHODS: In this phase 1, single-centre, dose-escalation, adjuvant-selection, open-label clinical trial, we recruited participants at the Radboud University Medical Center in Nijmegen, Netherlands, and sequentially assigned them to seven groups. Eligible participants were healthy, aged 18-55 years, and tested negative for SARS-CoV-2 and anti-SARS-CoV-2 antibodies. Participants were vaccinated intramuscularly on days 0 and 28 with 6 μg, 12 μg, 25 μg, 50 μg, or 70 μg of the cVLP-based COVID-19 vaccine (ABNCoV2). A subgroup received MF59-adjuvanted ABNCoV2. Follow-up was for 24 weeks after second vaccination. The primary objectives were to assess the safety and tolerability of ABNCoV2 and to identify a dose that optimises the tolerability-immunogenicity ratio 14 days after the first vaccination. The primary safety endpoint was the number of related grade 3 adverse events and serious adverse events in the intention-to-treat population. The primary immunogenicity endpoint was the concentration of ABNCoV2-specific antibodies. The trial is registered with ClinicalTrials.gov, NCT04839146.FINDINGS: 45 participants (six to nine per group) were enrolled between March 15 and July 15, 2021. Participants had a total of 249 at least possibly related solicited adverse events (185 grade 1, 63 grade 2, and one grade 3) within a week after vaccination. Two serious adverse events occurred; one was classified as a possible adverse reaction. Antibody titres were dose-dependent with levels plateauing at a vaccination dose of 25-70 μg ABNCoV2. After second vaccination, live virus neutralisation activity against major SARS-CoV-2 variants was high but was lower with an omicron (BA.1) variant. Vaccine-specific IFNγ+ CD4+ T cells were induced.INTERPRETATION: Immunisation with ABNCoV2 was well tolerated, safe, and resulted in a functional immune response. The data support the need for additional clinical development of ABNCoV2 as a second-generation SARS-CoV-2 vaccine. The modular cVLP platform will accelerate vaccine development, beyond SARS-CoV-2.FUNDING: EU, Carlsberg Foundation, and the Novo Nordisk Foundation.",

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author = "Smit, {Merel J} and Sander, {Adam F} and Ariaans, {Maud B P A} and Cyrielle Fougeroux and Constanze Heinzel and Rolf Fendel and Meral Esen and Kremsner, {Peter G} and {Ter Heine}, Rob and Wertheim, {Heiman F} and Manja Idorn and Paludan, {S{\o}ren Riis} and Underwood, {Alexander P} and Alekxander Binderup and Santseharay Ramirez and Jens Bukh and Max Soegaard and Erdogan, {Sayit M} and Tobias Gustavsson and Stine Clemmensen and Theander, {Thor G} and Ali Salanti and Mette Hamborg and {de Jongh}, {Willem A} and McCall, {Matthew B B} and Nielsen, {Morten A} and Mordm{\"u}ller, {Benjamin G} and {COUGH-1 trial study group} and Robert Dagil and Louise Goks{\o}yr and Hulen, {Thomas Morgan} and Brygger, {Christoph Mikkel Janitzek} and Khalif{\'e}, {Paul Karim} and Vidal-Calvo, {Elena Ethel}",

year = "2023",

doi = "10.1016/S2666-5247(22)00337-8",

language = "English",

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journal = "The Lancet Microbe",

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TY - JOUR

T1 - First-in-human use of a modular capsid virus-like vaccine platform

T2 - An open-label, non-randomised, phase 1 clinical trial of the SARS-CoV-2 vaccine ABNCoV2

AU - Smit, Merel J

AU - Sander, Adam F

AU - Ariaans, Maud B P A

AU - Fougeroux, Cyrielle

AU - Heinzel, Constanze

AU - Fendel, Rolf

AU - Esen, Meral

AU - Kremsner, Peter G

AU - Ter Heine, Rob

AU - Wertheim, Heiman F

AU - Idorn, Manja

AU - Paludan, Søren Riis

AU - Underwood, Alexander P

AU - Binderup, Alekxander

AU - Ramirez, Santseharay

AU - Bukh, Jens

AU - Soegaard, Max

AU - Erdogan, Sayit M

AU - Gustavsson, Tobias

AU - Clemmensen, Stine

AU - Theander, Thor G

AU - Salanti, Ali

AU - Hamborg, Mette

AU - de Jongh, Willem A

AU - McCall, Matthew B B

AU - Nielsen, Morten A

AU - Mordmüller, Benjamin G

AU - COUGH-1 trial study group

AU - Dagil, Robert

AU - Goksøyr, Louise

AU - Hulen, Thomas Morgan

AU - Brygger, Christoph Mikkel Janitzek

AU - Khalifé, Paul Karim

AU - Vidal-Calvo, Elena Ethel

PY - 2023

Y1 - 2023

N2 - BACKGROUND: Capsid virus-like particles (cVLP) have proven safe and immunogenic and can be a versatile platform to counter pandemics. We aimed to clinically test a modular cVLP COVID-19 vaccine in individuals who were naive to SARS-CoV-2.METHODS: In this phase 1, single-centre, dose-escalation, adjuvant-selection, open-label clinical trial, we recruited participants at the Radboud University Medical Center in Nijmegen, Netherlands, and sequentially assigned them to seven groups. Eligible participants were healthy, aged 18-55 years, and tested negative for SARS-CoV-2 and anti-SARS-CoV-2 antibodies. Participants were vaccinated intramuscularly on days 0 and 28 with 6 μg, 12 μg, 25 μg, 50 μg, or 70 μg of the cVLP-based COVID-19 vaccine (ABNCoV2). A subgroup received MF59-adjuvanted ABNCoV2. Follow-up was for 24 weeks after second vaccination. The primary objectives were to assess the safety and tolerability of ABNCoV2 and to identify a dose that optimises the tolerability-immunogenicity ratio 14 days after the first vaccination. The primary safety endpoint was the number of related grade 3 adverse events and serious adverse events in the intention-to-treat population. The primary immunogenicity endpoint was the concentration of ABNCoV2-specific antibodies. The trial is registered with ClinicalTrials.gov, NCT04839146.FINDINGS: 45 participants (six to nine per group) were enrolled between March 15 and July 15, 2021. Participants had a total of 249 at least possibly related solicited adverse events (185 grade 1, 63 grade 2, and one grade 3) within a week after vaccination. Two serious adverse events occurred; one was classified as a possible adverse reaction. Antibody titres were dose-dependent with levels plateauing at a vaccination dose of 25-70 μg ABNCoV2. After second vaccination, live virus neutralisation activity against major SARS-CoV-2 variants was high but was lower with an omicron (BA.1) variant. Vaccine-specific IFNγ+ CD4+ T cells were induced.INTERPRETATION: Immunisation with ABNCoV2 was well tolerated, safe, and resulted in a functional immune response. The data support the need for additional clinical development of ABNCoV2 as a second-generation SARS-CoV-2 vaccine. The modular cVLP platform will accelerate vaccine development, beyond SARS-CoV-2.FUNDING: EU, Carlsberg Foundation, and the Novo Nordisk Foundation.

AB - BACKGROUND: Capsid virus-like particles (cVLP) have proven safe and immunogenic and can be a versatile platform to counter pandemics. We aimed to clinically test a modular cVLP COVID-19 vaccine in individuals who were naive to SARS-CoV-2.METHODS: In this phase 1, single-centre, dose-escalation, adjuvant-selection, open-label clinical trial, we recruited participants at the Radboud University Medical Center in Nijmegen, Netherlands, and sequentially assigned them to seven groups. Eligible participants were healthy, aged 18-55 years, and tested negative for SARS-CoV-2 and anti-SARS-CoV-2 antibodies. Participants were vaccinated intramuscularly on days 0 and 28 with 6 μg, 12 μg, 25 μg, 50 μg, or 70 μg of the cVLP-based COVID-19 vaccine (ABNCoV2). A subgroup received MF59-adjuvanted ABNCoV2. Follow-up was for 24 weeks after second vaccination. The primary objectives were to assess the safety and tolerability of ABNCoV2 and to identify a dose that optimises the tolerability-immunogenicity ratio 14 days after the first vaccination. The primary safety endpoint was the number of related grade 3 adverse events and serious adverse events in the intention-to-treat population. The primary immunogenicity endpoint was the concentration of ABNCoV2-specific antibodies. The trial is registered with ClinicalTrials.gov, NCT04839146.FINDINGS: 45 participants (six to nine per group) were enrolled between March 15 and July 15, 2021. Participants had a total of 249 at least possibly related solicited adverse events (185 grade 1, 63 grade 2, and one grade 3) within a week after vaccination. Two serious adverse events occurred; one was classified as a possible adverse reaction. Antibody titres were dose-dependent with levels plateauing at a vaccination dose of 25-70 μg ABNCoV2. After second vaccination, live virus neutralisation activity against major SARS-CoV-2 variants was high but was lower with an omicron (BA.1) variant. Vaccine-specific IFNγ+ CD4+ T cells were induced.INTERPRETATION: Immunisation with ABNCoV2 was well tolerated, safe, and resulted in a functional immune response. The data support the need for additional clinical development of ABNCoV2 as a second-generation SARS-CoV-2 vaccine. The modular cVLP platform will accelerate vaccine development, beyond SARS-CoV-2.FUNDING: EU, Carlsberg Foundation, and the Novo Nordisk Foundation.

KW - Humans

KW - COVID-19 Vaccines

KW - Viral Vaccines/adverse effects

KW - COVID-19

KW - SARS-CoV-2

KW - Capsid

KW - Adjuvants, Immunologic

KW - Capsid Proteins

U2 - 10.1016/S2666-5247(22)00337-8

DO - 10.1016/S2666-5247(22)00337-8

M3 - Journal article

C2 - 36681093

VL - 4

SP - e140-e148

JO - The Lancet Microbe

JF - The Lancet Microbe

SN - 2666-5247

IS - 3

ER -