Immunogenicity and protective efficacy on non-adjuvanted CD40-targeting SARS-CoV-2 vaccines in non-human primates

BACKGROUND: The emergence of antigenically distinct SARS-CoV-2 variants increases the risk of immune escape and requires continually updated vaccines. In addition, short-lived specific immunity is a limitation faced by current COVID-19 mRNA vaccines against Sarbecoviruses. This underscores the need for new vaccine approaches providing lasting immunity against SARS-CoV-2. METHODS: Here, we demonstrate the capacity of two non-adjuvanted subunit vaccines to induce long-lasting and protective immunity against SARS-CoV-2 variants in macaques. We designed antibody-mediated vaccines (AMV) leveraging an anti-CD40 monoclonal antibody to enhance immune responses by targeting selected antigens to antigen-presenting cells through the CD40 receptor. The CD40.RBDv vaccine targets sequences from the original Wuhan RBD and a mutated RBD, while CD40.Pan.CoV incorporates a conserved nucleocapsid sequence and a mutated RBD region. FINDINGS: We show that both adjuvant-free vaccines induce robust and durable systemic and mucosal anti-RBD antibody responses that neutralise multiple SARS-CoV-2 variants in naive and SARS-CoV-2 convalescent animals, including recent variants such as XFG. In convalescents, mathematical modelling predicted persistence of vaccine-induced antibody for decades. Additionally, the vaccines boost immune responses in mRNA-vaccinated animals, demonstrating the efficiency of CD40-based vaccines as boosters. Both vaccines protect animals against B.1.617.2 Delta and BA.1 Omicron challenges. Viral control correlates with vaccine-induced systemic and mucosal antibody levels and T-cell responses. INTERPRETATION: These findings support the ability of AMV targeting CD40 to induce strong, long-lasting responses against adapted antigens and broad protection against evolving SARS-CoV-2 variants without requiring adjuvant. These two vaccine candidates are currently under clinical testing. FUNDING: The Investissements d'Avenir program (ANR-10-LABX-77-01 and ANR-11-INBS-0008), the PSPC COVID-19 - Project EVIDENCE.

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Publication Details

Journal
EBioMedicine
Published
2026-07-01
DOI
https://doi.org/10.1016/j.ebiom.2026.106361
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Immunogenicity and protective efficacy on non-adjuvanted CD40-targeting SARS-CoV-2 vaccines in non-human primates

Vanessa Contreras, Mathilde Galhaut, Anne-Sophie Gallouët, Nathalie Dereuddre‐Bosquet et al.
EBioMedicine
SARS-CoV-2 and COVID-19 Research
article

Immunogenicity and protective efficacy on non-adjuvanted CD40-targeting SARS-CoV-2 vaccines in non-human primates

Vanessa Contreras, Mathilde Galhaut, Anne-Sophie Gallouët, Nathalie Dereuddre‐Bosquet, Marie Alexandre, Francis Relouzat, Rodolphe Thiébaut, Victor Magneron, Roger Le Grand, Mélanie Prague, Romain Marlin, Delphine Planas, Isabelle Staropoli, Olivier Schwartz, Laëtitia Bossevot, Cécile Hérate, Wesley Gros, Sandra Zurawski, Véronique Godot, Mariangela Cavarelli, Mathieu Surénaud, Mireille Centlivre, Marie-Anne Rameix Welti, Yves Lévy, Loïc Pintore, Craig Fenwick, Sylvain Cardinaud, Giuseppe Pantaleo, Paul Mazet, Gerard Zurawski
article en

Abstract

BACKGROUND: The emergence of antigenically distinct SARS-CoV-2 variants increases the risk of immune escape and requires continually updated vaccines. In addition, short-lived specific immunity is a limitation faced by current COVID-19 mRNA vaccines against Sarbecoviruses. This underscores the need for new vaccine approaches providing lasting immunity against SARS-CoV-2. METHODS: Here, we demonstrate the capacity of two non-adjuvanted subunit vaccines to induce long-lasting and protective immunity against SARS-CoV-2 variants in macaques. We designed antibody-mediated vaccines (AMV) leveraging an anti-CD40 monoclonal antibody to enhance immune responses by targeting selected antigens to antigen-presenting cells through the CD40 receptor. The CD40.RBDv vaccine targets sequences from the original Wuhan RBD and a mutated RBD, while CD40.Pan.CoV incorporates a conserved nucleocapsid sequence and a mutated RBD region. FINDINGS: We show that both adjuvant-free vaccines induce robust and durable systemic and mucosal anti-RBD antibody responses that neutralise multiple SARS-CoV-2 variants in naive and SARS-CoV-2 convalescent animals, including recent variants such as XFG. In convalescents, mathematical modelling predicted persistence of vaccine-induced antibody for decades. Additionally, the vaccines boost immune responses in mRNA-vaccinated animals, demonstrating the efficiency of CD40-based vaccines as boosters. Both vaccines protect animals against B.1.617.2 Delta and BA.1 Omicron challenges. Viral control correlates with vaccine-induced systemic and mucosal antibody levels and T-cell responses. INTERPRETATION: These findings support the ability of AMV targeting CD40 to induce strong, long-lasting responses against adapted antigens and broad protection against evolving SARS-CoV-2 variants without requiring adjuvant. These two vaccine candidates are currently under clinical testing. FUNDING: The Investissements d'Avenir program (ANR-10-LABX-77-01 and ANR-11-INBS-0008), the PSPC COVID-19 - Project EVIDENCE.

EBioMedicineVol. 129
Université de Bordeaux (FR), Inserm (FR), Institut Pasteur (FR), Université Paris-Est Créteil (FR), Université Paris Cité (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Assistance Publique – Hôpitaux de Paris (FR), Bordeaux Population Health (FR), Institut de Recherche Vaccinale (FR), CEA Paris-Saclay (FR), Infectious Disease Models and Innovative Therapies (FR), Hôpital Albert-Chenevier (FR), Institut Mondor de Recherche Biomédicale (FR), Baylor Scott & White Health (US), University of Lausanne (CH)
Bpifrance, Agence Nationale de la Recherche, HORIZON EUROPE Reforming and enhancing the European Research and Innovation system
Zero hunger
Openalex Percentile: Top 8%
SARS-CoV-2 and COVID-19 Research
DOIOpen Access PDFOpenAlex
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