tetano
Editor, Senior Moderator
Hum Vaccin Immunother
. 2026 Dec;22(1):2697392.
doi: 10.1080/21645515.2026.2697392. Epub 2026 Jul 9.
T cell-associated immunity induced by heterologous recombinant BCG and purified protein vaccination confers cross-variant protection against SARS-CoV-2
Fábio Mambelli[SUP] 1 2 [/SUP], Alba M Gimenez[SUP] 1 2 [/SUP], Ana Carolina V S C de Araujo[SUP] 1 2 [/SUP], Karla K S Ramos[SUP] 1 2 [/SUP], Jéssica P Farias[SUP] 3 [/SUP], Carla L de Freitas[SUP] 2 [/SUP], Gabriela P Paludo[SUP] 2 4 [/SUP], Nelson Cortes[SUP] 1 2 [/SUP], Rúbens P Dos S Alves[SUP] 2 [/SUP], Paola Minoprio[SUP] 2 4 [/SUP], Luciana C C Leite[SUP] 5 [/SUP], Luis Carlos S Ferreira[SUP] 2 3 [/SUP], Sergio C Oliveira[SUP] 1 2 [/SUP]
Affiliations
Previously, we have developed a recombinant BCG-based vaccine (rBCG) expressing a chimeric protein with spike and nucleocapsid epitopes (rChimera) to combine BCG's innate immune training capacity with SARS-CoV-2-specific adaptive immune responses. The heterologous prime-boost rBCG/rChimera+Alum regimen induced strong humoral and cellular immunity, conferring protection against the ancestral Wuhan strain in K18-hACE2 mice. Here, we used knockout mice lacking functional B cells, CD4[SUP]+[/SUP], or CD8[SUP]+[/SUP] T lymphocytes expressing hACE2 to uncover the mechanisms of anti-viral immune protection, while also evaluating vaccine efficacy against JN.1. Vaccination induced high titers of anti-rChimera antibodies with modest neutralizing capacity against the Wuhan SARS-CoV-2 strain. Nonetheless, vaccinated B lymphocyte KO mice still showed reduced viral loads, suggesting that humoral immunity may not represent the predominant protective mechanism in this model. Vaccinated mice displayed a strong Th1-biased cellular profile characterized by increased IFN-γ production and multifunctional CD4[SUP]+[/SUP] T cell responses, alongside activated CD8[SUP]+[/SUP] T cells responses. CD4[SUP]+[/SUP] and CD8[SUP]+[/SUP] T cell-deficient animals exhibited loss of vaccine-associated protection, supporting an important contribution of T cells to viral control. Additionally, immunized IFN-γ knockout mice revealed only partial protection, suggesting that IFN-γ contributes to, but is not strictly required, for vaccine-induced immunity. We also observed that macrophages derived from vaccinated animals displayed enhanced inflammatory responsiveness following heterologous stimulation. Remarkably, vaccination conferred cross-protection against JN.1, despite lack of neutralization antibodies. These findings indicate that rBCG/rChimera+Alum vaccination induces an integrated innate and predominant T cell protective immunity cross-reactive with JN.1, supporting the rBCG-based platforms as a promising approach for COVID-19 vaccine development.
Keywords: BCG; COVID-19; JN.1; SARS-CoV-2; vaccine; variants.
. 2026 Dec;22(1):2697392.
doi: 10.1080/21645515.2026.2697392. Epub 2026 Jul 9.
T cell-associated immunity induced by heterologous recombinant BCG and purified protein vaccination confers cross-variant protection against SARS-CoV-2
Fábio Mambelli[SUP] 1 2 [/SUP], Alba M Gimenez[SUP] 1 2 [/SUP], Ana Carolina V S C de Araujo[SUP] 1 2 [/SUP], Karla K S Ramos[SUP] 1 2 [/SUP], Jéssica P Farias[SUP] 3 [/SUP], Carla L de Freitas[SUP] 2 [/SUP], Gabriela P Paludo[SUP] 2 4 [/SUP], Nelson Cortes[SUP] 1 2 [/SUP], Rúbens P Dos S Alves[SUP] 2 [/SUP], Paola Minoprio[SUP] 2 4 [/SUP], Luciana C C Leite[SUP] 5 [/SUP], Luis Carlos S Ferreira[SUP] 2 3 [/SUP], Sergio C Oliveira[SUP] 1 2 [/SUP]
Affiliations
- PMID: 42423335
- PMCID: PMC13353785
- DOI: 10.1080/21645515.2026.2697392
Previously, we have developed a recombinant BCG-based vaccine (rBCG) expressing a chimeric protein with spike and nucleocapsid epitopes (rChimera) to combine BCG's innate immune training capacity with SARS-CoV-2-specific adaptive immune responses. The heterologous prime-boost rBCG/rChimera+Alum regimen induced strong humoral and cellular immunity, conferring protection against the ancestral Wuhan strain in K18-hACE2 mice. Here, we used knockout mice lacking functional B cells, CD4[SUP]+[/SUP], or CD8[SUP]+[/SUP] T lymphocytes expressing hACE2 to uncover the mechanisms of anti-viral immune protection, while also evaluating vaccine efficacy against JN.1. Vaccination induced high titers of anti-rChimera antibodies with modest neutralizing capacity against the Wuhan SARS-CoV-2 strain. Nonetheless, vaccinated B lymphocyte KO mice still showed reduced viral loads, suggesting that humoral immunity may not represent the predominant protective mechanism in this model. Vaccinated mice displayed a strong Th1-biased cellular profile characterized by increased IFN-γ production and multifunctional CD4[SUP]+[/SUP] T cell responses, alongside activated CD8[SUP]+[/SUP] T cells responses. CD4[SUP]+[/SUP] and CD8[SUP]+[/SUP] T cell-deficient animals exhibited loss of vaccine-associated protection, supporting an important contribution of T cells to viral control. Additionally, immunized IFN-γ knockout mice revealed only partial protection, suggesting that IFN-γ contributes to, but is not strictly required, for vaccine-induced immunity. We also observed that macrophages derived from vaccinated animals displayed enhanced inflammatory responsiveness following heterologous stimulation. Remarkably, vaccination conferred cross-protection against JN.1, despite lack of neutralization antibodies. These findings indicate that rBCG/rChimera+Alum vaccination induces an integrated innate and predominant T cell protective immunity cross-reactive with JN.1, supporting the rBCG-based platforms as a promising approach for COVID-19 vaccine development.
Keywords: BCG; COVID-19; JN.1; SARS-CoV-2; vaccine; variants.