T cell-associated immunity induced by heterologous recombinant BCG and purified protein vaccination confers cross-variant protection against SARS-CoV-2.
This study suggests that a recombinant BCG-based vaccine can induce strong T cell immunity against SARS-CoV-2, but the role of humoral immunity appears limited.
Where it sits
this study against the rest of the kisspeptin (kp-10) corpusSummary and findings
This study evaluated a recombinant BCG-based vaccine (rBCG) expressing a chimeric protein against SARS-CoV-2 in K18-hACE2 mice. The vaccine regimen induced strong humoral and cellular immunity, with modest neutralizing capacity against the Wuhan strain. Vaccinated mice showed reduced viral loads and a strong Th1-biased cellular profile.
Abstract
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 <i>knockout</i> 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 <i>knockout</i> 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.
Background
This paper addresses the development of a recombinant BCG-based vaccine aimed at inducing immunity against SARS-CoV-2. Previous research indicated that BCG could enhance immune responses, but the specific mechanisms and efficacy against variants were not well understood. This study is significant as it explores the role of T cell immunity in vaccine-induced protection, particularly against emerging variants like JN.1.
Methods
The study utilized K18-hACE2 mice, including knockout models lacking functional B cells, CD4+, or CD8+ T lymphocytes. The vaccine regimen combined rBCG with a chimeric protein and Alum. The primary outcomes included the evaluation of humoral and cellular immune responses, as well as viral load measurements following vaccination.
Results
Vaccination induced high titers of anti-rChimera antibodies with modest neutralizing capacity against the Wuhan SARS-CoV-2 strain. Vaccinated B lymphocyte KO mice still showed reduced viral loads, indicating that humoral immunity may not be the predominant protective mechanism. The study reported increased IFN-γ production and multifunctional CD4+ T cell responses in vaccinated mice.
Interpretation
The findings suggest that T cell responses play a crucial role in the vaccine's protective efficacy, which aligns with previous literature emphasizing cellular immunity in viral control. However, the modest neutralizing capacity of antibodies raises questions about the overall effectiveness of humoral immunity. The use of knockout mice introduces confounds that may limit the generalizability of the results to human populations.
Key findings
- Vaccination induced high titers of anti-rChimera antibodies with modest neutralizing capacity against the Wuhan SARS-CoV-2 strain.
- Vaccinated B lymphocyte KO mice showed reduced viral loads, suggesting humoral immunity may not be the predominant protective mechanism.
- Vaccinated mice displayed increased IFN-γ production and multifunctional CD4+ T cell responses.
- CD4+ and CD8+ T cell-deficient animals exhibited loss of vaccine-associated protection.
- Vaccination conferred cross-protection against JN.1, despite lack of neutralization antibodies.
Limitations
- Utilized knockout mice, which may not fully represent human immune responses.
- Findings based on animal models, limiting direct applicability to humans.
- Lack of detailed quantitative results in the abstract.