mRNA vaccines redefine immune priming: systemic rethinking of CD8+ T cell activation pathways beyond conventional dendritic cell dependency

Indigenous knowledge systems view immune priming as a communal and ecological process, where the body's response is interconnected with environmental and social factors. The Western focus on dendritic cells and CD8+ T cells overlooks the role of collective immunity, where shared practices (e.g., diet, social cohesion) enhance resistance to pathogens. Indigenous communities have long used plant-based and ritualistic interventions to modulate immune responses, which could inform the design of mRNA vaccines that are culturally resonant and accessible. The redundancy in immune activation pathways observed in this study aligns with indigenous understandings of immune resilience as a dynamic, adaptive process rather than a fixed cellular mechanism.

The history of vaccine development is marred by colonial exploitation, where Western biomedical models were imposed on marginalized populations without regard for local knowledge or consent. The discovery of dendritic cells in the 1970s and their subsequent canonization as the primary pathway for CD8+ T cell priming reflects a Eurocentric bias in immunology, which has historically sidelined alternative models. The redundancy in mRNA vaccine priming challenges this dogma, echoing past scientific revolutions (e.g., the discovery of alternative complement pathways) that upended established paradigms. This study also parallels historical shifts in vaccine design, such as the move from live attenuated to subunit vaccines, which were initially met with skepticism but later became standard.

Cross-culturally, immune priming is understood through diverse lenses: in Ayurveda, the concept of *Ojas* (vital essence) governs immunity, while in TCM, the balance of *wei qi* (defensive energy) is key. African traditional medicine emphasizes the role of the microbiome and communal living in immune health, a perspective that aligns with the redundancy observed in mRNA vaccines. Indigenous Australian healing systems, such as those using *kangaroo apple* (*Solanum aviculare*), highlight the interconnectedness of immune responses with environmental and spiritual well-being. These traditions offer a holistic framework for understanding immune activation, which could inform the global adaptation of mRNA vaccines.

This study provides robust evidence that mRNA–lipid-nanoparticle vaccines engage both cDC1 and cDC2 cells redundantly for CD8+ T cell priming, challenging the long-held assumption that cDC1 cells are indispensable. The findings are grounded in rigorous experimental methodologies, including flow cytometry, antigen presentation assays, and in vivo mouse models, which validate the redundancy in immune activation. The study also highlights the adaptability of mRNA technology, which could enable the development of vaccines tailored to diverse genetic backgrounds and immune profiles. However, the focus on mechanistic novelty risks overshadowing the broader implications for vaccine equity and public health policy.

Artistic and spiritual traditions often depict immune responses as a dance of balance and harmony, mirroring the redundancy observed in mRNA vaccine priming. In Sufi poetry, the immune system is likened to a garden where harmony between different elements (e.g., cells, pathogens) is essential for health. Similarly, Buddhist teachings on *dependent origination* emphasize the interconnectedness of all phenomena, a principle that aligns with the holistic view of immunity. Indigenous Australian art, such as dot painting, visually represents the interconnectedness of the body and environment, offering a metaphor for immune resilience. These perspectives invite a more nuanced understanding of immune priming as a dynamic, adaptive process.

The redundancy in mRNA vaccine priming suggests a future where vaccines are designed to be modular, adaptable to diverse immune profiles and cultural contexts. This could enable the development of personalized vaccines that account for genetic, environmental, and social factors, moving beyond the one-size-fits-all approach. Scenario planning should consider the ethical implications of such adaptability, including the risk of exacerbating global inequities if access remains unequal. Additionally, future models could incorporate indigenous and traditional knowledge systems to create vaccines that are not only scientifically effective but also culturally resonant and community-driven.

Marginalized communities, particularly in the Global South, have long been skeptical of biomedical interventions due to histories of exploitation and exclusion from clinical trials. The lack of representation in vaccine research has led to distrust, as seen in the hesitancy toward COVID-19 vaccines in many communities. This study's findings could inform the design of vaccines that are more inclusive, but only if marginalized voices are centered in the research process. Indigenous scientists and healers, for example, could provide critical insights into how mRNA vaccines might be adapted to local immune profiles and cultural contexts. Without this inclusion, the promise of redundancy in immune priming risks becoming another top-down solution that fails to address structural inequities.