Severe acute syndrome coronavirus 2 (SARS-CoV-2) infection and its associated disease, COVID-19, are known to have a higher impact in old people (Mueller et al., Aging 2020). Vaccination is the most effective tool for the prevention of the serious symptomatology caused by SARS-CoV-2 and other viral infections, especially for vulnerable populations as elderly people. BNT162b2 mRNA vaccine, commonly known as Biontech/Pfizer vaccine, has shown high safety and efficacy against severe outcomes of COVID-19 (Walsh et al., N Engl J Med 2020). In spite of the promising results of this vaccine, lower levels of neutralizing antibodies are found in vaccinated elderly comparing with younger subjects (Müller et al., Clin Infect Dis 2021). Hence, a better understanding of the age-related immune dysfunction to SARS-CoV-2 vaccine is crucial for future vaccination strategies to improve older adults’ protection against this virus.
Immune aging is sustained by multifaceted remodeling of the innate and adaptive immunity. One of the most known changes of the immune aging is the involution of the thymus and the related memory inflation, characterized by an alteration of the naïve and memory T-cell proportions in the periphery skewing toward memory T-cells (Palmer et al., Front Immunol 2013). Remarkably, it has been described that thymic function failure predicts all-cause mortality in healthy elderly people (Ferrando-Martinez S et al., Age 2013) and has a relevant role in viral infections such as HIV-1 infection (Douek et al., Nature 1998).
The regulation of the immune response highly depends on the function of dendritic cells (DCs); however, their role in immune aging needs to be better understood. On one hand, plasmacytoid DCs (pDCs) control innate and adaptive immune system and induce cells’ antiviral state through type I interferon production, that inhibits the replication and spreading of viruses (Bencze et al., Int J Mol Sci 2021). On the other hand, CD1c+ myeloid DCs (mDCs), along with CD141+ mDCs, have an important role in CD4+ and CD8+ T-cell co-stimulation, respectively (Guermonprez et al., Annu Rev Immunol 2002). Furthermore, DC homing to different tissues is a critical factor for a suitable DC-mediated T cell stimulation. Importantly, mDC homing from blood to lungs has been described in COVID-19 patients (Sánchez-Cerrillo et al., J Clin Invest 2020).
Another key age-related immune defect is the phenomenon called inflammaging, a persistent increase in basal pro-inflammatory phenotype found in the elderly (Franceschi et al., Trends Endocrinol Metab 2017). Monocytes are one of the principal players of inflammation, which is a critical factor in COVID-19 progression, where monocyte-driven cytokine storm induces a hyper-inflammatory phenotype leading to a more severe symptomatology in COVID-19 patients (Vanderbeke et al., Nat Commun 2021). It is remarkable, that previous studies described the role of inflammatory monocytes in the suppression of vaccine responses (Mitchell et al., J Immunol 2012).
The study presented at CROI 2022 (Vitallé et al., Abstract 298) described the major immune alterations in old people associated to a lower response to the SARS-CoV-2 BNT162b2 mRNA vaccine. A cohort of vaccinated healthy elderly people (median 73 years) was studied and compared with a young population (median, 29 years). Old people showed thymic dysfunction and subsequent alteration of T-cell homeostasis, impaired DC homing and function and monocyte-mediated pro-inflammatory profile; factors that were associated to a lower SARS-CoV-2 vaccine response. The reversal of these immune defects in the elderly through specific adjuvants or other immunotherapeutic approaches might be important for the improvement of the current vaccination strategies and for the development of more efficient prototypes with a superior polyfunctional SARS-CoV-2 specific humoral and cellular response.
Joana Vitallé and Ezequiel Ruiz-Mateos
Institute of Biomedicine of Seville
Virgen del Rocío University Hospital
Spanish National Research Council (CSIC)