Significance: Immunity induced by the first-generation COVID-19 vaccines may not provide effective and durable protection, either due to waning immunity or due to poor antibody cross-reactivity to new variants. Typically, T cells recognize conserved nonmutable viral epitopes and development of T cell–based vaccines might provide broad immunity to SARS-CoV-2 variants. In this study, we show that adjuvanted spike protein–based experimental vaccines elicited potent respiratory or systemic CD4 and CD8 T cell memory and protected against SARS-CoV-2, in the absence of virus-neutralizing antibodies. Thus, development of T cell–based vaccines might be key to protect against antibody-escape SARS-CoV-2 variants that can potentially overcome immunity induced by current vaccines.

Although SARS-CoV-2 evolution seeds a continuous stream of antibody-evasive viral variants, COVID-19 mRNA vaccines provide robust protection against severe disease and hospitalization. Here, we asked whether mRNA vaccine–induced memory T cells limit lung SARS-CoV-2 replication and severe disease. We show that mice and humans receiving booster BioNTech mRNA vaccine developed potent CD8 T cell responses and showed similar kinetics of expansion and contraction of granzyme B/perforin-expressing effector CD8 T cells. Both monovalent and bivalent mRNA vaccines elicited strong expansion of a heterogeneous pool of terminal effectors and memory precursor effector CD8 T cells in spleen, inguinal and mediastinal lymph nodes, pulmonary vasculature, and most surprisingly in the airways, suggestive of systemic and regional surveillance. Furthermore, we document that: (a) CD8 T cell memory persists in multiple tissues for > 200 days; (b) following challenge with pathogenic SARS-CoV-2, circulating memory CD8 T cells rapidly extravasate to the lungs and promote expeditious viral clearance, by mechanisms that require CD4 T cell help; and (c) adoptively transferred splenic memory CD8 T cells traffic to the airways and promote lung SARS-CoV-2 clearance. These findings provide insights into the critical role of memory T cells in preventing severe lung disease following breakthrough infections with antibody-evasive SARS-CoV-2 variants.

Highly pathogenic avian influenza (HPAI) is a lethal disease of poultry that has recently spilled over into mammals, including dairy cattle and humans, heightening concerns for livestock health, food security, and pandemic emergence. While vaccines that induce neutralizing antibodies against hemagglutinin and neuraminidase provide strain-specific protection, durable cross-subtype immunity requires T-cell responses targeting conserved internal antigens such as nucleoprotein (NP). To leverage these conserved targets, we utilized a previously engineered mosaic nucleoprotein (MNP) incorporating T-cell epitopes from thousands of influenza A virus (IAV) strains, conferring broad protection against epidemic (H3N2) and pandemic (H1N1) IAV in mice. Here, we tested whether precision adjuvancy could differentially imprint adaptive immunity to MNP in cattle. Combination formulations paired the carbomer-based nano-emulsion Adjuplex (ADJ) with either a STING agonist (cyclic dinucleotides; CdN) or a TLR4 agonist (glucopyranosyl lipid A; GLA) to program distinct inflammatory milieus. Both formulations elicited circulating IFN-γ–producing T cell responses and NP-specific antibodies in serum and milk. However, STING activation via CdN generated more potent and consistent cellular and humoral immunity than TLR4 engagement. These data demonstrate that selective activation of innate sensing pathways functionally imprints adaptive immune magnitude and quality in a large animal host. By advancing a broadly protective, T-cell-focused vaccine strategy in cattle, this work supports a One Health framework to mitigate H5N1 transmission risk at the human–animal interface.