<p>Disrupted sleep is increasingly recognized as a factor influencing vaccine efficacy, yet the mechanisms by which sleep disruption affects vaccine-induced immunity remain incompletely understood. Sleep fragmentation, a hallmark of several common sleep disorders, may interfere with immune processes required for effective vaccination. Here, we show that chronic sleep fragmentation (CSF) markedly impairs immune responses to influenza vaccination. In a mouse model, two weeks of CSF before and during influenza vaccination significantly compromises antibody responses and reduces protection against lethal challenge, with lower neutralizing antibody titers, diminished IgG subclass responses, and decreased survival despite preserved antibody avidity. Single-cell RNA sequencing revealed transcriptional signatures associated with altered B cell maturation, impaired germinal center programs, and stress in antibody-producing plasma cells, including activation of unfolded protein response and oxidative stress pathways, alongside altered interactions between B and T cells. Clinically, analysis of 916,307 influenza-vaccinated adults shows that obstructive sleep apnea, a disorder characterized by recurrent sleep fragmentation, is associated with a higher risk of influenza infection than matched controls (0.7% vs. 0.4%; risk ratio 1.70). Taken together, this study demonstrates that CSF compromises vaccine-induced immune responses and highlights sleep health as a modifiable determinant of vaccine-associated protection.</p>