Individuals lacking functional natural killer (NK) cells suffer severe, recurrent infections with cytomegalovirus (CMV), highlighting the critical role of NK cells in antiviral defense. The goal of a new study published in Frontiers in Immunology was to elicit natural killer (NK)-cell antiviral responses as an accessory to conventional T- and B-cell based approaches.This longitudinal study examined blood samples collected from 40 CMV-seronegative adolescents to ascertain whether a CMV glycoprotein B (gB) vaccine, in the absence of CMV infection, can stimulate differentiation or expansion of CMV-associated subsets of NK cells. The findings revealed that participants uniformly lacked the CMV-dependent NKG2C+ subset of NK cells, suggesting that an adjuvanted CMV gBvaccine alone is an inadequate stimulus for sustained expansion of these cells. On the other hand, unexpected dynamic fluctuations in the frequency of NK cells lacking FcRγ, EAT-2 and SYK were observed, which were independent of vaccination or CMV infection. Meanwhile, FcRγ^neg NK cells in CMV infection are reported to express increased levels of the maturation marker CD57, the FcRγ^neg NK cells observed with CMV-negative vaccine cohort—express less CD57 than their FcRγ+ counterparts. The FcRγneg NK cells in CMV-negative individuals were also functionally distinct from this subset in CMV infection, exhibiting comparable IFN-γ production and degranulation as FcRγ⁺ NK cells in response to cytokine or antibody-dependent stimuli. The findings suggested that frequencies of some NK cell subsets may increase in response to unknown environmental or inflammatory signals, distinct from that which occurs after CMV infection. It was stated that a greater understanding of the nature of the signals driving CMV-independent accumulation of these subsets should permit development of mechanisms to facilitate vaccine-driven expansion of CMV-reactive NK cells.