Dynamics of adaptive natural killer cells in longitudinal analysis of CMV vaccine recipients

Abstract

Abstract Classical vaccine efforts focusing on the induction of B- and T-cell memory have proven ineffective in the protection against pathogens such as cytomegalovirus (CMV). Thus, CMV remains a significant public health threat. There is clear evidence that patients lacking natural killer (NK) cells suffer recurrent, severe infections with multiple herpesviruses, including CMV, highlighting the importance of NK cells in controlling this pathogen. In addition, several studies describe the expansion and persistence of phenotypically and functionally distinct murine (Ly49H+) and human (NKG2C+, FcRγneg, EAT-2neg, SYKneg) NK-cell subsets with putatively enhanced antiviral effector function upon CMV infection. Therefore, one potentially pioneering approach to creating an efficacious CMV vaccine would include the induction of such NK cell adaptations. To test this, we used longitudinal PBMC samples collected during a vaccine trial with HCMV gB in MF59 adjuvant administered to CMV negative adolescent females. We observed several patterns of transient and sustained elevations in the frequency of FcRγneg, EAT-2neg, and SYKneg subsets at various time points despite absence of detectable CMV infection in any trial participants. Surprisingly, these patterns were apparent in participants regardless of administration of vaccine or placebo. In contrast to previous cross-sectional studies, we present evidence that these CMV-reactive adaptive NK cells exhibit continuous oscillations in the blood of CMV negative individuals, suggesting that they may react to unknown environmental or inflammatory cues.