Immune Correlates of Protection Against Human Cytomegalovirus Acquisition, Replication, and Disease

Abstract

Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects and an etiology of significant morbidity and mortality in solid organ and hematopoietic stem cell transplant recipients. There is tremendous interest in developing a vaccine or immunotherapeutic to reduce the burden of HCMV-associated disease, yet after nearly a half-century of research and development in this field we remain without such an intervention. Defining immune correlates of protection is a process that enables targeted vaccine/immunotherapeutic discovery and informed evaluation of clinical performance. Outcomes in the HCMV field have previously been measured against a variety of clinical end points, including virus acquisition, systemic replication, and progression to disease. Herein we review immune correlates of protection against each of these end points in turn, showing that control of HCMV likely depends on a combination of innate immune factors, antibodies, and T-cell responses. Furthermore, protective immune responses are heterogeneous, with no single immune parameter predicting protection against all clinical outcomes and stages of HCMV infection. A detailed understanding of protective immune responses for a given clinical end point will inform immunogen selection and guide preclinical and clinical evaluation of vaccines or immunotherapeutics to prevent HCMV-mediated congenital and transplant disease.

Keywords: Cytomegalovirus; immune correlate; vaccine.

Figure 1.

Antibody-dependent, nonneutralizing functions that may have contributed to gB/MF59 vaccine efficacy. A, Complement-dependent cytotoxicity (CDC). Antibodies bind to viral proteins on the surface of infected cell, then are cross-linked by c1q. This action causes an enzymatic cascade, culminating in the assembly of the membrane attack complex in the infected cell membrane. B, Antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent respiratory burst (ADRB), results from antibody binding a viral protein on an infected cell, then engaging the Fc receptor on an immune effector cell. This immunologic bridge triggers release of cytotoxic granules, which destroy the infected cell. C, Antibody-dependent cellular phagocytosis (ADCP) occurs when an antibody binds a virion then engages the Fc receptor on a phagocyte, triggering engulfment (and presumed destruction) of the virion. Abbreviations: DCs, dendritic cells; NK, natural killer.