Lessons from Acquired Natural Immunity and Clinical Trials to Inform Next-Generation Human Cytomegalovirus Vaccine Development

Abstract

Human cytomegalovirus (HCMV) infection, the most common cause of congenital disease globally, affecting an estimated 1 million newborns annually, can result in lifelong sequelae in infants, such as sensorineural hearing loss and brain damage. HCMV infection also leads to a significant disease burden in immunocompromised individuals. Hence, an effective HCMV vaccine is urgently needed to prevent infection and HCMV-associated diseases. Unfortunately, despite more than five decades of vaccine development, no successful HCMV vaccine is available. This review summarizes what we have learned from acquired natural immunity, including innate and adaptive immunity; the successes and failures of HCMV vaccine human clinical trials; the progress in related animal models; and the analysis of protective immune responses during natural infection and vaccination settings. Finally, we propose novel vaccine strategies that will harness the knowledge of protective immunity and employ new technology and vaccine concepts to inform next-generation HCMV vaccine development.

Keywords: acquired natural immunity; animal model; clinical trial; human cytomegalovirus; immune correlates of protection; next-generation vaccine.

Figure 1

Schematic of next-generation HCMV vaccine development strategies. Dissection of protective immune responses during natural HCMV infection, the development of animal models, and lessons learned from human clinical trials led to our next-generation HCMV vaccine development proposal. These findings from iterative studies will further facilitate the highly relevant animal model development and a deep understanding of the protective immune component from both infection and vaccination settings to guide future HCMV vaccine development. Stepwise, hopefully, an effective HCMV vaccine will be licensed to the clinic by employing these strategies. Abbreviations: gB, glycoprotein B; HCMV, human cytomegalovirus; PC, pentamer complex. Figure adapted from images created with BioRender.com.

Figure 2

Schematic structure of HCMV and structural and antigenic domain mapping in the gB. (a) A simplified structural diagram of the HCMV virion. HCMV is a double-stranded DNA virus, with the genome encapsulated by capsid proteins. Many glycoprotein complexes are displayed on the surface of the virion, including gM/gN, and gH/gL heterodimers, the gH/gL/gO trimer, and the gH/gL/UL128/UL130/UL131a PC, viral Fc receptors, and the gB homotrimer. In addition, there are various tegument proteins between the capsid and viral envelope glycoproteins, including pp65. Focusing on an important immunogen and essential fusion protein, the prefusion (b) and postfusion (c) gB structures are shown (modeled after Reference 57) with domains colored to match each structural and antigenic domain shown in panel d. The domain map is based on the Towne strain. gB includes five structural domains (D-I through D-V) and five antigenic domains (AD-1 through AD-5). The signal sequence (S) is located at the N terminus before AD-2, which is composed of site 1 (S1) and site 2 (S2). Domains II, III, and IV are expressed nonlinearly, with a component of each domain expressed before Domain I and its two incorporated fusions loops. The furin cleavage site located near the middle of the amino acid sequence is noted with a black line. The MPR (blue), TM (maroon), and cytosolic domain are located toward the C terminus. Abbreviations: g, glycoprotein; HCMV, human cytomegalovirus; MPR, membrane-proximal region; PC, pentamer complex; TM, transmembrane. Figure adapted from images created with BioRender.com.