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. Expected final online publication date for the Annual Review of Virology, Volume 9 is September 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Primary, Secondary, and Tertiary Prevention of Congenital Cytomegalovirus Infection

“…These indicate not only that the immunity naturally induced by the virus is not perfect to protect against re-infection [83], but also that the immune correlates of protection (CoPs) are still unclear, leading to major difficulties for researchers to obtain potent neutralizing antibodies (NAbs) [84]. Therefore, in order to maximize the effectiveness of vaccine protection, researchers should consider exploiting both the precepts of innate and adaptive immunity [85]. Indeed, a global understanding and analysis of the mechanisms related to the immune responses developed during CMV infection, such as its replication mode or the ability of the virus to evade certain immune responses, would allow the identification of protective immunity components, thereby opening the possibility to mimic these immune responses through induced immunization [85].…”

“…Therefore, in order to maximize the effectiveness of vaccine protection, researchers should consider exploiting both the precepts of innate and adaptive immunity [85]. Indeed, a global understanding and analysis of the mechanisms related to the immune responses developed during CMV infection, such as its replication mode or the ability of the virus to evade certain immune responses, would allow the identification of protective immunity components, thereby opening the possibility to mimic these immune responses through induced immunization [85].…”

“…Innate immune responses include the natural killer (NK) cell response, which is the first line of defense against viral infection by allowing rapid antiviral functions to be performed by the host [84][85][86]. Currently, in the context of CMV infections, these cells are the best documented innate memory response on the subject [84].…”

“…Currently, in the context of CMV infections, these cells are the best documented innate memory response on the subject [84]. Conventional vaccination uses humoral and cellular responses mediated by B and T lymphocytes to provide protection against the virus [83,85]. In addition, responses developed during natural infection can block infection of different cell types, making NAb induction a major target for vaccine development [87,88].…”

Multivalent Human Cytomegalovirus Glycoprotein B Nucleoside-Modified mRNA Vaccines Demonstrate a Greater Breadth in T cell but not Antibody Responses

“…T cell immunity is crucial for controlling HCMV infection as well as generating broad antibody response, which is commonly assessed as a part of the immunogenicity of HCMV vaccine candidates 46,47 . Thus, a broad T cell response across gB genotype strains would also be desirable in HCMV vaccine candidates.…”