The immunological underpinnings of vaccinations to prevent cytomegalovirus disease

Abstract

A universal cytomegalovirus (CMV) vaccination promises to reduce the burden of the developmental damage that afflicts up to 0.5% of live births worldwide. An effective vaccination that prevents transplacental transmission would reduce CMV congenital disease and CMV-associated still births and leave populations less susceptible to opportunistic CMV disease. Thus, a vaccination against this virus has long been recognized for the potential of enormous health-care savings because congenital damage is life-long and existing anti-viral options are limited. Vaccine researchers, industry leaders, and regulatory representatives have discussed the challenges posed by clinical efficacy trials that would lead to a universal CMV vaccine, reviewing the links between infection and disease, and identifying settings where disrupting viral transmission might provide a surrogate endpoint for disease prevention. Reducing the complexity of such trials would facilitate vaccine development. Children and adolescents are the targets for universal vaccination, with the expectation of protecting the offspring of immunized women. Given that a majority of females worldwide experience CMV infection during childhood, a universal vaccine must boost natural immunity and reduce transmission due to reactivation and re-infection as well as primary infection during pregnancy. Although current vaccine strategies recognize the value of humoral and cellular immunity, the precise mechanisms that act at the placental interface remain elusive. Immunity resulting from natural infection appears to limit rather than prevent reactivation of latent viruses and susceptibility to re-infection, leaving a challenge for universal vaccination to improve upon natural immunity levels. Despite these hurdles, early phase clinical trials have achieved primary end points in CMV seronegative subjects. Efficacy studies must be expanded to mixed populations of CMV-naive and naturally infected subjects to understand the overall efficacy and potential. Together with CMV vaccine candidates currently in clinical development, additional promising preclinical strategies continue to come forward; however, these face limitations due to the insufficient understanding of host defense mechanisms that prevent transmission, as well as the age-old challenges of reaching the appropriate threshold of immunogenicity, efficacy, durability and potency. This review focuses on the current understanding of natural and CMV vaccine-induced protective immunity.

Production of Cytomegalovirus Dense Bodies by Scalable Bioprocess Methods Maintains Immunogenicity and Improves Neutralizing Antibody Titers

“…Cellular immunity is expected to be an important component of a successful HCMV vaccine (51)(52)(53). GT-DB induce a broad and robust T cell response (7).…”

Brain‐resident memory CD8+ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

“…However, HCMV infection or reactivation in immunocompromised or immunologically immature individuals can lead to severe or life-threatening disease (Ljungman et al, 2010, Kotton, 2010, Nigro and Adler, 2011). Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss (Dreher et al, 2014, McCormick and Mocarski, 2015, Boppana et al, 2013, Pati et al, 2013). HCMV is strictly species-specific virus; therefore, animal cytomegaloviruses are often used to investigate the immunobiology and pathogenesis of infection.…”

Congenital Cytomegalovirus Infection

“…Both T cell and antibody responses appear to be necessary to prevent congenital infection. [85][86][87] Initial vaccine studies began with attenuated laboratory strains of the virus (AD169 and Towne strains), but these could not match the levels of naturally acquired immunity. 84 Since that time, various vehicles have been explored for conferring immunity, including adjuvanted recombinant protein vaccines, vaccines using viral vectors or based on viruslike particles, or replication-impaired or replication-defective vaccines, and contemporary platforms such as dense body vaccines.…”