Phase 1 Clinical Trial of a Conditionally Replication-Defective Human Cytomegalovirus (CMV) Vaccine in CMV-Seronegative Subjects

Abstract

Background A conditionally replication-defective human cytomegalovirus (CMV) vaccine (V160) derived from AD169 and genetically engineered to express CMV pentameric complex (gH/gL/pUL128/pUL130/pUL131) was developed and evaluated for phase 1 vaccine safety and immunogenicity in CMV-seronegative and CMV-seropositive adults. Methods Subjects received 3 doses of V160 or placebo on day 1, month 1, and month 6. Four vaccine dose levels, formulated with or without aluminum phosphate adjuvant, were evaluated. Injection-site and systemic adverse events (AEs) and vaccine viral shedding were monitored. CMV-specific cellular and humoral responses were measured by interferon-gamma ELISPOT and virus neutralization assay up to 12 months after last dose. Results V160 was generally well-tolerated, with no serious AEs observed. Transient, mild-to-moderate injection-site and systemic AEs were reported more frequently in vaccinated subjects than placebo. Vaccine viral shedding was not detected in any subject, confirming the nonreplicating feature of V160. Robust neutralizing antibody titers were elicited and maintained through 12 months postvaccination. Cellular responses to structural and nonstructural viral proteins were observed, indicating de novo expression of viral genes postvaccination. Conclusions V160 displayed an acceptable safety profile. Levels of neutralizing antibodies and T-cell responses in CMV-seronegative subjects were within ranges observed following natural CMV infection. Clinical Trial Registration . NCT01986010.

A conditionally replication-defective cytomegalovirus vaccine elicits potent and diverse functional monoclonal antibodies in a phase I clinical trial

“…V160 is an experimental vaccine that is genetically modified from AD169 strain with the restored pentamer 27 , 28 . V160 has been evaluated in phase I clinical trial for safety and immunogenicity in both HCMV-seropositive and seronegative healthy subjects 29 . The vaccine can effectively elicit humoral immune responses qualitatively analogous to those of natural infection as assessed by measuring serum-neutralizing titers longitudinally after vaccination 29 , 30 .…”

“…V160 has been evaluated in phase I clinical trial for safety and immunogenicity in both HCMV-seropositive and seronegative healthy subjects 29 . The vaccine can effectively elicit humoral immune responses qualitatively analogous to those of natural infection as assessed by measuring serum-neutralizing titers longitudinally after vaccination 29 , 30 . However, the vaccine-induced humoral immune responses have only been analyzed as polyclonal immune sera.…”

Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy

“…A CMV vaccine candidate (V160) incorporating the pentameric complex was constructed from the live attenuated CMV AD169 strain that was further engineered to be replication-defective in the absence of a synthetic compound called Shield-1 [100]. Recently, this vaccine was found to be safe and elicited robust levels of neutralizing antibodies and T cell responses when administered to CMV-seronegative subjects in a phase 1 study [101,102]. Several other candidate vaccines are currently being evaluated in phase 1 and 2 trials in adult and pediatric HCT recipients [96].…”

Human Cytomegalovirus Congenital (cCMV) Infection Following Primary and Nonprimary Maternal Infection: Perspectives of Prevention through Vaccine Development

“…This replication-defective HCMV vaccine was named V160 and was shown to be immunogenic in several animal species [16,131]. In a Phase I study in seronegative subjects, the V160 vaccine was safe, well tolerated, and induced NAb as well as T-cell responses within the different ranges of natural immunity [132]. In April 2018, a double-blind, randomized, placebo-controlled Phase 2b, multi-center clinical trial was started under the sponsorship of Merck SD Corporation to evaluate the safety, tolerability, efficacy, and immunogenicity of a 2-dose and 3-dose regimen of V160 vaccine in healthy seronegative women 16-35 years of age.…”