A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial

Kharfan‐Dabaja, Mohamed A.; Boeckh, Michael; Wilck, Marissa B.; Langston, Amelia; Chu, Alice; Wloch, Mary K.; Guterwill, Don F; Smith, Larry; Rolland, Alain; Kenney, Richard T.

doi:10.1016/s1473-3099(11)70344-9

Cited by 217 publications

(178 citation statements)

References 29 publications

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“…Similar findings have been observed in heart transplant recipients with initial low levels of anti‐CMV T cell immunity that failed to develop protective immune responses following transplantation, resulting in increased frequency of CMV reactivation 39. Results from these human studies indicate the potential benefit of a CMV vaccine in reducing viral reactivation in patients with functional pretransplant antiviral immune responses, which wane after transplant 22. We chose to focus on the vaccine‐associated impact on CMV‐specific antibody responses since passive transfer of antiserum was highly efficacious.…”

Section: Discussionsupporting

confidence: 65%

Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts

Streblow¹,

Hwee

Kreklywich³

et al. 2015

American Journal of Transplantation

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Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV‐accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV‐naïve or H2O2‐inactivated RCMV‐vaccinated Lewis recipients. Recipients of RCMV‐infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection‐POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naïve recipients demonstrate that both T‐cell and B‐cell arms of the adaptive immune response provide protection against CMV‐accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti‐viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival.

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Section: Discussionsupporting

confidence: 65%

Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts

Streblow¹,

Hwee

Kreklywich³

et al. 2015

American Journal of Transplantation

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“…Though the primary endpoint of the study, the reduction of CMV viraemia requiring CMV-specific antiviral therapy, was not reached, there was a reduction in CMV viraemia episodes, defined as CMV copies >500/mL in the blood, in the vaccine arm. The immunogenicity analysis showed a statistically not significant increased rate of pp65, IFN-gamma producing T-cells in the vaccine cohort without a clear involvement of the B-cell compartment [118,119].…”

Section: Vaccinesmentioning

confidence: 77%

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

Madon

Giaccone

Festuccia

et al. 2016

Expert Review of Hematology

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“…A possible avenue for generation of suitable immunity might be to use DNAbased vaccines, which encode key antigens that can prime both B and T cells prior to gB [77]. In Phase II trials, this priming approach in combination with live boosting was shown to reduce HCMV viremia and also to increase the production of memory HCMV-specific antibodies [62,63]. To our knowledge, the DNA priming approach followed by gB/MF59 boosting has not been attempted.…”

Section: Hcmv-seropositive Adult Womenmentioning

confidence: 99%

“…Further trials of a DNA vaccine encoding HCMV gB and pp65 were performed in hematopoietic stem cell transplant patients. Results showed that the vaccine was well tolerated and reduced the occurrence and recurrence of HCMV viremia [63]. A brief summary of these trials is shown in Table 1.…”

mentioning

confidence: 98%

Human Cytomegalovirus Vaccination: Progress and Perspectives of Recombinant gB

Manghera

McLean

2016

Future Virol.

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A vaccine for Human cytomegalovirus (HCMV) remains a high priority as complications following infection are observed in immunocompromised individuals and in congenitally infected neonates. Numerous preclinical and clinical studies have investigated vaccine strategies ranging from live attenuated preparations, nucleic acid-based approaches and recombinant delivery systems to subunit vaccines. These have defined the importance of both cell-mediated and humoral immunity to viral gB in the control of HCMV infection. This review will cover clinical trials investigating vaccine approaches that have incorporated gB and discuss the future perspectives of the recombinant gB subunit vaccine for HCMV. BackgroundHuman cytomegalovirus (HCMV) is a ubiquitous pathogen, known to infect all human populations worldwide [1]. It is an enveloped dsDNA virus that is the largest member of the Herpesviridae family that also includes important pathogens, such as HSV-1 and HSV-2, EBV and varicella zoster virus (VZV), all of which are widespread in human populations [2]. The HCMV genome is approximately 230 kbp encoding 200-250 open reading frames, many of which facilitate immune evasion [3]. A recent study of the HCMV genome and translation products has suggested that it may be even more complex than anticipated with regulation of alternate transcripts allowing for numerous polypeptides to be expressed [4]. Transmission of HCMV predominantly occurs via body fluids, such as saliva, blood, urine and breast milk, leading to contact of the mucosal surfaces, primarily infecting epithelial and endothelial cells, followed by dissemination to numerous organs and tissues [5]. HCMV is, therefore, able to infect a wide range of cells including endothelial cells, epithelial cells, fibroblasts, smooth muscle cells, leukocytes and dendritic cells [5,6]. Similarly to other Herpesviridae family members, HCMV is capable of both lytic and latent infections [7], but primary infection and reactivation from latency are often asymptomatic in immunocompetent individuals [8]. HCMV infection and reactivation in both solid organ and hematopoietic stem cell transplant recipients, and fetal exposure in utero poses a major threat. Immunocompromised individuals, including AIDS patients [9,10] and transplant patients [11,12], are at increased risk of both reactivation or reinfection, and primary HCMV infection has serious consequences for the developing fetus in pregnant women [8]. It is estimated that HCMV congenital infection occurs in 0.5-2% of all annual pregnancies [13], and approximately 10% of infants with congenital HCMV infection present with clinical manifestations at birth, such as hearing loss and neurological developmental defects [14]. Additionally, late-onset hearing disorders can occur with both symptomatic and asymptomatic congenital infection, which [17], which may also be effective in treating congenital infections [18]. Based on the widespread prevalence of HCMV, limited treatment options and the potential for significant morbidity, an effective ...

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A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial

Abstract: Vical and US National Institute of Allergy and Infectious Diseases.

Cited by 217 publications

References 29 publications

Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts

Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

Human Cytomegalovirus Vaccination: Progress and Perspectives of Recombinant gB

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