The CMV vaccine is on the NIH list of the "most promising medical advance of 2013
Clinical Studies (studies involving people)
CMV Pilot Study
CMV seroprevalence and feasibility of CMV-vectored prophylactic immunization trial - IRB# STUDY00015598
Principal Investigator: M. Curlin
Study Clinician: K. Simpson
Funding: Bill & Melinda Gates Foundation
In this Pilot study, OHSU researchers hope to learn more about natural infection with a common virus called cytomegalovirus, or CMV. Knowing more about how often people are exposed to CMV in the community will help us prepare for future vaccine studies in which CMV is used as part of a vaccine to prevent infections such as HIV and tuberculosis.
The goal of this research study is to help researchers learn:
- The percentage of persons exposed to CMV
- How likely spouses or partners are to have the same exposure status;and
- The percentage of people that would be eligible to participate in future vaccine studies.
If you are interested in learning more about the study, including how to participate, please visit the study web site at www.ohsu.edu/vaccineresearch. You may also contact a recruitment coordinator at 503-494-0076, or by e-mail at email@example.com to find out more information and to see if you qualify to participate.
HIV Vaccine study
CMV seroprevalence and feasibility of CMV-vectored prophylactic immunization trial - pending
Principal Investigator M. Curlin
Study Clinician: K. Simpson
Funding: Bill & Melinda Gates Foundation
Status: Anticipated start 2017
Pre-clinical studies (laboratory studies)
L. Picker, S. Hansen, M. Axthelm, K. Früh, J. Nelson, J. Sacha , P. Caposio, D. Streblow, V. DeFilippis, H. Park, A. Okoye
A central program of the VGTI is the development of Cytomegalovirus (CMV) as a novel vector platform. The spectacular success of CMV vectors in protecting monkeys against highly virulent SIV has put CMV-vectored vaccines at the forefront of AIDS vaccine development. These results have received world-wide attention and the VGTI has been able to secure extensive funding from private foundations and the NIH to further the clinical development of this platform. We expect this program to continue to flourish and increase. We also anticipate the clinical development of these vectors will require increased investment in GMP manufacturing infrastructure.
This success is a direct result of multiple research groups at the VGTI contributing their strengths and expertise to this program:
- L. Picker is the director of this program and responsible for the overall scientific direction.
- S. Hansen is responsible for the non-human primate immunological analysis of CMV-vectors
- M. Axthelm is in charge of non-human primate veterinary care
- K. Früh is the co-director of the CMV vector program particularly with respect to vector design and manufacturing. Dr. Früh also heads the VGTI spinoff company TomegaVax and part of this work is funded via a phase II SBIR to TomegaVax with Eric Bruening PhD (COO) as Principal Investigator.
- J. Nelson is responsible for the improved vector design and testing of 2nd generation vectors
- P. Caposio is in charge of manufacturing and testing vectors in humanized mouse models
- D. Streblow directs research towards understanding the role of viral chemokines in tropism and T cell priming
- V. DeFilippis is responsible for optimizing vector manufacturing by developing production cell lines
- J. Sacha directs research towards understanding immunological principles that govern CMV-vector induced T cell priming
L. Picker, S. Hansen, M. Axthelm, K. Früh, J. Nelson, P. Caposio
The Bacille Calmette-Guérin (BCG) vaccine, created in 1921, is the only existing vaccine against TB. Unfortunately, it only provides some protection against severe forms of pediatric TB, but is unreliable against adult pulmonary TB which accounts for most of the disease burden worldwide. The world-wide reemergence of TB, including multi-drug resistant TB renders the development of novel TB vaccines a high priority for global health. We have demonstrated in rhesus macaques that CMV-vectored TB vaccines are far superior to BCG in limiting disease, dissemination and ultimately death, of immunized animals. Based on these highly encouraging results, we are advancing these studies in rhesus macaques including pre-clinical work in preparation for clinical development.
K. Früh, L. Picker, S. Hansen, M. Axthelm
Malaria is a global burden with >600,000 deaths, most of them children, and with >200 million clinical cases annually. Malaria can be prevented through a combination of chemoprophylaxis and personal protection measures. However, both require strict compliance and chemoprophylaxis cannot be used over longer periods of time. The development of a vaccine against malaria is therefore one of the highest priorities for global health research. Since it is known that cellular immunity to the pre-erythrocytic stage of the malaria parasite can provide sterile immunity against Plasmodium parasites there is a very strong rationale for using CMV-vectors in malaria vaccine development. In collaboration with the Naval Medical Research Center (NMRC) in Bethesda we performed a pilot study using CMV vectors to express a mixture of pre-erythrocytic and erythrocytic antigens in rhesus macaques. Preliminary results suggest that CMV-vectored malaria vaccines were able to reduce the pre-erythrocytic parasite burden. Based on these encouraging results we now applied for Department of Defense funding for continuation of this program. We are also in discussion with the malaria vaccine initiative (MVI/PATH). We anticipate that this program will grow over the coming years depending on funding success.
S. Wong, K. Früh, L. Picker, S. Hansen, M. Axthelm
KS caused by a gamm-2 herpesvirus (KSHV) and is the leading cancer in sub-saharan Africa. Funded by an NIH R21 exploratory grant, Dr. Wong and his collaborators are currently exploring in the rhesus rhadinovirus model whether CMV-vectors can prevent RRV-induced B cell hyperplasia. Depending on the outcome of this pilot experiment, we are appling for additional grants to further develop this program.
Cervical Cancer Vaccine
K. Früh, L. Picker, S. Hansen, M. Axthelm
While there is a prophylactic vaccine against human papillomavirus (HPV) the causative agent of cervical cancer, this vaccine is unable to clear HPV once the infection has been established, leaving infected women at risk for the development of cervical cancer. With funding by TomegaVax (SBIR) and by the Oregeon Nanotechnology and Microtechnologies Institute (Onami), we explore whether CMV-vectored HPV vaccine can prevent tumor formation in murine models and induce T cells in the cervix of female macaques. If successful, we will seek industry funding to develop a CMV-based therapeutic HPV vaccine.
Prostate Cancer Vaccine
D. Streblow, K. Früh, L. Picker, S. Hansen, M. Axthelm
A therapeutic vaccine against prostate cancer developed by Dendreon was the first cancer vaccine ever to be approved. The vaccine is expensive, difficult to generate and it does not provide the durable protection needed in a post-op setting. With a pilot grant from the Knight Cancer Institute we are currently examining whether CMV-vectors carrying the rhesus equivalent of the Dendreon antigen are able to elicit T cell responses to this self-antigen in rhesus macaques. If successful, we will seek funding from the NCI and other sources to develop a CMV-based cancer vaccine
Genital Herpes Vaccine
D. Streblow, K. Früh, L. Picker, S. Hansen, M. Axthelm, P. Caposio, J. Nelson
An approved vaccine for genital herpes is currently not available. Funded by TomegaVax (STTR as well as industry funding) Dr Streblow determines whether CMV vectors can protect against HSV2 in murine models. Using a novel HCMV vector platform (VGTI-1) developed by P. Caposio and J. Nelson with funding from TomegVax (SBIR), Drs Früh and Hansen further determine whether VGTI-1-vectored HSV2 vaccines induce lasting immune responses in the female genital tract of rhesus macaques. Our plan is to develop a CMV-based, therapeutic genital herpes vaccine using industry funding.
J. Sacha, K. Früh, L. Picker, S. Hansen, M. Axthelm
The reason why flu vaccines need to be given every year is that antibody responses are highly strain specific and short-lived. In contrast, the long-lived T cell responses induced by CMV vectors might overcome this problem. To determine whether T cells induced by CMV can prevent highly pathogenic flu in non-human primates, we will test CMV vectors against 1918 flu, a highly virulent virus that sickened and killed millions and is highly pathogenic in monkeys.
Other Exploratory CMV Vaccines
We are in the process of generating preliminary data for grant submissions using CMV vectors against the following diseases;each of these diseases has a strong rationale for testing CMV vectors and, except for HBV (note the HBV vaccine only works to prevent infection but cannot eradicate established infections), there are currently no approved vaccines:
- Chikungunya Virus (CHIKV) D. Streblow, V. DeFilippis
- Chagas disease D. Streblow
- Dengue Virus J. Nelson
- Hepatitis B K. Früh
- Hepatitis C J. Nelson
CMV Disease Program
The CMV disease program encompasses basic science questions concerning mechanisms of viral persistence, replication and latency as well as animal model development to understand viral pathogenesis as describe in the following programs:
HCMV miRNA Regulation of Latency, Secretion, and Virion Maturation
J. Nelson. P. Caposio, R. Skalsky
Regulation of how the HCMV (Human cytomegalovirus) miRNAs target several members of the IL-1 and TNFa signaling pathways leading to NFkB activation, is a critical determinant of whether HCMV reactivates or remains latent. This project characterizes the role of these miRNAs in targeting NFkB activation in invitro and humanized mouse models (see below). We have initially observed that deletion of two of these miRNAs results in a virus that can establish latency but cannot reactivate. These results may be important for the generation of an HCMV vaccine vector that is safe. In addition, the HCMV encoded miRNAs target cellular genes in the secretory pathway that affect three important processes during viral infection. Using this information we are designing an HCMV vaccine vector that lacks the HCMV miRNAs that mediate these processes with the expectation that we can increase immunity to antigens inserted into these vectors by increasing cell surface MHC I, as well as, inflammatory cytokines besides attenuating the virus.
Generation of a Humanized Mouse Model to Study HCMV Latency, Reactivation, and Immune Response
P. Caposio, D. Streblow, William Flemming (Hematology), Morgan Hakki (Infectious Disease) and J. Nelson
HCMV remains a serious complication in patients receiving allogeneic hematopoietic stem-cell transplantation (HSCT). Myeloid lineage cells are one of the cellular reservoirs of latent HCMV and many groups have established in vitro cell systems to examine mechanisms of viral latency. Although these in vitro myeloid systems have proved useful to explore HCMV latency, an animal model is needed to assess the relevance of these findings. We have reported the first humanized mouse model in which human CD34+ hematopoietic progenitor cells (HPCs) engrafted NOD-scidIL2Rc null (NSG) mice infected with HCMV can support a latent viral infection. Moreover, we have shown that HCMV reactivates in human macrophages following G-CSF-induced mobilization of bone-marrow hematopoietic cells. These data recapitulate observations made in bone marrow transplant patients receiving G-CSF mobilized cells from HCMV seropositive donors. These observations also provide definitive evidence that CD34+ HPCs and monocytes harbor latent HCMV that results in dissemination and increased expression of virus in macrophages upon differentiation. The model is being used to analyze mechanisms of reactivation in HSCT patients as well as potential cellular sources of latent virus in collaboration with Harv Flemming (Knight Cancer Institute) and Morgan Hakki (Infectious Disease) and to study characteristics of growth persistence and immune response of the HCMV/HIV vaccine.
Role of CMV in the Acceleration of Transplant Vascular Sclerosis in Solid Organ Transplant Patients
D. Streblow and Susan Orloff (Liver Transplantation)
Approximately 75% of the solid organ donor/recipient population is infected with HCMV. As such, the majority of transplant recipients are themselves HCMV positive and/or receive infected donor allografts, which makes it very difficult to avoid this important problem. However, the viral mechanisms involved in HCMV reactivation from latency and subsequent acceleration of vascular disease and rejection are unknown. To date no vaccine exists to prevent CMV-disease and resistance to antiviral therapeutics renders them less effective in the clinic. To address this, we are characterizing CMV immunity and identifying biomarkers of CMV-induced rejection in a human cardiac transplant cohort at OHSU. We have established a rat heart transplant model of CR that closely recapitulates this human transplant scenario. In the model, RCMV infection significantly accelerates the time to develop CR and increases the degree of transplant vascular sclerosis (TVS). This represents a unique and powerful animal model that allows us to define the critical host and viral mechanisms that drive the vascular disease associated with CR.