Triplex Vaccine for CMV Prevention Post-Stem Cell Transplant

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 100

Duration: 128 days

7 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well Triplex vaccine works in preventing cytomegalovirus (CMV) infection in patients undergoing a hematopoietic stem cell transplantation. CMV is a virus that may be carried for life and does not cause illness in most healthy individuals. However, in people whose immune systems are lowered (such as those undergoing stem cell transplantation), CMV can reproduce and cause disease and even death. The Triplex vaccine is made up of 3 small pieces of CMV deoxyribonucleic acid (DNA) (the chemical form of genes) placed into a weakened virus called modified vaccinia Ankara (MVA) that may help produce immunity (the ability to recognize and respond to an infection) and reduce the risk of developing complications related to CMV infection.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but certain medications are not allowed from the time of stem cell transplant to 70 days after. These include some antiviral drugs and live vaccines, so it's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the Triplex Vaccine for CMV prevention post-stem cell transplant?

Research shows that the Triplex Vaccine, which is designed to boost the body's immune response against cytomegalovirus (CMV), was well-tolerated and helped increase specific immune cells in patients who received a stem cell transplant. This suggests it could help prevent CMV reactivation, reducing the need for antiviral drugs. ^{1 2 3 4 5}

Is the Triplex Vaccine safe for humans?

The Triplex Vaccine has been tested in healthy adults and recipients of stem cell transplants, showing it is generally safe with no serious side effects related to the vaccine. Some mild and temporary reactions were observed, but overall, it was well-tolerated. ^{1 2 3 5 6}

What makes the Triplex Vaccine unique for CMV prevention after stem cell transplant?

The Triplex Vaccine is unique because it uses a modified vaccinia Ankara (MVA) virus to deliver three specific CMV antigens, which helps stimulate a strong and durable immune response against CMV. This approach is different from other treatments as it focuses on enhancing the body's own immune system to prevent CMV infection, rather than using antiviral drugs. ^{6 7 8 9 10}

Research Team

Ryotaro Nakamura, M.D.

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with certain blood cancers like leukemia and lymphoma, who are undergoing stem cell transplantation and are at risk of CMV infection. They must be CMV positive, agree to use contraception, and not have received any prior investigational CMV vaccines or treatments that could affect the immune system.

Inclusion Criteria

Participant must be willing to comply with study and/or follow-up procedures, including willingness to be followed for one year post-HCT

My leukemia is in an early or slightly advanced stage.

I have a blood cancer that is not multiple myeloma or aplastic anemia, as judged appropriate by the study's lead doctors.

Exclusion Criteria

I haven't taken immunosuppressive drugs for an autoimmune disease in the last 5 years.

My condition is advanced and includes CML in blast crisis, AML/ALL beyond 2nd remission, multiple myeloma, or aplastic anemia.

I have undergone specific treatments within 30 days before or up to 180 days after a stem cell transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive letermovir per standard of care on days 7-100 and either the Triplex vaccine or placebo on days 100 and 128 post-HCT

128 days

Multiple visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety, CMV reactivation, and other outcomes up to 365 days post-HCT

237 days

Regular monitoring visits, including qPCR tests every two weeks from Day 100 to Day 180

Long-term follow-up

Participants are followed for an additional 2 years post-HCT to assess long-term outcomes

2 years

Treatment Details

Interventions

• Letermovir
• Multi-peptide CMV-Modified Vaccinia Ankara Vaccine
• Placebo Administration

Trial Overview The study tests the Triplex vaccine's effectiveness in preventing CMV infection post-stem cell transplant. The vaccine contains three pieces of CMV DNA within a weakened virus to stimulate immunity against this potentially harmful virus in immunocompromised individuals.

Participant Groups

Group I: Arm I (letermovir, Triplex) Experimental Treatment 2 Interventions

Patients receive letermovir per SOC on days 7-100 and multi-peptide CMV-modified vaccinia Ankara vaccine IM on days 100 and 128 post-HCT.

Group II: Arm II (letermovir, placebo) Active Control 2 Interventions

Patients receive letermovir per SOC on days 7-100 and placebo IM on days 100 and 128 post-HCT.

Multi-peptide CMV-Modified Vaccinia Ankara Vaccine is already approved in United States, European Union for the following indications:

Approved in United States as Triplex Vaccine for:

• Prevention of clinically significant CMV viremia in transplant recipients

Approved in European Union as Triplex Vaccine for:

• Prevention of clinically significant CMV viremia in transplant recipients

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Vaccinating healthy donors with the Triplex vaccine before hematopoietic cell transplant (HCT) significantly increased levels of CMV-specific T cells in recipients, indicating enhanced immune protection against cytomegalovirus (CMV).

The Triplex vaccine was well-tolerated with minimal adverse events, and the approach shows promise for reducing the need for antiviral prophylaxis, which can hinder the development of CMV-specific immunity post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus-specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis. La Rosa, C., Aldoss, I., Park, Y., et al.[2023]

In a phase 2 trial involving 102 high-risk CMV-seropositive hematopoietic stem cell transplant recipients, the Triplex vaccine showed a trend towards reducing CMV reactivation, with 9.8% of Triplex recipients experiencing reactivation compared to 19.6% in the placebo group.

The Triplex vaccine was found to be safe, with no serious adverse events or deaths related to the vaccine, and it successfully increased levels of CMV-specific T cells, suggesting it effectively enhances the immune response against CMV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial. Aldoss, I., La Rosa, C., Baden, LR., et al.[2023]

The developed CMV vaccine, based on modified vaccinia Ankara (MVA), successfully expresses three key CMV antigens and shows strong immunogenicity, stimulating both primary and memory immune responses in mouse models.

In human studies, the vaccine effectively activates existing CMV-specific CD4(+) and CD8(+) T cell responses in healthy CMV-positive individuals and patients shortly after hematopoietic cell transplant, indicating its potential for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector. Wang, Z., Zhou, W., Srivastava, T., et al.[2022]

In a phase 2 clinical trial involving 20 patients with lymphoma or myeloma, the Triplex vaccine significantly enhanced the reconstitution of adaptive natural killer (NK) cells and CMV-specific T cells after autologous hematopoietic cell transplantation (auto-HCT), particularly in CMV-seronegative patients.

The vaccine led to a notable increase in adaptive NK cells and CMV-specific T cells, suggesting a potential for improved immune response post-transplant, although further research is needed to assess the clinical benefits of these immune enhancements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation. Rashidi, A., La Rosa, C., Curtsinger, J., et al.[2023]

The CMVPepVax vaccine demonstrated safety in a phase 1b trial with 36 CMV-seropositive patients undergoing stem-cell transplantation, showing no adverse effects on transplant outcomes or unexpected serious adverse events.

Patients receiving the CMVPepVax vaccine had significantly better relapse-free survival compared to those under observation, suggesting potential clinical benefits that warrant further investigation in a phase 2 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Nakamura, R., La Rosa, C., Longmate, J., et al.[2022]

The Triplex vaccine, which uses a modified vaccinia Ankara (MVA) platform to target three key cytomegalovirus (CMV) antigens, was found to be safe in a clinical trial involving 24 healthy adults, with no serious adverse events reported and only mild, transient side effects.

The vaccine successfully induced strong and lasting CMV-specific T-cell responses, even in individuals without prior immunity to CMV, suggesting its potential effectiveness for broader populations, including patients undergoing hematopoietic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults. La Rosa, C., Longmate, J., Martinez, J., et al.[2021]

Modified vaccinia Ankara (MVA) effectively infects human immune cells, particularly monocytes and dendritic cells, leading to strong activation and a Th-1-polarizing cytokine response, which is crucial for immunotherapy applications.

The interaction between MVA-infected leukocytes and uninfected immature dendritic cells results in the complete maturation of dendritic cells, enhancing their ability to stimulate T cells, suggesting a promising strategy for vaccine development and immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uptake of antigens from modified vaccinia Ankara virus-infected leukocytes enhances the immunostimulatory capacity of dendritic cells. Flechsig, C., Suezer, Y., Kapp, M., et al.[2020]

The modified vaccinia Ankara (MVA) vaccine encoding the carcinoembryonic antigen (CEA) and costimulatory molecules induced strong CD4+ and CD8+ T-cell responses in mice, demonstrating its potential as an effective cancer vaccine.

A diversified vaccination regimen using MVA-CEA/TRICOM as a prime followed by rF-CEA/TRICOM as a boost resulted in significantly better antitumor responses and increased survival compared to traditional regimens, highlighting the efficacy of this approach in enhancing immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified vaccinia virus ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses. Hodge, JW., Poole, DJ., Aarts, WM., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus-specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Early evaluation of the safety, reactogenicity, and immune response after a single dose of modified vaccinia Ankara-Bavaria Nordic vaccine against mpox in children: a national outbreak response. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Harnessing the unique local immunostimulatory properties of modified vaccinia Ankara (MVA) virus to generate superior tumor-specific immune responses and antitumor activity in a diversified prime and boost vaccine regimen. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Uptake of antigens from modified vaccinia Ankara virus-infected leukocytes enhances the immunostimulatory capacity of dendritic cells. [2020]

10. United States pubmed.ncbi.nlm.nih.gov

Modified vaccinia virus ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses. [2020]