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CMV Vaccine Program

CMV Vaccine Candidate (VBI-1501A) Overview

VBI is developing a prophylactic vaccine to prevent cytomegalovirus (“CMV”) infection. CMV is a leading cause of prenatal developmental delays. VBI has completed work for GMP manufacturing of its lead candidate for use in Phase I trials. VBI expects to evaluate safety, tolerability, and also immunological proof of concept in humans during Phase I trials by measuring CMV neutralizing antibodies in fibroblasts and epithelial cells.

Achieved and Anticipated Program Milestones
  • Q2 2015: Initiated Formal Toxicology
  • Q3 2015: Started GMP Clinical Batch
  • Q1 2016: Complete Formal Toxicology and File IND
  • H1 2016: Phase I Start
  • H1 2017: Interim Readout

Electron microscopy image of VBI’s CMV Vaccine Candidate, VBI-1501A, captured at The Scripps Institute.

CMV Medical Need

CMV is a common virus that infects one in every two people in many developed countries.1 Most CMV infections are “silent,” meaning most people who are infected with CMV exhibit no signs or symptoms. However, CMV can cause serious disease in newborns when a mother is infected during pregnancy – this is known as congenital CMV infection.

Market Need and Opportunity
  • Each year, approximately 5,000 U.S. infants will develop permanent problems due to CMV, some of them severe, including deafness, blindness, and mental retardation.2
  • In the U.S., the direct economic costs of CMV infection exceeds $2.0B annually.3
  • CMV affects more live births than Down Syndrome or Fetal Alcohol Syndrome,4 making it a key public health priority and a strong candidate for recommended universal vaccination among certain high-risk populations.5
  • Demand for a CMV vaccine could exceed 7.6M doses by 2030;6 with pricing similar to HPV at $140 per dose,7 the prophylactic CMV vaccine market could exceed $1B annually.
U.S. Children Born With or Developing Long-Term Medical Conditions

Source: Cannon, M. J., and K. F. Davis. 2005. Washing our hands of the congenital cytomegalovirus disease epidemic. BMC Public Health 5:70

CMV Vaccine Candidate Design

VBI’s eVLP Platform gives rise to a CMV vaccine candidate capable of generating a potent and durable immune response.

eVLP Vaccine Characteristics
  • Highly Immunogenic: eVLP immune responses are comparable to or better than a natural infection by closely mimicking the structure of the target virus.8
  • Customizable: eVLPs provide the ability to rationally design a vaccine by including different antigens and controlling their relative expression.
  • Safe: Unlike live-attenuated vaccines, eVLPs cannot revert back to an infectious state.
  • Commercially Viable: Unlike some vectored delivery approaches, eVLP-based vaccines are manufactured and purified using scalable methods, and VBI has demonstrated commercially-suitable yields.9

Dr. David E. Anderson, VBI’s Chief Scientific Officer, discusses the design of VBI’s CMV Vaccine Candidate (VBI-1501A).

Scientific Literature Supporting VBI's CMV Vaccine Development Approach

A review of CMV vaccine development which summarizes the data supporting the feasibility of a prophylactic vaccine against CMV. Adler SP. Human CMV vaccine trials: what if CMV caused a rash?. J Clin Virol. 2008;41(3):231-6.
A Phase II trial of an adjuvanted recombinant gB protein with projected 50% efficacy against congenital transmission of CMV. Pass RF, Zhang C, Evans A, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med. 2009;360(12):1191-9.
An analysis of samples from the clinical trial of adjuvanted gB protein (Pass RF 2009) demonstrates that the vaccine induced nAb titers were able to prevent fibroblast cell infection comparable to naturally acquired immunity; however, titers were approximately ten times below naturally acquired immunity against CMV infection of epithelial cells. Cui X, Meza BP, Adler SP, Mcvoy MA. Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. Vaccine. 2008;26(45):5760-6.
A phase II trial of an adjuvanted recombinant gB protein in the solid organ transplant setting with evidence of efficacy including reduced viremia and reduced duration of anti-viral treatment. Griffiths PD, Stanton A, Mccarrell E, et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011;377(9773):1256-63.
nAbs against gB, but not components of the pentameric complex, are capable of preventing CMV infection of placental trophoblast progenitor cells – a critical cell type infected during congenital transmission of CMV. Zydek M, Petitt M, Fang-hoover J, et al. HCMV infection of human trophoblast progenitor cells of the placenta is neutralized by a human monoclonal antibody to glycoprotein B and not by antibodies to the pentamer complex. Viruses. 2014;6(3):1346-64.

Preclinical Highlights

  • Neutralization of CMV up to 32X greater than natural immunity in multiple preclinical animal models.10
  • Structure of the eVLP platform generates stronger neutralizing antibodies than does immunization with the same (gB) target protein alone.11 gB antigen is a major antigen for the induction of neutralizing antibodies against CMV.12
  • Potent neutralization in fibroblasts and epithelial cells, two clinically-relevant cell types that are susceptible to CMV infection.13
  • Durable and high titer antibodies anticipated to impart long-lasting immunity in vaccine recipients.14
  • Potent immunity alone or in combination with alum, a safe, FDA-approved adjuvant.15
eVLP Expression of the CMV gB Antigen Induces Antibodies with Potent and Broad Neutralizing Activity

Dr. David E. Anderson, VBI’s Chief Scientific Officer, discusses how eVLPs, and an optimized form of the CMV gB antigen, can be used to develop a potentially efficacious CMV vaccine in a study published in Clinical and Vaccine Immunology.

Neutralizing antibody titers for individual mice immunized with comparable doses of optimized gB-G eVLPs (VBI-1501), gB eVLPs or recombinant protein.

eVLP presentation of the gB antigen improves responses relative to recombinant gB protein; VBI’s modified form of gB (gB-G) further improves responses.16

Neutralizing antibody titers of rabbits 28 days after a second vaccination with VBI-1501A, compared to CMV+ donors in two clinically relevant, CMV-susceptible cell lines.

After two vaccinations, VBI-1501A stimulates CMV neutralizing antibodies comparable to natural levels of immunity.17

Phase I Study

Benchmarking against natural immunity may allow for human proof of concept in a Phase I clinical trial.

Study Design
  • Population: ~125 CMV-Negative Healthy Adults
  • Design: Staggered Enrollment with Vaccinations at 0, 2, and 6 Months
  • Expected Duration: 20 Months
  • Primary Endpoint: Safety and Tolerability
  • Secondary Endpoint: Anti-CMV nAb Effective in Fibroblasts / Epithelial Cells
    • nAb are neutralizing antibodies that indicate acquired CMV immunity18
    • Interim potency data available after second immunization

References

  1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553672/
  2. http://www.cdc.gov/cmv/trends-stats.html
  3. Stratton KR et al,  Committee to Study Priorities for Vaccine Development, Inst. of Med.; Washington, DC
  4. Cannon, M. J., and K. F. Davis. 2005. Washing our hands of the congenital cytomegalovirus disease epidemic. BMC Public Health 5:70
  5. Stratton KR et al,  Committee to Study Priorities for Vaccine Development, Inst. of Med.; Washington, DC
  6. Estimates adapted from Vakzine Analytics, CMV Marketview, August 2012
  7. Lilja AE (2013) Vaccine 30, 6980-6990
  8. VBI Studies: 15BC04, 15BC19
  9. VBI Studies: 15CH19, 15CH38
  10. VBI Studies: 15BC19
  11. VBI Studies: 15BC04
  12. http://www.ncbi.nlm.nih.gov/pubmed/10466818
  13. VBI Studies: 15BC04, 15BC19, 15BC39
  14. VBI Studies: 15BC19
  15. VBI Studies: 15BC19, 15BC3
  16. VBI Studies: 15BC04
  17. VBI Studies: RA-44
  18. Nozawa, N (2009) J Clin Virol 46S4, S58-63

Recent CMV Program News and Insights

VBI Vaccines to Continue Enrolling Participants in the Phase I Trial of its Preventative Cytomegalovirus Vaccine Candidate Following Successful Data Safety Monitoring Board Review

By | Cytomegalovirus ("CMV"), Press Releases | No Comments
VBI Vaccines Inc. (Nasdaq: VBIV) (TSX: VBV) (“VBI”) today announced that, following a review of safety data from the limited safety immunization period, the Data Safety Monitoring Board (“DSMB”) has no objection to VBI continuing with the enrollment of participants...
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