Cytomegalovirus (CMV) as Vaccine-vectors

Many Ags are weakly immunogenic and bind poorly to TCR on CD8 T cells, which poses a substantial challenge to the development of vaccines targeting intracellular pathogens or tumors. Vaccination based on CMV vaccine vectors has shown unparalleled T cell-based protection in experimental models of immunized animals, providing new strategies for targeting intracellular microbes or cancer treatment.

Introduction of Cytomegalovirus

Cytomegalovirus (CMV) is a member of the β-subfamily of herpesviruses, a family of viruses that are thought to have been evolved with their hosts for about 180 million years. CMV has established an asymptomatic latent/sustainable infection in most people around the world and continues to exist in the life of the host. Importantly, reactivation of latency occurs periodically throughout the body, requiring constant immunosurveillance to maintain host disease free. In fact, immunosuppressed patients are at risk of CMV reactivation, which may lead to increased morbidity and mortality.

Cytomegalovirus as Vaccine-vectors

Even though CMV can cause significant morbidity in immunocompromised individuals and can be found in a variety of human cancers, its potential as a vaccine vector has attracted considerable attention due to its ability to induce memory inflation. CMV-driven T cells can also migrate to almost all tissues of the body in a stable state. Most importantly, recombinant CMV can be used to induce memory inflation of T cells specific for the recombinant antigens both in mice and non-human primates. Furthermore, unlike many viruses, CMV is able to reinfect previously infected individuals, even in CMV seropositive individuals, allowing CMV vectors for vaccination and booster immunization. Vaccination strategies based on CMV vaccine vectors have shown unparalleled T cell-based immune protection in animal experimental models. Because of these characteristics, CMV-based vaccines provide a new strategy for the treatment of some complex diseases in the clinic and has been used as a vaccine vector in a few settings.

Features of Cytomegalovirus Vectors

Several features of cytomegalovirus make them attractive candidates as vaccine vectors. These features include the following:

• Large double-stranded genomes suitable for insertion of foreign genes
• Species specificity for their native hosts
• The ability to provide sustained stimulation of the immune system by establishing persistent and latent infections

Modification of CMV Vectors

Higher safety can be achieved by using a defective virus as a vaccine vector. CMV encodes many genes involved in an immune invasion that are non-essential for viral growth in vitro. The deletion of these genes leads to attenuated viruses in the body, which allows us to dramatically manipulate their virulence and immune response.

• CMV has several immune-invasive genes that prevent surface expression of NKG2D ligands. In mouse CMV (MCMV), most of these genes belong to the m145 immunoglobulin family, which include the m145, m152 and m155 gene products that target MULT-1, RAE-1 and H60, respectively. The new MCMV-based vaccine vector expressing NKG2D ligand in place of its viral regulator m145 can induce a strong CD8⁺ T cell response and anti-viral antibodies.
• The glycoprotein L (gL) of MCMV forms a heterodimer with glycoprotein H (gH) in the viral envelope, and this heterodimer is essential for the virus to enter the cell. Variants of MCMV lacking glycoprotein L (ΔgL-MCMV) produced CD8⁺ T cells and memory inflation that lasted more than a year. Creative Biolabs generate ΔgLMCMV on the complement cell line, which provides the gL protein in trans, thus producing virions that could go through one round of infection in vivo. Likewise, a spread-defective variant of MCMV lacking the essential virion protein M94 was shown to persist in the lungs of immune competent mice for at least 1 year after infection.
• Removal of US11 protein from wild-type rhesus CMV (RhCMV) resulted in the induction of conventional CD8⁺ T cells that recognize both classical and non-canonical epitopes. Unconventional CD8⁺ T cell epitopes are peptides presented by the non-polymorphic MHC-I molecule MHC-E, or by MHC-II molecules. An unconventional reaction is observed by deleting the RhCMV of UL128 and UL130. Additional deletions of US11 result in CD8⁺ T cells recognizing conventional classical and unconventional epitopes, but not conventional non-canonical epitopes.

Fig.2 Genetically distinct RhCMV vectors elicit four different CD8⁺ T cell responses each recognizing non-overlapping sets of peptides. (Früh and Picker. 2017)

The CMV-based vector represents a novel vaccine platform that maintains a high frequency of non-exhausted effector memory T cells in CMV seropositive and seronegative individuals. Creative Biolabs genetically engineers CMV vectors to induce highly diverse and highly persistent CD8⁺ T cell responses and provides safe and efficient vaccine vectors to customers worldwide. If you have any needs, please contact us as soon as possible.

Reference

1. Früh K and Picker L. (2017). CD8⁺ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination. Current Opinion in Immunology, 47:52.

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