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An MVA vaccine for delivery of a UL128 complex and preventing CMV infection

A complex and vaccine technology, applied in the field of vaccine compositions for preventing HCMV infection, preventing HCMV from invading cells, and treating HCMV infection

Active Publication Date: 2015-08-12
CITY OF HOPE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there are no approved vaccines to prevent HCMV infection and / or disease, however, the Institute of Medicine of the National Academy of Sciences issued a report in 2000, due to the improvements to human health that such a vaccine would bring and put the development of HCMV vaccine in the highest priority category

Method used

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  • An MVA vaccine for delivery of a UL128 complex and preventing CMV infection
  • An MVA vaccine for delivery of a UL128 complex and preventing CMV infection
  • An MVA vaccine for delivery of a UL128 complex and preventing CMV infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: A Vaccine Introducing Broadly Neutralizing Antibodies in CMV Nascent Rhesus Monkeys that Inhibits the Main Entry Point of CMV Infection in Rhesus Monkeys

[0077] Viruses and cells. MVA propagation in baby hamster kidney (BHK) cells, and preparation and storage of virus stocks were performed according to previously reported protocols (Wang et al. 2010). Chicken embryonic fibroblasts (CEF) used for MVA propagation were maintained in serum-free medium for virus production (VP-SFM; Invitrogen).

[0078]MVA expressing a full-length pentamer of the five subunits RhUL128, RhUL130, RhUL131, RhgL, and RhgH (MVA-RhUL128C), with an alternate transmembrane (TM) site deletion, was generated by BAC technology as described below Versions of gH express the MVA of this 5-subunit pentamer (MVA-RhUL128C[Delta]), or the MVA of the RhUL128, RhUL130, and UL131A subunits. MVAs expressing RhUL128 or RhUL130 alone were generated by a routine protocol in eukaryotic cells as previou...

Embodiment 2

[0118] Example 2: Construction and expression of HCMV UL128C pentamer expressed from MVA

[0119] MVA expression of the human UL128C subunit. MVA expressing 5 subunit pentamers of full length human UL128, UL130, UL131, gL and gH (H-UL128C-MVA) was generated by BAC technique similar to Example 1.

[0120] Such as Figure 8 As shown, all five subunits of human UL128C (H-UL128C) were successfully expressed and individual subunits were detected by either mAb (gH, UL128, UL130) or polyclonal antisera (UL131A, gL). The MWs of the individual subunits are consistent with published data, providing strong evidence that MVA-based expression is accurate and reliable for the structure of these subunits expressed from HCMV. Figure 8 Compositions containing alternating gH structures (e.g., gH, gHΔTM lacking the transmembrane region) co-expressed with the other four H-UL128C subunits are shown (a composition with alternating gHΔTM is represented by UL128CΔ, and Full-length gH (gH-FL) is...

Embodiment 3

[0122] Example 3: Construction and evaluation of clinically acceptable MVA-BAC for human use

[0123] Preclinical studies with RhCMV were facilitated by a previously constructed MVA-BAC vector (Cottingham 2008). All vaccines using RhCMV compounds use this MVA-BAC combination. However, because the origin of MVA is unknown, a different vaccine vector will be used for human use. The MVA MBA will also be constructed in such a way that vector sequences can be deleted after viral recombination to avoid retention of any unwanted functional bacterial sequences, a property that may be necessary for FDA approval. The vector components will be inserted into the TK site to recombine the insertion site for transgene expression. The construction of MVA-BAC for humans was followed by using the 1974-MVA provided by Dr. Bernard Moss of NIAID. The clinical use of MVA has allowed the development of a variety of vaccines, many of which are now entering clinical trials. Therefore, 1974-MVA s...

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Abstract

In one embodiment, an expression system for expressing a UL128 complex is provided herein. The expression system may include a bacterial artificial chromosome (BAC) construct, wherein the BAC construct comprises a viral vector inserted with a set of DNA sequences that encode a UL128 complex. In another embodiment, a vaccine composition for preventing HCMV infection is provided. The vaccine composition may include a viral or bacterial vector capable of expressing a UL128 complex and a pharmaceutically acceptable carrier, adjuvant, additive or combination thereof or additional vector expressing a protein adjuvant. The viral vector may be an MVA and the UL128 complex includes five HCMV proteins or antigenic fragments thereof: UL128, UL130, UL131A, gL, and gH. In some embodiments, the viral vector is further inserted with one or more additional DNA sequences that encode one or more additional HCMVHCMV proteins or antigenic fragments thereof such as pp65, gB or both, or such as gM / gN or gO.

Description

[0001] Statement of Government Rights and Interests [0002] This invention was made with Government support under Grant No. AI063356 awarded by the National Institute of Allergy and Infectious Diseases (US) and CA030206 awarded by the National Cancer Institute (US). The US Government has certain rights in this invention. [0003] priority statement [0004] This application claims the benefit of priority to US Patent Provisional Application No. 61 / 676846, filed July 27, 2012, which is hereby incorporated by reference in its entirety. Background technique [0005] The cytomegalovirus (CMV) genome is large (greater than 200kbp), and the human cytomegalovirus (HCMV) encodes ≥165 open reading frames (ORFs), which encode proteins that enable it to infect a variety of cell types, establish latency, and recover from latency Reactivation and lifelong persistence in immune competent hosts (Murphy et al. 2003; Barry & Chang 2007; Hansen et al. 2003; Jarvis & Nelson 2007; Rivailler et...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/38A61K39/245C07K14/045
CPCC12N2710/24143A61K39/12A61K39/245A61K2039/70A61K2039/5256C12N2710/16122C12N2800/204C07K14/005A61K2039/5254C12N7/00C12N2799/023C12N2710/16134A61P31/12
Inventor 唐·J·戴蒙德费利克斯·乌索彼得·A·巴瑞
Owner CITY OF HOPE
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