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Progress Reported in the Development of Third Generation Smallpox Vaccines

By Michael Mair, March 3, 2006

The 4th Annual American Society for Microbiology (ASM) Biodefense Research Meeting was held on February 15-18, 2006 in Washington DC.[1] Among the abstracts presented at the meeting were several pertaining to the development of potentially safer smallpox vaccines.[2] Five abstracts were presented regarding LC16m8, an attenuated, replication-competent vaccinia virus strain, which Vaxgen, Inc. (Vaxgen) is developing as a third-generation smallpox vaccine in collaboration with the Chemo-Sero Therapeutic Research Institute (KAKETSUKEN) in Japan.[3]

Among the data reported for LC16m8 were:

A single dose of LC16m8 protected A/NCR mice 10 and 50 days post vaccination against a lethal intranasal challenge with ectromelia virus at 80' and 4,375' LD50 levels[4]
A single dose of LC16m8 protected cynomolgus monkeys against a lethal challenge with monkeypox virus (Zaire 79 strain) administered intravenously 60 days post-vaccination[5]
In a clinical trial conducted in Japan among healthy adults with LC16m8, the clinical take rate for primary vaccinees was 94% and 86% for those being re-vaccinated.[6] The study also found that vaccination with LC16m8 was "frequently associated with axillary lymph node swelling but no life threatening neurological or cardiovascular disorders"[6]

Scientists from Bavarian Nordic A/S (Bavarian Nordic) presented data from a Phase I clinical trial of IMVAMUNE™ -- Bavarian Nordic's candidate smallpox vaccine -- in subjects with atopic dermatitis.[7] IMVAMUNE™ is based on a strain of modified vaccinia Ankara (MVA) virus.[8] MVA is a replication-incompetent vaccinia virus strain (i.e., it does not replicate in humans) that is expected to have a better safety profile than conventional smallpox vaccines, which are based on replication-competent vaccinia virus strains. Persons with atopic dermatitis are at an increased risk for a severe adverse reaction to vaccination with conventional smallpox vaccines. The scientists reported that no serious adverse events were reported among subjects with atopic dermatitis who were vaccinated with IMVAMUNE™.[7]

On a related front, on February 16, Bavarian Nordic announced that it has filed a patent infringement action against Acambis plc and Acambis Inc. at the Commercial Court in Vienna, Austria.[9] According to the press release, this "legal action has been initiated to enforce Bavarian Nordic's patent recently granted by the European Patent Office (EPO) which covers the company's MVA-BN® technology."[9]

MVA-BN® is Bavarian Nordic's "proprietary and patented core technology" and is based on a monoclonal modified vaccinia Ankara (MVA) virus strain.[10] Bavarian Nordic's smallpox vaccine, IMVAMUNE™, is based on MVA-BN® as well other vaccines that Bavarian Nordic is developing against other diseases (e.g., HIV, Dengue, cancer).

The patent, which was granted on December 28, 2005, "gives Bavarian Nordic the sole right to produce, market and sell MVA-BN®, and derivatives thereof with the same biological characteristics and safety profile as well as recombinant viruses thereof in Europe" and covers Bavarian Nordis's candidate smallpox vaccine, IMVAMUNE™.[9]

Bavarian Nordic contends that Acambis' MVA-based smallpox vaccine, MVA3000,[11] infringes on Bavarian Nordic's patent rights. If Bavarian Nordic is successful in its patent infringement actions, it "will be in a position to stop Acambis from engaging in the manufacturing, marketing and sale of any infringing MVA smallpox vaccine products in Austria and to seek monetary damages."[9]

Bavarian Nordic also is involved in similar legal action with Acambis in the United States, in which Bavarian Nordic and Acambis are competing for contracts to sell their MVA-based smallpox vaccines to the federal government for the Strategic National Stockpile (SNS).[12] Bavrian Nordic has filed patent infringement action against Acambis' MVA smallpox vaccine products with the U.S. International Trade Commission seeking a permanent exclusion order and a permanent cease and desist order, and has filed a misappropriation of trade secrets case against Acambis plc and Acambis Inc. in the U.S. District Court, District of Delaware seeking unspecified monetary damages and injunctive relief. In a press release regarding Bavarian Nordic's legal actions in the United States, Acambis stated that it "believes the claims [by Bavarian Nordic] are without foundation."[11]

References

ASM Biodefense 2006. American Society for Microbiology. 2006. Available at: http://www.asmbiodefense.org/. Accessed March 2, 2006.
ASM Biodefense Meeting 2006 - Accepted Abstracts. American Society for Microbiology. 2006. Available at: http://www.asmbiodefense.org/acceptedabstracts.htm. Accessed March 2, 2006.
LC16m8: VaxGen's Attenuated Smallpox Vaccine. VaxGen, Inc. Available at: http://www.b2i.us/profiles/investor/fullpage.asp?f=1&BzID=923&to=cp&Nav=0&LangID=1&s=0&ID=1466. Accessed March 2, 2006.
Empig C, Higgins K, Schriewer J, Buller RM. Abstract 83(E) - Attenuated smallpox vaccine LC16m8 protects mice from high-dose lethal intranasal ectromelia challenge administered 10 and 50 days post-vaccination. ASM Biodefense Meeting 2006. February 16, 2006. Available at: http://www.asmbiodefense.org/pdf/2006-thurs-abstracts.pdf. Accessed March 1, 2006.
Empig C, Higgins K, Edghill-Smith Y, Silvera P. Abstract 211(E) - Attenuated smallpox vaccine LC16m8 protects cynomolgus monkeys from lethal IV monkeypox-Zaire challenge. ASM Biodefense Meeting 2006. February 17, 2006. Accessed March 3, 2006.
Fujii T, Kanatani Y, Matsumura T, et al. Abstract 196(E) - Clinical evaluation of attenuated smallpox vaccine LC16m8 in Japan. ASM Biodefense Meeting 2006. February 17, 2006. Available at: http://www.asmbiodefense.org/pdf/2006-fri-abstracts.pdf. Accessed March 2, 2006.
von Sonnenburg F, Perona P, Schunk M, et al. Abstract 79(E) - First clinical experience with a third generation smallpox vaccine in subjects with atopic dermatitis. ASM Biodefense Meeting 2006. February 16, 2006. Available at: http://www.asmbiodefense.org/pdf/2006-thurs-abstracts.pdf. Accessed March 2, 2006.
IMVAMUNE™. Bavarian Nordic A/S. Available at: http://www.bavarian-nordic.com/imvamune. Accessed March 2, 2006.
Bavarian Nordic A/S further enforces its intellectual property rights against Acambis. Bavarian Nordic A/S. February 16, 2005. Available at: http://www.bavarian-nordic.com/01-06_UK. Accessed March 2, 2006.
Bavarian Nordic's MVA-BN®. Bavarian Nordic A/S. Available at: http://www.bavarian-nordic.com/mva-bn_bavarian_nordic. Accessed March 3, 2006.
MVA3000. Acambis plc. Available at: http://www.acambis.com/default.asp?id=1220. Accessed March 2, 2006.
Mair M. Proposals for third generation smallpox vaccine submitted to HHS. Biosecurity Briefing, Center for Biosecurity. October 6, 2005. Available at: http://www.upmc-biosecurity.org/bb/archive/cntrmeasure/smallpox/smpxvaccprophhs.html. Accessed March 3, 2006.

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