Vaccinia virus, live, Modified Vaccinia Ankara strain - Imvanex; Imvamune; MVA smallpox vaccine - MVA-BN; MVA3000
Status: being added to biodefense stockpiles of U.S. and other countries; BLA filing expected in 2013; EMA/EU approval in Aug. 2013
Organizations involved:
Bavarian Nordic A/S – Manuf.; R&D; Tech.; Patent dispute; World mark.
GlaxoSmithKline plc – Former
Impfstoffwerk Dessau Tornau GmbH (IDT) – Manuf.
Acambis plc – Manuf.; R&D; Tech.; Patent dispute
Baxter Hyland Immuno – Manuf.; R&D; Tech.
National Inst. of Allergy & Infectious Diseases (NIAID) – R&D
National Institutes of Health – Parent
Therion Biologics Corp. – R&D
INCELL Corp. LLC – R&D
Cross ref.: See Smallpox Vaccine Products entry (#535).
Description: MVA-BN (Imvamune in U.S.; Invanex in EU) is a lyophilized formulation of live non-infectious Modified Vaccinia Ankara (MVA) strain of vaccinia virus originally developed and used in for smallpox vaccination in Germany, now being stockpiled by various governments. MVA, as manufactured by Bavarian Nordic, involves culture of the virus in chicken embryo fibroblast (CEF) cell culture using serum-free culture media, followed by purification and lyophilization (freeze-drying).
Besides being a viable smallpox vaccine for general use, the MVA virus is less infective or pathogenic in humans than other smallpox vaccines, e.g., Dryvax,, making it attractive for use in those for whom regular smallpox vaccines entail a risk of disseminated, systemic other dangerous infections from the live virus, e.g, HIV-infected, cancer patients, pregnant women, infants, persons with eczema, others with immune suppression, etc.
Multiple organizations have and are developing smallpox vaccines based on MVA, Bavarian Nordic A/S (formerly in collaboration with GlaxoSmithKline) appears to be well in the lead in terms of commercial development with its MVA-BN vaccine (Imvamune). including recently receiving a major U.S. government civilian procurement contract (RFP-III). Bavarian Nordic has also received a U.S. patent broadly covering MVA (see the Tech. transfer section).
Acambis plc and its partner, Baxter Hyland Immuno, have developed and manufactured an MVA vaccine, MVA3000, under contract to the U.S. and other governments, but will no longer receive federal contracts for its MVA vaccine. Bavarian Nordic with Imvamune is on track to be the major supplier for the U.S. stockpile. Bavarian Nordic and Acambis recently settled patent disputes concerning MVA vaccines, with Acambis taking a license from Bavarian Nordic. With this Acambis is free to continue development of MVA3000. [However, with the loss of the U.S. government funding and as major customer, Acambis could deemphasize (slow) or even halt development]. The contacts, patents and related disputes concerning MVA vaccines, Imvamune and MVA3000, are further discussed below.
[Note, because of lack of information to differentiate between MVA-based smallpox vaccines (Imvamune and MVA3000) and with only one, Imvamune, receiving continued funding in the U.S. and having a long record of use, this monograph tends to concentrate on Imvamune].
Biological.: MVA was derived from the Ankara vaccinia strain CVA. In the mid-1950s, CVA was used in Germany as a smallpox vaccine. In 1958, CVA was used to develop an attenuated replication-defective vaccine strain, designated Modified Vaccinia Ankara (MVA). MVA virus was generated by 516 serial passages of CVA on chicken embryo fibroblasts (see Mayr, A., et al., Infection, 3, 6-14, 1975). The resulting MVA virus has six major deletions of about 31 kilobases (DNA), including at least two host-range genes. MVA is highly host cell restricted to avian cells. Studies in a variety of animal models have shown that MVA is largely avirulent. Some current strains of MVA have been shown capable of productive replication in a few human cell lines, particularly HaCa, while the MVA-BN (sub)strain (from Bavarian Nordic) has not been shown capable of productive replication in any human cell line tested. This indicates that MVA-BN will not replicate or productively infect humans.
Vaccinia virus-based smallpox vaccines entail a risk of systemic infection in persons with compromised immune systems. Compared to the NYCBH strain used in prior (Dryvax and Aventis Pasteur vaccines) and upcoming (ACAM1000 and ACAM-2000) U.S. smallpox vaccines and other strains formerly used in other vaccines internationally, MVA is less aggressive in establishing infection (less pathogenic). MVA has been shown generally safe in persons with suppressed immune systems, including HIV/AIDS, cancer patients, transplant recipients, pregnant women, infants, persons with eczema, and other populations for which smallpox vaccines are generally contraindicated due to concerns about extensive skin and systemic infections. These and other groups that may be excluded from receiving smallpox vaccines may include up to 30% of the U.S. population. MVA has the reputation as probably the safest smallpox vaccine, based on its record of actual use.
MVA was used to vaccinate over 120,000 people in Germany as part of smallpox eradication efforts in the 1970s. Its use included high-risk patients. Compared to other vaccinia-based vaccines, MVA has demonstrated diminished virulence/infectiousness and induces a good specific immune response, but requires a higher dose of live virus than other more infectious vaccines. Although shown to be safe, smallpox was not endemic in Germany at the time, and its efficacy against wild variola virus remains unknown.
Besides use in immune compromised and others at-risk, MVA may be useful in prime-boost smallpox vaccination regimens. These could involve initial vaccination with an MVA vaccine, followed by a conventional, more potent (immunogenic) but also more infective conventional smallpox vaccine. Or, a much different vaccine, e.g., a DNA or recombinant subunit vaccine, could be followed an MVA vaccine. Prime-boost regimens may be safer and more effective than vaccination with any individual vaccine. Similar regimens have shown promise with HIV vaccines, e.g., recombinant HIV envelope vaccine, followed by an ALVAC canarypox virus vector HIV envelope vaccine (from Virogenetics/Sanofi Pasteur).
[Bavarian Nordic is also currently manufacturing a conventional smallpox vaccine, Elstree-BN, based on the Elstree stain of vaccinia virus used in prior international vaccination programs. See the related entry].
Nomenclature: Smallpox Vaccine/MVA [BIO]; Imvanex [TR EU]; Imvamune [TR US]; vaccinia virus, live, modified vaccinia Ankara [SY]; Modified Vaccinia Ankara [SY]; MVA [SY]; MVA-BN [SY]
Companies.: Imvamune was developed, is manufactured and marketed by Bavarian Nordic. All rights to the development of are now controlled by Bavarian Nordic. Bavarian Nordic initiated the development of MVA-BN (trade name IMVAMUNE in the U.S. and IMVANEX in Europe) in 1999 and began the first clinical study in 2001. The majority of development costs have been supported by the U.S. Department of Human Health Services - both the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health, and the Biomedical Advanced Research and Development Authority (BARDA). Contracts with NIAID in 2003 and 2004 and other NIAID resources funded much of the product development work and nearly all of the clinical development that underpinned the European marketing application. Advanced development and manufacturing of MVA-BN was successfully transitioned to BARDA with a Project BioShield procurement contract in 2007.
In July 2004, Bavarian Nordic A/S entered into a strategic collaboration for MVA-BN (Imvamune) commercial development and marketing with GlaxoSmithKline plc (GSK). [As discussed below, this collaboration was ended in May 2007]. Bavarian Nordic was to initially be responsible for manufacturing, e.g., for clinical supplies (and its government contracts) GSK joined the company in its U.S. government contracts and clinical trials. Bavarian Nordic eventually would transfer its MVA manufacturing and other technology to GSK, which would manufacture and market Imvamune in most international markets, including North and South America, Japan as well as a number of important European markets, including Great Britain and France. Bavarian Nordic will continue to manufacture and market Imvamune to all German-speaking countries, the Nordic countries, the Baltic States, China, the Middle East and South East Asia.
The company’s May 2003 acquisition of GTB GenTherapeutika Berlin-Buch GmbH (Berlin, Germany) from Schering AG included a facility now being used for MVA-BN manufacture. Bavarian Nordic purchased from Orion Pharma AB a facility in Kvistgård, Denmark, to be used for large-scale manufacture of MVA-BN. The facility came online in Sept. 2005, starting production of test lots, with capacity of 120 million vaccine doses per year (to be one of Europe’s largest vaccine manufacturing facilities). The company reports having invested $30 million in improving the facility. The facility received approval from the Danish Medicines Agency (Laegemiddelstyrelsen) in Sept. 2006 for manufacturing, analysis and release of vaccines for use in clinical trials and emergency situations. This covers Bavarian Nordic’s need for manufacturing of smallpox vaccine for the RFP-III order and other markets for emergency use of smallpox vaccines (i.e, the company can begin its commercial manufacturing of MVA-BN).
Bavarian Nordic had previously contracted for manufacture of Imvamune with Impfstoffwerk Dessau Tornau GmbH (IDT; Tornau, former East Germany), presumably, until its own expanded capacity came online. IDT manufactured 1 million doses of Imvamune in 2005.
Bavarian Nordic has also previously sold tens of millions of doses of Imvamune to current, expected, and follow-on foreign government contracts.
In Aug. 2002, the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), issued its first Request for Proposals (RFP I-A) for MVA vaccine development and manufacture. In Feb. 2003, Bavarian Nordic A/S and Acambis plc (and its partner, Baxter Hyland Immuno) both received contracts from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, for research and development of new MVA smallpox vaccines and Phase I trials. Both companies are also pursuing commercial development of MVA vaccines. These contracts provided $20 million first-year funding on a cost-plus-fixed-fee basis. The companies retain exclusive commercialization rights to any resulting vaccines. Through RFP I-A, Bavarian Nordic manufactured 5,000 doses of prototype MVA for IND, preclinical and Phase I trials; and Acambis received an initial $9.2 million for development of its MVA vaccine candidate, manufacture of several thousand doses, and clinical testing in a Phase I trial.
A second RFP, RFP I-B, was issued in Aug. 2002 (essentially a contract follow-on). Having met its milestones and with MVA-BN judged to be a viable candidate vaccine, in Sept. 2003 Bavarian Nordic received a contract extension (won RFP I-B) with an additional $23 million funding expansion of U.S. Phase I and II trials in immune compromised subjects. Candidate MVA vaccines manufactured by both contractors entered Phase I trials in spring 2004.
In Dec. 2001, Bavarian Nordic received a Greek government contract for supply of MVA-BN; and in Sept 2002, received a contract from the German Armed Forces. The company has 10 or more supply MVA-BN contracts with various governments, mostly European.
In Dec. 2003, a second NIAID/NIH MVA development RFP, RFP II, was issued for large-scale manufacture of MVA. The incumbents, Acambis/Baxter and Bavarian Nordic/GSK both received contracts.
In Sept. 2004, two further RFP II contracts were awarded to Bavarian Nordic A/S (in collaboration with GlaxoSmithKline plc) and Acambis, Inc. (in collaboration with Baxter) totaling $177 million.
Bavarian Nordic (and GSK) received a three-year contract (RFP II) valued at $141+ million (including an extension) from NIAID, NIH, for development and manufacture of Imvamune for the U.S. biodefense stockpile. This RFP II contract “with a base value of over $100 million” calls for the manufacture of 500,000 doses of Imvamune within 11 months of contract award using the final validated production process. The government also had an option to purchase an additional 2.5 million doses during the contract period for $41+ million. The total contract for 3 million doses is valued at $141+ million (or >$47/dose). The contract also supports further clinical development of Imvamune and validation of animal models. This is the third smallpox vaccine development contract awarded to Bavarian Nordic from NIAID.
Acambis Inc. (and Baxter) received the RFP II contract potentially for 3 million doses worth up to $131 million (~$44/dose). As with the Bavarian Nordic contract, the core component, worth ~$76 million, requires Acambis to manufacture, fill, finish and release 500,000 single-dose vials of MVA vaccine and to carry out development work. A clinical testing program expected to continue into 2007 includes: safety and immunogenicity studies in healthy adults and target- population subjects; a dose-response study; and trials involving both vaccinia-naive and previously vaccinated subjects. The optional part, worth an additional $55 million, would require manufacture, fill, finish, and release of up to a further 2.5 million single-dose vials of MVA.
In Sept. 2005, Bavarian Nordic reported completion in less than 11 months from start of its new 9,000 m2 vaccine manufacturing facility in Kvistgaard, Denmark. NNE prepared the detailed design and managed the construction of the facility, as well as the project management. The plant has a capacity to manufacture 40--60 million doses/year of Imvamune, and uses disposable production technology. The company claimed, “As a result, Bavarian Nordic is now the only company in the world that is able to commercially supply the growing demand for MVA-based safe smallpox vaccines.” Ultimately, the plant will have the capacity to produce 180 million doses/year. The facility was designed for Bavarian Nordic’s MVA-BN production process, which has special sterility and biocontainment requirements. Biocontainment requirements for MVA-BN call for a BioSafety Level-1 (BSL-1) facility, but to ensure flexibility and maintain the possibility of producing other products in the facility at a later date, the facility complies with BSL-2 and can meet BSL-3 regulations with minor modifications. Bavarian Nordic decided not to implement an overall data-collection system and process-control system, because of the time needed for validation. Everything except for process utilities is controlled and recorded in the master batch journal or by local data-collection systems at appropriate locations in the production process, with a possibility for inclusion later in an overall data-collection system.
In Oct. 2005, Acambis (source for MVA3000) and Bavarian Nordic (source for Imvamune/MAV-BM) submitted their bids in response to another Request for Proposals, RFP-III (DHHS-ORDC-V&B-05-06), RFP-3 or RPF III. Contract award(s) were expected from NIAID, NIH, in 2006, but have not been announced yet. Under RFP-III, NIAID will award one or two five-year contracts to manufacture MVA vaccines for the U.S. Strategic National Stockpile. The value of RFP-III is expected to be about $900 million, with an additional $1 billion expected to be granted for the maintenance of vaccine stocks during 2007-2013. This is expected to eventually include the purchase of up about 80 million doses of MVA smallpox vaccine. The first order of 20 million doses is to expected to be delivered within 18 months from the award of the contract. GlaxoSmithKline collaborated with Bavarian Nordic in its bid for RFP-III. Acambis plc also bid for RFP-III, but was later excluded, leaving only Bavarian Nordic/GSK.
In Dec. 2005, Acambis (and Baxter) reported delivery of 500,000 doses of MVA3000 under its existing federal contract (RFP II). In early 2006, Bavarian Nordic delivered 500,000 doses of Imvamune under its RFP II contract. These deliveries fulfilled a core requirement of the RFP II contracts awarded in Sept. 2004 for the manufacture and development of MVA vaccines.
In Nov. 2006, it was announced that Acambis was no longer a candidate for the U.S. government’s major procurement of an MVA vaccine under RFP III. Thus, Acambis had received on contract in Feb. 2003 for $9.2 million, and a second awarded in September 2004 worth $76 million for clinical testing and manufacture of 500,000 doses of MVA3000. Bavarian Nordic will now be the sole source supplier/contractor of MVA vaccines for the next contract, RFP III. This development strongly suggests that Acambis will have to halt development of its vaccine, or settle for small, niche market sales to other countries.
In Feb. 2007, GlaxoSmithKline (GSK) and Bavarian Nordic ended their collaboration for the development and marketing of Imvamune, which had included GSK being a backup manufacturer of Imvamune.
In May 2007, with RFP-III not yet formally awarded, Bavarian Nordic announced that the U.S. government intended to order another 20 million doses of Imvamune, and that a contract was being negotiated for a reported “contractual value of up to DKK 3 billion.”
On June 4, 2007, DHHS awarded Bavarian Nordic RFP-III -- a five-year contract for 20 million doses of Imvamune valued at more than $500 million (over $25/dose), with options that if exercised extend the value to $1.6 billion and the performance period of the contract. The contract options allow for the government to procure up to an additional 60 million doses, and would support additional clinical studies for extending the license to include HIV-infected, pediatric, and geriatric populations. This contract is the first next-generation, or completely new, product procurement under the U.S. government’s BioShield program. It also is the first contract ever to make advance payments as milestones in development and production are reached. Congress passed legislation (Pandemic All Hazards Preparedness Act) in 2006 that grants DHHS additional authorities to provide milestone-based advance payments to companies. After the RFP-3 contract was signed, Bavarian Nordic successfully fulfilled all the requirements relating to the development of physical safety, IT security, validation of production and test processes, etc. underlying an advance payment of $50 million and the two milestone payments of $25 million each.
In Oct. 2007, NIAID/NIH extended the existing contract RFP-2 with Bavarian Nordic to include the initiation of a larger Phase II study with Imvamune in persons diagnosed with atopic dermatitis. The contract extension will prolong the original contract to 2010 and has a value of $15 million, with the majority of revenue expected at the end of 2008 and beginning of 2009. The original RFP-2 contract, awarded in 2004, included a Phase II study with in persons diagnosed with atopic dermatitis. However the need for more clinical safety data in this population has increased due to requirements from FDA to support an Emergency Use Authorization (EUA).
In Oct. 2007, Bavarian Nordic invoiced an advance payment of $50 million under RFP-III for delivery of 20 million doses of vaccine.
In Dec. 2007, Bavarian Nordic received another $25 million milestone payment from its RFP-III contract. Bavarian Nordic had already received an advance payment of $50 million and a milestone payment of $25 million. Thus, the company received $100 million in 2007 from the RFP-3 contract.
In Nov. 2008, Bavarian Nordic invoiced for another $25 million milestone payment from its RFP-III contract (to manufacture and deliver 20 million doses). This was triggered by the submission of a clinical safety report from a large Phase II study with IMVAMUNE in HIV infected subjects.
In 2008, Bavarian Nordic was awarded a contract by the Canadian government for the acquisition of 20,000 doses of IMVAMUNE which were subsequently delivered and accepted under a Canadian Special Access Programme. Under the contract, the Canadian Authorities provide Bavarian Nordic with milestone-based funding for the filing of the New Drug Submission (NDS) for IMVAMUNE in Canada. The company apparently filed for Canadian approval in late 2009.
Initial deliveries of vaccine to the government took place in 2009.
In Nov. 2009, NIAID/NIHBARDA issued a $40 contract to Bavarian Nordic to develop a lyophilized (freeze-dried) version of Imvamune, which could be kept longer than the existing liquid form that must be frozen for storage. At the time, Bavarian Nordic had received $680 million in contracts for Imvamune from the U.S. government, which had ordered 20 million doses of the vaccine in its liquid-frozen form and has the option of buying another 60 million doses.
In July 2010, Bavarian Nordic delivered 1 million doses of its smallpox vaccine IMVAMUNE to the U.S. Strategic National Stockpile for use in the event of a smallpox bioterrorism attack on the U.S., and claimed, "IMVAMUNE is the first vaccine successfully developed under Project BioShield." At this time, under its BARDA contract, Bavarian Nordic will deliver 20 million doses of IMVAMUNE to the U.S. Strategic National Stockpile, with an option for 60 million more doses.
In June 2011. Bavarian Nordic A/S signed a contract with Danish Defence for the delivery of IMVAMUNE, and signed a contract with an unspecified European NATO country for the delivery of IMVAMUNE. The vaccines will be delivered in 2011. The size and value of the contracts are undisclosed (but were small enough not to affect company financial reporting).
In Aug. 2013, with EU approval, it was reported that "Currently, a national stockpile sufficient to protect 10 million Americans is being delivered."
Manufacture: In March 2005, Bavarian Nordic reported, “Substantial test-runs on the manufacturing process have shown that Bavarian Nordic will be able to produce approximately 40-60 million doses of Imvamune per year. Production is due to start this summer.” A few weeks earlier, the company reported that its new MVA clinical supplies production facility in Berlin, Germany, was “now ready to produce within its own manufacturing network large quantities of clinical trial materials for the company.” This facility uses the same production method for the manufacture of clinical trial materials as in the manufacture of commercial quantities of Imvamune. With the new facility on-line, the company expected to initiate several new trials in 2005, including three Phase II trials in more than 2,000 persons by the end of the year. The company also reported that preparation for large-scale manufacture at the Kvistgård, Denmark site is progressing as planned, with commercial production expected to begin in the summer of 2005.
Dr. Anton Mayr (Bavarian Nordic) is generally attributed as the original developer of MVA-BN, with this being or derived from MVA 572 FHE - 22.02.1974 (MVA 572) harvested inn Feb. 1974, using an MVA strain developed and passaged at the Institut fur Mikrobiologie and Infektionskrankeheiten der Tiere, Ludwid-Maximilians-Universitat Munchen. This strain's development including 572 passages in chicken embryo fibroblast cell culture, and was shared by Dr. Mayr for decades with poxvirus researchers worldwide (with Dr. Mayr claiming MVA was provided only for research purposes).
Status: As discussed in the Status section above, Bavarian Nordic is manufacturing Imvamune for addition to the U.S. biodefense vaccine stockpile and is taking steps to receive full FDA approval.
FDA has granted both Imvamune from Bavarian Nordic and MVA3000 from Acambis fast track designation for their MVA BLAs, allowing submission and review of portions of the BLA as they are completed.
Bavarian Nordic expected Imvamune to receive an Emergency Use Authorization (EUF) from CBER, FDA, in 2008, which would allow the vaccine to be used based on data from 2,000 patients. BLA completion is expected in 2008.
In 2008, three out of five Phase II studies for FDA approval had been completed, with very promising results. When the HIV Phase II-data package is available - expected late in 2008 - and has been accepted by the FDA, Bavarian Nordic can begin delivering the vaccine to the U.S. national stockpile and thus begin invoicing for the vaccine.
In March 2009, Bavarian Nordic held an end of Phase II meeting with the FDA to discuss the Phase III development, its formal discussions with the agency regarding use of the animal rule (allowing approval of certain products where clinical trials are not appropriate, based on animal and limited clinical testing). This review path will push the initiation of the Phase III studies into late 2010, leading to the submission of a BLA in 2013.
On Aug. 7, 2013, the European Commission granted marketing authorization for IMVANEX (MVA-BN) for active immunization against smallpox disease for the general adult population, including people with weakened immune systems (people diagnosed with HIV or atopic dermatitis). This is the first European approval of a novel biodefense vaccine developed through a successful public-private partnership with the U.S. government; and this was the first formal approval for Imvanex.
Tech. transfer: Bavarian Nordic A/S received U.S. 6,761,893, Modified vaccinia ankara virus variant,” on July 13, 2004. This patent covers the MVA-BN virus (Im-va-mune) and recombinant derivatives (i.e., both the present virus/vaccine and recombinant versions), use of MVA-BN as a vector for delivery of other vaccines, use of MVA-BN and related vaccines in healthy and immune compromised recipients, and use in prime-boost vaccination regimens. MVA-BN was deposited with the European Collection of Cell Cultures (ECACC V00083008), with this strain apparently the one used in Imvamune. U.S. 6,913,752, “Modified Vaccinia Ankara virus variant,” July 5, 2005, similarly covers the MVA-BN virus (Im-va-mune) and recombinant derivatives and includes claims for MVA vaccinia strain 575, deposited as European Collection of Cell Cultures (ECACC) V00120707.
Bavarian Nordic has received other MVA-BN-related U.S. patents including 7,189,536, “ Modified vaccinia ankara virus variant,” with claims including MVA-BN and derivatives cultured in chicken embryo fibroblasts, remaining nonreplicative in human cells, inducing higher specific immune responses than strain 575, and MVA-BN deposited as ECACC V00083008. U.S. 7,097,842, “Modified vaccinia virus ankara for the vaccination of neonate,” includes claims for MVA-derived vaccinia virus suitable for neonatal or prenatal vaccinations and induction of cellular immune responses. U.S. 7,094,412, “Poxvirus containing formulations and process for preparing stable poxvirus containing compositions,” includes claims for stable, freeze-dried formulations. U.S. 6,924,137, “Method for virus propagation,” includes claims for culture of poxviruses, including MVA-BN, at temperatures below 37˚C, with increased virus propagation at the decreased temperatures.
On Dec. 28, 2005, the European Patent Office (EPO) issued a patent (1335987) to Bavarian Nordic that covers MVA-BN technology. The patent belongs to the same patent family as the earlier-issued US patents (6,791,893 and 6,913,752). In May 2006, Acambis filed an opposition to this patent, following a similar filing by its European manufacturing partner, Baxter.
Bavarian Nordic also filed patent infringement claims in the U.S. in Aug. 2005 seeking to prohibit Acambis from importing or selling its MVA vaccine in the U.S. Also, in Aug. 2005, Bavarian Nordic filed a complaint with the U.S. International Trade Commission (ITC) alleging unfair competition in import trade by Acambis under Section 337 of the Tariff Act of 1930, and infringement of its patents and use of proprietary intellectual property (MVA strains and dosing information improperly obtained). The company is seeking to prohibit Acambis from importing or selling its MVA vaccine in the U.S.
According to Acambis, Bavarian Nordic’s patents are invalid and unenforceable, believing it can show evidence that MVA-BN is not novel, the patents are unenforceable through lack of enablement, that Bavarian Nordic failed to provide the U.S. patent office with prior art related to its claims, and that the patents rely on scant scientific evidence. Acambis asserts that MVA-BN is not novel because all MVA viruses, including MVA-BN and prior art strains, have similar replication characteristics.
The claims asserted by Bavarian Nordic against Acambis included how Acambis came into possession of its MVA strain to develop MVA3000. Acambis (OraVax) obtained a sample of MVA-BN from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, which had obtained it, presumably with the understanding it could be used for vaccine development, from the strains original developer, Dr. Mayr, affiliated with Bavarian Nordic. Dr. Mayr did not place in writing any restriction on the NIH’s use of MVA and did not restrict the use of the MVA strain he provided to the NIH. When the NIH released its first RFP, it made its MVA strain publicly available, stating that “collaborative opportunities from NIAID are available to all legitimate parties and include: the availability of a master seed stock of MVA from NIAID...” Acambis received the NIH MVA under a Material Transfer Agreement that granted Acambis “worldwide, non-exclusive rights to make, have made, and use” the NIH MVA “to sell and have sold, and to offer to sell Commercial Products in the Field of Use of Smallpox Vaccines.” During the procurement process for the first MVA contract, NIAID stated to Acambis that “prior to distribution of the material, NIAID determined that it is within its rights to transfer the material to other parties.”
Bavarian Nordic has initiated infringement suits against Acambis in various territories. This includes filing suit in Austria, where MVA3000 is manufactured. The company is seeking to stop Acambis from manufacturing or selling MVA vaccines in Austria, plus monetary damages.
In Sept. 2006, a U.S. International Trade Commission (ITC) administrative law judge somewhat surprisingly concluded that two MVA patents held by Bavarian Nordic were invalid and denied the company’s request for an exclusionary order. Bavarian Nordic responded that it found inconsistencies in the conclusion and was fully confident of having the decision reversed by the full ITC Commission, or by a Federal appeals court. However, even a final adverse decision against the company will have no impact on the validity of its MVA-BN patents, since decisions of the ITC are not considered binding in U.S. federal courts, which ultimately will rule on the validity on patents.
On May 15, 2007, only days before start of its trial, the U.S. Federal Court in the District of Delaware dismissed Bavarian Nordic’s pending claims of conversion, unfair competition and unfair trade acts on summary judgment. The Court ruled that there were no facts in dispute and that no existing case law supports a finding in favor of Bavarian Nordic; and that despite Imvamune originating from virus from Dr. Anton Mayr (Bavarian Nordic), subsequent passages turned the reproduced biological material (MVA 572 FHE - 22.02.1974 or MVA 572) into different personal property and that such material therefore cannot be converted. By the 1990s, precise records concerning the history and source of MVA 572 were not available, but Dr. Mayr was generally recognized as the source, having published about its development, including 572 passages in chicken embryo fibroblast cell culture, and having shared it with poxvirus researchers worldwide for decades. The order basically holds that anyone can use a live biological material as the starting material, however obtained, and avoid liability for conversion by simply reproducing the material. If upheld, this ruling could affect interpretation of ownership of various cell lines. Bavarian Nordic was “confident that this decision will be reversed on appeal."
In July 2007, Acambis and Bavarian Nordic concluded a settlement ending all of their disputes concerning MVA patents. Acambis took a license from Bavarian Nordic, paid an unspecified up-front licensing fee, and will pay unspecified milestone and royalties payments for its MVA vaccine(s). Both companies are now free to develop their respective products with a strong intellectual property position. This also means that others developing non-infectious strains of MVA-based smallpox vaccines are well-advised to either license or carefully avoid Bavarian Nordic’s patent, particularly 6,761,893.
In July 2007, Bavarian Nordic received another European Patent covering MVA. EP 1 420 822 belongs to the same patent family as the issued U.S. 7,097,842.
Other organizations, e.g., the National Institutes of Health (NIH) and Virogenetics/Sanofi Pasteur, have developed vaccinia and other poxvirus-based vaccine patent portfolios that may cover aspects of MVA vaccines. To date, there has been no public indication that these or other organizations are or will challenge ongoing MVA vaccine development. or demand royalties.
Trials: In Dec. 2002, Therion Biologics and the National Institute of Allergy and Infectious Diseases (NIAID) initiated a Phase I trial in healthy vaccinia-naive volunteers with TBC-MVA derived from the MVA vaccine strain. This was the first MVA vaccine to enter U.S. trials.
In May 2004, Bavaria Nordic began a Phase I U.S. trial with its MVA-BN vaccine, Imvamune, comparing Imvamune with Dryvax (see #536) in patients with atopic disorders (such as eczema), a group of patients normally at very high risk for serious vaccinia virus infection, even death, from vaccinia virus infection from conventional smallpox vaccines. A Phase I trial in HIV patients started in 3rd quarter 2004.
In March 2005, Bavarian Nordic reported that Imvamune, “has been shown to be safer and faster in protecting against smallpox infection than traditional smallpox vaccines in development or stockpiled by the government,” and that Imvamune is “expected to be effective in protecting against smallpox infection three days after just one vaccination compared to traditional vaccines (i.e. DryVax) that show protection only after more than 10 to 14 days after vaccination and have a known risk of severe complications.”
In Feb. 2005, Bavarian Nordic reported completion of a Phase II dose-finding study in 165 healthy volunteers; and a Phase l study in 86 healthy volunteers. Ongoing studies include a Phase II study in HIV-infected patients; a Phase I comparing Imvamune to DryVax; and a Phase I study in patients with atopic disorders. Planned studies include three Phase II studies in 2,000 subjects in 2005.
In April 2005, Acambis reported initial results from a double-blind, placebo-controlled, U.S. Phase I trial of MVA3000 in 88 healthy adult volunteers with no prior smallpox vaccinations. At the highest dose and after two doses, 97% of subjects seroconverted to vaccinia virus-specific antibodies and 82% developed vaccinia virus-neutralizing antibodies after two doses. No subjects experienced unexpected or serious adverse events. Also in April 2005, Acambis began a Phase II trial in healthy adults.
In July 2005, a Phase II trial began with Imvamune in HIV-infected patients to determine safety and efficacy in these potentially immune suppressed patients. This followed completion of enrolment and vaccination in a Phase I trial with patients with atopic dermatitis. If Imvamune is found safe in these at-risk populations, this will support its safety in the general population.
In late 2005, three new Phase II studies were initiated with Imvamune in more than 1,200 persons. In 2006, Bavarian Nordic initiated a 5,000-subject Phase III trial(s) expected to support U.S. and other approvals of Imvamune.
In Aug. 2006, Acambis reported results from a randomized, double-blind, placebo-controlled trial Phase II trial of MVA3000 in 590 healthy adult subjects in this which multiple dose levels of MVA3000 were tested against placebo. Of the enrolled subjects 361 had never received a smallpox vaccine, and 229 had previously been vaccinated against smallpox. In vaccine-naive subjects vaccinated at the highest dose level, immunogenicity results were consistent with the findings from an earlier Phase I trial, with 75% of subjects seroconverting after two doses. In previously vaccinated subjects, 88% of subjects vaccinated at the highest dose level seroconverted after two doses.
In Dec. 2006, Bavarian Nordic reported results from its Phase II trial of Imvamune in 91 HIV-infected subjects (CD4 > 350 cells/µL) and 60 healthy subjects. Imvamune was equally well tolerated in HIV infected and healthy subjects. Immunogenicity data showed that 96% of HIV infected subjects previously not vaccinated against smallpox (vaccinia naïve) had a detectable antibody response two weeks after a booster (second) vaccination, which turned out to be equivalent to the healthy control group. The trial confirmed the safety of Imvamune, and provided the first clear evidence that this vaccine is as equally immunogenic in immune suppressed, particularly HIV-infected, subjects as healthy subjects. The company also reported that over 1,200 persons (healthy volunteers, people with atopic dermatitis and HIV-infection) had been vaccinated in three Phase II trials with Imvamune without serious or unexpected side-effects. Bavarian Nordic is also developing a HIV nef antigen vaccine (MVA nef) using MVA-BN as a live viral vaccine vector. Early trials have shown that this vaccine induces an immunogenic response without serious adverse events in HIV-infected persons with more advanced infection (CD4 >250 cells/µL).
In 2007, clinical testing was showing that Imvamune may offer protection against smallpox virus infection in 3-4 days, while protection from current vaccines takes 10-14 days. The optimal dose needed to induce adequate human immunity has not yet been determined..
In Nov. 2007, Bavarian Nordic reported the successful completion of a large, placebo-controlled Phase II trial in 745 healthy subjects who received either one or two doses of Imvamune. The results were a pivotal step on the path to moving Imvamune into Phase III registration trials in order to achieve a BLA for healthy subjects. This study, together with other Phase II studies in immune-compromised persons, was considered pivotal for obtaining an Emergency Use Authorization (EUA), which Bavarian Nordic expected to receive in the second-half of 2008. The purpose of this study, aside from assessing general immune response and safety, was to compare cardiac safety in different study groups following vaccination with Imvamune. The large amount of safety data collected from the 745 people who completed this study confirmed the promising safety and tolerability profile of Imvamune. Imvamune did not result in any clinically significant abnormal cardiac findings and no cardiac events (e.g. cases of myo-/pericarditis). Vaccination resulted in seroconversion (detectable immune responses) in almost all subjects (98.9%) previously not vaccinated against smallpox. Similarly, a single vaccination with Imvamune boosted the immune response in the majority of people who had historically been vaccinated against smallpox. This study completed the Phase II development of Imvamune in healthy subjects, with Phase III studies staring in 2008.
Market: MVA-based smallpox vaccines cost more than other vaccines, e.g., ACAM2000, currently being acquired and stockpiled in large-scale under U.S. an other governments’ contracts (see related entries above). MVA requires a much higher dosage (more virus) to elicit comparable immune responses.
Many presume that, besides immune compromised and others at-risk, MVA vaccines will eventually be used to vaccinate health care professionals. This group had spurned the failed federal vaccination program with Dryvax (see #536), primarily due to the vaccine’s well known adverse effects.
R&D: In May 2004, INCELL Corporation LLC (San Antonio, TX) received a U.S. Air Force contract for development of an oral smallpox vaccine based on MVA.
In Aug. 2006, Emergent BioSolutions Inc. completed acquisition of Vivacs GmbH (Munich, Germany). This included a worldwide license to a modified vaccinia virus Ankara (MVA) strain owned by the Bavarian State Ministry of the Environment, Public Health and Consumer Protection (StMUGV). Emergent also gain exclusive rights to Vivacs’ proprietary MVAtor platform technology, involving use of MVA as a live vaccine vector for presentation of other (non-vaccinia) immunogens. Emergent BioSolutions, active in biodefense vaccines, has assembled infrastructure and technology to develop an MVA vaccine using a strain other than MVA-BN.
Index Terms:
Companies involvement:
Full monograph
541 Smallpox Vaccine/MVA
Nomenclature:
Imvamune [TR US]
Imvanex [TR EU]
Smallpox Vaccine/MVA [BIO]
Modified Vaccinia Ankara smallpox vaccine [SY]
MVA smallpox vaccine [SY]
MVA3000 [SY]
vaccinia virus, live, Modified Vaccinia Ankara strain [SY]
variola virus vaccine [SY]
FDA Class: Biologic BLA
biopharmaceutical products
chicken source materials
vaccines, live
vaccines, viral
chicken embryo (egg) culture
chicken embryo (egg) culture
CTH
Earle's balanced salt solution
Earle's balanced salt solution
mammalian cell culture
MM 294-1/pLW 45, Escherichia coli (E. coli)
murine tumor cells C-127 (C127)
murine tumor cells C-127 (C127)
murine tumor cells C-127 (C127)
vaccines, viral
vaccines, viral
virus culture
apheresis (hemapheresis)
BHK-21 (C-13)
BHK-21 (C-13)
conjugates
conjugates
priority review status
EU666 Biodefense stockpile
EU200 Currently Approved in EU
UM100 Controlled/Gov't Distribution in US
US666 Biodefense stockpile
US001 FDA application expected
EM160 Controlled/Gov't Distribution in EU
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