November 1, 2006 (Vol. 26, No. 19)
New Technology, Such as Viral Vectors, Makes Vaccines More Commercially Viable
The vaccine industry is a hotbed of activity. News of vaccines moving through the clinical pipeline and reaching the market, novel vaccine and viral vector technology emanating from industry and academia, and new disease targets, immunization strategies, and target populations appear regularly on health-related news services. These advances are expanding the spectrum of vaccines and opening new markets with highly attractive commercial potential.
A range of viral vectors for use in vaccines and gene therapy are now in the clinic, led by adenovirus-vectors and recombinant pox virus vectors. Recent progress in the market, however, such as the approval of Gardasil®, Merck’s (www.merck.com) vaccine against HPV and two oral, live attenuated vaccines against rotavirus infection—Merck’s RotaTeq® and GlaxoSmith-Kline’s (GSK; www.gsk.com) Rotarix®, is what has brought renewed excitement in this once ho-hum field. “Gardasil really opened up people’s eyes,” says Dana Leach, senior vp of business development and COO of Pharmexa (www.pharmexa.com). “It straddles the divide as it is an antiviral vaccine with potentially an anticancer effect.”
Other recent additions to the vaccine toolkit include a shingles vaccine (Zostavax™, Merck) to prevent against reactivity of varicella zoster, the chickenpox virus, and accelular pertussis boosters, which also protect against diphtheria and tetanus (Boostrix, GlaxoSmithKline; Adacel, sanofi-aventis (www.sanofi-aventis.com).
Just five years ago, however, vaccines were not viewed as commercially attractive products. The approval of Gardasil, significant financial investments to develop vaccines against bioterrorism agents, a new focus on pandemic flu, and the hope surrounding cancer vaccines potentially prolonging survival and enabling the use of lower doses of chemotherapeutic drugs has created a paradigm shift, says Jens Vollmar, M.D., medical director at Bavarian Nordic (www.bavarian-nordic.com).
It has clearly been an extraordinarily visible year for vaccines, says Dino Dina, M.D., CEO of Dynavax (www.dynavax.com). It is interesting, Dina notes, that despite these innovations and the recognition in the industry that vaccines have the potential to be billion-dollar products, “there are no commercial-level independent companies—they are all part of big pharma.”
In the future, protective vaccines against a range of infections that plague travelers and even therapeutic vaccines to combat metabolic disorders, such as diabetes, will be key components of the discovery and development pipelines in a growing number of biotech companies and represent attractive in-house and licensing opportunities for big pharma.
The HIV vaccine market is also growing, according to Dr. Vollmar. “In the past it was thought feasible and necessary to have a vaccine that would give sterilizing immunity. But now, a partially protective vaccine that would not prevent the infection but rather would control the HIV virus when it enters the body would be seen as a major breakthrough. Even such an imperfect vaccine that could keep the viral load at a low level could provide a tremendous benefit in HIV endemic regions. It would prolong the period of latency and help control the epidemic by reducing the transmission to other persons.”
The growing elderly population is another attractive group being targeted for vaccine development, with prophylactic vaccines for age-related disorders, such as Alzheimer’s disease and therapeutic cancer immunotherapies, in development. Cell culture-based influenza vaccines and needleless flu shots, as well as pandemic flu vaccines and immunizations against potential bioterrorism agents are other examples of vaccine targets that would expand traditional age groups for immunization.
Viral Vector Platforms Evolve
Leach sums up the evolving history of vaccine technology as follows: “Protein vaccines have not been particularly good at developing T-cell responses, DNA vaccines have not been particularly good at developing antibody responses, and plasmid DNA has not been particularly good in humans. Viral vectors and other special delivery methods will hopefully bridge that gap.”
Pharmexa’s lead therapeutic vaccine, based on its GV1001 technology targeting telomerase, is a peptide vaccine that targets both helper T cells and cytolytic T cells. Telomerase represents a different type of cancer vaccine target, according to Leach, “because it is a functional target and is necessary for maintaining the immortality of cancer cells.” The most advanced application of GV1001 is in pancreatic cancer, with Phase III trials under way.
Therapeutic cancer vaccines will likely require multiple serial vaccinations to maintain an anticancer effect. “Multiple vaccinations is a technical hurdle to be overcome when using a viral vector,” says Leach. The risk is that the patient’s immune response to the viral vector used to deliver an antigenic payload will dominate the response to the target antigens.
Strategies being evaluated to overcome the multiple vaccination issue include prime-boost approaches or alternating use of different viral vectors. A group of researchers working with the Cancer Research Institute/Ludwig Institute for Cancer Research’s Cancer Vaccine Collaborative reported in PNAS promising clinical findings in late-stage metastatic melanoma using a prime-boost strategy to induce a therapeutic immune response. A small number of patients received multiple doses of a recombinant vaccinia vector carrying the NY-ESO-1 tumor antigen and a recombinant fowlpox-NY-ESO-1 vaccine. The treatment stimulated both humoral and cellular immune responses with evidence of disease stabilization, delayed progression, and even tumor regression.
Alan Kingsman, Ph.D., CEO of Oxford BioMedica (www.oxfordbiomedica.co.uk), on the other hand, sees the field of cancer immunotherapy moving toward more highly engineered vaccines that will incorporate novel tumor antigens and ultimately combinations of antigens that can elicit an even more potent immune response.
Oxford Biomedica’s cancer immunotherapy products are designed to drive an immune response against self-antigens and would be administered in cycles of multiple vaccinations. From both a medical and economic perspective, this represents a significant shift in perspective from traditional prophylactic vaccine administration.
TroVax, Oxford Biomedica’s lead product, delivers the 5T4 cancer antigen using a pox (modified vaccinia ankara, or MVA) virus vector and has potential use in most solid tumors. Phase III trials are set to begin in renal cell carcinoma, with ongoing Phase II studies in colorectal, breast, and prostate cancer.
In general, “viral vectors and molecular techniques are gaining momentum,” asserts Bill Enright, senior director and head of vaccine business development at GenVec (www.genvec.com). They offer three key advantages: the ability to engineer vaccines for defined targets, a choice of different vectors with distinct benefits, and the ability to manufacture large quantities of vaccine cost effectively in cell culture.
Selected for its versatility, tolerability, and broad applicability, the adenoviral vector-based vaccine platform employed by GenVec for the development of its prophylactic vaccines for HIV, malaria, foot and mouth disease in animals, and influenza enables vaccine production in cell culture. The company’s multistage malaria vaccine contains two antigens that target both the blood and liver stages of infection.
With four therapeutic viral vector-based products in development, Transgene (www.transgene.fr) is pursuing the cancer and infectious disease markets. Its vaccine strategy involves introducing immunostimulatory molecules and viral or tumor-associated antigens.
Transgene’s lead product, TG4010, targets non-small-cell-lung cancer in combination with chemotherapy and is in a Phase IIb study in Europe in patients with advanced-stage disease. The vaccine is comprised of an MVA-based vector and the MUC1 tumor-associated antigen.
“MVA is a very safe vector—nonreplicative and nonintegrative,” says Jean-Yves Bonnefoy, Ph.D., vp of R&D. “This virus allows you to bring into it quite a significant chunk of foreign DNA. Additionally, based on data we are accumulating in man, immunity to MVA does not seem to be a handicap—and that is a major plus.”
Transgene’s TG4001 vaccine is indicated for the treatment of HPV-induced precancerous cervical lesions. The MVA vector expresses the E6 and E7 antigens of HPV16 together with IL-2. Phase II results were reported in April: 18 women with high-grade cervical intraepithelial neoplasia (CIN 2/3) related to HPV16 infection received three injections of the vaccine. Of the 18 women, 10 had normal colposcopic evaluations of the cervix at six months, nine had no evidence of CIN 2/3, and nine had no HPV16 mRNA. “This is the first time it has been shown that a therapeutic vaccine has worked on a chronic infection,” says Philippe Poncet, CFO. Larger studies are planed to confirm these results.
TG1042, an adenovirus-vectored vaccine expressing interferon-g, has completed a Phase I/II trial in patients with cutaneous B-cell or T-cell lymphoma who have failed radiotherapy. The goal is to induce a nonspecific local immune response.
Over the past year, Dr. Bonnefoy has also observed growing recognition of the potential value of combining new classes of therapeutic vaccines with existing cancer treatment strategies to take advantage of their complementary and sometimes synergistic effects. The addition of immunotherapy may allow for the use of lower doses of chemotherapeutic agents with improved outcomes.
Avant Immunotherapeutics (www.avantimmune.com) collaborated with GSK on the development of Rotarix and is producing several oral, single-dose vaccines against bacterial targets aimed at preventing diarrhea and enteric diseases. Although the company’s bacterial vector platform is based on live attenuated cholera or typhoid fever vaccines, it believes that it can use this technology to vector viral antigens to protect against viral disease, according to Una S. Ryan, Ph.D., president and CEO of Avant.
Following promising Phase II results of its CholeraGarde® cholera vaccine this summer, Avant reported that the International Vaccine Institute had received a $21-million grant from the Bill & Melinda Gates Foundation for a Cholera Vaccine Initiative that will include further trials of CholeraGarde, including immunization concurrent with measles vaccination and use in HIV-positive patients. Phase III trials planned for Bangladesh are designed to compare vaccinated villages (vaccination of adults, children, and infants) with unvaccinated villages for disease incidence.
Avant’s typhoid fever vaccine is in Phase I/II testing, with a Phase II study anticipated to get under way in the first half of 2007. Its cholesterol ester transfer protein (CETP) vaccine aims to raise levels of HDL and has completed Phase II testing. The company has reformulated the CETP vaccine with a new adjuvant, a TLR ligand, and is now testing this new vaccine formulation.
The company plans to apply its bacterial vaccine platform as vectors for delivering various disease antigens, such as enterotoxigenic E. coli or plague. According to Dr. Ryan, one of the company’s ultimate goals is to combine several of its vaccines to create a super-protectant against the many potential causes of traveler’s diarrhea. Another planned application of the technology is to develop a preventive vaccine for pandemic flu.
Lentigen (www.lentigen.com) is leveraging its LentiMax™ lentiviral vector system in a recently announced partnership with Dharmacon (www.dharmacon.com) to develop and manufacture lentiviral expression reagents for gene-silencing applications. The lentiviral reagents will deliver shRNA expression vectors into cells for RNAi-mediated gene silencing.
On the therapeutic front, Lentigen continues to develop its lentiviral vector system as a manufacturing platform for vaccine, Mab, and therapeutic protein production. Its lead target is pandemic and seasonal influenza. Within five weeks the company can produce virus-like particle-based vaccines containing three to four viral proteins, including a hemagglutinin neuraminidase targeting the desired virus strain, according to Boro Dropulic, Ph.D., founder and CEO of Lentigen.
Other advantages of the lentiviral platform include the ability to produce virus-like particles (VLPs) in standard manufacturing cell lines and long harvest times, because VLPs do not kill the cells. Ongoing collaborations in the area of gene therapy focus mainly on cancer with additional projects in regenerative medicine and infectious diseases.
Influenza-Seasonal and Pandemic
Vaxin (www.vaxin.com) is also developing adenovirus-vectored vaccines, including human influenza vaccine, a vaccine against Alzheimer’s disease, and an immunization to protect poultry against avian influenza.
Two types of flu vaccines are in development. One type includes improved conventional influenza vaccines incorporating adjuvants to boost the immune response. These will not, however, prevent against new influenza strains that present a risk for pandemic flu.
VaxInnate (www.vaxinnate.com) is exploring the role of the innate immune system in regulating adaptive immunity. The company is identifying ligands that activate Toll-like receptor (TLR) pathways to stimulate a more potent immune response to disease antigens.
The company’s lead flu vaccine program targets an antigen conserved across influenza A strains, linked to a ligand for TLR-5. Jeff Powell, Ph.D., vp of research, says that the vaccine “has the potential to provide an antibody response that could protect for more than one year and cross multiple strains,” and he anticipates that the vaccine will enter the clinic next year.
Dynavax is developing a universal flu vaccine using invariant genes and proteins, based on the company’s TLR-9 agonist-based immunostimulatory sequence (ISS) technology. The vaccine contains two proteins: recombinant nuclear protein (NP), which is invariant across all influenza A strains, and M2E, a matrix surface protein that induces formation of cytotoxic antibodies capable of destroying infected cells.
“We have shown that immunization with NP can protect mice against challenge with pandemic flu strains,” says Dina. “The animal data, including studies in primates, are supportive that the vaccine will work in humans.” It will enter the clinic in about 15 months. Dina envisions the combined use of these core proteins with other company’s influenza vaccines to augment their potency and broaden their protection to cover potential pandemic flu strains.
In addition, the company has a heplisav hepatitis B vaccine in Phase III studies and Dynavax hopes to bring it to market within two years. Also, a collaboration with the NIH focuses on development of third-generation, lyophilized anthrax vaccine that could be stored for long periods of time at room temperature. In addition, the company recently announced a research collaboration and license agreement with AstraZeneca(www.astrazeneca.com) for the discovery and development of TLR-9 agonist-based therapies for the treatment of asthma and chronic obstructive pulmonary disease.
PowderMed’s (www.powdermed.com) H3 DNA vaccine against influenza is about to enter the clinic. Healthy volunteers will be immunized and later challenged with a weakened version of the H3N2 strain of influenza virus. The vaccine consists of gold particles coated with DNA delivered using a needle-free system. PowderMed is leveraging this same technology to develop an avian flu vaccine.
Crucell’s (www.crucell.com) H9N2 virosomal vaccine is already in large-scale clinical trials to protect against avian influenza virus infection in humans. About 560 healthy adult volunteers will receive one of three H9N2 vaccines: either a whole virion vaccine without an adjuvant; a whole virion vaccine with an alum adjuvant; or a virosomal subunit vaccine. The trial will also assess an intradermal delivery route with the aim of reducing the amount of antigen needed.
Evolving HIV Vaccines
HIV vaccines may not offer the pizzazz of a blockbuster new drug or a pandemic flu vaccine, with the largest markets in developing countries. Consequently, there will be substantial pressure on vaccine producers to keep costs low, as well as provide HIV vaccines free of cost to poor nations. Yet many companies are pursuing the challenging task of developing and testing a preventive HIV vaccine, and others are bent on pursuing therapeutic vaccines that can overcome the challenge of creating a successful immunotherapeutic for a patient population that is immunologically compromised.
The unmet need is great, and the number and diversity of vaccine strategies is growing, with a variety of vaccines now in clinical testing. The Chinese government recently announced results of the country’s first human trial of an HIV vaccine. In the U.S., big pharma is leading the way, with Merck’s candidate adenoviral vector-based vaccine in Phase II studies, and competing DNA and recombinant protein products in the clinic at Sanofi-Aventis, Wyeth(www.wyeth.com), Novartis(www.novartis.com), and GlaxoSmithKline.
Bavarian Nordic’s vaccines are all based on MVA, an attenuated pox virus. A therapeutic HIV (MVA nef) vaccine is in Phase II studies, with a prophylactic vaccine strategy against HIV also in clinical development. Imvamune®, a prophylactic third-generation vaccine for smallpox, delivers the naked MVA viral vector and is currently in large Phase II trials and is providing safety data to support the company’s other vaccine programs.
Pharmexa’s multiepitope EP 1090 vaccine to treat HIV is in Phase I/II studies with ongoing trials experimenting with naked DNA, new delivery systems, and alternative viral vectors aimed at enhancing the immune response.
Bavarian Nordic and Pharmexa are collaborating on a prophylactic prime-boost HIV vaccine strategy. Bavarian Nordic has both preventive and therapeutic HIV vaccine candidates in the pipeline. Vical’s (www.vical.com) prime-boost strategy combines immunization with a plasmid DNA vaccine and an adenoviral vector-based vaccine and is in a Phase II trial.
GenVec’s therapeutic HIV vaccine also relies on a prime-boost approach; it entered the clinic this summer. The NIH-sponsored Vaccine Research Center is conducting a Phase I study to assess a DNA prime/GenVec adenovector-based boost vaccine strategy to treat HIV infection. The HIV vaccine targets multiple clades (A,B, and C) and multiple antigens (a gag-pol fusion protein) and “will be a worldwide vaccine,” says Bill Enright of GenVec. A Phase II efficacy trial in 10,000–15,000 patients is planned for early 2007.
Other products in development include CytRxs(www.cytrx.com) DP6-001 prime-boost vaccine regimen, Mymetics’(www.mymetics.com), AlphaVax’ (www.alphavax.com) prophylactic vaccines, and Bio-Bridge Science’s (www.bio-bridge-science) oral HIV vaccine.
The NIH awarded CytoPulse Sciences (www.cytopulse.com) a $2-million grant to commercialize its Easy Vax DNA vaccine delivery system. The grant will fund a two-year project to develop a pilot manufacturing system for the device, evaluate the device in humans, and complete development and test the safety and efficacy of a dengue DNA vaccine as a model for the delivery of polynucleotide vaccines against biodefense pathogens.
The Easy Vax consists of an array of hundreds of small needles coated with the vaccine. In the presence of an electric field, the DNA penetrates dendritic cells in the skin, which then present the foreign material to stimulate an immune response.
Vaxin presented encouraging results of animal tests with its E. coli-vectored cutaneous vaccines in the journal Infection and Immunity. According to the company, 90% of mice given a topical E. coli-based tetanus vaccine survived lethal challenge with Clostridium tetani, while untreated mice died. Similarly, 55% of mice treated with a cutaneous E. coli-vectored anthrax vaccine survived lethal intranasal challenge with Bacillus anthracis spores.
Earlier this year, BioVex (www.biovex.com) initiated a Phase II trial of OncoVEXGMCSF in malignant melanoma and in head and neck cancer. The vaccine delivers an oncolytic virus that kills tumor cells and induces them to secrete GMCSF.
Intercell’s (www.intercell.com) therapeutic vaccine for hepatitis C is in Phase II trials.
Ark Therapeutics Group (www.arktherapeutics.com) reported positive results from a Phase II trial of its Trinam® gene-therapy product for preventing blood vessel blockage in kidney dialysis patients that have undergone vascular access graft surgery. The grafts of treated patients remained functional on average more than five times longer than those of the control group. Trinam delivers the gene for vascular endothelial growth factor in an adenoviral vector (Ad-VEGF-D).
Nabi Biopharmaceuticals’ (www.nabi.com) NicVAX® targeting nicotine addiction to promote smoking cessation entered a Phase IIb proof-of-concept study in May 2006, with results expected in mid-2007. The company’s StaphVAX® vaccine to prevent hospital-acquired Staphylococcus aureus did not meet the primary endpoint in Phase III trials. Based on a subsequent review of the program, Nabi has decided to pursue development of StaphVAX and is modifying the structural characteristics of the vaccine and various product-testing procedures.
Cytos Biotechnology (www.cytos.com) is developing several therapeutic vaccines as part of its Immunodrugs™ program. CYT-009-GhrQb, an obesity vaccine designed to induce ghrelin-specific antibodies, is in a Phase I/II trial. Other products in the clinic include Immunodrugs targeting nicotine addiction and Alzheimer’s disease, allergy, asthma, and atopic dermatitis, psoriasis, hypertension, and melanoma.
In October, a report in the New England Journal of Medicine presented positive treatment results of a Phase II/III trial with Tolamba™, an immunotherapeutic vaccine comprised of a TLR9 agonist linked purified Amb a 1, the main ragweed allergen. The treatment was well-tolerated and reduced allergy symptoms, including ragweed-induced allergic rhinitis, with symptom relief extending at least through the second ragweed season.
In late summer, Protein Sciences (PSC, www.proteinsciences.com) licensed its FluBlok recombinant influenza vaccine to Japan-based UMN Pharma (www.umn pharma.com). The agreement grants UMN rights to manufacture and market the vaccine in Japan for both annual and pandemic flu use. PSC plans to file a BLA for FluBlok in early 2007.
Based on disappointing results of a Phase III trial in patients with advanced pancreatic cancer, Therion Biologics (www.therionbio.com) announced that it would not file a BLA for Panvac-VF for this indication. The therapeutic vaccine is also being tested in patients with advanced ovarian, colorectal, or non-small-cell-lung cancer.
The company’s Prostvac-VF vaccine did not meets its primary efficacy endpoint of improving progression-free survival in men with advanced prostate cancer in a Phase II trial completed earlier this year. Study results did, however, suggest that the vaccine may be beneficial in patients with less advanced Dendreon (www.dendreon.com) submitted the clinical and nonclinical sections of its rolling submission of a BLA to the FDA for sipuleucel-T (Provenge®), the company’s active immunotherapeutic for the treatment of asymptomatic patients with metastatic, androgen-independent (hormone refractory) prostate cancer. The submission contains clinical trial data supporting an overall survival advantage of four and a half months on average compared to placebo. Dendreon’s second product candidate, Lapuleucel-T, targets Her2/new positive cancers.