Abstract
Agenus reports increased survival rates for its brain cancer vaccine
First vaccines developed for avian influenza A H7N9 virus
Ovarian cancer vaccine shows promise in early clinical trial
No increased risk of GBS following vaccination
Heroin vaccine blocks relapse in animal study
New pediatric vaccine approved in Europe
Safe antigen delivery: Engineered type-III secretion system in bacterial mini-cells
Universal influenza T-cell vaccine effective in an elderly population
Agenus reports increased survival rates for its brain cancer vaccine
The US biotech company Agenus (Lexington, MA) recently reported positive results from a Phase 2 trial of its brain cancer vaccine candidate Prophage G-100. Vaccination resulted in significant increases in both progression-free and overall survival compared to control treatment.
The Phase 2 trial included 46 newly-diagnosed glioblastoma multiforme (GBM) patients, who were treated with the vaccine Prophage G-100 in addition to the current standard of care (SOC)—radiation and temozolomide—or only SOC. Progression-free survival averaged 17 months for those who received the vaccine, compared to 7 months in the non-vaccinated group, representing a 146% increase. Overall survival was increased by 60%, with patients in the vaccinated group living nearly eight months longer on average than those in the control group.
“Those numbers exceed the standard of care by a significant margin,” said Dr Garo Armen, CEO and founder of Agenus Inc. “It’s good news for us, and good news for patients.”
According to a company statement, most of the enrolled patients are still being followed, and both sets of data “will continue to mature as more data are collected“.
The company is pondering options for a Phase 3 trial. One possibility would be a trial in conjunction with a biomarker, which can better predict the vaccine’s chance of success in patients.
“Certainly this program needs to be taken forward,” Dr Armen said. “The question is in what way to maximize the chances of success.”
Agenus was co-founded in 1994 by Garo Armen and Pramod Srivastava, initially under the name Antigenics. To date, the company has no drug approved yet, but readouts of data from Phase 3 trials of its MAGE-A3 vaccine, developed together with GlaxoSmithKline (GSK), are expected later this year. MAGE-A3 is under investigation for treating both melanoma and non-small cell lung cancer.
First vaccines developed for avian influenza A H7N9 virus
A novel avian influenza A H7N9 virus that infects humans was identified on March 30, 2013, in China. The virus is highly pathogenic, killing approximately 20% of the infected subjects. Its spread has been difficult to control in China, because infected birds display no symptoms. While human-to-human transmission of the virus has been rare, genetic changes in the strain could increase contagion and create a pandemic.
In a new study published in The Lancet,1 Chinese researchers correlated genomic sequences from avian influenza viruses with ecological information and performed phylogenetic and coalescent analyses to extrapolate the potential origins of the virus and possible routes of reassortment events. The team, led by Prof. George F Gao from the Chinese Academy of Sciences in Beijing, found that the novel H7N9 virus originated from multiple reassortment events. The HA gene might have originated from avian influenza viruses of duck origin, and the NA gene might have transferred from migratory birds infected with avian influenza viruses along the east Asian flyway. The six internal genes of this virus probably originated from two different groups of H9N2 avian influenza viruses, which were isolated from chickens. Ducks and chickens probably acted as intermediate hosts leading to the emergence of this virulent H7N9 virus. Diversity among isolates implies that the H7N9 virus has evolved into at least two different lineages. The authors suggest that extensive global surveillance is needed, and domestic-poultry-to-person transmission should be closely watched.
In order to prepare for a potential pandemic threat, scientists around the globe have started to work on vaccines against this novel H7N9 virus. At least three companies have announced success in developing candidate H7N9 vaccines.
The international company Greffex recently announced the creation of a comprehensive vaccine for H7N9 avian influenza, using the company’s proprietary GREVAX technology.While most vaccines take several months to develop, this technology enabled scientists to create a vaccine only one month after the virus was characterized. GREVAX technology allows the development of vaccine antigens using a plug-and-play design that can be rapidly applied to multiple emerging infectious diseases.
Another vaccine development company, Protein Sciences Corporation, has also announced the completion of the vector required to manufacture a vaccine against the H7N9 influenza virus. With its proprietary recombinant technology, Protein Sciences can develop vaccines for potentially lethal viruses without using a live pathogen, thereby avoiding putting personnel in danger. The company is prepared to begin manufacturing within a few days of receiving orders for the H7N9 vaccine.
Finally, the biopharmaceutical company Medicago recently announced that it has successfully produced a new virus-like particle (VLP) vaccine candidate for the H7N9 virus. To produce their vaccine, Medicago only requires the genetic sequence of the viral strain, thus limiting the delays that occur using traditional manufacturing systems. The H7N9 VLP vaccine is being purified in preparation for immunogenicity studies in animal models.
It remains to be seen whether any of these vaccines will provide adequate protection against H7N9 infection. A new study, published in the May issue of Human Vaccines & Immunotherapeutics,2 predicts that—due to the low immunogenicity of H7N9 according to bioinformatics—a conventional vaccine for this strain will be weakly immunogenic. In their paper, Dr Anne De Groot and colleagues conclude that novel strategies for improving vaccine immunogenicity will be needed.
References
1. Liu D, et al. Lancet 2013; 381:1926-32; PMID: 23643111; 10.1016/S0140-6736(13)60938-1
2. De Groot AS, et al. Hum Vaccin Immunother 2013; 9:950-6; 10.4161/hv.24939
Ovarian cancer vaccine shows promise in early clinical trial
A personalized ovarian cancer vaccine was successfully tested in a small study at the University of Pennsylvania. Results were presented at the recent American Association for Cancer Research (AACR 2013) annual meeting.
The personalized vaccine is developed in only seven days from trial participants‘ own dendritic cells primed with their tumor cells. It is designed to recognize and trigger an immune response to attack the tumor. In the Phase 1 trial, patients received repeated doses of the vaccine in combination with Roche’s Avastin, which limits blood supply to the tumor.
A total of 65% (20 of 31) of the women responded with either stable disease or a partial response. In these cases, the vaccine elicited tumor-specific T-cell responses against ovarian cancer antigens. The remaining 11 patients who showed no response to the vaccine were given adoptive T-cell therapy as a second wave of treatment, in which 73% of the 11 demonstrated a clear clinical benefit, such as tumor shrinkage.
“We are preventing progression of already existing disease,” Dr Lana Kandalaft from the University of Pennsylvania School of Medicine told Bloomberg. “Most of the patients are now on maintenance vaccine, just to keep the system going. We have not seen them recur. We are seeing how long they can go.”
In one particular case, disease had remained stable for 45 months, which is unusual considering that most advanced ovarian cancer patients are dead within five years. If such an improvement can be replicated in other patients, the treatment could have a big impact on a cancer that kills more than 14,000 women in the US each year. At the very least, the two-step vaccine T-cell treatment shows a potential approach to overcoming cancer’s resistance mechanisms.
No increased risk of GBS following vaccination
No link between vaccines and Guillain-Barré once again was found in a new large study performed by the Kaiser Permanente Vaccine Study Center in Oakland (CA). Study results were recently published in the journal Clinical Infectious Diseases.1
Cases of the nerve-degenerative Guillain-Barré syndrome (GBS) have been reported following a wide range of vaccines. However, a clear association has only been established with the 1976 H1N1 inactivated influenza vaccine, and more recently, The Lancet found a correlation between GBS and the 2009 batch of H1N1 vaccines.2
A long-term review of data for non-pandemic vaccines was lacking, and the new Kaiser Permanente study set out to fill this gap. The researchers identified hospitalized GBS cases at Kaiser Permanente Northern California (KPNC) from 1995 through 2006. Using a case-centered design, they compared the odds of vaccination in the 6 and 10 weeks prior to onset of GBS to the odds of vaccination during the same time intervals in all vaccinated individuals in the entire KPNC population.
The researchers confirmed 415 incident cases of GBS during the study period, which included more than 30 million person-years. Incidence peaked during the winter months. The autoimmune syndrome often arises after an infection, and this was picked up by the data review. Two-thirds of the cases had a documented gastrointestinal or respiratory infection in the weeks prior to developing GBS. Links between GBS and vaccinations were much weaker. In 6% of cases, vaccines were received 6 weeks before the onset of GBS. Of the 25 people who developed GBS after receiving a vaccine, 18 had just been immunized against flu, two against pneumonia, three against tetanus and another three against hepatitis.
Taken together, this large retrospective study found no evidence of an increased risk of GBS following vaccinations of any kind, including influenza vaccination.
Dr Daniel Salmon, a vaccine safety expert from the Johns Hopkins University told Reuters: “The take home message is vaccines are not causing Guillain-Barré Syndrome at a rate, if at all, that would possibly make the benefits of vaccination not worthwhile.”
References
1. Baxter R, et al. Clin Infect Dis 2013; 57:197-204; PMID: 23580737; 10.1093/cid/cit222
2. Salmon DA, et al. Lancet 2013; 381:1461-8; PMID:23498095; http://10.1016/S0140-6736(12)62189-8.
Heroin vaccine blocks relapse in animal study
A new vaccine candidate against heroin, developed by scientists at The Scripps Research Institute (TSRI), has shown promise in preclinical animal studies. The vaccine targets heroin and its psychoactive breakdown products in the bloodstream, and successfully prevents them from reaching the brain.
Heroine addiction is estimated to affect 10 million people worldwide. In addition to psychotherapeutic and pharmacotherapeutic interventions, a vaccine against heroin could be one strategy to minimize the potential for further drug abuse. Developing vaccines against different drugs has been challenging because common drug molecules are too small and simple to sufficiently stimulate the immune system on their own. In the case of heroin, vaccine development has been further complicated by heroin’s rapid metabolism to 6-acetylmorphine and morphine.
The new treatment developed at TSRI has overcome these problems by affixing key fragments of heroin to a larger, more immune-stimulating carrier protein. Moreover, this “dynamic“ vaccine creates antibodies against heroin and its psychoactive metabolites, 6-acetylmorphine and morphine.
Preclinical results for the TSRI heroin vaccine were recently published in the Proceedings of the National Academy of Sciences.1 The study presents evidence of effective and continuous sequestration of brain-permeable constituents of heroin in the bloodstream following vaccination. The result is efficient blockade of heroin activity in treated rats, preventing various features of drugs of abuse: heroin reward, drug-induced reinstatement of drug seeking, and reescalation of compulsive heroin self-administration following abstinence in dependent rats. Even in subjects with a history of dependence, the dynamic vaccine shows the capability to significantly devalue the reinforcing and motivating properties of heroin.
“Heroin-addicted rats deprived of the drug will normally resume using it compulsively if they regain access, but our vaccine stops this from happening,” said Dr George Koob, who chairs TSRI’s addiction research group, the Committee on the Neurobiology of Addictive Disorders. The vaccine does not target opioid receptors or common opioid pharmacotherapeutics, thus in humans it could be used in combination with available treatment options.
Dr Kim Janda from TSRI expects to make minor changes to the heroin vaccine for trials in humans, but said, “We think it is now about as good as it can be.” He is now seeking a pharmaceutical company partner to sponsor those clinical trials and, assuming that they go well, to eventually market the vaccine.
Reference
1. Liu D, et al. Proc Natl Acad Sci USA 2013; 110:9036-41; PMID:23650354; 10.1073/pnas.1219159110
New pediatric vaccine approved in Europe
Sanofi Pasteur MSD‘s pediatric vaccine Hexyon/Hexacima has recently been approved by the European Commission.
The combination vaccine Hexacima offers protection against six diseases in one shot: Diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and Haemophilus influenzae type b (Hib). Hexacima is the only fully liquid, ready-to-use vaccine of its kind. It can be used as primary or a booster vaccination, and is given as three doses at least four weeks apart in accordance with official recommendations.
“Hexyon/Hexacima ready-to-use, 6-in-1 pediatric vaccine will raise the standard of care of vaccination for millions of children,” said Dr Olivier Charmeil, President and CEO of Sanofi Pasteur. “It reduces the number of vaccination visits for infants, and it is more convenient for parents to complete the recommended vaccination schedule and thus better protect their children against six major childhood diseases. We will introduce Hexyon/Hexacima vaccine in countries that are looking for improved and effective solutions for public immunization programs.”
Clinical studies on over 5000 infants were the basis for the EC’s decision to approve the new vaccine, which will be launched to global markets under the name Hexaxim.
Another 6-in-1 vaccine (Infanrix-Hexa, GSK) has been available in the EU market for many years. Five of the vaccine components are supplied as a liquid in a syringe, which is used to hydrate lyophilized Hib vaccine supplied in a separate vial.
Safe antigen delivery: Engineered type-III secretion system in bacterial mini-cells
While live attenuated vaccines are often more immunogenic than subunit vaccines, they have inherent safety issues. Researchers from Yale University were able to circumvent the problem by using bacteria’s own cellular mistakes to deliver a safe vaccine.
Type-III protein secretion systems are being considered for vaccine development as virtually any protein antigen can be engineered for delivery by these nanomachines into the class I antigen presentation pathway to stimulate antigen-specific CD8+ T cells. A limitation in the use of this system is that it requires live virulence-attenuated bacteria, which may preclude its use in certain populations such as children and the immunocompromised.
Now, scientists at Yale have developed a new trick, exploiting a mutation that causes bacteria to create “mini-cells” when they improperly divide. These non-replicating mini-cells contain no DNA and are therefore not pathogenic and extremely safe. The research team, headed by Dr Jorge Galan, successfully assembled the Salmonella typhimurium type III protein secretion system within these bacterial mini-cells. The engineered system was shown to be functional and capable of delivering heterologous antigens to the class I antigen presentation pathway stimulating immune responses both in vitro and in vivo. The study results were recently published in the journal Nature Communications.1
“We have managed to assemble a functional protein-injection machine within bacterial mini-cells, and the amazing thing is that it works,” said Dr Galan, senior author of the paper and Professor of Microbial Pathogenesis and chair of the Section of Microbial Pathogenesis at Yale.
This antigen delivery platform allows to deliver antigens that trigger an immune response without causing an infection, thereby offering a novel approach for vaccine development and cellular immunotherapy. According to Dr Galan, the system could be used to combat cancer as well as a wide variety of infectious diseases.
Reference
1. Carleton HA, et al. Nat Commun. 2013;4:1590; PMID:23481398; 10.1038/ncomms2594
Universal influenza T-cell vaccine effective in an elderly population
The UK based company Immune Targeting Systems (ITS) recently announced positive data from a Phase 2a clinical trial of its lead pan-strain influenza A T-cell vaccine, Flunisyn, in the elderly population.
In contrast to conventional influenza vaccines that induce an antibody response against the virus, Flunisyn vaccination stimulates the production of T cells that recognise and destroy influenza-infected cells. T-cell vaccines offer many clinical advantages over conventional vaccines, especially against rapidly mutating viruses. They can promote immune responses to conserved parts of the influenza virus located within the internal regions of the virus particle that are not presented to the humoral arm of the immune system. Flunisyn is therefore applicable to multiple seasonal and pandemic influenza strains, unlike conventional seasonal influenza vaccines which are strain specific and must be newly produced every year. Another limitation of current seasonal flu vaccines is their low efficacy in the elderly, chronically ill and young children. Earlier this year, the US Centers for Disease Control and Prevention reported that the current season’s flu vaccine is only 9% effective in the over-65 population.
Two previous Phase 1 trials in healthy adult volunteers showed that Flunisyn generated statistically significant cell-mediated immune (CMI) responses to the vaccine and was safe and well tolerated in vaccinated groups compared to placebo. From both trials, the T-cell responses induced by Flunisyn were able to recognize multiple strains of influenza A.
The new Phase 2a study tested Flunisyn in the elderly population, a group where conventional influenza vaccine is poorly effective. Even in this population, Flunisyn induced a robust CMI across a number of influenza antigens, with a responder frequency of 95%. The vaccine was found to have a good safety profile and did not negatively impact on the antibody response to conventional influenza vaccine (TIV) in subjects who received both Flunisyn and TIV. Study results were presented at the recent World Vaccine Congress in Washington D.C. However, it remains to be proven whether a cross-reactive T-cell response of this type will result in clinical efficacy against a range of antigenically divergent influenza strains.
Dr Campbell Bunce, ITS’ R&D Director explained: “Flunisyn represents a real breakthrough—a vaccine that does not need to be re-manufactured each flu season to match circulating strains of influenza virus and because of its synthetic design the vaccine can be produced in quantities to protect the global population.”
Flunisyn also addresses the key demands of the US Food & Drug Administration (FDA), the European Medicines Agency (EMA), and World Health Organization (WHO): prophylactic protection against multiple strains of both seasonal and pandemic influenza, effectiveness for at-risk groups, amenability to repeated dosing, potential for combined vaccination with traditional vaccines and inexpensive, large scale manufacture and stockpiling potential for global population coverage and management of pandemic outbreaks—if it proves to be clinically efficacious.