Promising results of a vaccine against glioblastoma multiforme (GBM) tumors in prolonging patients’ lives have been presented at the American Society of Clinical Oncology Annual Meeting in Chicago (IL, USA) earlier in June.
The vaccine induces immune responses against epithelial growth factor receptor variant III (EGFRvIII), a protein present in approximately half of GBM tumors but absent in normal tissues. This leads to the killing of these tumor cells and prevents their regrowth. The study was carried out at Duke University’s Preston Robert Tisch Brain Tumor Center (NC, USA).
The study involved 23 GMB patients receiving standard therapy. The patients received the vaccine monthly in conjunction with temozolomide, which appeared to enhance the immune response to EGFRvIII. “This reflected something of a surprising conclusion, because it stands to reason that chemotherapy (temozolomide), which suppresses the body’s immune system, would make the vaccine less effective,” said the lead investigator John Sampson of Duke University. “What we found was that the opposite is true. While the body is recovering from chemotherapy, immune response is actually stronger as the immune system overcompensates in order to right itself. It’s the perfect time to introduce a vaccine.”
Vaccinated patients survived for 33.1 months following diagnosis, whereas GMB patients receiving only standard therapy only lived for 14.3 months on average. Vaccinated patients also showed longer survival time without tumor regrowth and progression (16.6 vs 6.4 months in nonvaccinated patients).
“We’re more than doubling survival time in this (vaccinated) group, and we have some patients who are 4, 5 or 6 years out from diagnosis, which is virtually unheard of in these people,” said Sampson. “This vaccine represents a very promising therapy for a cancer that comes out of the blue and robs people of something most of us take for granted – time. The possibility of doubling expected survival – with few if any side effects – would represent a big step and a lot of hope for this group of patients.”
The vaccine will enter a Phase III clinical trial at more than 20 sites across the USA.
Sources: Sampson JH, Archer GE, Bigner DD et al. Effect of EGFRvIII-targeted vaccine (CDX-110) on immune response and TTP when given with simultaneous standard and continuous temozolomide in patients with GBM. Presented at: American Society of Clinical Oncology Annual Meeting, Chicago, IL, USA 30 May–3 June 2008; Duke University School of Medicine, NC, USA http://medschool.duke.edu
US FDA grants fast-track status to Wyeth’s 13-valent pneumococcal conjugate vaccine
An investigational vaccine, manufactured by Wyeth Pharmaceuticals (PA, USA), containing six pneumococcal serotypes (1, 3, 5, 6A, 7F and 19A) in addition to the seven serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) currently included in the company’s vaccine Prevnar® (also known as PCV7), has been granted fast-track status by the US FDA.
Pneumococcal disease is caused by the bacterium Streptococcus pneumoniae and is a leading cause of death in children under 5 years of age. Infections can be invasive (such as bacteremia) or localized (such as pneumonia and otitis media).
“While the incidence of pneumococcal disease has been substantially reduced since our introduction of Prevnar in the United States, pneumococcal disease remains a health threat to children, specifically as emerging strains, such as 19A, become more prevalent,” said Emilio Emini, executive vice president of Wyeth Pharmaceuticals. Wyeth is now seeking to extend its Prevnar pediatric indication to include new pneumococcal serotypes. “We are very pleased that the FDA has granted fast-track designation to our investigational 13-valent vaccine for pediatric use”, said Emini.
Fast-track designation allows Wyeth’s new vaccine to be reviewed by the FDA in sections while the whole application is being completed. The company plans to complete the US filing of its new vaccine for pediatric use in early 2009, while the vaccine is being studied in several Phase III clinical trials worldwide in both infants and adults.
Source: Wyeth Pharmaceuticals, PA, USA www.wyeth.com
Novel ‘pseudoinfectious’ vaccines produced against West Nile and Japanese encephalitis
Researchers at the University of Texas Medical Branch (UTMB; TX, USA) have developed novel vaccines to protect against West Nile and Japanese encephalitis viruses. The vaccines were produced using a pioneering technique that the researchers hope will promote the future development of ground-breaking vaccines against other diseases, such as dengue virus and yellow fever.
Current methods to control West Nile virus revolve around mosquito control by elimination of breeding sites and through the use of mosquito repellents. These methods have their own drawbacks, and a vaccine would provide a more favorable approach to dealing with this growing problem.
A number of vaccines exist to control Japanese encephalitis, but all suffer from different problems. The concept of these new vaccines was formulated by Peter Mason and Ilya Frolov of the UTMB. These ‘single-cycle’ or ‘pseudoinfectious’ vaccines contain genetically modified flaviviruses, and thus ensure that each virus only infects a single cell. This renders the virus ‘crippled’ and prevents the virus spreading, yet the virus can still produce viral proteins necessary in the induction of immune protection. “With these vaccines, we mimic a viral infection and get amplification of the antigens that are important for stimulating an immune response without amplification of the virus”, said Mason.
In order to create the West Nile vaccine, scientists deleted the part of the West Nile virus genome that codes for a capsid (C) protein – a crucial protein for the virus to move between cells. In doing so, large quantities of virus particles were produced that had capsids but lacked the ability to pass the capsid gene on to their progeny.
“A vaccine virus particle grown in the C-protein-expressing cells can only infect one cell in a vaccinated individual,” explained Mason. “Once it gets into that cell, in order to make a new particle, it needs the C protein – and cells in the vaccinated host do not have the gene to make the C protein. But it can still make all the immunogenic proteins that the virus normally makes, and it can still generate strong immunity.”
The C protein-less West Nile virus genome was used to create the Japanese encephalitis vaccine in combination with a process called chimerization, which involves replacing the genes for two immunogenic proteins with their Japanese encephalitis virus counterparts.
Flaviviruses cause immense human affliction, with a small number of successful vaccines being produced. The creation of a range of chimerized single-cycle flavivirus vaccines holds great promise as protection against a variety of other diseases caused by flaviviruses.
Sources: Ishikawa T, Widman DG, Bourne N, Konishi E, Mason PW. Construction and evaluation of a chimeric pseudoinfectious virus vaccine to prevent Japanese encephalitis. Vaccine 26(22), 2772–2781 (2008); University of Texas Medical Branch, TX, USA www.utmb.edu
GlaxoSmithKline’s pre-pandemic bird flu vaccine, Prepandrix™, approved for use in the EU
Trade name: Prepandrix™
Manufacturer: GlaxoSmithKline
Indication: Prevention of H5N1 influenza in subjects 18–60 years of age
A positive step forward in movements to control a potential global bird flu pandemic were made this month with the European Commission’s approval of GlaxoSmithKline (GSK)’s Prepandrix™ vaccine across all 27 member states of the EU. The vaccine is designed to be administered to populations in a pre-emptive fashion to help stop the spread of the deadly H5N1 virus, in the event of it mutating into a form that can jump from human-to-human, which many experts believe is inevitable. According to WHO records, since 2003, 382 infections, including 241 deaths have been confirmed as a result of the virus, which is normally only transmitted to humans from infected birds. Since the first reported case of a person infected with H5N1 in Hong Kong in 1997, the virus has spread among birds in Asia, Africa and many parts of Europe. Experts believe that the proliferation of the virus within bird populations may lead to an increase in the chance of the emergence of new form that can more easily infect humans, and result in a global pandemic that would potentially affect millions.
The new vaccine is based on current strains of the H5N1 virus from Vietnam and Indonesia and is believed to be more effective than current vaccines based on earlier strains, which may struggle to protect patients against small mutations in the virus.
“This vaccine marks a significant step in the world’s ability to cope with an influenza pandemic”, said Jean-Pierre Garnier.
Despite the very recent regulatory approval of Prepandrix, countries such as the USA, Switzerland and Finland have already begun to create stockpiles of the vaccine in preparation for future H5N1 outbreaks in humans.
Source: GlaxoSmithKline www.gsk.com
Juvaris BioTherapeutics’ adjuvant enters a Phase I clinical trial
Adjuvant name: JVRS-100
Adjuvant nature: Cationic lipid–DNA complex
Manufacturer: Juvaris BioTherapeutics, CA, USA
Clinical trial: Phase I, randomized, double-blind, controlled
Aim: Safety, tolerability and immunogenicity (dose-sparing effect)
A lead product of Juvaris BioTherapeutics, Inc. (CA, USA), the adjuvant JVRS-100, will enter a Phase I clinical trial to test its safety, tolerability and immunogenicity when coadministered with a commercial influenza vaccine.
JVRS-100 is a cationic lipid–DNA complex designed to target Toll-like receptors and enhance immune responses when accompanying a vaccine. In a recent online article of the FASEB Journal, JVRS-100 mixed with Fluzone®, an influenza vaccine by Sanofi Pasteur, resulted in a significant increase in antibody titers in tested animals (mice, rabbits and nonhuman primates) compared with the vaccine alone. The adjuvant also enhanced cellular (T-cell) immune responses. The dose-sparing effect of JVRS-100 was also demonstrated using other prophylactic and therapeutic vaccines.
“JVRS-100 has demonstrated the ability to significantly increase immune responses of existing vaccines in preclinical studies, providing a potential opportunity to improve influenza vaccine efficacy,” said Grant Pickering, president and chief executive officer of Juvaris. “This double-blind trial will evaluate varying dose amounts of JVRS-100 and is designed to provide safety information, dose determination and the primary immunological response data used to determine efficacy for adjuvanted vaccines. While one influenza vaccine will be used in the study, we believe the results will inform about the broad applicability of JVRS-100 for use with many available vaccines.”
Worldwide, approximately 1 billion people catch seasonal influenza each year, with 5 million severe cases and 500,000 deaths, mostly in the elderly. Although influenza vaccines are commercially available, they are effective in only 30% of the elderly. Adjuvants are substances that may help reducing the antigen dose while boosting the vaccine effectiveness, thus a good universal adjuvant is always desirable in vaccine development.
This randomized, double-blind, controlled Phase I trial will enroll 128 healthy subjects. Adjuvant effects of different JVRS-100 doses coadministered with an influenza vaccine will be assessed in comparison with the vaccine alone. The study will also evaluate dose-sparing effect of JVRS-100 coadministered with vaccines containing low antigen doses.
“There is a great need to improve upon the efficacy of influenza vaccines particularly given their ineffectiveness in the elderly, who stand to benefit the most from vaccination, but unfortunately receive the least amount of protection,” said Eric Sheldon, an investigator of the clinical trial. “The JVRS-100 adjuvant has demonstrated promising preclinical activity and we look forward to evaluating this candidate in a randomized Phase I trial.”
Sources: Callejo B, Lay M, Carroll TD et al. Adjuvanting of Fluzone® with JVRS-100 in mice, rabbits and non-human primates demonstrates increased immunogenicity and dose-sparing. FASEB J. 22, 1068.26 (2008); Juvaris BioTherapeutics, Inc, CA, USA www.juvaris.com