A new malaria vaccine test center will be established in 2008 at the Seattle Biomedical Research Institute (SBRI; WA, USA) in collaboration with the PATH Malaria Vaccine Initiative (MVI; MD, USA). The new Human Challenge Center will serve as the foundation of the Malaria Clinical Trials Center, which also includes the existing SBRI Center for Mosquito Production and Malaria Infection Research.
Worldwide, the malaria parasite Plasmodium falciparum causes more than 1 million deaths annually. The Human Challenge Center will be one of only a few facilities of its kind in the world to provide human testing of malaria vaccine candidates. Various vaccine candidates are being studied that target P. falciparum at different stages of the disease, from the early pre-erythrocytic stage to the destructive blood-stage infection.
“This center will allow us to greatly increase our ability to evaluate whether a new vaccine formulation should advance to testing in clinical trials in malaria-endemic populations,” said MVI director Christian Loucq. “We are particularly excited by the center’s location in Seattle, a community where many people have an interest in global health issues and, as a result, are willing to volunteer for such an important cause – to help save the lives of young children in some of the world’s poorest countries.”
Human challenge is a critical phase in vaccine R&D. The center can provide high-standard healthcare to volunteers and ensure their safety when each clinical trial is being carried out according to US FDA protocols. Results from these human studies will be highly valuable to the malaria research community.
“We see an opportunity here to provide the entire malaria-vaccine research community with additional capacity for testing the many exciting approaches to fighting this disease that are being developed not just at SBRI, but by scientists around the world,” said SBRI’s president and founder Ken Stuart. “Our role is to help the PATH MVI continue to stock the malaria vaccine pipeline with a large cadre of strong candidates backed by hard evidence of their potential effectiveness.”
“By accelerating the search for new malaria vaccines, this center will bring us closer to the ultimate goal of eradicating malaria,” said Regina Rabinovich of the Bill & Melinda Gates Foundation, which provides funding to both SBRI and MVI.
Source: PATH Malaria Vaccine Initiative: www.malariavaccine.org
T-cell receptor mimic (TCRm™) technology for vaccine development
Technology: T-cell receptor mimic (TCRm™)
Manufacturer: Receptor Logic Ltd, TX, USA
Product: Antibodies mimicking T-cell receptors in binding to MHC-presented epitopes
Application: Immunology research, vaccine development
A new agreement has been reached by Receptor Logic Ltd (TX, USA) and Sanofi Pasteur (the vaccine division of Sanofi Aventis Group), in which Receptor Logic will develop T-cell receptor mimics (TCRm™) exclusively for Sanofi Pasteur’ vaccine research.
The new technology TCRm allows the production of specific antibodies that only bind to MHC-presented epitopes of 8–11 amino acids. As such, TCRm will interact with antigen-presenting cells in the same way T-cell receptors would, via the MHC–peptide complex. Applications of TCRm vary from immunology research to therapeutic and diagnostic approaches.
Custom-made TCRm will be used in Sanofi Pasteur’s vaccine research programs. “Receptor Logic has developed a powerful tool [TCRm] aimed at measuring immune presentation. Sanofi Pasteur’s interest in this novel approach supports the potential value of this technology towards the development of vaccines and drugs in the future,” commented Tony Taylor, Senior Vice President of Emergent Technologies, a venture company that funds and manages Receptor Logic.
Source: Receptor Logic Ltd, TX, USA: www.receptorlogic.com
Silencing FOX03a could extend the survival of memory T cells that are crucial in controlling HIV
New findings of a protein, FOX03a, whose inactivation may be the key to control HIV infection, have been published in the March issue of the journal Nature Medicine.
“HIV infection is characterized by the slow demise of T-cells, in particular central memory cells, which can mediate life-long protection against viruses,” said Rafick-Pierre Sekaly, the lead author of the study. “Our group has found how the key protein, FOX03a, is vital to the survival of central memory cells that are defective in HIV-infected individuals even if they are treated.”
The researchers studied the central memory (TCM) and effector memory (TEM) CD4+ T cells from three subject groups: HIV-positive patients successfully treated (ST) with antiviral therapies, HIV-positive patients who do not show any symptoms despite no treatment being administered (elite controllers), and HIV-negative subjects. The TCM and TEM cells, which are essential to HIV control, from the elite controllers survived longer than those from ST or HIV-negative subjects, thanks to the inactivation of FOX03a protein.
“Given their perfect resistance to HIV infection, elite controllers represent the ideal study group to examine how proteins are responsible for the maintenance of an immune system with good antiviral memory,” said coauthor Elias El Haddad. “This is the first study to examine, in people rather than animals, what shields the body’s immune system from infection and to pinpoint the fundamental role of FOX03a in defending the body.”
The study was funded in part by public (Genome Canada and Genome Quebec) as well as private (BD Biosciences) sources. “Public–private collaborations such as this play an important role in advancing medical research,” said Robert Balderas of BD Biosciences, also a coauthor of the study. “BD Biosciences was pleased to provide powerful research instruments, reagents and technical expertise to support this breakthrough research.”
Paul L’Archevêque, president and chief executive officer of Genome Quebec, also commented: “This discovery, the first such study in humans, is a major step forward in the understanding of how our immune system responds to life-threatening infections such as HIV. This advance stems directly from research cofinanced by Genome Quebec, which demonstrates the impact that genomic research can have in improving healthcare.”
Sources: van Grevenynghe J, Procopio FA, Zhong HE et al. Transcription factor FOXO3a controls the persistence of memory CD4+ T cells during HIV infection. Nat. Med. 14, 266–274 (2008); Université de Montréal, QC, Canada: www.umontreal.ca
DNA vaccine candidate for melanoma reaches final stage of Phase I clinical trial
Stage: Phase Ia/Ib
Aim: Safety and immunogenicity
Vaccine: DNA encoding tyrosinase
Delivery: TriGrid™ electroporation
Patient: Stage IIb–IV melanoma
Melanoma patients are being recruited for the final stage of a Phase I clinical trial using a DNA vaccine delivered by the TriGrid™ electroporation system (Ichor Medical Systems, CA, USA). The vaccine contains DNA encoding a type of tyrosinase, which is a common protein found in melanoma cells and is a target for vaccination. The DNA vaccine was developed by researchers at the Memorial Sloan-Kettering Cancer Center (NY, USA).
“We believe that the immune system can be trained to recognize cancer as something that is foreign and dangerous. But delivering enough of the DNA vaccine into cells so that the encoded antigen can be produced in sufficient amounts to cause an immune response has been a significant challenge,” said the study’s principal investigator Jedd Wolchok, a medical oncologist at Memorial Sloan-Kettering.
DNA vaccines need to be delivered inside the target cells, where the DNA can be expressed into antigens and immune responses can be triggered. Electroporation utilizes a low-voltage electric current to create a temporary opening on the cell surface, through which DNA can enter. Ichor’s TriGrid system has been shown to increase the DNA delivery efficacy over 100-times compared with other methods.
In the earlier stage of the trial, the melanoma DNA vaccine was delivered with TriGrid electroporation five-times over 15 weeks to six patients, three at the low dose and three at the medium dose. The highest dose of the vaccine will be tested in this final stage of the trial.
“We are delighted to be collaborating with Memorial Sloan-Kettering’s prestigious team,” said Ichor’s chief executive officer Bob Bernard. “DNA-based vaccines hold tremendous promise to treat numerous serious diseases. We are hopeful that results of this and other studies now in progress will show the TriGrid to be an enabling platform for the entire field of DNA-based vaccines.”
Source: Ichor Medical Systems, Inc., CA, USA: www.ichorms.com; Memorial Sloan-Kettering Cancer Center, NY, USA: www.mskcc.org Inhibiting
New potential target for tumor vaccine
A recent publication in the March issue of the journal Nature Medicine has revealed that the protein A20 could serve as a new target for tumor vaccines.
The suppression effect of Treg cells keeps the immune system under control to avoid autoreactive immune responses. However, at the same time, it limits the efficacy of vaccination approaches that aim to elicit immune responses against tumor cells. Researchers from the University of Southern California (CA, USA) have identified a new protein (A20) that plays an important role in inhibiting dendritic cells (DCs) from producing inflammatory cytokines and signals.
‘A20-silenced DCs showed spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines and had different effects on T-cell subsets,’ wrote the authors. These DCs were able to overcome the suppression effect of Treg cells, and the resulting immune responses could target and destroy various tumors in mice, which were resistant to current vaccination strategies.
The authors concluded that A20 is ‘an antigen presentation attenuator in control of anti-tumor immune responses during both the priming and the effector phases and provides a strategy to overcome Treg cell-mediated suppression in an antigen-specific manner, reducing the need to directly target Treg cells.’
Source: Song XT, Kabler KE, Shen L, Rollins L, Huang XF, Chen SY. A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression. Nat. Med. DOI:10.1038/nm1721 (2008).
New funding for innovative breakthroughs in AIDS vaccine research
VaxDesign Corp. (FL, USA) has received new funding for its Modular Immune In vitro Construct (MIMIC™) system. The funding is part of the new Innovation Fund, which was set up by the International AIDS Vaccine Initiative (IAVI) for potential technology breakthroughs in AIDS vaccine research.
The MIMIC is an automated, in vitro testing system where immune cells from a person are cultured in a coin-sized well of a multiple-well plate. The cells are then challenged with a test vaccine, and innate and adaptive immune responses (including humoral and cellular immunity) are measured. Using the MIMIC system, immune responses from many different individuals can be screened and predicted simultaneously and quickly without the need of animal studies.
“Currently, preclinical testing of AIDS vaccines is a labor-intensive, lengthy and expensive process. We hope this pioneering technology will enable us to rapidly test AIDS vaccine candidates and predict their effectiveness in humans in a way that has never before been possible with animal models,” said Wayne Koff, IAVI’s Senior Vice President. “What’s more, by collecting immune cells from different donors, promising vaccine candidates can be tested in diverse populations before they enter human testing.”
“HIV is a formidable adversary, and evaluating AIDS vaccine candidates will be the ultimate test for our MIMIC technology. We are excited to partner with IAVI to help develop the next generation of AIDS vaccine candidates,” said William Warren, president and chief executive officer of VaxDesign.
Yellow fever and rabies vaccines will be tested first on the MIMIC system to see whether the in vitro prediction matches what is observed in vaccinated humans. If successful, the MIMIC system will be used to screen novel AIDS vaccine immunogens at the IAVI’s AIDS Vaccine Development Laboratory in Brooklyn (New York, USA).
“Now more than ever, the AIDS vaccine field needs out-of-the-box concepts that can help us develop better candidates for testing,” said Seth Berkley, IAVI President and Chief Executive Officer. “VaxDesign’s novel technology is one of many hidden gems that we plan to seek out and develop for AIDS vaccine research.”
The IAVI’s Innovation Fund aims to support biotechnology companies whose novel ideas may help solve problems in AIDS vaccine research. Successful companies are able to receive their award after only 8 weeks following application. The fund is initially set up for 3 years with a total of US$10 million to be awarded, half of which comes from the Bill & Melinda Gates Foundation.
“The Gates Foundation is proud to support IAVI in exploring innovative approaches for addressing the challenges of discovering an effective HIV vaccine,” said José Esparza, senior advisor on HIV vaccines for the Gates Foundation. “IAVI and its partners have a track record of advancing novel vaccine technologies, and of moving promising concepts rapidly into development.”
Source: International AIDS Vaccine Initiative: www.iavi.org; VaxDesign Corp., FL, USA: www.vaxdesign.com
New finding may pave the way to a streptococcal vaccine
A modified M1 protein from the bacterium Streptococcus was shown to become stable and could be used as a vaccine component. Results have been published in the March issue of the journal Science.
Group A Streptococcus (GAS) is a common yet virulent group of bacteria, causing many human diseases including pneumonia, upper respiratory tract and wound infections. Toxins released by certain GAS strains can cause rash in scarlet fever and muscle necrosis in necrotizing fasciitis, a life-threatening ‘flesh-eating’ disease. Antistreptococcal antibodies following throat infections can also cause damages to various tissues, especially heart valves, leading to rheumatic fever, an acute inflammatory disease. Worldwide, GAS affects more than 600 million people and kills 400,000 each year.
A research team from the University of California San Diego (CA, USA) has studied the structure of M1 protein, a surface protein of GAS that protects the bacteria from white blood cells. “Using x-ray crystallography, we determined that M1 protein has an irregular, unstable structure,” said the lead author Partho Ghosh. “This is a crude analogy, but if you imagine that M1 protein is a zipper, then the front half of the molecule is zipped up. However, unfavorable amino acids prevent the molecule from zipping up all the way,” explained Case McNamara, first author of the study.
M1 unstable structure makes this important protein a difficult target for study and use as a vaccine antigen. This characteristic also allows M1 protein to perform various functions, while mimicking proteins of human tissues, especially the heart. Antibodies against M1 protein can also targets heart muscles, leading to autoimmune responses, such as rheumatic fever.
“We created a modified version of M1 with a more stable structure, and found that it is just as effective at eliciting an immune reaction, but safer than the original version of M1, which has serious drawbacks to its use in a vaccine,” said Ghosh. “It was clear from the literature that mutations of unfavorable amino acids to favorable amino acids would allow the molecule to continue to zip up,” added McNamara.
“Certain antibodies that are produced by the immune system against M1 protein have been shown to cross-react with normal human tissues including heart muscle, potentially triggering the serious autoimmune disease known as rheumatic fever. M1 protein can also act as a toxin, producing clotting abnormalities and lung injury when injected into mice. Therefore, our results with modified M1 provide very novel insight about the role of M proteins in invasive GAS disease and rheumatic heart disease,” summarized coauthor Victor Nizet.
Antibodies against the modified, stabilized M1 protein was much less reactive against heart muscle, did not cause complications, such as lung injuries in mice, while remaining protective against GAS. ‘Idealized M proteins appear to have promise as vaccine immunogens,’ the authors concluded.
Sources: McNamara C, Zinkernagel AS, Macheboeuf P, Cunningham MW, Nizet V, Ghosh P. Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence. Science 319(5868), 1405–1408 (2008); University of California San Diego, CA, USA: www.ucsd.edu