Tonight we honor a University of New Mexico researcher and inventor who has devoted his life’s work to developing a new way to make vaccines. This new technology has nearly limitless potential to treat infectious and chronic diseases that have so far eluded effective, longlasting therapeutic treatments.
“I have been working on vaccine development using nanoparticle-based platforms for over 20 years. Overall, the aim of my work is to develop simple, effective vaccines that make an impact on human health worldwide,” explained Dr.Bryce Chackerian, recipient of the 2017 STC.UNM Innovation Fellow Award.
Dr. Chackerian received his B.A. in molecular biology at the University of California, Berkeley, and his Ph.D. in microbiology from the University of Washington. As a postdoctoral fellow studying virology and immunology, he then trained in Dr. John Schiller’s laboratory at the National Cancer Institute. Dr. Schiller is a National Institutes of Health (NIH) distinguished investigator and deputy chief of the Laboratory of Cellular Oncology at the National Cancer Institute (NCI). It was at the NCI, that Dr. Chackerian began to study virus-like particles (VLPs) as vehicles for developing vaccines.
“I am very pleased to be able to congratulate Bryce for receiving this well-deserved and aptly named STC.UNM Innovation Fellow Award; Bryce has certainly demonstrated that he is an innovative fellow,” said Dr. Schiller, who recalled his work with Dr. Chackerian: “Bryce joined my lab as a postdoc after receiving his Ph.D. at the University of Washington, where, under the direction of Julie Overbaugh, he developed an innovative assay for monitoring HIV infection that became the standard in the field. After discussions of possible projects, he had the intuition (and boldness) to take on the highest risk/highest potential project we discussed, namely to develop a vaccine strategy to break B cell tolerance to self-proteins.”
The goal was to essentially fool the immune system into thinking that it was experiencing a virus infection and so generate large amounts of antibodies to self-peptides displayed on the virus surface, as routinely happens to the virion surface proteins during fulminant virus infections. Bryce reasoned that a key feature that alerts the immune system to make a potent antibody response against a virus is the uniquely high density of the repetitive elements on the virus surface. To mimic this aspect of virion structure, he developed a novel method to display self-polypeptides at high density on the surface of HPV virus-like particles, structures that we had previously generated and which serve as the basis of the current HPV vaccines. Bryce was remarkably successful in both the technological development of strategy and in the proof-of-concept demonstration that the approach could work.
In a highly cited publication in the Journal of Clinical Investigation, he showed that virus-like display of a circulating pro-inflammatory self-protein, called TNF-alpha, could induce a thousand-fold high level of antibodies against this protein than previous vaccination strategies, leading to protection from TNF-induced arthritis in a mouse model. He went on to define what features of virus-like display were critical for breaking B cell tolerance to self. These fundamental insights made it possible for Bryce, and others, to develop more “user-friendly” virus-like display platforms for the induction of antibodies against a variety of self-proteins. In this regard, Bryce has been especially fortunate to have a long-term collaboration with UNM’s David Peabody, an expert in the structure and function of bacterial viruses.
I believe that Bryce’s work is destined to have a major impact on public health. Monoclonal antibody therapies have been remarkably successful in combating a wide range of chronic diseases, from inflammatory disease to cardiovascular disease and cancer. However, the cost of the long-term administration of manufactured monoclonal antibodies is prohibitive for most of the world. Bryce’s breakthrough in developing vaccines that can induce the patient’s own body to make antibodies against the same chronic disease targets holds great potential for bringing the promise of monoclonal antibody therapies to the masses.”
In 2004 Dr. Chackerian joined the Department of Molecular Genetics & Microbiology at the University of New Mexico. He is also a member of the UNM Comprehensive Cancer Center and the Center for Infectious Diseases and Immunity. His laboratory focuses on vaccine development— particularly the use of virus particles as platforms for antigen display. Using this novel platform, the UNM inventors are busy discovering and developing new vaccine candidates to some of the world’s most problematic infectious and chronic diseases.
UNM Technologies—Vaccine Engineering
Dr. Chackerian has worked closely with Dr. David Peabody, an expert in the structure and function of bacterial viruses, to construct VLPs from RNA bacteriophages and develop an innovative VLP technology platform that allows for rapid vaccine discovery. The bacteriophages (viruses that infect bacteria) can be produced at high yields, are very adaptable to protein engineering and are non-infectious. The technology platform integrates epitope (the part of the antigen molecule where antibodies attach) identification (antigen/antibody binding) with the VLP structure’s highly immunogenic display.
VLPs are nanostructures that occur naturally and self-assemble as virus-like particles from many virus families, such as those that include the HIV virus, the Hepatitis C virus and bacteriophages. VLPs lack the viral genetic material necessary for infection; but, they retain their external structure for repetitive, high-density antigen display that mimic the organization of native viruses but are unable to replicate. They are multivalent structures, meaning there are many places on the structure where attachment to the antigen or antibody can occur.
VLPs can also be synthesized and engineered in the lab, and are an especially useful and effective way to produce vaccines against the viruses from which they are derived. The VLPs serve as very effective scaffolds for packing antigens in dense, repetitive arrays that then provoke a highly immunogenic and long-lasting response. Because VLPs lack genetic material, they may provide a safer alternative to traditional vaccines, which use live-attenuated or inactivated viruses. Another critical advantage of VLPs is that they can be used to boost the antibody response to many molecules, such as self-antigens that are expressed in chronic diseases and cancers.
The bacteriophage VLPs that Dr. Chackerian uses in the platform technology are made from Leviviruses, specifically MS2, PP7, AP205, and Qß. The VLPs can be grown in large amounts in bacteria (in this case E. coli) and have a naturally encapsidated single-stranded RNA. The genetic material of the antigen is inserted into the VLP and displayed on its surface. To avoid the protein folding that can result from this process and interfere with VLP assembly, the inventors have engineered a coat protein (the shell enclosing the genetic material) of the MS2 RNA bacteriophage that is very stable and highly tolerant of foreign insertions that allow for the recovery of the genetic material. Using this flexible platform based on bacteriophage MS2 VLPs, the inventors can display specific epitopes on the surface of VLPs and test for an immune response. They have been able to create very large, diverse libraries of VLPs that display random peptide (small antigen) sequences.
The technology is an improvement over current phage display methods which cannot display foreign antigens in high enough density to be powerfully immunogenic. Current methods require that a synthetic version of the identified epitope be made and then linked to a more immunogenic carrier protein. Because the new structural carrier is no longer linked to the original phage structure, the epitope often loses its ability to induce antibodies that can mimic the selected antibody. The innovation in the UNM vaccine discovery technology integrates the identification of the epitope and the vaccine function on the same structural platform into a single particle so that the VLP becomes the vaccine.
Using this flexible platform with an expanding number of available monoclonal antibodies (lab-made antibodies), Dr. Chackerian has identified VLP’s that induce neutralizing antibodies against a number of viruses, pathogens, and chronic diseases, such as Human Papillomavirus (HPV); Nipah Virus; blood-stage malaria; Staphylococcus aureus (including the antibiotic-resistant MRSA strain); the Respiratory Syncytial Virus (RSV); LDL cholesterol and triglycerides associated with heart disease; and tau proteins associated with Alzheimer’s Disease and traumatic brain injuries.
Cervical cancer is the second most common and fifth deadliest cancer in women worldwide. Eighty-five percent of cervical cancers occur in developing countries. The UNM HPV vaccine is a second generation, universal vaccine that targets the L2 epitope on a PP7 bacteriophage VLP. It has broad, long-lasting protection with a single dose against diverse subtypes of the virus. Current HPV vaccines are type specific against two high-risk subtypes that are associated with cervical cancers but provide suboptimal protection against other high-risk subtypes causing cervical cancer and anogenital cancers.
Current HPV vaccines are also expensive, require a series of shots, and refrigeration—all obstacles to effective distribution in developing countries. Recent conversion and testing of the UNM vaccine in dry powder form by Dr. Chackerian and his co-inventors have shown that the dry-powder form of the vaccine retained its immunogenicity after storing at 37 C° (98.6 F°) for 14 months. This could have an enormous impact on the cost and distribution of the vaccine in the developing world.
Malaria remains a public health problem globally, particularly in sub-Saharan Africa and South Asia where, according to the Centers for Disease Control and Prevention, the disease led to approximately 214 million cases and caused 438,000 deaths in 2015. Most of the victims are young children. Untreated malaria can lead to severe complications and death. The Plasmodium falciparum parasite causes the severest type of malaria. Symptoms of malaria appear
during blood-stage infection when the parasite has invaded red blood cells. The UNM malaria vaccine uses a MS2 bacteriophage VLP that targets the AIKK epitope of the P.falciparum protein RH5 (an adhesion molecule necessary for red blood cell invasion) that potently inhibits parasite invasion.
The HPV and malaria vaccines are in clinical development with the NIH/NIAID product development program and biotechnology company Agilvax. The importance of innovations in vaccine development, particularly to developing countries, cannot be underestimated. Vaccines that are more effective, faster to create, and cheaper to make are a global need that require our ingenuity to treat preventable infectious diseases and the new and unknown ones on the horizon. And now an entirely new class of vaccines is being developed for chronic diseases, the new treatment frontier.
The STC.UNM Board of Directors is honored to present the 2017 STC.UNM Innovation Fellow Award to Dr. Bryce Chackerian.
Sandra Begay
Chair
STC.UNM Board of Directors