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, long-lasting therapeutic treatments.
“My work aims to apply a new platform for peptide display and affinity selection, based on the virus-like particles (VLPs) of RNA bacteriophage MS2, to the discovery of candidate vaccine epitopes. It is satisfying to see that what began as pure, curiosity-driven research on the RNA phages, is now being applied directly to problems of human health,” explained Dr. David Peabody, recipient of the 2017 STC.UNM Innovation Fellow Award.
An expert in the structure and function of bacterial viruses, Dr. Peabody received his B.S. in zoology from Brigham Young University and his Ph.D. in biochemistry from the University of Utah. As a postdoctoral fellow studying biochemistry, he trained in the laboratory of Nobel laureate Dr. Paul Berg at the Stanford University Medical School where he focused on gene regulation in mammalian cells and artificially constructed recombinants.
Subsequent to his postdoctoral studies, Dr. Peabody’s research focused on analyzing the genetic and biochemical relationship between coat protein structure and its ability to specifically recognize RNA as a model for virus assembly. Dr. Peabody and his collaborators studied the protein’s binding ability and related it to the molecule’s structure. Dr. Peter Stockley, professor of biological chemistry at the University of Leeds’ Astbury Centre for Structural Molecular Biology, who has collaborated with Dr. Peabody, explains:
“David is world renowned for his elegant genetic dissection of the functions of a simple virus. Bacteriophage MS2, and its close relatives, are some of the simplest infectious organisms on the planet yet, since their discovery in the early 1960s, they have been used to establish multiple fundamental biological principles for the first time. This role continues to the present with a recent landmark EM structure published in Nature, and of course the ongoing use of these systems by David and his colleagues for development of novel vaccines.
David’s natural modesty means that at times he has not received the kudos he deserves from his scientific peers. I got to know him when he came to my laboratory for a short period of sabbatical research. His modesty hides a razor sharp intellect that appears to have an astonishing capacity to formulate elegant genetic assays to uncover the critical features of RNA phage replication and assembly. The clarity of his thinking on these topics, and the beauty of the resulting experiments, often leaves me asking myself “now why didn’t I think of that?”
Relevant to his current award, it is worth mentioning the development and execution of his research program that has resulted in potential real world impacts in the field of synthetic vaccines. In 1996, (Nucleic Acids Research, 24, 2359) David showed that by using genetic engineering it is possible to fuse two polypeptide chains of the MS2 coat protein. This molecule functions in the phage lifecycle as a non-covalent dimer, but David showed it would work successfully if the dimer is made of conjoined monomers. This by itself would have been a trite result, but he went onto use the fused dimer system to interrogate the coat protein-genomic RNA interaction. The RNA phages use an assembly mechanism that depends on multiple coat protein dimer-genomic RNA contacts. We have termed this Packaging Signal-mediated Assembly. The highest affinity-packaging signal is a piece of RNA that forms a structure known as a stem-loop that binds across both monomers of a coat protein dimer. By mutating one-half of his fused dimer at a time, David was able to define the RNA binding sites in each half of the dimer. This work validated the interpretation of X-ray structural data in which we had been involved.
David then built on that finding (Arch Biochem Biophys, 347, 85) showing that genetic dimerization of the coat protein allowed him to insert foreign peptide epitopes into the three-dimensional structure of the protein in such a way that it did not prevent assembly into Virus-like Particles (VLPs). Later he was able to demonstrate that MS2 assembled with the fused coat protein dimer could be used for peptide display, akin to the single-stranded DNA filamentous viruses. This is a landmark achievement in the field for single-stranded RNA viruses (J.Mol.Biol. 380, 252 & 409, 225). Those papers mark the start of his collaboration with his colleague, Dr. Bryce Chackerian, who has expertise in immunology. Together they represent a formidable team, evidence of which can be seen in two recent papers on potential applications of the MS2 technology that David pioneered.
In one (Malaria J, 13, 326) they showed that a monoclonal antibody that binds an essential malarial protein, RH5, blocking infection by the parasite, can be used to select from a degenerate sequence pool VLPs of MS2 carrying a peptide whose sequence matches part of that target protein. Reversing the experiment they showed that such VLPs elicit antiparasite neutralizing antibodies. Using similar approaches they have shown that MS2 VLPs carrying a peptide from the minor coat protein of human papilloma virus (HPV) are highly immunogenic, creating neutralizing antibodies that cross-react with other known highly pathogenic strains of the virus. They have also shown that it is possible to formulate this MS2-based vaccine candidate as a dry powder avoiding issues with the “cold chain” which are so critical for uses in the less developed world (Vaccine, 33, 3346). Malaria and HPV are responsible for huge numbers of deaths every year and are currently lacking effective vaccines. These developments are therefore extremely exciting and newsworthy.
In summary, David’s career and achievements span from fundamental science to direct application in biomedicine. They illustrate the importance of model systems for identification and characterization of basic biological principles and how these can be turned to useful products in areas distinct from the original investigation. I congratulate David on his award and think it fully deserved.”
In 1984, Dr. Peabody joined the Department of Molecular Genetics & Microbiology at the University of New Mexico.
UNM technologies—Vaccine Engineering
Dr. Peabody has worked closely with Dr. Bryce Chackerian, an expert in vaccine development, 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 selfantigens
that are expressed in chronic diseases and cancers.
The bacteriophage VLPs that Dr. Peabody 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- tranded 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. Peabody 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); 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. Peabody 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. David S. Peabody.
Sandra Begay
Chair
STC.UNM Board of Directors