Vaccine development is an expensive, multi-year effort from conception to patient administration. The problems of time and expense with vaccine development are often associated with “whole microbe”-based vaccine approach and classical methods of production, e.g. fertilized chicken eggs. Classic passivation of an infectious microbial agent by chemical treatment or biological re-engineering to modify known/established virulent genes, requires substantial resource investments and regulatory approval. Yet, despite these hurdles, vaccines are one of the most effective ways to prevent infectious disease proliferation. With the advent of modern molecular biology methods, sub-unit vaccines have become an interesting alternative. This approach involves cloning and expression of immunogenic microbial proteins only, not growing and attenuating live microbes. While more convenient, subunit vaccines have their challenges, e.g. antigen/immunogen epitope discovery (isolating the agent responsible for eliciting a protective immune response), epitope purification and epitope conjugation remain significant challenges. This approach, however, holds the potential for enabling rapid development of new protective vaccines consistent with responding to emerging threats. The possibility of bioterrorism as well as emerging infectious pathogens (West Nile Virus, Yellow Fever, Coronaviruses, etc.) require novel, rapid and inexpensive approaches to accelerate vaccine development to protect against these threats.
LLNL is interested in developing a universal platform for the delivery and presentation of any protein antigen, including toxin, viral and bacterial proteins, with apparent concomitant adjuvant activity to enhance the host immune response.
LLNL and University of Texas Medical Branch (UTMB) have used nickel-chelating nanolipoprotein particles (Ni-NLPs) as a universal vaccine platform for five main reasons:
- the approach is scalable enabling chemical manufacturing approaches, avoiding timely and expensive bio-processing, i.e., growing in fertilized chicken eggs;
- nickel-chelating ability of the Ni-NLPs allows conjugation of any (His)-tagged protein or other immunogenic molecule, opening the door to thousands of potential antigens;
- Ni-NLPs can act as articulate delivery systems, similar in size to certain pathogens while also enabling patterned, oriented and concentrated/clustered antigen presentation;
- formation of Ni-NLPs is amenable to the incorporation of secondary additives to enhance immune response (e.g. non-human scaffold proteins, chemokines, cytokines, pattern-recognition receptor agonists and immune stimulatory molecules, synthetic or natural, known or unknown at this time); and
- additional adjuvants, can be incorporated into Ni-NLPs for further enhanced immunogenic ability.
More information on Ni-NLPs can be found in recent publications:
- Bioconjugate Chemistry, 2009, Vol. 20, Issue 3, pp.460-465
- Bioconjugate Chemistry, 2010, Vol. 21, Issue 7, pp. 1321-1330
This invention can be developed for rapid sub-unit vaccine development. By conjugating any of the thousands of His-tagged biomolecules, e.g. proteins, peptides, toxins, carbohydrates and the like to Ni-NLP constructs, an effective protective vaccine construct can be realized. Protection of armed forces and the general public can be realized potentially with direct, systematic and compliant product development.
Initial tests have been performed in mice inoculated with West Nile Virus (WNV) conjugated with Ni-NLPs and then challenged with WNV. The survival rate is greater than eighty percent relative to non-inoculated control animals. Other systems LLNL is looking to test include tularemia, H5/NI, H1/N1, etc. LLNL has filed U.S. Patent applications:
- US2009/0192299 "Nanolipoprotein Particles and Related Methods and Systems for Protein Capture, Solubilization, and/or Purification"
- US2009/0311276 "Nanolipoprotein Particles and Related Compositions, Methods and Systems"
- US2010/0092567 "Immunostimulatory Nanoparticles and Related Compositions, Methods and Systems"
- US2011/0059549 "Methods and Systems for Producing Nanolipoprotein Particles"