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Feinen B.,Center for Biologics Evaluation and Research | Petrovsky N.,Vaxine Pty Ltd | Verma A.,Center for Biologics Evaluation and Research | Merkel T.J.,Center for Biologics Evaluation and Research
Clinical and Vaccine Immunology | Year: 2014

Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Petrovsky N.,Vaxine Pty Ltd
Expert Review of Vaccines | Year: 2013

Interview with Jenaid Rees, Commissioning Editor Nikolai Petrovsky is the Chairman and Research Director of Vaxine Pty Ltd, an Australian biotech company that specializes in novel vaccine adjuvants. He also holds the position of Director of Endocrinology at Flinders Medical Centre (Adelaide, Australia), Professor of Medicine at Flinders University, Vice President and Secretary General of the International Immunomics Society and serves on the Editorial Board of our sister journal, Expert Review of Clinical Immunology. He completed his PhD at the University of Melbourne (Victoria, Australia) then moved to Canberra (Australia) where he held conjoint positions at the Canberra Hospital, University of Sydney, Canberra University, Australian National University and the National Health Sciences Centre. In 2004, he moved to his current position at Flinders Medical Centre. His research interests include vaccine adjuvants, autoimmunity and immuno informatics. In 2009, his company Vaxine won the AMP Innovation Award at the Telstra business awards and Australia's coolest company award from Australian Anthill magazine. He has been an investigator for major international diabetes studies including ADVANCE, FIELD and DREAM and is a principal investigator on several large grants from the NIH. He has authored over 140 scientific papers, and his team has developed novel vaccines against influenza, hepatitis B, sting allergy, malaria, Japanese encephalitis, rabies and HIV, in addition to developing the world's first effective H1N1/2009pdm (swine flu) pandemic influenza vaccine. © 2013 Informa UK Ltd.

Petrovsky N.,Flinders University | Petrovsky N.,Vaxine Pty Ltd
Drug Safety | Year: 2015

Use of highly pure antigens to improve vaccine safety has led to reduced vaccine immunogenicity and efficacy. This has led to the need to use adjuvants to improve vaccine immunogenicity. The ideal adjuvant should maximize vaccine immunogenicity without compromising tolerability or safety. Unfortunately, adjuvant research has lagged behind other vaccine areas such as antigen discovery, with the consequence that only a very limited number of adjuvants based on aluminium salts, monophosphoryl lipid A and oil emulsions are currently approved for human use. Recent strategic initiatives to support adjuvant development by the National Institutes of Health should translate into greater adjuvant choices in the future. Mechanistic studies have been valuable for better understanding of adjuvant action, but mechanisms of adjuvant toxicity are less well understood. The inflammatory or danger-signal model of adjuvant action implies that increased vaccine reactogenicity is the inevitable price for improved immunogenicity. Hence, adjuvant reactogenicity may be avoidable only if it is possible to separate inflammation from adjuvant action. The biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer’s disease. While existing adjuvants based on aluminium salts have a strong safety record, there are ongoing needs for new adjuvants and more intensive research into adjuvants and their effects. © 2015, Springer International Publishing Switzerland.

Cooper P.D.,Vaxine Pty Ltd | Cooper P.D.,Australian National University | Petrovsky N.,Vaxine Pty Ltd
Glycobiology | Year: 2011

We report a novel isoform of -d-[2 → 1] poly(fructo-furanosyl) -d-glucose termed delta inulin (DI), comparing it with previously described alpha (AI), beta (BI) and gamma (GI) isoforms. In vitro, DI is the most immunologically active weight/weight in human complement activation and in binding to monocytes and regulating their chemokine production and cell surface protein expression. In vivo, this translates into potent immune adjuvant activity, enhancing humoral and cellular responses against co-administered antigens. As a biocompatible polysaccharide particle, DI is safe and well tolerated by subcutaneous or intramuscular injection. Physico-chemically, DI forms as an insoluble precipitate from an aqueous solution of suitable AI, BI or GI held at 37-48°C, whereas the precipitate from the same solution at lower temperatures has the properties of AI or GI. DI can also be produced by heat conversion of GI suspensions at 56°C, whereas GI is converted from AI at 45°C. DI is distinguished from GI by its higher temperature of solution in dilute aqueous suspension and by its lower solubility in dimethyl sulfoxide, both consistent with greater hydrogen bonding in DI's polymer packing structure. DI suspensions can be dissolved by heat, re-precipitated by cooling as AI and finally re-converted back to DI by repeated heat treatment. Thus, DI, like the previously described inulin isoforms, reflects the formation of a distinct polymer aggregate packing structure via reversible noncovalent bonding. DI forms the basis for a potent new human vaccine adjuvant and further swells the growing family of carbohydrate structures with immunological activity. © 2010 The Author.

Petrovsky N.,Flinders University | Petrovsky N.,Vaxine Pty Ltd | Cooper P.D.,Vaxine Pty Ltd | Cooper P.D.,Cancer Research Laboratory
Expert Review of Vaccines | Year: 2011

The role for adjuvants in human vaccines has been a matter of vigorous scientific debate, with the field hindered by the fact that for over 80 years, aluminum salts were the only adjuvants approved for human use. To this day, alum-based adjuvants, alone or combined with additional immune activators, remain the only adjuvants approved for use in the USA. This situation has not been helped by the fact that the mechanism of action of most adjuvants has been poorly understood. A relative lack of resources and funding for adjuvant development has only helped to maintain alum's relative monopoly. To seriously challenge alum's supremacy a new adjuvant has many major hurdles to overcome, not least being alum's simplicity, tolerability, safety record and minimal cost. Carbohydrate structures play critical roles in immune system function and carbohydrates also have the virtue of a strong safety and tolerability record. A number of carbohydrate compounds from plant, bacterial, yeast and synthetic sources have emerged as promising vaccine adjuvant candidates. Carbohydrates are readily biodegradable and therefore unlikely to cause problems of long-term tissue deposits seen with alum adjuvants. Above all, the Holy Grail of human adjuvant development is to identify a compound that combines potent vaccine enhancement with maximum tolerability and safety. This has proved to be a tough challenge for many adjuvant contenders. Nevertheless, carbohydrate-based compounds have many favorable properties that could place them in a unique position to challenge alum's monopoly over human vaccine usage. © 2011 Expert Reviews Ltd.

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