Status of acute systemic toxicity testing requirements and data uses by U.S. regulatory agencies

Strickland, Judy; Clippinger, Amy J.; Brown, Jerram L.; Allen, David; Jacobs, Abigail; Matheson, Joanna; Lowit, Anna; Reinke, Emily N.; Johnson, Mark S.; Quinn, Michael J.; Mattie, David R.; Fitzpatrick, Suzanne; Ahir, Surender; Kleinstreuer, Nicole; Casey, Warren

doi:10.1016/j.yrtph.2018.01.022

Cited by 73 publications

(56 citation statements)

References 11 publications

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“…To assess general tolerability and immunogenicity, we evaluated LNP-formulated and unformulated ANDV DNA vaccine in rabbits. Here we chose to do a dose-probing study; that is, a single rabbit was utilized per dose over a range of doses 20 . Decreasing concentrations of the ANDV DNA vaccine, or off-target DNA plasmid sharing the same backbone (pWRG7077), were injected intramuscularly using a DSJI (PharmaJet Stratis ® ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Lipid Nanoparticle Formulation Increases Efficiency of DNA-Vectored Vaccines/Immunoprophylaxis in Animals Including Transchromosomic Bovines

Mucker

Karmali

Vega

et al. 2020

Sci Rep

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The use of nucleic acid as a drug substance for vaccines and other gene-based medicines continues to evolve. Here, we have used a technology originally developed for mRNA in vivo delivery to enhance the immunogenicity of DNA vaccines. We demonstrate that neutralizing antibodies produced in rabbits and nonhuman primates injected with lipid nanoparticle (LNP)-formulated Andes virus or Zika virus DNA vaccines are elevated over unformulated vaccine. Using a plasmid encoding an anti-poxvirus monoclonal antibody (as a reporter of protein expression), we showed that improved immunogenicity is likely due to increased in vivo DNA delivery, resulting in more target protein. Specifically, after four days, up to 30 ng/mL of functional monoclonal antibody were detected in the serum of rabbits injected with the LNP-formulated DNA. We pragmatically applied the technology to the production of human neutralizing antibodies in a transchromosomic (Tc) bovine for use as a passive immunoprophylactic. Production of neutralizing antibody was increased by >10-fold while utilizing 10 times less DNA in the Tc bovine. This work provides a proof-of-concept that LNP formulation of DNA vaccines can be used to produce more potent active vaccines, passive countermeasures (e.g., Tc bovine), and as a means to produce more potent DnA-launched immunotherapies. It is now possible to rapidly determine the genomic sequence of emerging infectious disease threats, even before the microbe has been isolated. That is, nonspecific amplification and sequencing of nucleic acid can be performed when virus is difficult to propagate and/or in samples where viable virus no longer exists. This genomic information can then be used to design and synthesize candidate nucleic acid-based vaccines. The vaccines can be used as active vaccines, or as passive vaccines to produce antibody-based medical countermeasures. In order to increase the potency of plasmid DNA vaccines, we have explored the possibility of formulating the DNA using lipid nanoparticles (LNPs). The microbes targeted in this research include Andes virus (ANDV) and Zika virus (ZIKV). ANDV is a South American, New World hantavirus and member of the Family Hantaviridae, Order Bunyavirales. The enveloped virion contains a single stranded, tripartite, negative sense RNA genome. The three segments, S, M, and L, encode the nucleocapsid protein (N), the envelope glycoproteins (G n /G c), and the RNA-dependent RNA polymerase, respectively. ANDV is rodent-borne and causes a severe disease referred to as hantavirus pulmonary syndrome (HPS) in humans. ANDV is the only hantavirus known to transmit person-to-person. The case fatality rate of this virus is >35% even in modern intensive care units. There are no vaccines or drugs approved to prevent or treat HPS 1 .

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Section: Resultsmentioning

confidence: 99%

Lipid Nanoparticle Formulation Increases Efficiency of DNA-Vectored Vaccines/Immunoprophylaxis in Animals Including Transchromosomic Bovines

Mucker

Karmali

Vega

et al. 2020

Sci Rep

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“…Acute toxicity testing is a fundamental test for assessing safety (Donohue & Salminen, 1996) and has been applied in various safety assessment studies (Strickland et al., 2020). In the acute toxicity study, the maximum tolerated dose (LD 0) was 21 g/kg.…”

Section: Discussionmentioning

confidence: 99%

Safety evaluation of aqueous extracts of Sanghuangporus vaninii fruiting body in Sprague–Dawley rats

Huo

Sun

et al. 2020

Food Science & Nutrition

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Sanghuangporus vaninii, called “Sanghuang,” is orally used for health care, tumor, and inflammation treatment in Asia. However, the safety of S. vaninii has not been evaluated. The major compounds analysis showed that aqueous extracts of S. vaninii fruiting body were rich in polysaccharides, nucleotides, and polyphenols. Then, the aqueous was given orally to Sprague–Dawley rats for toxical test. In acute toxicity study, the maximum tolerated dose was 21 g/kg. In 17‐week repeated dose toxicity experiment, all rats had no abnormal reaction among control group, low dose group (0.15 g/kg) and middle dose group (1.00 g/kg). At high dose group (6.00 g/kg), the feces began to darken on 16th day (D16), and turned to drug stained stool on D21, all rats recovered on the 3rd day (D92) of recovery period. During the whole experiment, there were no animal death and no treatment‐related changes in any of the parameters under the all doses. These results indicated the No‐Observed Adverse Effect Level of aqueous extract of S. vaninii fruiting body was 1.0 g/kg.

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“…Accepted methods are available for most acute and topical toxicities. Also, acute systemic toxicity may be predicted, possibly in combination with a limited number of animal experiments (Hamm et al 2017;Strickland et al 2018).…”

Section: Safety Testing Of Drugs and Vaccinesmentioning

confidence: 99%

Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines

et al. 2020

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The COVID-19-inducing virus, SARS-CoV2, is likely to remain a threat to human health unless efficient drugs or vaccines become available. Given the extent of the current pandemic (people in over one hundred countries infected) and its disastrous effect on world economy (associated with limitations of human rights), speedy drug discovery is critical. In this situation, past investments into the development of new (animal-free) approach methods (NAM) for drug safety, efficacy, and quality evaluation can be leveraged. For this, we provide an overview of repurposing ideas to shortcut drug development times. Animal-based testing would be too lengthy, and it largely fails, when a pathogen is species-specific or if the desired drug is based on specific features of human biology. Fortunately, industry has already largely shifted to NAM, and some public funding programs have advanced the development of animal-free technologies. For instance, NAM can predict genotoxicity (a major aspect of carcinogenicity) within days, human antibodies targeting virus epitopes can be generated in molecular biology laboratories within weeks, and various human cell-based organoids are available to test virus infectivity and the biological processes controlling them. The European Medicines Agency (EMA) has formed an expert group to pave the way for the use of such approaches for accelerated drug development. This situation illustrates the importance of diversification in drug discovery strategies and clearly shows the shortcomings of an approach that invests 95% of resources into a single technology (animal experimentation) in the face of challenges that require alternative approaches.

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Status of acute systemic toxicity testing requirements and data uses by U.S. regulatory agencies

Cited by 73 publications

References 11 publications

Lipid Nanoparticle Formulation Increases Efficiency of DNA-Vectored Vaccines/Immunoprophylaxis in Animals Including Transchromosomic Bovines

Lipid Nanoparticle Formulation Increases Efficiency of DNA-Vectored Vaccines/Immunoprophylaxis in Animals Including Transchromosomic Bovines

Safety evaluation of aqueous extracts of Sanghuangporus vaninii fruiting body in Sprague–Dawley rats

Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines

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