Equine Polyclonal Antibodies Prevent Acute Chikungunya Virus Infection in Mice

Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen that causes chikungunya disease (CHIK); the disease is characterized by fever, muscle ache, rash, and arthralgia. This arthralgia can be debilitating and long-lasting, seriously impacting quality of life for years. Currently, there is no specific therapy available for CHIKV infection. We have developed a despeciated equine polyclonal antibody (CHIKV-EIG) treatment against CHIKV and evaluated its protective efficacy in mouse models of CHIKV infection. In immunocompromised (IFNAR−/−) mice infected with CHIKV, daily treatment for five consecutive days with CHIKV-EIG administered at 100 mg/kg starting on the day of infection prevented mortality, reduced viremia, and improved clinical condition as measured by body weight loss. These beneficial effects were seen even when treatment was delayed to 1 day after infection. In immunocompetent mice, CHIKV-EIG treatment reduced virus induced arthritis (including footpad swelling), arthralgia-associated cytokines, viremia, and tissue virus loads in a dose-dependent fashion. Collectively, these results suggest that CHIKV-EIG is effective at preventing CHIK and could be a viable candidate for further development as a treatment for human disease

Pharmacokinetic and Pharmacodynamic Effects of Polyclonal Antibodies against SARS-CoV2 in Mice

Despite ongoing vaccination efforts to prevent SARS-CoV-2 infections, treatment tools are still necessary to address the ongoing COVID-19 pandemic. We report here that COVID-HIGIV, a human immunoglobulin product for treatment of COVID-19, provided a significant survival benefit in SARS-CoV-2 infected transgenic mice compared to controls. COVID-HIGIV also has similar pharmacokinetic profiles in healthy and SARS-CoV-2 infected mice over time after intravenous administration, with identical or comparable Tmax, Cmax, AUC0–∞ and Cl. AUC0–last increased and mean residence time, T1/2, and Vd reduced in infected animals compared to healthy animals. These data suggest that COVID-HIGIV may be an effective treatment for SARS-CoV-2 infection when given early after exposure

Efficacy of equine botulism antitoxin in botulism poisoning in a guinea pig model.

BackgroundBotulism is a disease caused by neurogenic toxins that block acetylcholine release, resulting in potentially life threatening neuroparalysis. Seven distinct serotypes of botulinum neurotoxins (BoNTs) have been described and are found in nature world-wide. This, combined with ease of production, make BoNTs a significant bioweapon threat. An essential countermeasure to this threat is an antitoxin to remove circulating toxin. An antitoxin, tradename BAT (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine)), has been developed and its efficacy evaluated against all seven serotypes in guinea pigs.Methods and findingsStudies were conducted to establish the lethal dose and clinical course of intoxication for all seven toxins, and post-exposure prophylactic efficacy of BAT product. Animals were monitored for signs of intoxication and mortality for 14 days. Guinea pig intramuscular LD50s (GPIMLD50) for all BoNTs ranged from 2.0 (serotype C) to 73.2 (serotype E) of mouse intraperitoneal LD50 units. A dose of 4x GPIMLD50 was identified as the appropriate toxin dose for use in subsequent efficacy and post-exposure prophylaxis studies. The main clinical signs observed included hind limb paralysis, weak limb, change in breathing rate/pattern, and forced abdominal respiration. Mean time to onset of clinical signs ranged from 12 hours (serotype E) to 39 hours (serotype G). Twelve hours post-intoxication was selected as the appropriate time point for intervention for all serotypes apart from E where 6 hours was selected because of the rapid onset and progression of clinical signs. Post-exposure treatment with BAT product resulted in a significantly (p0.008 scaled human dose for serotypes A, B, C, F and G, at >0.2x for serotype D and >0.04x for serotype E.ConclusionsThese studies confirm the efficacy of BAT as a post-exposure prophylactic therapy against all seven known BoNT serotypes

Combination therapy with antibiotics and anthrax immune globulin intravenous (AIGIV) is potentially more effective than antibiotics alone in rabbit model of inhalational anthrax.

BACKGROUND: We have evaluated the therapeutic efficacy of AIGIV when given in combination with levofloxacin and the effective window of treatment to assess the added benefit provided by AIGIV over standard antibiotic treatment alone in a New Zealand white rabbit model of inhalational anthrax. METHODS: Rabbits were exposed to lethal dose of aerosolized spores of Bacillus anthracis (Ames strain) and treated intravenously with either placebo, (normal immune globulin intravenous, IGIV) or 15 U/kg of AIGIV, along with oral levofloxacin treatment at various time points (30-96 hours) after anthrax exposure. RESULTS: The majority of treated animals (>88%) survived in both treatment groups when treatment was initiated within 60 hours of post-exposure. However, reduced survival of 55%, 33% and 25% was observed for placebo + levofloxacin group when the treatment was initiated at 72, 84 and 96 hours post-exposure, respectively. Conversely, a survival rate of 65%, 40% and 71% was observed in the AIGIV + levofloxacin treated groups at these time points. CONCLUSIONS: The combination of AIGIV with antibiotics provided an improvement in survival compared to levofloxacin treatment alone when treatment was delayed up to 96 hours post-anthrax exposure. Additionally, AIGIV treatment when given as an adjunct therapy at any of the time points tested did not interfere with the efficacy of levofloxacin

Therapeutic efficacy of equine botulism antitoxin in Rhesus macaques.

There are currently no licensed vaccines available for prevention of botulism in humans. The vaccination is not desirable due to expanding therapeutic indications of botulinum toxins. The only available specific treatment for botulism is antitoxin to remove circulating toxin, thus, preventing further neuronal damage. BAT® (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine)) has been developed and its therapeutic efficacy evaluated against botulinum neurotoxin serotype A (BoNT/A) in Rhesus macaques.In a post-exposure prophylaxis (PEP) study, animals were exposed to 4x LD50/kg of BoNT/A and administered intravenously with either BAT (1x or 0.1x scaled human dose), or placebo at 4 hours post-exposure. The animals were monitored for 14 days. For the therapeutic intervention studies, animals were exposed to a 1.7x LD50/kg of BoNT/A and treated intravenously with either placebo or BAT at a 1x scaled human dose at the onset of clinical signs. Animals were monitored on an hourly basis for 14 or 21 days. In the PEP study, all animals tolerated equine based antitoxin without any adverse clinical signs. A 100% survival was observed in groups treated with the BAT compared to 0% survival in those treated with the placebo (p<0.001, Fisher's exact test). BAT antitoxin prevented the development of signs of neurotoxicity of botulinum toxin. In a therapeutic study, treatment with the BAT at scaled 1x human dose after the onset of clinical signs significantly enhanced survival compared to the placebo (46.6% vs. 0%, p<0.0001, Fisher's exact test). Additionally, treatment with the BAT delayed the progression of signs (muscular weakness, respiratory distress, oral/nasal discharge) of toxin intoxication and reduced the severity of the disease.A single dose of BAT, when administered to symptomatic monkeys, resulted in a statistically significant survival benefit compared to the placebo. Additionally, BAT completely protected monkeys from the clinical signs of intoxication and subsequent death when administered as PEP treatment. These data in part supported the licensure of BAT under the Animal Rule in the United States by the Food and Drug Administration

Summary of mean time to death and survival of rabbits in two sequential combination treatment studies.

1<p>Survival rates for each group at day 30 post exposure.</p>2<p>Time-to-death and overall survival rates between groups by pairwise Log-rank test. NA- Log-rank test was not possible due to no deaths occurred in either group.</p>3<p>A total of 9 animals were exposed to anthrax spores but two were excluded from survival analysis due to death related to gavage error. - Not determined due to lack of sufficient number of deaths.</p>4<p>Survival rates for each group at day 32 post exposure.</p>5<p>Comparing overall-survival between the groups. *Two animals from 72 hours and one animal from 84 hours group were non bacteremic at the time of treatment.</p><p>Summary of mean time to death and survival of rabbits in two sequential combination treatment studies.</p

Post-Treatment Mean PA levels in Sera from Study 2 Rabbits.

<p>Animals received combination treatment with Placebo+ levofloxacin or AIGIV + levofloxacin at 60, 72, 84 and 96 hour post-exposure. AIGIV was given IV as a slow infusion at 15 U/kg of body weight and levofloxacin at 50 mg/kg given orally once a day for 3 days. The levels of PA were significantly reduced (P<0.05; ANOVA model and Wilcoxon rank sum test) following treatment with AIGIV and levofloxacin compared to treatment with IGIV and levofloxacin. PI = Post-Infusion PC = Post-Challenge.</p

Pre-Treatment (Post-Challenge) and Post-Treatment Mean PA levels in Sera from Study 1 Rabbits.

<p>New Zealand white rabbits were exposed to 200×LD₅₀ doses of aerosolized <i>B. anthracis</i> spores and serum collected at different time points Post-Challenge (A) and Post-Infusion (B) was tested by electro-chemiluminiscence (ECL) assay for detection and quantitation of <i>B. anthracis</i> protective antigen (PA). Animals received combination treatment with Placebo+ levofloxacin or AIGIV + levofloxacin at 30, 36, 48 and 60 hours post-exposure. AIGIV was given IV as a slow infusion at 15 U/kg of body weight and levofloxacin at 50 mg/kg given orally once a day for 3 days. PI = Post-Infusion PC = Post-Challenge.</p