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. 2021 Jan 1;113(1):32-42.
doi: 10.1002/bdr2.1815. Epub 2020 Oct 16.

Developmental and reproductive safety evaluation of AV7909 anthrax vaccine candidate in rats

Eve Mylchreest  1 , M Autumn Smiley  1 , Jeff D Ballin  2 , Bruna Blauth  3 , Jeffry Shearer  3 , Joshua Reece  3 , Boris Ionin  3 , Vladimir Savransky  3
Affiliations

Developmental and reproductive safety evaluation of AV7909 anthrax vaccine candidate in rats

Eve Mylchreest et al. Birth Defects Res. .

Abstract

The AV7909 vaccine, consists of the Anthrax Vaccine Adsorbed (AVA) bulk drug substance and the immunostimulatory Toll-like receptor 9 agonist oligodeoxynucleotide adjuvant CPG 7909. The purpose of this research was to evaluate the potential maternal, reproductive, and developmental toxicity of AV7909 in rats to support licensure for use in women of childbearing potential. Groups of first generation (F0 ) female Sprague Dawley rats were dosed by intramuscular injection with water for injection, adjuvant or AV7909 at a volume of 0.5 ml/dose. Each rat received three vaccinations: 14 days prior to start of the mating period, on the first day of the mating period and on gestation day (GD) 7. There was no maternal mortality. Body weights, weight gain, and food consumption were comparable between groups. Findings in F0 females were limited to transient injection site edema and nodules consistent with immunostimulatory effects of the vaccine and adjuvant. Administration of AV7909 did not affect mating, fertility, pregnancy, embryo-fetal viability, growth, or morphologic development, parturition, maternal care of offspring or postnatal survival, growth, or development. There was no evidence of systemic inflammation in pregnant rats, based on evaluation of serum concentrations of the acute phase proteins alpha-2-macroglobulin and alpha-1-acid glycoprotein on GD 21. Anthrax lethal toxin-neutralizing antibodies were detected in AV7909-vaccinated F0 females. The antibodies were also detected in the sera of fetuses and F1 pups. Exposure of the fetuses and pups to maternally derived anthrax lethal toxin-neutralizing antibodies was not associated with developmental toxicity.

Keywords: AV7909; anthrax vaccine; developmental toxicity; rat; reproductive toxicity.

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Conflict of interest statement

BB, JS, JR, BI, and VS are current or former employees of Emergent BioSolutions, Inc. EM, JB and AS are employees of Battelle, a Contract Research Organization where safety studies have been performed on a contractual basis for Emergent BioSolutions, Inc.

Figures

FIGURE 1
FIGURE 1
Experimental design
FIGURE 2
FIGURE 2
Body weights in F0 females during premating (a), gestation (b), and lactation (c). Data are presented as mean and standard deviation. Adjusted body weight (GD 21 body weight minus gravid uterus weight) was 345.1, 345.8, and 350.7 g in the control, adjuvant, and AV7909 groups, respectively. There were no statistically significant differences compared with control (p < .05)
FIGURE 3
FIGURE 3
F1 offspring body weights (a) and developmental landmark achievement (b and c) during the postnatal period. Data are presented as mean of litter means and standard deviation (a) or as mean, median, maximum, minimum, and first and third quartile, with outlier data points shown (b, c). There were no statistically significant differences compared with control (p < .05). All pups had a positive bilateral pupil response on PND 21 (data not shown)
FIGURE 4
FIGURE 4
Anthrax lethal toxin‐neutralizing antibodies in the AV7909 group. Data are presented as mean, median, maximum, minimum, and first and third quartile, with outlier data points shown. Mean (standard deviation) NF50 was 14.4 (8.8), 10.0 (4.4), and 1.3 in F0 females, F1 pups, and F1 fetuses, respectively. Antibodies were not detected in the control or adjuvant groups
FIGURE 5
FIGURE 5
Serum concentration of AGP (a) and A2M (b) in F0 females on gestation day 21. Data are presented as mean, median, maximum, minimum, and first and third quartile, with outlier data points shown. The mean (standard deviation) for AGP was 45 (32), 34 (9), and 33 (11) μg/ml in the control, adjuvant, and AV7909 groups, respectively. The mean (standard deviation) for A2M was 1,189 (419), 1,121 (403), and 884 (196) μg/ml, respectively. AGP, alpha‐1‐acid glycoprotein; A2M, alpha‐2‐macroglobulin
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