IMVAMUNE® and ACAM2000® Provide Different Protection against Disease When Administered Postexposure in an Intranasal Monkeypox Challenge Prairie Dog Model
<p>Clinical disease progression. This schematic presents a comparison of the timing of major stages of disease progression in natural human smallpox infection (<b>A</b>) and natural prairie dog monkeypox infection (<b>B</b>). The major disease stages captured include infection (I) or challenge (C), incubation (dark gray bar), febrile prodrome (light gray bars), rash (white bar), and endpoint (black bar). For human smallpox infection, the prodromal symptom represented is fever. For prairie dog monkeypox infection, the prodromal-like symptoms represented are inappetence (left light gray bar) and weight loss (right light gray bar). Endpoint represents either resolution of lesions/survival or death. The remaining rows show the results of the 2× LD<sub>50</sub> study for unvaccinated animals (<b>C</b>), animals vaccinated (V) on Day 1 with ACAM2000<sup>®</sup> (<b>D</b>) or IMVAMUNE<sup>®</sup> (<b>E</b>), or animals vaccinated on Day 3 with ACAM2000<sup>®</sup> (<b>F</b>) or IMVAMUNE<sup>®</sup> (<b>G</b>). For study data, the bars (color coded as described above) represent the range of days postexposure when the onset of each stage was observed in each individual animal. The fractions in the boxes represent the number of study animals that manifested clinical signs of each stage over the total number of animals in that group.</p> "> Figure 2
<p>Survival benefits of post-exposure vaccination. Kaplan–Meier survival curves are shown for animals challenged with 170× LD<sub>50</sub> dose and vaccinated on Day 1 (<b>A</b>) or Day 3 (<b>B</b>) postexposure with Dryvax<sup>®</sup> (white squares), ACAM2000<sup>®</sup> (black squares), IMVAMUNE<sup>®</sup> (black triangles), or PBS (gray circles). Animals challenged with a 2× LD<sub>50</sub> dose of MPXV and vaccinated 1 (<b>C</b>) or 3 (<b>D</b>) days postexposure with ACAM2000<sup>®</sup> (black squares), IMVAMUNE<sup>®</sup> (black triangles), or unvaccinated (gray circles) are also shown. Fractions represent the cumulative number of animals censored at each time-point over the total numbers of animals in each group. Some symbols are sized differently for clarity of superimposed data. When compared to the unvaccinated control survival curve, none of the vaccinated survival curves showed statistically significant differences by log-rank (Mantel–Cox) test (<span class="html-italic">p</span> > 0.05).</p> "> Figure 3
<p>Weight loss. Group median weight changes by percentage at each time-point are shown for animals challenged with 2× LD<sub>50</sub> dose of monkeypox virus and either unvaccinated (gray circles) or vaccinated 1 day postexposure (<b>A</b>) or 3 days postexposure (<b>B</b>) with ACAM2000<sup>®</sup> (black squares) or IMVAMUNE<sup>®</sup> (black triangles). Euthanized animals for each vaccine group are indicated on the day of euthanasia (same symbols as above). When compared to the unvaccinated animals, only Day 3 ACAM2000<sup>®</sup>-vaccinated animals showed statistically significant differences from Day 21 on by two-way ANOVA (<span class="html-italic">p</span> < 0.05). Percent weight changes are also shown for vaccinated survivors (filled black squares), vaccinated nonsurvivors (open black squares), unvaccinated survivors (filled gray circles), and unvaccinated nonsurvivors (open gray circles) vaccinated on Day 1 (<b>C</b>) or Day 3 (<b>D</b>) postexposure. When compared to the unvaccinated survivor controls, Day 1 vaccinated nonsurvivors showed significantly more weight loss on Day 13. On Day 16, both vaccinated and unvaccinated nonsurvivors showed significantly more weight loss regardless of vaccination timing by two-way ANOVA (<span class="html-italic">p</span> < 0.05).</p> "> Figure 4
<p>Rash burden. Group median peak (Day 16) lesion counts are shown for all animals that received 170× LD<sub>50</sub> MPXV dose (<b>A</b>) and 2× LD<sub>50</sub> (<b>B</b>) for both Day 1 (left symbol) and Day 3 (right symbol) for all groups—unvaccinated (gray circles), Dryvax<sup>®</sup>-vaccinated (white square – 170× LD<sub>50</sub> study only) ACAM2000<sup>®</sup>-vaccinated (black squares) and IMVAMUNE<sup>®</sup>-vaccinated animals (black triangles). No significant differences were seen between vaccine group or vaccination timing by two-way ANOVA (<span class="html-italic">p</span> < 0.05). Group median secondary lesion counts at each time-point are shown for animals challenged with 2× LD<sub>50</sub> dose of monkeypox virus and either unvaccinated (gray circles) or vaccinated 1 day postexposure (<b>C</b>) or 3 days postexposure (<b>D</b>) with ACAM2000<sup>®</sup> (black squares) or IMVAMUNE<sup>®</sup> (black triangles). Euthanized animals for each vaccine group are indicated on the day of euthanasia (same symbols as above). Only animals vaccinated with IMVAMUNE<sup>®</sup> on Day 1 postexposure differed significantly from unvaccinated controls by two-way ANOVA (<span class="html-italic">p</span> < 0.05).</p> "> Figure 5
<p>Humoral immune response. Total antibodies (geometric mean titers) at each time-point for animals challenged with 170× LD<sub>50</sub> dose (<b>A</b>) or 2× LD<sub>50</sub> dose (<b>B</b>) of monkeypox virus and unvaccinated (gray circles) or vaccinated 1 day postexposure with Dryvax<sup>®</sup> (white squares), ACAM2000<sup>®</sup> (black squares), or IMVAMUNE<sup>®</sup> (black triangles) showed significant increases from Day 0 to Day 14 by two-way ANOVA (<span class="html-italic">p</span> < 0.05). A similar analysis of neutralizing antibody titers from animals challenged with 2× LD<sub>50</sub> dose and vaccinated on Day 1 (<b>C</b>) or Day 3 (<b>D</b>) postexposure is keyed the same and showed no significant difference between unvaccinated and vaccinated animals by two-way ANOVA. Geometric mean titers from peak neutralizing antibody response (Day 14) are shown for both surviving and nonsurviving animals challenged with 2× LD<sub>50</sub> dose of monkeypox virus and vaccinated 1 (<b>E</b>) or 3 (<b>F</b>) days postexposure, with no significant differences as measured by one-way ANOVA.</p> "> Figure 6
<p>Viral DNA in Blood and Oral Swabs. Total viral DNA (genome equivalents/mL) found in blood (<b>A</b>) and oral swabs (<b>B</b>) from animals challenged with 170× LD<sub>50</sub> dose of MPXV and unvaccinated (gray circles) or vaccinated 1 day postexposure with Dryvax<sup>®</sup> (white squares), ACAM2000<sup>®</sup> (black squares), or IMVAMUNE<sup>®</sup> (black triangles). Only Dryvax<sup>®</sup>-vaccinated animals had significantly lower levels of viral DNA in blood and only ACAM 2000<sup>®</sup>-vaccinated animals had significantly lower levels of viral DNA from oral swabs by Kruskal–Wallis test (<span class="html-italic">p</span> < 0.05). For animals receiving a 2× LD<sub>50</sub> dose, neither IMVAMUNE<sup>®</sup> or ACAM2000<sup>®</sup> vaccination significantly decreased viral load in blood (<b>C</b>) or oral swabs (<b>D</b>) by Kruskal–Wallis test (<span class="html-italic">p</span> < 0.05).</p> "> Figure 7
<p>Protein targets for antibody response determined by proteome microarray. Sera from animals challenged with a 2× LD<sub>50</sub> dose of monkeypox virus and vaccinated 1 day postexposure were analyzed by microarray. Proteins where fold-increases in reactivity were ≥1.5 are displayed as a heat map (<b>A</b>) with average fold-increase for unvaccinated (Columns 1 and 2), IMVAMUNE<sup>®</sup>-vaccinated (Columns 3 and 4), and ACAM2000<sup>®</sup>-vaccinated (Columns 5 and 6) nonsurvivors (odd numbered columns) and survivors (even numbered columns). The total number of protein targets with a ≥1.5 fold-increase in reactivity with animal serum is shown for all groups of animals (<b>B</b>), subgrouped by survivors (gray column) and nonsurvivors (black column). The Venn diagram (<b>C</b>) describes the overlap of protein targets with a ≥1.5 fold-increase in reactivity among the groups, with the most reactive targets per group highlighted (bold).</p> "> Figure 8
<p>Jennerian pustule “takes”. Kaplan–Meier survival curves for animals from previous and current studies challenged with 2× LD<sub>50</sub> dose of monkeypox virus and vaccinated with ACAM2000<sup>®</sup> or Dryvax<sup>®</sup> either 30 days prior to challenge or 1 or 3 days postexposure (<b>A</b>) and which manifested a take at the vaccine site (black squares) or did not (gray circles). Survival was significantly higher for animals who manifested a take by log-rank (Mantel–Cox) test (* <span class="html-italic">p</span> > 0.05). Comparison of multiple studies with animals challenged with 2× LD<sub>50</sub> dose of monkeypox virus and vaccinated with ACAM2000<sup>®</sup> or Dryvax<sup>®</sup> at Day −30 pre-exposure, 1 day postexposure, or 3 days postexposure (<b>B</b>), showing percentage of animals that manifested a take (brown) or did not manifest a take (black).</p> "> Figure 9
<p>Relative risk analysis. In animals challenged with 2× LD<sub>50</sub> MPXV dose, the relative risk of survival (<b>A</b>) and mitigation of primary (<b>B</b>) and secondary lesions (<b>C</b>) are shown for IMVAMUNE<sup>®</sup> (left) and ACAM2000<sup>®</sup> (right) vaccination. No differences between the vaccines reached significance by Fisher’s exact test.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Black-Tailed Prairie Dogs (Cynomys ludovicianus)
2.2. Viruses
2.3. MPXV Virus Challenges
2.4. Post-Exposure Smallpox Vaccination
2.5. Weight, Body Condition, and Inappetence Measurements
2.6. Rash Burden Measurements
2.7. Blood and Oral Swab Sampling
2.8. OPXV-Generic Quantitative PCR (qPCR)
2.9. Enzyme-Linked Immunosorbent Assays (ELISAs)
2.10. High-Content Screening–Green Fluorescent Protein (HCS-GFP) Neutralization Assay
2.11. Vaccinia Virus Proteome Arrays
2.12. Statistical Analysis
3. Results
3.1. Clinical Disease Progression
3.2. Survival Benefits
3.3. Weight Loss
3.4. Rash Burden
3.5. Humoral Immune Response
3.6. Viral DNA in Blood and Oral Swabs
3.7. Vaccinia Virus Proteome Arrays
3.8. Jennerian Pustules (“Takes”)
3.9. Relative Risk Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Keckler, M.S.; Salzer, J.S.; Patel, N.; Townsend, M.B.; Nakazawa, Y.J.; Doty, J.B.; Gallardo-Romero, N.F.; Satheshkumar, P.S.; Carroll, D.S.; Karem, K.L.; et al. IMVAMUNE® and ACAM2000® Provide Different Protection against Disease When Administered Postexposure in an Intranasal Monkeypox Challenge Prairie Dog Model. Vaccines 2020, 8, 396. https://doi.org/10.3390/vaccines8030396
Keckler MS, Salzer JS, Patel N, Townsend MB, Nakazawa YJ, Doty JB, Gallardo-Romero NF, Satheshkumar PS, Carroll DS, Karem KL, et al. IMVAMUNE® and ACAM2000® Provide Different Protection against Disease When Administered Postexposure in an Intranasal Monkeypox Challenge Prairie Dog Model. Vaccines. 2020; 8(3):396. https://doi.org/10.3390/vaccines8030396
Chicago/Turabian StyleKeckler, M. Shannon, Johanna S Salzer, Nishi Patel, Michael B Townsend, Yoshinori J Nakazawa, Jeffrey B Doty, Nadia F Gallardo-Romero, Panayampalli S Satheshkumar, Darin S Carroll, Kevin L Karem, and et al. 2020. "IMVAMUNE® and ACAM2000® Provide Different Protection against Disease When Administered Postexposure in an Intranasal Monkeypox Challenge Prairie Dog Model" Vaccines 8, no. 3: 396. https://doi.org/10.3390/vaccines8030396