Abstract
Haemophilus ducreyi causes chancroid and is a major cause of cutaneous ulcers in children. Due to environmental reservoirs, both class I and class II H. ducreyi strains persist in cutaneous ulcer regions of endemicity following mass drug administration of azithromycin, suggesting the need for a vaccine. The hemoglobin receptor (HgbA) is a leading vaccine candidate, but its efficacy in animal models is class specific. Controlled human infection models can be used to evaluate vaccines, but only a class I strain (35000HP) has been characterized in this model. As a prelude to evaluating HgbA vaccines in the human model, we tested here whether a derivative of 35000HP containing a class II hgbA allele (FX548) is as virulent as 35000HP in humans. In eight volunteers infected at three sites with each strain, the papule formation rate was 95.8% for 35000HP versus 62.5% for FX548 (P 0.021). Excluding doses of FX548 that were 2-fold higher than those of 35000HP, the pustule formation rate was 25% for 35000HP versus 11.7% for FX548 (P 0.0053). By Western blot analysis, FX548 and 35000HP expressed equivalent amounts of HgbA in whole-cell lysates and outer membranes. The growth of FX548 and 35000HP was similar in media containing hemoglobin or hemin. By whole-genome sequencing and single-nucleotide polymorphism analysis, FX548 contained no mutations in open reading frames other than hgbA. We conclude that by an unknown mechanism, FX548 is partially attenuated in humans and is not a suitable strain for HgbA vaccine efficacy trials in the model.
| Original language | English (US) |
|---|---|
| Article number | e00112 |
| Journal | Infection and Immunity |
| Volume | 87 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jan 1 2019 |
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Keywords
- Haemophilus ducreyi
- Hemoglobin
- Vaccines
ASJC Scopus subject areas
- Parasitology
- Microbiology
- Immunology
- Infectious Diseases
Cite this
A Class I Haemophilus ducreyi Strain Containing a Class II hgbA Allele Is Partially Attenuated in Humans : Implications for HGBA vaccine efficacy trials. / Leduc, Isabelle; Fortney, Kate R.; Janowicz, Diane; Zwickl, Beth; Ellinger, Sheila; Katz, Barry; Lin, Huaiying; Dong, Qunfeng; Spinola, Stanley.
In: Infection and Immunity, Vol. 87, No. 7, e00112, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A Class I Haemophilus ducreyi Strain Containing a Class II hgbA Allele Is Partially Attenuated in Humans
T2 - Implications for HGBA vaccine efficacy trials
AU - Leduc, Isabelle
AU - Fortney, Kate R.
AU - Janowicz, Diane
AU - Zwickl, Beth
AU - Ellinger, Sheila
AU - Katz, Barry
AU - Lin, Huaiying
AU - Dong, Qunfeng
AU - Spinola, Stanley
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Haemophilus ducreyi causes chancroid and is a major cause of cutaneous ulcers in children. Due to environmental reservoirs, both class I and class II H. ducreyi strains persist in cutaneous ulcer regions of endemicity following mass drug administration of azithromycin, suggesting the need for a vaccine. The hemoglobin receptor (HgbA) is a leading vaccine candidate, but its efficacy in animal models is class specific. Controlled human infection models can be used to evaluate vaccines, but only a class I strain (35000HP) has been characterized in this model. As a prelude to evaluating HgbA vaccines in the human model, we tested here whether a derivative of 35000HP containing a class II hgbA allele (FX548) is as virulent as 35000HP in humans. In eight volunteers infected at three sites with each strain, the papule formation rate was 95.8% for 35000HP versus 62.5% for FX548 (P 0.021). Excluding doses of FX548 that were 2-fold higher than those of 35000HP, the pustule formation rate was 25% for 35000HP versus 11.7% for FX548 (P 0.0053). By Western blot analysis, FX548 and 35000HP expressed equivalent amounts of HgbA in whole-cell lysates and outer membranes. The growth of FX548 and 35000HP was similar in media containing hemoglobin or hemin. By whole-genome sequencing and single-nucleotide polymorphism analysis, FX548 contained no mutations in open reading frames other than hgbA. We conclude that by an unknown mechanism, FX548 is partially attenuated in humans and is not a suitable strain for HgbA vaccine efficacy trials in the model.
AB - Haemophilus ducreyi causes chancroid and is a major cause of cutaneous ulcers in children. Due to environmental reservoirs, both class I and class II H. ducreyi strains persist in cutaneous ulcer regions of endemicity following mass drug administration of azithromycin, suggesting the need for a vaccine. The hemoglobin receptor (HgbA) is a leading vaccine candidate, but its efficacy in animal models is class specific. Controlled human infection models can be used to evaluate vaccines, but only a class I strain (35000HP) has been characterized in this model. As a prelude to evaluating HgbA vaccines in the human model, we tested here whether a derivative of 35000HP containing a class II hgbA allele (FX548) is as virulent as 35000HP in humans. In eight volunteers infected at three sites with each strain, the papule formation rate was 95.8% for 35000HP versus 62.5% for FX548 (P 0.021). Excluding doses of FX548 that were 2-fold higher than those of 35000HP, the pustule formation rate was 25% for 35000HP versus 11.7% for FX548 (P 0.0053). By Western blot analysis, FX548 and 35000HP expressed equivalent amounts of HgbA in whole-cell lysates and outer membranes. The growth of FX548 and 35000HP was similar in media containing hemoglobin or hemin. By whole-genome sequencing and single-nucleotide polymorphism analysis, FX548 contained no mutations in open reading frames other than hgbA. We conclude that by an unknown mechanism, FX548 is partially attenuated in humans and is not a suitable strain for HgbA vaccine efficacy trials in the model.
KW - Haemophilus ducreyi
KW - Hemoglobin
KW - Vaccines
UR - http://www.scopus.com/inward/record.url?scp=85068123032&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068123032&partnerID=8YFLogxK
U2 - 10.1128/IAI.00112-19
DO - 10.1128/IAI.00112-19
M3 - Article
C2 - 31036601
AN - SCOPUS:85068123032
VL - 87
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 7
M1 - e00112
ER -