Reduced efficacy of an anti-toxin vaccine from senescence-driven attenuation of toxin virulence
Xin Du, Ching Wen Tseng, Elisabet Bjånes, Hunter Gage, Jaclyn Swan, Chih-Ming Tsai, Irshad A. Hajam, Cesia Gonzalez, Brian Lin, Victor Nizet, George Y. Liu
Xin Du, Ching Wen Tseng, Elisabet Bjånes, Hunter Gage, Jaclyn Swan, Chih-Ming Tsai, Irshad A. Hajam, Cesia Gonzalez, Brian Lin, Victor Nizet, George Y. Liu
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Research Article Infectious disease Microbiology

Reduced efficacy of an anti-toxin vaccine from senescence-driven attenuation of toxin virulence

Abstract

It remains unclear why vaccines targeting prominent microbial virulence factors often fail in clinical trials. Because microbial virulence depends on interaction with the host immune system, we investigated how changes in host immune function alter vaccine efficacy. Using a vaccine against Staphylococcus aureus α-toxin (Hla), which targets host metalloprotease ADAM10 on myeloid cells, we show that Hla virulence is reduced in aged mice due to diminished ADAM10 activity and impaired myeloid cell function. Depletion of myeloid cells with cyclophosphamide in young mice similarly reduced toxin virulence. Immunization against Hla conferred strong protection against S. aureus infection in young but not aged mice. These findings indicate that pathogenic functions of microbial factors characterized in immunocompetent young animals may not predict virulence or vaccine efficacy in immunocompromised hosts. These findings underscore the need to account for host immune status in the development and evaluation of vaccines targeting microbial virulence factors.

Authors

Xin Du, Ching Wen Tseng, Elisabet Bjånes, Hunter Gage, Jaclyn Swan, Chih-Ming Tsai, Irshad A. Hajam, Cesia Gonzalez, Brian Lin, Victor Nizet, George Y. Liu

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Figure 1

Evaluation of Hla as a virulence factor and vaccine target in aged mice.

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Evaluation of Hla as a virulence factor and vaccine target in aged mice....
(A) Schematic: Young and aged mice were immunized subcutaneously (s.c.) against Hla (left) or administered intraperitoneally mouse anti-Hla serum from Hla toxoid–vaccinated mice (right), then challenged s.c. with Hla, WT or Δhla S. aureus (USA300). (B) Active immunization: Skin lesion sizes 3 and 7 days after Hla challenge (n = 5–9 mice). (C) Passive immunization: Skin lesion sizes 3 and 7 days after Hla challenge (n = 5–9). (D) Active immunization: Skin lesion sizes 3 days after WT or Δhla S. aureus (USA300) subcutaneous infection (n = 9–11 young, 4–7 aged). (E) Passive immunization: Skin lesion sizes 3 days after WT or Δhla S. aureus (USA300) subcutaneous infection (n = 9–11 young, 4–7 aged). (F–H) Bacterial burden in the skin, spleen, and kidneys of previously unimmunized young and aged mice, 3 days after S. aureus challenge (n = 5 young mice, 4 aged mice). Line in A–H represents the median. *P < 0.05; **P < 0.01; ***P < 0.001 by Kruskal-Wallis non-parametric 1-way ANOVA test (B–H). NS, not significant; USA300 WT, S. aureus USA300 WT strain SF8300; USA300 Δhla, S. aureus USA300 SF8300 Hla isogenic mutant. Each data point represents an individual mouse. Arrows at days 3, 7, 14, and 21 denote the time when skin lesions were assessed. The schematic in A was created in BioRender (https://BioRender.com/49kavfj, https://BioRender.com/nqcey3h).