Non-protective immune imprint underlies failure of Staphylococcus aureus IsdB vaccine

Tsai, Chuen-Tinn; Caldera, J.R.; Hajam, Irshad Ahmed; Chiang, Audris; Tsai, Chia-Hung Dylan; Li, Haining; Díez, María Lázaro; Gonzalez, Cesia; Trieu, Desmond; Martins, Gislâine A.; Underhill, David; Arditi, Moshe; Lewis, Nathan E.; Liu, George Y.

doi:10.1016/j.chom.2022.06.006

Cited by 47 publications

(33 citation statements)

References 37 publications

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“…Importantly, mortality was associated with low endogenous levels of IL-17 in patients before receiving the vaccine 62 . Together with the findings of Tsai et al 13 , it is likely that several mechanisms may contribute to the difficulty in vaccinating previously exposed individuals. Specifically, prior exposure may both (i) imprint non-protective antibodies that may be recalled upon vaccination, and (ii) establish non-protective T cell memory that interferes with vaccine-elicited protective T cell responses.…”

Section: Discussionmentioning

confidence: 70%

“…Future studies will address the epitope-specificity and function of vaccine-elicited antibodies to confirm that primary infection does not interfere with humoral immune responses. This is of particular importance because Tsai et al recently reported that prior S. aureus infection inhibits the efficacy of vaccination with IsdB in mouse models 48 . In their study, they found that inhibition was mediated by recall by vaccination of non-protective IsdB-specific antibodies originally elicited by infection.…”

Section: Discussionmentioning

confidence: 99%

“…Francis called these patterned responses "Original Antigenic Sin" 12 . Whether human exposure to S. aureus contributes to the failure of vaccine efforts is not clear, but Tsai et al recently reported that S. aureus infection may imprint non-protective antibody responses that interfere with protective antibodies elicited by vaccination 13 .…”

Section: Introductionmentioning

confidence: 99%

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Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy

Teymournejad

Beesetty

et al. 2022

Preprint

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Staphylococcus aureus infections are a major public health issue and a vaccine is urgently needed. Despite considerable promise in preclinical models, all vaccines tested thus far have failed to protect humans against S. aureus. Unlike laboratory mice, humans are exposed to S. aureus throughout life. In the current study, we hypothesized that prior exposure to S. aureus “imprints” the immune response to inhibit vaccine-mediated protection. We established a mouse model in which S. aureus skin and soft tissue infection (SSTI) is followed by vaccination and secondary SSTI. Unlike naïve mice, S. aureus-sensitized mice were incompletely protected against secondary SSTI by vaccination with the inactivated α-hemolysin (Hla) mutant HlaH35L. Inhibition of protection was specific for the HlaH35L vaccine and required hla expression during primary SSTI. Surprisingly, inhibition occurred at the level of vaccine-elicited effector T cells; hla expression during primary infection limited the expansion of T cells and dendritic cells and impaired vaccine-specific T cell responses. Importantly, the T cell-stimulating adjuvant CAF01 rescued inhibition and restored vaccine-mediated protection. Together, these findings identify a potential mechanism for the failure of translation of promising S. aureus vaccines from mouse models to clinical practice and suggest a path forward to prevent these devastating infections.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy

Teymournejad

Beesetty

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Although it was highly immunogenic and effective to the laboratory animals, its use as a vaccine target did not reduce the rate of S. aureus infections and was associated with increased mortality (45). Possible explanations have been recently reported that non-protective antibodies can be imprinted by prior S. aureus exposure and the IsdB vaccine recalls non-protective humoral memory and further its efficacy is reduced by antibody competition (46). Also, the functional redundancy in terms of bacterial iron transport and strain variation in iron-regulated proteins would result in the ineffectiveness of the IsdB vaccine (8).…”

Section: Discussionmentioning

confidence: 99%

In silico Design of Multi-epitope Vaccines Targeting Iron-regulated lipoproteins of Staphylococcus aureus Using Immunoinformactics

Bae¹,

Shin²

2022

J Bacteriol Virol.

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Staphylococcus aureus (S. aureus) is one of the dangerous pathogens involved in serious infections with high risk for morbidity and mortality. Development of effective vaccines against S. aureus strains is urgently needed, but successful vaccines are not available yet. In this study, we designed five types of multi-epitope vaccine constructs, targeting lipoproteins associated bacterial iron metabolism, which are IsdE, SstD, SirA, HtsA, and SitC. Using immunoinformatic approaches, we selected various sequences as potent B cell and T cell epitopes and constructed virtual vaccines with linkers and N-terminal adjuvants. The vaccine constructs were evaluated and compared with respect to their physicochemical and structural properties as well as immunologic and allergenic profiles. Immune simulation studies showed the vaccines would increase immune cell populations and antibody and cytokine responses. The vaccine constructs had similar physicochemical and immunological characteristics, while specific constructs showed distinct immunestimulatory properties. With a further investigation of the vaccine constructs on in vivo host testings, the newly designed S. aureus iron-regulated lipoprotein vaccines would help us to prevent S. aureus infection with greater efficacy and better safety.

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“…CircRNAs are also capable of being translated, which may allow researchers to obtain antibodies against specific pathogens through manipulating circRNA translation. Recently, it has been revealed that the interference of non-protective antibody may explain the failure of S. aureus vaccine, which suggests a delicate competition between antibodies targeting different subdomains of antigen ( Tsai et al, 2022 ). This strategy has also been applied in a study discussed earlier ( Qu et al, 2022 ), which undoubtedly enhances another possibility for utilizing the platform based on RNA-level treatment strategies.…”

Section: Emerging Applications Of Noncoding Rnas In Mastitismentioning

confidence: 99%

Emerging roles of noncoding micro RNAs and circular RNAs in bovine mastitis: Regulation, breeding, diagnosis, and therapy

et al. 2022

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Bovine mastitis is one of the most troublesome and costly problems in the modern dairy industry, which is not only difficult to monitor, but can also cause economic losses while having significant implications on public health. However, efficacious preventative methods and therapy are still lacking. Moreover, new drugs and therapeutic targets are in increasing demand due to antibiotic restrictions. In recent years, noncoding RNAs have gained popularity as a topic in pathological and genetic studies. Meanwhile, there is growing evidence that they play a role in regulating various biological processes and developing novel treatment platforms. In light of this, this review focuses on two types of noncoding RNAs, micro RNAs and circular RNAs, and summarizes their characterizations, relationships, potential applications as selection markers, diagnostic or treatment targets and potential applications in RNA-based therapy, in order to shed new light on further research.

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Non-protective immune imprint underlies failure of Staphylococcus aureus IsdB vaccine

Cited by 47 publications

References 37 publications

Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy

Toxin expression during Staphylococcus aureus infection imprints host immunity to inhibit vaccine efficacy

In silico Design of Multi-epitope Vaccines Targeting Iron-regulated lipoproteins of Staphylococcus aureus Using Immunoinformactics

Emerging roles of noncoding micro RNAs and circular RNAs in bovine mastitis: Regulation, breeding, diagnosis, and therapy

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