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  4. Developing and Evaluating Animal Models for Studying the Safety and Efficacy of Vaccines Against Anthrax, Staphylococcal Infections, and Pertussis
  1. Science & Research (Biologics)

Developing and Evaluating Animal Models for Studying the Safety and Efficacy of Vaccines Against Anthrax, Staphylococcal Infections, and Pertussis

Principal Investigator: Tod Merkel, PhD
Office / Division / Lab: OVRR / DBPAP / LRSP

General Overview

Our laboratory is studying the interaction between humans and three important bacterial pathogens, Bordetella pertussis (causes whooping cough), Bacillus anthracis (anthrax), and Staphylococcus aureus (causes skin disease, "blood poisoning," toxic shock syndrome). In order to gain a more complete understanding of these interactions, we identify and characterize the bacterial gene products that are required to establish infection and cause disease. In addition, we develop and use animal models and techniques for studying the immune system to identify and characterize the host immune response to the bacterial pathogens.

In order to help develop new vaccines and treatments for these diseases we are characterizing both the gene products that bacteria need to infect humans and the immune system responses that protect against disease. The new knowledge gained from our studies will help us to evaluate the efficacy of new vaccines to prevent--and drugs to treat--pertussis, staphylococcal diseases and anthrax.

Our expertise in the biology and pathogenesis (disease-causing mechanisms) of the organisms targeted by the products we regulate enables us to identify and define potential problems with these products, which we communicate to their developers and manufacturers. Indeed, we frequently can offer advice to these sponsors on how to address such concerns.

Since it is not possible to challenge human volunteers with anthrax toxin to test the efficacy of new anthrax vaccines, the approval of new anthrax vaccines will require extrapolating the results of tests in animals to humans. This will require us to develop a thorough understanding of the pathogenesis of B. anthracis in animal models of the disease, as well as the response of their immune system to anthrax infection.

Because advancements in our understanding of transmission of B. pertussis and disease progression is hindered by the lack of good animal models, our advances in aerosol biology and our animal model development promises to significantly advance our ability to develop and license new pertussis vaccines. In addition to contributing to scientific knowledge, our work in animal model development makes us aware of the practical hurdles involved in conducting these animal model studies. This knowledge will help us to evaluate data submitted by manufacturers of such vaccines as part of the FDA process of regulating these products.

Scientific Overview

We study the early steps of B. anthracis infection of the host and the role of the innate immune response in controlling the spread of pathogens during these stages of infection. The goals of our research are to 1) identify the components of the innate immune response that control of B. anthracis infection and the bacterial factors required for evading the innate immune response; and 2) characterize the interaction of the pathogen with the immune system. On a parallel track, we are developing a cost-effective mouse aerosol challenge model for screening candidate vaccines and therapeutics for the treatment of anthrax.

Our laboratory is also studying the regulation of the expression of Bordetella pertussis virulence factors by the two-component regulatory system encoded by the bvg locus The BvgS protein mediates the phosphorylation of BvgA, which upon phosphorylation activates transcription of B. pertussis virulence factors. In addition to the set of genes that is activated by the bvg locus, we identified bvgR, as the gene encoding the repressor of the bvg-repressed genes and risA as the gene encoding the activator of the bvg-repressed genes. Our group also recently demonstrated that the expression of the bvg-repressed genes enhances survival of B. pertussis in aerosols, thereby increasing the likelihood that a B. pertussis cell expelled from an infected host will survive long enough to be inhaled by a naive host.

Our results suggest that the bvg locus of B. pertussis mediates the transition between two environments: inside the host where the bvg-activated virulence factors are required, and outside the host where the bvg-repressed aerosol tolerance factors are required. Our ongoing work is focused on understanding transmission of B. pertussis and evaluating efficacy of pertussis vaccines in transmission and infection models.

We are also working to evaluate the ability of Staphylococcal aureus antigens to contribute to vaccine efficacy. Our goal is to identify antigens or combinations of antigens that confer protection against multiple forms of staphylococcal disease. My group is establishing systemic, implant, pulmonary, and skin models of staphylococcal infection. We will clone, express, and purify selected S. aureus antigens and use them to vaccinate groups of mice; then challenge each type of vaccinated animal model to determine the ability of each antigen to confer protection against these various S. aureus infections. This work will significantly advance public health efforts to develop effective vaccines that prevent staphylococcal disease.

Publications

  1. Front Microbiol 2024 Mar 7;15:1305097
    The contribution of BvgR, RisA, and RisS to global gene regulation, intracellular cyclic-di-GMP levels, motility, and biofilm formation in Bordetella bronchiseptica.
    Nicholson TL, Waack U, Fleming DS, Chen Q, Miller LC, Merkel TJ, Stibitz S
  2. J Infect Dis 2024 Feb 15;229(2):376-83
    Repeated B. pertussis infections are required to reprogram acellular pertussis vaccine-primed host responses in the baboon model.
    Kapil P, Wang Y, Zimmerman L, Gaykema M, Merkel TJ
  3. Cell Host Microbe 2023 Aug 9;31(8):1404-16.e4
    T cell reactivity to Bordetella pertussis is highly diverse regardless of childhood vaccination.
    da Silva Antunes R, Garrigan E, Quiambao LG, Dhanda SK, Marrama D, Westernberg L, Wang E, Abawi A, Sutherland A, Armstrong SK, Brickman TJ, Sidney J, Frazier A, Merkel TJ, Peters B, Sette A
  4. J Infect Dis 2023 Feb 15;227(4):583-91
    Antigen discovery for next-generation pertussis vaccines using immunoproteomics and transposon directed insertion sequencing.
    Gregg KA, Wang Y, Warfel J, Schoenfeld E, Jankowska E, Cipollo JF, Mayho M, Boinett C, Prasad D, Brickman TJ, Armstrong SK, Parkhill J, Da Silva Antunes R, Sette A, Papin JF, Wolf R, Merkel TJ
  5. Sci Rep 2020 Sep 14;10(1):15002
    Tracheal colonization factor A (TcfA) is a biomarker for rapid and specific detection of Bordetella pertussis.
    Burnham-Marusich AR, Olsen RK, Scarbrough J, Kvam A, Yang W, Zimmerman L, Dunn JJ, Merkel T, Kozel TR
  6. Clin Infect Dis 2020 Jul 11;71(2):412-4
    Toward a controlled human infection model of pertussis.
    Merkel TJ
  7. J Immunol Res 2020 Apr 2;2020:8202067
    Development and validation of a Bordetella pertussis whole-genome screening strategy.
    da Silva Antunes R, Quiambao LG, Sutherland A, Soldevila F, Dhanda SK, Armstrong SK, Brickman TJ, Merkel T, Peters B, Sette A
  8. Clin Infect Dis 2020 Jan 1;70(1):152-61
    Asymptomatic infection and transmission of pertussis in households: a systematic review.
    Craig R, Kunkel E, Crowcroft NS, Fitzpatrick MC, de Melker H, Althouse BM, Merkel T, Scarpino SV, Koelle K, Friedman L, Arnold C, Bolotin S
  9. Toxins 2019 Sep 21;11(10):557
    Pertussis toxin: a key component in pertussis vaccines?
    Gregg KA, Merkel TJ
  10. Curr Opin Immunol 2019 Aug;59:72-8
    Pertussis vaccines and protective immunity.
    Kapil P, Merkel TJ
  11. Infect Immun 2018 Nov;86(11):e00511-18
    Histopathology of Bordetella pertussis in the baboon model.
    Zimmerman LI, Papin JF, Warfel J, Wolf RF, Kosanke SD, Merkel TJ
  12. J Infect Dis 2018 Apr 15;217(8):1231-6
    Maternal vaccination with a mono-component pertussis toxoid vaccine is sufficient to protect infants in a baboon model of whooping cough.
    Kapil P, Papin JF, Wolf RF, Zimmerman LI, Wagner LD, Merkel TJ
  13. J Bacteriol 2017 Nov;199(22):e00475-17
    Activation of Bvg-repressed genes in Bordetella pertussis by RisA requires cross-talk from a non co-operonic histidine kinase RisK.
    Chen Q, Ng V, Warfel JM, Merkel TJ, Stibitz S
  14. J Infect 2017 Jun;74 Suppl 1:S114-9
    Pertussis disease and transmission and host responses: insights from the baboon model of pertussis.
    Pinto MV, Merkel TJ
  15. Clin Vaccine Immunol 2017 May 5;24(5):e00071-17
    Erratum for Carbonetti et al., "Highlights of the 11th International Bordetella Symposium: from basic biology to vaccine development".
    Carbonetti NH, Wirsing von Konig CH, Lan R, Jacob-Dubuisson F, Cotter PA, Deora R, Merkel TJ, van Els CA, Locht C, Hozbor D, Rodriguez ME
  16. Clin Vaccine Immunol 2017 Jan 5;24(1):e00370-16
    Use of a toxin neutralization assay to characterize the serologic response to adenylate cyclase toxin after infection with Bordetella pertussis.
    Eby JC, Gray MC, Warfel JM, Merkel TJ, Hewlett EL
  17. Clin Vaccine Immunol 2016 Nov 4;23(11):842-50
    Highlights of the 11th International Bordetella Symposium: from basic biology to vaccine development.
    Carbonetti NH, Wirsing von Konig CH, Lan R, Jacob-Dubuisson F, Cotter PA, Deora R, Merkel TJ, van Els CA, Locht C, Hozbor D, Rodriguez ME
  18. Sci Rep 2016 Sep 13;6:32774
    The multifaceted RisA regulon of Bordetella pertussis.
    Coutte L, Huot L, Antoine R, Slupek S, Merkel TJ, Chen Q, Stibitz S, Hot D, Locht C
  19. Pathog Dis 2015 Nov;73(8):ftv068
    Bordetella pertussis transmission.
    Trainor E, Nicholson TL, Merkel TJ
  20. Clin Vaccine Immunol 2015 Nov 11;23(1):47-54
    Comparison of three whole-cell pertussis vaccines in the baboon model of pertussis.
    Warfel JM, Zimmerman LI, Merkel TJ
  21. Genome Announc 2015 Jul 16;3(4):e00842-15
    Erratum for Boinett et al., Complete Genome Sequence of Bordetella pertussis D420.
    Boinett CJ, Harris SR, Langridge GC, Trainor EA, Merkel TJ, Parkhill J
  22. Genome Announc 2015 Jun 11;3(3):e00657-15
    Complete Genome Sequence of Bordetella pertussis D420.
    Boinett CJ, Harris SR, Langridge GC, Trainor EA, Merkel TJ, Parkhill J

 

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