Immunology Study Notes on TLR4 Agonist and Pertussis Vaccines

Author Information

  • Megan A. DeJong, M. Allison Wolf, Graham J. Bitzer, Jesse M. Hall, Nicholas A. Fitzgerald, Gage M. Pyles, Annalisa B. Huckaby, Jonathan E. Petty, Katherine Lee, Mariette Barbier, Justin R. Bevere, Robert K. Ernst, F. Heath Damron

Abstract

  • Acellular pertussis vaccines show waning protection over time, necessitating improved formulations.

  • Options for improvement include different adjuvants and administration routes, with a focus on intranasal (IN) vs. intramuscular (IM) vaccination.

  • This study investigates TLR4 agonist (BECC438b) added to both IM and IN acellular formulations for their immune response in murine models against Bordetella pertussis infection.

  • Results indicate variations in immune polarization between administration routes, with IN vaccination promoting a Th1 response.

Keywords

  • Bordetella pertussis, whooping cough, DTaP, adjuvants, TLR4 agonist, immune response.

Introduction

  • Background on Pertussis:

    • Resurgence of whooping cough despite widespread vaccination since the 1950s, attributed to acellular pertussis (aP) vaccines like DTaP (Diphtheria, Tetanus, Pertussis).

  • Differences Between aP and wP Vaccines:

    • aP vaccines generally induce a Th2 dominant immune response, losing critical antigens like pertactin (PRN) and showing waning immunity.

    • wP vaccines promote a Th1 response, are more effective at inducing lasting immunity with various antigens present.

Vaccine Formulations and Administration Routes

  • Current Formulation Issues:

    • aP uses alum as an adjuvant, leading to rapid waning of antibody levels and incomplete immunity.

  • Intramuscular (IM) Vaccination:

    • Delivers vaccine directly to draining lymph nodes, inducing a systemic immune response.

    • However, does not prevent nasal colonization.

  • Intranasal (IN) Vaccination:

    • Activates a localized immune response, potentially more akin to natural infection.

    • Produces antigen-specific IgA, bolstering mucosal immunity and reducing upper respiratory tract colonization.

BECC438b as an Adjuvant

  • Description of TLR4 Agonist (BECC438b):

    • Derived from lipid A, engineered to enhance Th1 responses while mitigating adverse effects of traditional LPS.

    • Aims to harness protective aspects of wP while maintaining the safety profile of aP.

Research Design and Methods

  • Vaccine Composition:

    • GSK Infanrix (1/40th human dose) with BECC438b (50 µg per dose), maintaining alum presence.

  • Animal Models:

    • Female CD-1 mice were vaccinated with DTaP alone or with BECC438b, using both IM and IN routes.

    • Mice were challenged with B. pertussis two weeks post-vaccination.

    • Evaluated bacterial burden, immune responses (antibody levels, cytokine profiles), and histopathological changes post-challenge.

Results

  • Bacterial Burden:

    • IN DTaP vaccination resulted in lower bacterial counts in both nasal cavity and lungs compared to mock vaccination.

    • IM DTaP + BECC438b showed lower lung colonization than IM DTaP alone, affirming its potential as an effective adjuvant.

  • Serological Responses:

    • Analysis of IgG isotypes determined Th2 responses predominated in IM administration while IN DTaP + BECC438b favored Th1 responses.

    • Increased IgA and IgM levels post IN vaccination suggest robust mucosal immunity.

  • Inflammation and Cytokine Profiles:

    • Higher inflammation scores associated with IN DTaP + BECC438b vaccinations were observed, indicating stronger immune responses in lungs.

    • Cytokines like CXCL13 were elevated, supporting immune cell recruitment post-vaccination.

Conclusion

  • Implications of Findings:

    • IN administration of DTaP combined with BECC438b increases protection and induces a Th1-dominated immune response, reflecting effects similar to natural infection.

    • Highlights potential advancements in creating next-generation pertussis vaccines that ensure better mucosal and systemic immunity.

Future Directions

  • Continued evaluation of BECC438b’s effects in pre-clinical models and potential applications in humans.

  • Investigation into varying dosages and combination formulations to enhance vaccine efficacy and longevity of immune response.