Improved pertussis vaccines based on adjuvants that induce cell-mediated immunity

Abstract

Bordetella pertussis is a Gram-negative bacterium that causes the severe and sometimes lethal respiratory disease whooping cough in infants and children. There has been a recent resurgence in the number of cases of pertussis in several countries with high vaccine coverage. This has been linked with waning or ineffective immunity induced by current acellular pertussis vaccines. These acellular pertussis vaccines are formulated with alum as the adjuvant, which promotes strong antibody responses but is less effective at inducing Th1-type responses crucial for effective bacterial clearance. Studies in animal models have demonstrated that replacing alum with alternative adjuvants, such as toll-like receptor agonists, can promote more robust cell-mediated immunity and confer a high level of protection against infection following respiratory challenge.

Keywords::

• adjuvant
• alum
• Bordetella pertussis
• cell-mediated immunity
• pertussis vaccine
• Th1 cell
• TLR agonist
• whooping cough

Financial & competing interests disclosure

This work was supported by Science Foundation Ireland. AC Allen was supported by an Ussher Fellowship from Trinity College Dublin. K HG Mills receives grant support from Science Foundation Ireland and is a co-founder and share holder in Opsona Therapeutics and TriMod Therapeutics, university spin-out companies involved in the development of immunotherapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Whooping cough causes high morbidity and mortality in children and the incidence of this respiratory infection is increasing despite high vaccine coverage.

• The efficacious whole cell pertussis vaccine was replaced with the acellular vaccine due to safety issues, but the acellular vaccine does not confer the same level of protective immunity as the whole cell pertussis vaccine and this may reflect the choice of antigens or adjuvant.

• Alum is the default adjuvant chosen for human vaccines due to its safety profile, but it promotes a mixed Th2/Th17 response, rather than the Th1 response crucial for Bordetella pertussis clearance from the respiratory tract.

• Studies in a baboon model have indicated that current acellular pertussis vaccines prevent disease but not infection or transmission of B. pertussis, and these findings need to be confirmed in humans.

• Alternative adjuvants such as toll-like receptor agonists or IL-12 have been shown to skew the immune response from Th2 to Th1 and confer greater protection than alum-adjuvanted vaccines in murine respiratory challenge models.

• Replacement of alum with a more Th1-promoting adjuvant should help to improve the efficacy of the acellular pertussis vaccine, but this may be logistically difficult because of the fact that acellular pertussis vaccines are part of combination vaccines used for childhood immunization, all formulated with alum.

• Addition of Th1-promoting adjuvants to existing alum-formulated vaccines may also be possible, but introduction of stand-alone reformulated Th1-inducing pertussis vaccines for adolescent and adult booster may be more achievable. However, it remains to be seen if these will shift Th2 responses already induced with alum-adjuvanted vaccines.

• Regardless of the approach, there is an urgent need to address the considerable morbidity and mortality still caused by B. pertussis in children worldwide.

Notes