Abstract
Pertussis is still observed in many countries despite of high vaccine coverage. Acellular pertussis (aP) vaccination is widely implemented in many countries as primary series in infants and as boosters in school-entry/adolescents/adults (including pregnant women in some). One novel strategy to improve the reactivation of aP-vaccine primed immunity could be to include genetically- detoxified pertussis toxin and novel adjuvants in aP vaccine boosters. Their preclinical evaluation is not straightforward, as it requires mimicking the human situation where T and B memory cells may persist longer than vaccine-induced circulating antibodies. Toward this objective, we developed a novel murine model including two consecutive adoptive transfers of the memory cells induced by priming and boosting, respectively. Using this model, we assessed the capacity of three novel aP vaccine candidates including genetically-detoxified pertussis toxin, pertactin, filamentous hemagglutinin, and fimbriae adsorbed to aluminum hydroxide, supplemented—or not—with Toll-Like-Receptor 4 or 9 agonists (TLR4A, TLR9A), to reactivate aP vaccine-induced immune memory and protection, reflected by bacterial clearance. In the conventional murine immunization model, TLR4A- and TLR9A-containing aP formulations induced similar aP-specific IgG antibody responses and protection against bacterial lung colonization as current aP vaccines, despite IL-5 down-modulation by both TLR4A and TLR9A and IL-17 up-modulation by TLR4A. In the absence of serum antibodies at time of boosting or exposure, TLR4A- and TLR9A-containing formulations both enhanced vaccine antibody recall compared to current aP formulations. Unexpectedly, however, protection was only increased by the TLR9A-containing vaccine, through both earlier bacterial control and accelerated clearance. This suggests that TLR9A-containing aP vaccines may better reactivate aP vaccine-primed pertussis memory and enhance protection than current or TLR4A-adjuvanted aP vaccines.
Highlights
B. pertussis (Bp), the causative agent of whooping cough, is a gram-negative bacterium highly transmissible in humans across all ages and an important cause of morbidity and mortality in infants worldwide
We show here that this model readily discriminates among Toll-like Receptor (TLR) agonists-adjuvanted modified Tdap vaccines and identifies TLR9A as more effective than TLR4A against Bp challenge
The shortcomings of current acellular pertussis (aP) vaccines raise the need of third-generation pertussis vaccines
Summary
B. pertussis (Bp), the causative agent of whooping cough, is a gram-negative bacterium highly transmissible in humans across all ages and an important cause of morbidity and mortality in infants worldwide. Introduced in 1950s, whole-cell pertussis (wP) vaccines dramatically reduced disease incidence in infants and young children. Vaccine-associated reactogenicity and unjustified fears of vaccine-induced encephalopathy affected public confidence and compliance. This lead in the late 1990s to their replacement in most developed countries by less reactogenic acellular pertussis (aP) vaccines [1]. Pediatric aP vaccines are composed of 1–5 Bp antigens adsorbed to Alum, combined with diphtheria (DT) and tetanus (TT) toxoids (DTaP) ± polio, Haemophilus influenzae b and hepatitis B antigens. Adolescent/adult booster vaccines (Tdap) include lower amounts of DT and Bp antigens
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