Lipopolysaccharide Analogs Improve Efficacy of Acellular Pertussis Vaccine and Reduce Type I Hypersensitivity in Mice

Abstract

Pertussis is an infectious disease of the respiratory tract that is caused by the gram-negative bacterium Bordetella pertussis. Although acellular pertussis (aP) vaccines are safe, they are not fully effective and thus require improvement. In contrast to whole-cell pertussis (wP) vaccines, aP vaccines do not contain lipopolysaccharide (LPS). Monophosphoryl lipid A (MPL) and Neisseria meningitidis LpxL2 LPS have been shown to display immune-stimulating activity while exerting little endotoxin activity. Therefore, we evaluated whether these LPS analogs could increase the efficacy of the aP vaccine. Mice were vaccinated with diphtheriatetanus-aP vaccine with aluminum, MPL, or LpxL2 LPS adjuvant before intranasal challenge with B. pertussis. Compared to vaccination with the aluminum adjuvant, vaccination with either LPS analog resulted in lower colonization and a higher pertussis toxin-specific serum immunoglobulin G level, indicating increased efficacy. Vaccination with either LPS analog resulted in reduced lung eosinophilia, reduced eosinophil numbers in the bronchoalveolar lavage fluid, and the ex vivo production of interleukin-4 (IL-4) by bronchial lymph node cells and IL-5 by spleen cells, suggesting reduced type I hypersensitivity. Vaccination with either LPS analog increased serum IL-6 levels, although these levels remained well below the level induced by wP, suggesting that supplementation with LPS analogs may induce some reactogenicity but reactogenicity considerably less than that induced by the wP vaccine. In conclusion, these results indicate that supplementation with LPS analogs forms a promising strategy that can be used to improve aP vaccines.Pertussis is caused by Bordetella pertussis infection of the respiratory tract and is among the 10 infectious diseases with the highest rates of morbidity and mortality worldwide. After introduction of whole-cell pertussis (wP) vaccines in the 1950s, the incidence of pertussis has decreased significantly. Although they are efficacious, wP vaccines were found to be reactogenic, leading to concerns about their safety in the 1970s. Therefore, acellular pertussis (aP) vaccines that comprise purified B. pertussis proteins have been developed. In many countries, pertussis has recently reemerged, despite the high rates of vaccine coverage (13). Several approaches to reducing disease incidence and severity have been suggested, one of them being the improvement of the existing aP vaccines.In contrast to wP vaccines, aP vaccines are devoid of lipopolysaccharide (LPS). By engaging Toll-like receptor 4 (TLR4), this molecule induces Th1 adaptive immunity (12,15,22,29,39). Consequently, concerns have been raised with respect to the relative efficacies of aP vaccines compared with those of wP vaccines as well as those of simultaneously administered vaccines, such as diphtheria, tetanus, polio, and Haemophilus influenzae type b (Hib) vaccines. In fact, this concern has been substantiated by an increase in the incidence of invasive Hib disease in the United Kingdom that coincided...

No pain no gain? Adjuvant effects of alum and monophosphoryl lipid A in pertussis and HPV vaccines

“…First, test the addition of MPL to DTaP and Tdap vaccines. Just one group appears to have tested a generic form of MPL as an additive for DTaP, reporting in 2007 that it improved efficacy, but only in mice and durability was not assessed [68]. Next, advance our understanding of the extent to which transient vaccine side effects are associated with desired immunization outcomes in vaccine trials.…”

Evaluation of a Whole-Blood Cytokine Release Assay for Use in Measuring Endotoxin Activity of Group B Neisseria meningitidis Vaccines Made from Lipid A Acylation Mutants

“…Since the ⌬lpxL2 NOMV vaccine contained only one-sixth as much LPS as the penta-acyl NOMV vaccine, one might have expected to see a greater difference between the LPSs in the ⌬lpxL2 NOMV and the ⌬lpxL1 NOMV vaccines. Other studies involving tetra-acyl LPS or lipid A and lipid A-like molecules have indicated that these molecules appear to be nonpyrogenic or antipyrogenic (14,15,28). Investigators have previously demonstrated that the lipid A from neisserial ⌬lpxL1 and ⌬lpxL2 mutants binds to human MD-2 and TLR4 because they have been used as competitive inhibitors of hexa-acyl lipid A (2,40,42).…”

“…Currently, an increasing number of LPS-related molecules are being investigated for use for the treatment of sepsis (20) or for use as vaccines or vaccine adjuvants (13,14,30). One group of vaccine candidates that includes LPS as a major component is based on native outer membrane vesicles (NOMVs) from group B N. meningitidis.…”

The Role of Bacterial Lipopolysaccharides as Immune Modulator in Vaccine and Drug Development

“…However, further investigations showed that both LPS derivatives are antagonists of human TLR4 (hTLR4) [124] and therefore are inadequate as adjuvant for humans, in contrast to mice. In spite of this disappointment as potential adjuvant molecules, genetically detoxified LpxL2 and LpxL1 LPS reduce the toxicity of native OMVs preparations in N. meningitidis [125] and whole-cell B. pertussis vaccines [126] and therefore they have been currently proposed to solve the unacceptable side effects of OMVs-based vaccines generated by LPS [66]. However, due to these molecules are hTLR4 antagonists, one could expect negative effects after activation of the immune system.…”