Investigations of Enantiopure Nicotine Haptens Using an Adjuvanting Carrier in Anti-Nicotine Vaccine Development

Jacob, Nicholas T.; Lockner, Jonathan W.; Schlosburg, Joel E.; Ellis, Beverly A.; Eubanks, Lisa M.; Janda, Kim D.

doi:10.1021/acs.jmedchem.5b01676

Cited by 20 publications

(20 citation statements)

References 39 publications

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“…[9] In addition, a stimulating/carrier protein is always a necessity in NP-based nicotine vaccine, as it will stimulate T-helper cell formation that is required for B cell maturation. [9, 28] Meanwhile, conjugating protein antigen to the surface of NPs could promote its delivery and presentation. [29, 30] In our previous nanovaccine design, hapten was conjugated to the surface of protein antigens.…”

Section: Introductionmentioning

confidence: 99%

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization

Zhao

Harmon

et al. 2017

Biomaterials

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A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized in this study to combat nicotine addiction. A series of nanovaccines, which had nicotine-haptens localized on carrier protein (LPKN), nanoparticle surface (LPNK), or both (LPNKN), were designed to study the impact of hapten localization on their immunological efficacy. All three nanovaccines were efficiently taken up and processed by dendritic cells. LPNKN induced a significantly higher immunogenicity against nicotine and a significantly lower anti-carrier protein antibody level compared to LPKN and LPNK. Meanwhile, it was found that the anti-nicotine antibodies elicited by LPKN and LPNKN bind nicotine stronger than those elicited by LPKN, and LPNK and LPNKN resulted in a more balanced Th1-Th2 immunity than LPKN. Moreover, LPNKN exhibited the best ability to block nicotine from entering the brain of mice. Collectively, the results demonstrated that the immunological efficacy of the hybrid nanoparticle-based nicotine vaccine could be enhanced by modulating hapten localization, providing a promising strategy to combatting nicotine addiction.

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Section: Introductionmentioning

confidence: 99%

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization

Zhao

Harmon

et al. 2017

Biomaterials

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“…In order to induce systemic anti-nicotine antibodies to sequester nicotine from circulation, current vaccine formulations place emphasis on hapten molecule design, adjuvant(s)/carrier systems and the number of haptens per carrier molecule [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]. A drawback of parenteral nicotine vaccines could be that they are targeting nicotine once in the circulatory system, which might not be sufficient or fast enough to neutralize nicotine and prevent it from reaching the brain; this occurs within 7–10 seconds of cigarette smoke inhalation [22].…”

Section: Introductionmentioning

confidence: 99%

Evaluating the immunogenicity of an intranasal vaccine against nicotine in mice using the Adjuvant Finlay Proteoliposome (AFPL1)

Fraleigh

Boudreau

Bhardwaj

et al. 2016

Heliyon

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Tobacco smoking is recognized as a global pandemic resulting in 6 million deaths per year. Despite a variety of anti-smoking products available to aid with tobacco cessation, the majority of people who attempt to quit smoking relapse within 6 months due to the addictive nature of nicotine. An immunotherapy approach could offer a promising treatment option by inducing a potent selective antibody response against nicotine in order to block its distribution to the brain and its addictive effects in the central nervous system. Our nicotine vaccine candidate was administered intranasally using the Neisseria meningitidis serogroup B Adjuvant Finlay Proteoliposome 1 (AFPL1) as a part of the delivery system. This system was designed to generate a robust immune response by stimulating IL-1β production through Toll-like receptor 4 (TLR4), a potent mechanism for mucosal immunity. The vaccine induced high antibody titers in mice sera in addition to inducing mucosal antibodies. The efficacy of our vaccine was demonstrated using in vivo challenge experiments with radioactive [3H]-nicotine, followed by an analysis of nicotine distribution in the lung, liver, blood and brain. Our results were encouraging as the nicotine concentration in the brain tissue of mice vaccinated with our candidate vaccine was four times lower than in non-vaccinated controls; suggesting that the anti-nicotine antibodies were able to block nicotine from crossing the blood brain barrier. In summary, we have developed a novel nicotine vaccine for the treatment of tobacco addiction by intranasal administration and also demonstrated that the AFPL1 can be used as a potential adjuvant for this vaccine design.

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“…Herein, we explore two strategies for improving Ab responses with this carrier. The first employs enantiopure (-) nicotine haptens to improve functional Ab activity [23,24]. The second utilizes a bivalent formulation with two structurally distinct haptens to increase Ab responses even further [25–28].…”

Section: Introductionmentioning

confidence: 99%

Construction of an enantiopure bivalent nicotine vaccine using synthetic peptides

2017

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Clinical outcomes of anti-nicotine vaccines may be improved through enhancements in serum antibody affinity and concentration. Two strategies were explored to improve vaccine efficacy in outbred mice: the use of enantiopure haptens and formulation of a bivalent vaccine. Vaccines incorporating natural (-) nicotine haptens improved relative antibody affinities >10-fold over (+) haptens, stimulated a two-fold boost in nicotine serum binding capacity, and following injection with 3 cigarette equivalents of nicotine, prevented a larger proportion of nicotine (>85%) from reaching the brain. The activity of a bivalent vaccine containing (-) 3’AmNic and (-) 1’SNic haptens was then compared to dose-matched monovalent groups. It was confirmed that antisera generated by these structurally distinct haptens have minimal cross-reactivity and stimulate different B cell populations. Equivalent antibody affinities were detected between the three groups, but the bivalent group showed two-fold higher titers and an additive increase in nicotine serum binding capacity as compared to the monovalent groups. Mice immunized with the bivalent formulation also performed better in a nicotine challenge experiment, and prevented >85% of a nicotine dose equivalent to 12 cigarettes from reaching the brain. Overall, enantiopure conjugate vaccines appear to improve serum antibody affinity, while multivalent formulations increase total antibody concentration. These findings may help improve the performance of future clinical candidate vaccines.

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Investigations of Enantiopure Nicotine Haptens Using an Adjuvanting Carrier in Anti-Nicotine Vaccine Development

Cited by 20 publications

References 39 publications

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization

Evaluating the immunogenicity of an intranasal vaccine against nicotine in mice using the Adjuvant Finlay Proteoliposome (AFPL1)

Construction of an enantiopure bivalent nicotine vaccine using synthetic peptides

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