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Assessing Neutralized Nicotine Distribution Using Mice Vaccinated with the Mucosal Conjugate Nicotine Vaccine.

ABSTRACT: Tobacco smoking continues to be a global epidemic and the leading preventable cause of cancer and cardiovascular disease. Nicotine vaccines have been investigated as an alternative to currently available smoking cessation strategies as a means to increase rates of success and long-term abstinence. Recently, we demonstrated that a mucosal nicotine vaccine was able to induce robust mucosal and systemic antibodies when delivered heterologously using intranasal and intramuscular routes. Herein, we investigated the neutralization ability of the anti-nicotine antibodies using both intranasal and intracardiac nicotine challenges. Combining the extraction of lyophilized organ samples with RP-HPLC methods, we were able to recover between 47% and 56% of the nicotine administered from the blood, brain, heart, and lungs up to 10 min after challenge, suggesting that the interaction of the antibodies with nicotine forms a stable complex independently of the route of vaccination or challenge. Although both challenge routes can be used for assessing systemic antibodies, only the intranasal administration of nicotine, which is more physiologically similar to the inhalation of nicotine, permitted the crucial interaction of nicotine with the mucosal antibodies generated using the heterologous vaccination route. Notably, these results were obtained 6 months after the final vaccination, demonstrating stable mucosal and systemic antibody responses.

SUBMITTER: Fraleigh NL

PROVIDER: S-EPMC7913222 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Assessing Neutralized Nicotine Distribution Using Mice Vaccinated with the Mucosal Conjugate Nicotine Vaccine.

Fraleigh Nya L NL Lewicky Jordan D JD Martel Alexandrine L AL Diaz-Mitoma Francisco F Le Hoang-Thanh HT

Vaccines 20210203 2

Tobacco smoking continues to be a global epidemic and the leading preventable cause of cancer and cardiovascular disease. Nicotine vaccines have been investigated as an alternative to currently available smoking cessation strategies as a means to increase rates of success and long-term abstinence. Recently, we demonstrated that a mucosal nicotine vaccine was able to induce robust mucosal and systemic antibodies when delivered heterologously using intranasal and intramuscular routes. Herein, we i ...[more]

PMID: 33546163

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Project description:ImportanceFollowing routine use of 13-valent pneumococcal conjugate vaccine (PCV13) in children in 2010, invasive pneumococcal disease rates have decreased substantially in children and adults. In 2014, the Advisory Committee for Immunization Practices recommended routine use of PCV13 among adults aged 65 years or older; previously only 23-valent pneumococcal polysaccharide vaccine (PPV23) was recommended.ObjectiveTo estimate the association between the incidence of hospitalized all-cause pneumonia and lower respiratory tract infections (LRTI) and PCV13 vaccination among older adults at Kaiser Permanente Northern California (KPNC).Design, setting, and participantsThis retrospective cohort study included adults at KPNC aged 65 years or older between July 1, 2015, and June 30, 2018, born after 1936 with no known history of PPV23 or PCV13 receipt before age 65. The study took place at an integrated health care system with an annual membership more than 4 million individuals, approximately 15% of whom are 65 years or older and broadly representative of the region. Data analysis took place from July 2018 to December 2021, and data collection took place from November 2016 to June 2018.ExposuresPCV13 vaccination status was ascertained from the electronic medical record (EMR). Individuals were considered vaccinated 14 days following immunization.Main outcomes and measuresFirst hospitalized all-cause pneumonia was identified in the EMR using primary/secondary discharge diagnosis International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. First hospitalized LRTI was identified using pneumonia codes and acute bronchitis codes. Relative risk (RR) of first pneumonia or LRTI hospitalization of individuals who were PCV13 vaccinated vs PCV13 unvaccinated was estimated using Poisson regressions adjusted for sex, race, ethnicity, age, influenza vaccine receipt, PPV23 receipt since age 65, pneumonia risk factors, health care use, and season. Vaccine effectiveness (VE) was estimated as (1-RR) × 100%.ResultsOf 192 061 adults, 107 957 (56%) were female and 139 024 (72%) were White individuals. PCV13 coverage increased from 0 in 2014 to 135 608 (76.9%) by 2018. There were 3488 individuals with 3766 pneumonia hospitalizations and 3846 individuals with 4173 LRTI hospitalizations. PCV13 was associated with an adjusted VE of 10.0% (95% CI, 2.4-17.0; P = .01) against hospitalized pneumonia and 9.4% (95% CI, 2.1-16.1; P = .01) against hospitalized LRTI.Conclusions and relevanceIn the context of a robust pediatric PCV13 immunization program, PCV13 vaccination of adults aged 65 years or older was associated with significant reductions in hospitalizations for all-cause pneumonia and LRTI. Vaccinating older adults with PCVs may provide broader public health benefit against pneumonia hospitalizations.

Project description:Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. One utilizes a competition enzyme-linked immunoabsorbent assay (ELISA) to profile the interactions of nicotine haptens or hapten-protein conjugates with nicotine specific antibodies, both polyclonal and monoclonal. Another relies on computational modeling of the interactions between haptens and amino acid residues near the conjugation site of the carrier protein to infer linker-carrier protein conjugation effect on antinicotine antibody response. Using these two in vitro methods, we ranked the haptens with different linkers for their potential as viable vaccine candidates. The ELISA-based hapten ranking was in an agreement with the results obtained by in vivo nicotine pharmacokinetic analysis. A correlation was found between the average binding affinity (IC50) of the haptens to an anti-Nic monoclonal antibody and the average brain nicotine concentration in the immunized mice. The computational modeling of hapten and carrier protein interactions helps exclude conjugates with strong linker-carrier conjugation effects and low in vivo efficacy. The simplicity of these in vitro screening strategies should facilitate the selection and development of more effective nicotine conjugate vaccines. In addition, these data highlight a previously under-appreciated contribution of linkers and hapten-protein conjugations to conjugate vaccine immunogenicity by virtue of their inclusion in the epitope that binds and activates B cells.

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Dataset Information

Assessing Neutralized Nicotine Distribution Using Mice Vaccinated with the Mucosal Conjugate Nicotine Vaccine.

Publications

Assessing Neutralized Nicotine Distribution Using Mice Vaccinated with the Mucosal Conjugate Nicotine Vaccine.

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