High immunogenicity of nicotine vaccines obtained by intradermal delivery with safe adjuvants.

Vaccine. 2012 Dec 17;31(1):159-64.

Chen X, Pravetoni M, Bhayana B, Pentel PR, Wu MX.

Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA 02114, United States.

 

Abstract

Immunotherapy for tobacco addiction may offer a safe, alternative treatment if the immunogenicity of the current nicotine vaccines can be improved. We show here that intradermal (ID) immunization induces the production of antibody directed against nicotine (NicAb) at a much higher level than conventional intramuscular (IM) immunization. The magnitude and duration of NicAb production was further increased robustly by non-inflammatory laser vaccine adjuvant (LVA), slightly inflammatory monophosphoryl lipid A (MPL) or a combination of MPL and CpG adjuvants. Consequently, significantly fewer vaccination doses were required to attain a high level of NicAb production for an extended period of time and reduce nicotine entry into the brain in the presence of LVA, MPL or MPL/CpG adjuvant, respectively. Yet, the potency of these adjuvants to augment ID nicotine vaccine immunogenicity came at the expense of local skin reactogenicity, with LVA causing little skin reaction and MPL/CpG stimulating overt skin irritation. These observations underscore a necessity of a balance between optimal adjuvant potency and undesired local reactogenicity. In summary, our study presents a novel approach to significantly improve nicotine vaccine immunogenicity by a combination of safe cutaneous vaccine adjuvants with ID immunization. Copyright © 2012 Elsevier Ltd.

PMID: 23123021

 

Supplement

Smoking is among the leading causes of preventable deaths in the world and nicotine in tobacco products is the major substance that initiates and maintains nicotine addiction. Currently, there are no effective treatments against nicotine addiction. Nicotine vaccines recently emerged as a possible treatment of nicotine addiction by production of anti-nicotine antibodies (NicAb) that sequester nicotine in the blood and prevent nicotine entry into the brain to trigger reinforcing reactions. Yet, current nicotine vaccines induce relatively low NicAb titer and increased abstinence rate was only obtained in ~30% of vaccinees, who developed relatively high NicAb titer. Thus, improving nicotine vaccine immunogenicity is the key to a successful anti-nicotine immunotherapy.

Growing evidence has shown that more potent immune responses can be induced by intradermal (ID) immunization than intramuscular (IM) immunization because of the rich of antigen-presenting cells in the skin. Inspired by these findings, we evaluated whether ID injection of nicotine vaccine induced more NicAb production than IM immunization in murine models.

Indeed, ID injection of Nic-KLH (nicotine hapten conjugated to Keyhole Limpet Hemocyanin) induced 5-15 times higher NicAb titer than IM injection depending on a dose of the vaccine (1). Moreover, addition of adjuvants could further boost NicAb production. For instance, a physical non-inflammatory laser vaccine adjuvant (LVA) (2), toll-like receptor 4 (TLR4) agonist monophosphoryl lipid a (MPL), or a combinatorial MPL/CpG (CpG oligonucleotide, a TLR9 agonist) induced 2.5, 5, and 10 times higher NicAb titer with reduced doses as compared to multiple doses of ID immunization alone or 1.8, 3.6, and 7.2 times higher NicAb titer as compared to multiple doses of IM immunization in the presence of Alum adjuvant, an immunization procedure that resembles clinical trials (1). The duration of the peak NicAb titer was also significantly prolonged by inclusion of LVA, MPL, and MPL/CpG adjuvant as compared to ID or IM immunization alone or IM immunization in the presence of Alum adjuvant (1).

Lastly we asked whether the higher NicAb titer induced by adjuvant-incorporated ID immunization contributed to more significant blockade on nicotine entry into the brain following nicotine challenge. We found that ID immunization alone blocked nicotine entry into the brain by 40%, and incorporation of LVA, MPL, and MPL/CpG increased the blockade to 60%, 69%, and 77%, respectively (1). As current nicotine vaccines induced relatively high NicAb titer in only 30% vaccinees, modification of vaccine administration to ID route and incorporation of potent adjuvants might significantly enhance NicAb production (figure 1) and abstinence rate.

Xinyuan Chen-1

Figure 1. Modification of nicotine vaccine administration from IM to ID route and incorporation of potent cutaneous adjuvants significantly boost NicAb production.  Two doses of adjuvant-incorporated ID immunization induce much higher NicAb titer and maintain the peak NicAb titer longer than 5-6 doses of Alum-incorporated IM immunization.

 

References:

  1. Chen X, Pravetoni M, Bhayana B, Pentel PR, Wu MX. High immunogenicity of nicotine vaccines obtained by intradermal delivery with safe adjuvants. Vaccine. 2012;31(1):159-64.
  2. Chen X, Kim P, Farinelli B, Doukas A, Yun SH, Gelfand JA, Anderson RR, Wu MX. A novel laser vaccine adjuvant increases the motility of antigen presenting cells. PLoS One. 2010;5(10):e13776.

Acknowledgements: This study was supported by the National Institutes of Health Grants AI070785 and RC1 DA028378 (M.X.W.) and DA10714 (P.R.P.).

Contact:

Mei X. Wu, Ph.D.

Wellman Center for Photomedicine

Massachusetts General Hospital

50 Blossom Street, Edwards 222

Boston, MA 02114

mwu2@partners.org

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