Table of Contents

Volume 5, Issue 4

  April 2009

  Pages 193 - 276

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald W. Ellis and Eva Maria Riedmann
Page 193
http://dx.doi.org/10.4161/hv.5.4.8713
PDF




SPECIAL FOCUS REVIEWS

Open Access Article

Vaccines for cocaine abuse

Frank M. Orson, Berma M. Kinsey, Rana A.K. Singh, Yan Wu and Thomas R. Kosten
Pages 194 - 199
http://dx.doi.org/10.4161/hv.5.4.7457
Abstract | PDF

Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies  to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials.  The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.

Open Access Article

Vaccines against nicotine

Erich H. Cerny and Thomas Cerny
Pages 200 - 205
http://dx.doi.org/10.4161/hv.5.4.7310
Abstract | PDF

Medications against any dependence-inducing drug face a dilemma: if they are efficient, they will induce withdrawal symptoms and the patient is likely to stop taking his medication. Anti drug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting rather with the drug in the blood than with a receptor in the brain, the vaccines are in addition free of side effects due to central interaction. For drugs like nicotine interacting with different types of receptors in many organs, this is a further advantage. There are three reasons, that anti drug vaccines have first been developed against nicotine. Firstly, in most parts of the world 20- to 50% of the adult population smoke and any smoking cessation treatment will have an important impact on public health and be commercially a very attractive product. The second reason are the smokers themselves, which would like to quit in significant numbers and which have shown good compliance for any form of treatment. Thirdly, the quantities of cocaine or heroine taken by dependant persons are higher than the quantity of nicotine per cigarette, which makes an anti nicotine vaccine the easier vaccine project.


Three anti nicotine vaccines are today in an advanced stage of clinical evaluation. We report here how those vaccines work, on the progress of the trials and future developments to expect. Results show that the efficiency of the vaccines is directly related to the antibody levels of the probates, a fact which will help to optimize further the vaccine effect. We expect the vaccines to appear on the market during a time window between 2009 and 2011.

Open Access Article

Development of active and passive human vaccines to treat methamphetamine addiction

W. Brooks Gentry, Daniela Rüedi-Bettschen and S. Michael Owens
Pages 206 - 213
http://dx.doi.org/10.4161/hv.5.4.7456
Abstract | PDF

Methamphetamine (METH) abuse is a major worldwide epidemic, with no specific medications for treatment of chronic or acute effects. Anti-METH antibodies have the potential to save lives and reduce the crippling effects of METH abuse. While they are not expected to be the magic bullet to immediately cure addiction, immunotherapy could provide a breakthrough medication to continuously block or attenuate METH effects during a comprehensive addiction recovery plan. A unique challenge for METH antibody antagonists is the need to protect the brain from the complex direct and indirect adverse effects of long-term METH use. To meet this challenge, a new generation of passive monoclonal antibodies and active immunization therapies are at an advanced stage of preclinical development. Both of these vaccines could play an essential role in a well planned recovery program from human METH addiction by providing long-lasting protection from the rewarding and reinforcing effect of METH.

Open Access Article

Vaccines against morphine/heroine and its use as effective medication for preventing relapse to opiate addictive behaviors

Benito Anton, Alberto Salazar, Anabel Florez, Maura Matus, Rodrigo Marin and Jorge-Alberto Hernandez
Pages 214 - 229
http://dx.doi.org/10.4161/hv.5.4.7556
Abstract | PDF

Current pharmacotherapies for treating morphine/heroin dependence are designed to substitute or block addiction by targeting the drug itself rather than the brain.  Heroin addict is still being exposed to addictive opiates, and consequently may develop tolerance to and experience withdrawal and drug´s toxic effects from the treatment with high incidence of relapse to addictive drug consumption.  As for other drugs of abuse, an alternative approach for morphine/heroin addiction is an antibody-based antagonism of heroin´s brain entry.  This review summarizes the literature examining important aspects of neurobiological and pharmacological processes involved in opiate dependence.  Thereafter, classical pharmacological interventions for opiate dependence treatment and its major clinical limitations are reviewed.  Finally, relevant preclinical studies are examined for comparisons in the design, use, immunogenic profile and efficacy of several models of morphine/heroin vaccine as immunologic interventions on the pharmacokinetics and behavioral of morphine/heroin in the rat as animal model.




RESEARCH PAPERS

Open Access Article

Transcutaneous delivery of tetanus toxin Hc fragment induces superior tetanus toxin neutralizing antibody response compared to tetanus toxoid

Louise Johnston, Fatme Mawas, Rob Tierney, Omar Qazi, Neil Fairweather and Dorothea Sesardic
Pages 230 - 236
http://dx.doi.org/10.4161/hv.5.4.6877
Abstract | PDF

Transcutaneous immunisation is a promising vaccination delivery strategy which targets potent immune cells residing in the outer layer of the skin. In this study, the immunogenicity and neutralizing potency of the non-toxic Hc fragment of tetanus toxin (HcWT) and a mutant of Hc lacking ganglioside binding activity were compared with that of tetanus toxoid (TTxd) following transcutaneous immunisation (TCI) of mice. Mice immunised with HcWT in the absence of an adjuvant induced highest anti-toxoid and anti-Hc antibody titres, with a significant increase in the toxin neutralising antibody response compared with TTxd. These results are in contrast to previous studies employing subcutaneous delivery, where TTxd was found to be a more potent immunogen than the Hc fragment of the toxin. We conclude that the HcWT protein is more immunogenic than TTxd when given via the transcutaneous route. Our results suggest that TCI may provide an opportunity for effective delivery of toxin-like antigens which harbour protective epitopes and that traditional toxoid proteins may not be optimal antigens for skin immunisation.

Open Access Article

Veterans' attitudes to influenza vaccination in the setting of shortage of vaccine, 2004-2005

Andrea L. Benin, Dawn Learsy-Cahill, Rita Das, Sue Kancir, Barbara Welch and Richard A. Martinello
Pages 237 - 241
http://dx.doi.org/10.4161/hv.5.4.6808
Abstract | PDF

Objectives: To inform strategies for vaccinating elderly veterans, the objectives were to determine the proportion of veterans ≥65 years old vaccinated against influenza during the 2004-05 vaccine-shortage, the place they received vaccine, the reasons why they were/were not vaccinated, and their attitudes to the shortage.

Methods: Survey-questionnaire mailed to a random sample of veterans ≥ 65 years-old. The questionnaire was derived from qualitative interviews during December 2004.

Results: Among 682 respondents, 87% were vaccinated during 2004-05. More participants received vaccine at the Veterans’ Administration hospital than previously (67% vs. 57%, P<.0001). Only 28% perceived themselves as being at high risk from influenza even though all participants met ≥1 high-risk criteria. Among unvaccinated participants, 21% were unvaccinated so that someone else could have their dose (“altruism”). For 61%, the shortage led to feeling heightened urgency for vaccination; those participants were more apt to be vaccinated (96% v. 77%, P<.001). Of those not vaccinated during the previous season, only 20% reported feeling urgency associated with the shortage, versus 65% of those vaccinated previously (P<.0001).

Conclusion: The climate of shortage led to a heightened sense of urgency for vaccination that was most prominent among veterans who were vaccinated in the past. It also may have led to vaccination for a small proportion not previously vaccinated against influenza. In contrast, other elderly veterans may have been motivated to avoid vaccination for altruistic reasons or because of confusion about their risk-status. Outreach and communication about vaccination should target both those who may feel urgency to be vaccinated as well as those who may inappropriately avoid vaccination.

Open Access Article

Five year safety and immunogenicity of GlaxoSmithKline's candidate malaria vaccine RTS,S/AS02 following administration to semi-immune adult men living in a malaria-endemic region of The Gambia

Kalifa Bojang, Paul Milligan, Margaret Pinder, Tom Doherty, Amanda Leach, Opokua Ofori-Anyinam, Marc Lievens, Kent Kester, Kurt Schaecher, W. Ripley Ballou and Joe Cohen
Pages 242 - 247
http://dx.doi.org/10.4161/hv.5.4.7050
Abstract | PDF

RTS,S is a pre-erythrocytic malaria vaccine candidate antigen based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a novel Adjuvant System (AS02). The first field efficacy of RTS,S/AS02 against infection was demonstrated in a trial initiated in The Gambia in 1998. This paper presents the five year safety and immunogenicity follow up of the 306 men who were enrolled in the original trial.

In the primary study men aged 18 to 45 years were randomized to receive either RTS,S/AS02 or rabies vaccine at 0, 1, 5 months followed by a booster dose at month 19. The subjects were observed for long term safety and immunogenicity continuously until month 58.

Of the 153 subjects in each group at enrollment, 80 (52%) subjects in the RTS,S/AS02 group and 83 (54%) subjects in the rabies group returned for the final long-term follow-up visit at month 58. The main reason for non-attendance at month 58 was migration (76% of all drop-outs). Nine subjects in the RTS,S/AS02 group and 7 in the rabies group experienced serious adverse events (SAEs) over the 58 month surveillance period, of which 7 had a fatal outcome (5 RTS,S/AS02 and 2 rabies group). None of the SAEs with fatal outcome were attributed to the study vaccine. Anti-CS antibody persistence compared to control was observed for five years, although titres had waned from post-booster levels; similar responses in anti-HBs antibody persistence were observed in initially HBsAg seronegative subjects. This study provides the first indication of the long-term safety and persistence of anti-CS and anti-HBs antibodies of the RTS,S vaccine candidate in combination with the novel AS02 Adjuvant System.

Open Access Article

Comparative evaluation of the immunogenicity of combined hepatitis A and B vaccine by a prospective and retrospective trial

Bernd Wolters, Tobias Müller, R. Stefan Ross, Ralf Clauberg, Uwe Werfel, Hedwig Roggendorf, Cornelius Siggelkow, Thomas Hausen and Michael Roggendorf
Pages 248 - 253
http://dx.doi.org/10.4161/hv.5.4.7051
Abstract | PDF

In the past, immunogenicity of hepatitis A and B vaccines needed to be questioned in persons of advanced age, especially in those of 40 years and older.

We performed a comparative multicenter prospective and retrospective study with the combined hepatitis A and B vaccine Twinrix® to identify factors influencing the results of the vaccination in a population of all age groups.

Out of 489 subjects enrolled, 241 were vaccinated in a prospective study (group 1) and 248 subjects in a retrospective study (group 2) in 17 German centers with median age of 40.1 (14-79) years. Following three applications of the combined hepatitis A/B vaccine we found 96.2% with protective antibodies against HAV and 88.7% were protected against HBV.

With increasing age the subjects developed decreasing anti-HBs antibody levels whereas the seroprotection rate was significantly reduced by age (p<0.05) in the retrospective study group only. Subjects with arterial hypertension and thyroid disease showed significantly decreased protection rates. The timing of the HBV antibody control seems to be important especially in low-responders because protective antibodies may drop below the detection limit within some month.

The combined hepatitis A and B vaccine Twinrix® proved to be highly effective against HBV, although antibody concentrations and seroprotection rates decreased with increasing age.

Open Access Article

Staphylococcus aureus capsule type 8 antibodies provide inconsistent efficacy in murine Models of staphylococcal infection

James Cook, Robert Hepler, Greg Pancari, Nelly Kuklin, Hongxia Fan, Xin-min Wang, Leslie Cope, Charles Tan, Joseph Joyce, Jan Onishi, Donna Montgomery, Annaliesa Anderson and Tessie McNeely
Pages 254 - 263
http://dx.doi.org/10.4161/hv.5.4.6765
Abstract | PDF

Staphylococcus aureus is a clinically important capsule-forming bacterium. The capsule polysaccharide (CPs) occurs as different chemical structures depending on the serotype of the organism, but one form, capsular polysaccharide type 8 (CPs8) found in clinical isolates, is largely unstudied. The potential of CPs8 as a vaccine target was evaluated using two approaches. The first approach used a conjugate vaccine, made by chemically linking purified CPs8 to the outer membrane protein complex of N. meningitidis serotype B (OMPC). In efficacy studies, the CPs8-OMPC conjugate vaccine was immunogenic in Balb/c mice, however the immune response gave no protection from death after a lethal intravenous (iv) challenge with S. aureus Becker. In the second approach, two monoclonal antibodies were produced against CPs8 (MAbs 8E8 and 1C10). These were found to have functional activity in an opsonophagocytic killing assay (OPA), and provided protection from a lethal challenge when bacteria were pre-opsonized ex vivo before intra-peritoneal (ip) challenge. However, MAb 8E8 was not efficacious in the lethal challenge model, in which antibodies were passively transferred to the peritoneum and the animals were infected via the tail vein 18-24 h later. Additionally, the monoclonal antibodies did not opsonize capsule-expressing S. aureus Becker obtained from in vivo growth conditions. These results indicated that functional capsule antibodies may not be sufficient for protection from S. aureus under all in vivo conditions.




COMMENTARIES

Open Access Article

Lactococcus lactis as a live vector for mucosal delivery of therapeutic proteins

Luis G. Bermúdez-Humarán
Pages 264 - 267
http://dx.doi.org/10.4161/hv.5.4.7553
Abstract | PDF

Food-grade lactic acid bacteria (LAB) have been safely consumed by humans for centuries in fermented foods. Lactococcus lactis, a LAB widely used in the dairy industry as a starter, can be genetically engineered to efficiently produce a large variety of proteins. This feature has been recently exploited by scientists for the development of a new generation of vectors to deliver therapeutic proteins to the mucosal tissues. The successful Phase I clinical trial with a L. lactis strain secreting interleukin-10 for Crohn’s disease has been opened new horizons for the use of genetically engineered LAB as delivery vehicles. This commentary reviews the current advances made with L. lactis as live vector for the mucosal delivery of therapeutic proteins.

Open Access Article

HIV-1 vaccine design: Harnessing diverse lymphocytes to conquer a diverse pathogen

Sherri L. Surman, Robert Sealy, Bart G. Jones and Julia L. Hurwitz
Pages 268 - 271
http://dx.doi.org/10.4161/hv.5.4.7706
Abstract | PDF

In the Fall of 2007, the HIV-1 research field received news that their front-runner vaccine was not protective. In response to this disappointment, scientists are now reviewing the intricacies of the immune response toward HIV-1 to develop new and better strategies for vaccine development. Decades ago, researchers recognized the impressive amino acid and carbohydrate diversity of HIV-1, and the associated obstacles to vaccine development. At first glance, the diversity and other unique features of HIV-1 may seem insurmountable, but attention to vaccine successes in other fields serves to renew optimism. The newly-licensed rotavirus and papillomavirus cocktail vaccines remind scientists that diverse pathogens can be conquered and that the chronic nature of a virus infection need not thwart successful vaccine design. Here we describe current efforts to gain insights from other vaccine fields and to adopt a cocktail vaccine approach for the prevention of HIV-1 infections in humans.