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British Medical Bulletin 62:175-186 (2002)
© 2002 The British Council

Life-style vaccines

Pascal Mettens and Philippe Monteyne

GlaxoSmithKline Biologicals, Rixensart, Belgium


   Abstract
Top
 Abstract
Introduction
 Contraceptive vaccines
 Vaccination and drug addiction
 Vaccination and dental caries
 Conclusions
 Acknowledgements
 References
 
Multiple immunotherapy approaches are under development to treat various chronic diseases or conditions. Thanks to dramatic technological improvements, the field of vaccinology can now extend from prophylaxis to therapy, and from infectious diseases to dysimmune disorders like cancer or autoimmunity, or even to non-immune related conditions, including neurological or cardiovascular disorders. Life-style vaccines defined as vaccines to manage chronic conditions in healthy individuals can, therefore, also be envisaged. Three examples will be reviewed and discussed here, from both technical and ethical aspects: contraceptive vaccines, vaccines to treat addictions, and anti-dental caries vaccines.


   Introduction
Top
 Abstract
 Introduction
Contraceptive vaccines
 Vaccination and drug addiction
 Vaccination and dental caries
 Conclusions
 Acknowledgements
 References
 
Vaccines have classically been developed to prevent infectious diseases. Thanks to a technological revolution in molecular biology, immunology and other vaccine-related techniques along with an enhanced understanding of disease mechanisms, it is possible to consider immune-related approaches to the treatment of various diseases rather than limiting immune approaches to the prevention of infectious diseases. In theory, multiple immunotherapy products can now be envisaged for every major therapeutic category from anti-infectives to autoimmune disorders, oncology, cardiovascular or neurological conditions. In that context, life-style vaccines, defined as vaccines to manage chronic conditions in healthy individuals, can also be developed. Three major examples of such candidate vaccines will be further discussed in the present paper: contraceptive vaccines, vaccines to treat drug addiction, and anti-caries vaccines.

The following general criteria can be utilized in evaluating potential opportunities for developing new immunotherapeutics:

  • • The target must be accessible to the immune system
  • • The target must be identified and must be neutralized by an induced immune response, i.e. decreased or eliminated, in order to achieve clinical effect.
  • • The target must be specific for the target tissue
  • • Unmet needs must exist in the conventional treatment of this disease (too frequent dosing, not well-controlled with current medication, compliance issues, etc)
  • • The disease or condition should ideally be chronic to achieve maximum benefit from a vaccine approach

With these prerequisites, it is clear that immunotherapy may not be suitable for all conditions and diseases. However, vaccine products inherently offer certain advantages over traditional pharmaceuticals which can translate directly into patient benefits and preferences:

  • • Vaccines offer a specificity for targets which can result in enhanced efficacy with fewer unwanted or adverse effects
  • • Vaccines can provide longer duration of action which translates into ease of use, increased compliance and, in certain situations, better control and monitoring of treatment

Potential disadvantages of vaccine products, however, must also be considered:

  • • Onset of action will require time to reach adequate immune stimulation. Therefore, these products should not be envisaged for acute conditions
  • • Theoretical concerns with regard to the autoimmune potential of ‘self’ antigens and the consequences of immune complex formation may limit these products to medically significant diseases until clinical experience can be obtained, which may be a major limitation to the development of life-style vaccines in general
  • • Use of ‘self’ antigens also represents an obstacle to mounting adequate immune responses. Powerful adjuvants and other vaccine tools may, therefore, be needed with a risk of inducing local reactivity
  • • Inadequate control of the response may eliminate use in conditions where the duration of response can be a disadvantage or where the need for immediate reversibility is required. This will have to be discussed in the context of contraceptive vaccines
  • • Because an immune response must be stimulated from within each patient, a heterogeneous response can be anticipated. Variation of response in individuals and the potential for lack of or low response in elderly or compromised immune systems should be evaluated. This may limit a potential target population
  • • Currently vaccines are still mainly envisaged for i.m. injection and need further development to more friendly modes of administration

These potential issues will be further discussed while reviewing the three chosen examples: contraception, addiction and dental caries.


   Contraceptive vaccines
Top
 Abstract
 Introduction
 Contraceptive vaccines
Vaccination and drug addiction
 Vaccination and dental caries
 Conclusions
 Acknowledgements
 References
 
Current approaches to contraception are essentially based on hormonal control, condoms and surgery. Vaccination against hormones controlling reproduction is a promising immunological approach to contraception. It may rely on hormones that control the production of gametes or are involved in the survival of the fertilized egg. On the other hand, contraceptive vaccines could also induce antibodies against surface proteins of the gametes in order to block fertilization of ova by sperm.

We will review practical examples of such approaches. It should be emphasized that different ethical considerations relate to a vaccine that prevents fertilization and a vaccine that targets already fertilized eggs.

Hormonal control

Both in women and men, gametogenesis is controlled by the gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH). The production of these hormones in the pituitary gland and their secretion is regulated by the hypothalamic gonadotropin releasing hormone (GnRH) also termed LH-releasing hormone (LH-RH). FSH and LH also control gonadal steroidogenesis through interaction with their receptors, FSH-R and LH-R. Distinct hormones have been tested as vaccine targets in men and women1,2.

Men as a target population
 The first vaccine approach was based on GnRH. A phase I study showed that a GnRH vaccine could be safe, effective and reversible. A reduction in gonadotropins was observed without any adverse effects. However, since this vaccine decreases testosterone levels, supplemental androgen is needed to maintain libido3.

Several forms of GnRH with high sequence homology have been isolated from primate brain. Antibodies induced by a vaccine based on GnRH should be highly specific for a particular GnRH molecule. An antifertility vaccine has been described that induces antibodies against a single GnRH subspecies with negligible cross-reactivity towards other GnRH isoforms4.

It is worth mentioning that vaccines which induce antibodies against GnRH might play a role in the immunotherapy of prostatic hypertrophy and sex hormone-dependent male and female cancers5. Early clinical trials with such a vaccine have been conducted in patients with advanced metastasing carcinoma of the prostate6.

A second approach to male contraception might rely on immunization against the gonadotropin FSH. FSH, together with androgens, regulates spermatogenesis in Sertoli cells whereas LH acts on Leydig cells and is responsible for the production of androgens (testosterone). Antibodies induced by a FSH vaccine should not cross-react with LH, since the decrease in LH may inhibit the induction of testosterone leading to a potential loss of libido. FSH-specific peptides that do not cross-react with LH have been tested in rabbits7,8. Vaccination of mice with peptides from FSH and LH receptors induced some reversible contraception9,10. Finally, encouraging results were obtained when male volunteers were vaccinated with ovine FSH as this reduced sperm counts without any sign of autoimmune reaction11.

A male immunocontraceptive would revolutionize the whole field of reproduction and probably address some important requests. At the moment, however, a vaccine targeting a male auto-antigen without inducing significant adverse reactions is still far from being available.

Women as a target population
 In women, FSH regulates the production of ova and LH induces ovulation at the end of folliculogenesis. FSH and LH secretion is controlled by the hypothalamic gonadoliberin GnRH/LH-RH. All these hormones have been considered as potential targets for a contraceptive vaccine.

A GnRH-based vaccine was used as a potentially effective contraceptive in several animal models12 with vaccine effects being reversible13.

As previously discussed for male contraception, immunization with FSH may induce antibodies that cross-react with LH. Moreover, active immunization against FSH may not induce antibody titres high enough to completely block conception14. To improve the specificity of FSH-based vaccination, Ferro and Stimson15 tested different peptides of FSH conjugated to tetanus toxoid (TT). For some peptides, all animals immunized showed disrupted oestrous cycles due to suppression of oestradiol levels.

The human chorionic gonadotropin (hCG) is produced by trophoblast cells of the fertilized egg and stimulates the corpus luteum to secrete progesterone needed to establish and maintain pregnancy. Phase I and II clinical trials conducted by the National Institute of Immunology in New Delhi16 showed that a vaccine with the ß-subunit of hCG linked to the {alpha}-subunit of ovine LH and conjugated to TT or diphtheria toxoid (DT) could prevent pregnancy. This vaccine had been shown to be safe and reversible in some animals, which was confirmed in human trials when antibody titres fell below the protective level17.

Blocking fertilization

Another contraceptive approach consists of inhibiting fertilization through the induction of antibodies which block the binding of sperm to ova. The targets used to induce such immune responses are surface proteins of sperm involved in fertilization or their ligands on the ova.

Sperm surface proteins
 In theory, sperm antigens represent interesting targets because of their tissue specificity and involvement in fertility. High titres of antibodies targeted to the local genital tract could induce reversible infertility. Several sperm antigens have been proposed and partly tested as potential candidates for vaccine development such as lactate dehydrogenase C4, PH-20, sperm protein (SP)-10, fertilization antigen (FA)-1, FA-2, cleavage signal (CS)-1, NZ-1 and NZ-218, DE19, and 4LP-1220. Furthermore, molecules involved in sperm binding to zona pellucida (ZP), a pivotal tissue-specific event in the fertilization process, might constitute promising candidates for immunocontraception.

It is worth mentioning that these sperm antigens can also be used as vaccine candidates in females. Indeed, the induction of antibodies against sperm in the vagina would neutralize the fertilization capacities of the male gametes.

Egg surface protein of zona pellucida
 Vaccines formulated with ZP antigens can suppress fertility very effectively in some animal models21,22. In some cases, this vaccine approach is, however, associated with adverse autoimmune reactions in the ovaries and ovarian pathology characterized by disruption of folliculogenesis and depletion of the primordial follicle pool23,24a. Both single and triple ZP3 peptide vaccines have been evaluated in primates in vivo. No detrimental effects on ovarian function were observed. The resulting high titre antibodies bound exclusively to the ZP of marmoset and human ovarian sections. It could suppress in vitro human sperm–egg binding by approximately 60%, but did not prevent pregnancy in actively immunized female marmosets24b. In vivo, active immunization of bonnet monkeys against the glycoprotein ZP3 established some reversible infertility22.

Further research is required to identify a combination of ZP epitopes that is able to induce infertility without any side-effects.

General comments on contraceptive vaccines

In addition to the previously mentioned distinct ethical considerations relating to vaccines that prevent fertilization and those that target fertilized eggs, additional major ethical considerations might be raised. Indeed, a ‘perfect’ vaccine that should be acceptable today for the industrialised world still looks elusive, i.e. a vaccine with no significant reactogenicity, with total protection against fertilization, perfect reversibility, and perfect control of the duration of action. If such levels of ‘perfection’ cannot be achieved today, one could argue that less perfect vaccines might already address the needs from non-industrialised countries. This is the subject of a major ethical debate which we will not address here, but which should be considered for further development of contraceptive vaccines.


   Vaccination and drug addiction
Top
 Abstract
 Introduction
 Contraceptive vaccines
 Vaccination and drug addiction
Vaccination and dental caries
 Conclusions
 Acknowledgements
 References
 
Two examples of drug addiction will be described here: addiction to cocaine and nicotine.

Cocaine addiction and nicotine dependence are major health concerns, and new strategies for the treatment of drug abuse are urgently needed. Addiction usually depends on activation of receptors expressed by cells of the central nervous system. Vaccination is expected to induce antibodies against systemic drug molecules and thereby block their further uptake into the brain. However, cocaine and nicotine are molecules too small to be immunogenic; they can be considered as haptens and need to be linked to a carrier. Moreover, a vaccine has to be formulated with appropriate adjuvants in order to induce a high and long-lasting antibody response to neutralize these drugs.

Cocaine

Current development of two different anti-cocaine vaccine approaches will be reviewed.

TA-CD from Xenova
 Xenova's vaccine (TA-CD) is a cocaine derivative coupled to the recombinant cholera toxin B (rCTB) carrier protein. In preclinical studies, vaccine-induced antibodies inhibited the passage of cocaine to the brain25. Treatment with cocaine-specific antibodies suppressed the positive effects of cocaine in rats in a self-administration model26,27.

A phase I study showed that the product was safe and well tolerated, with no serious adverse effects. The study involved 34 patients with a history of cocaine addiction who received three intramuscular (i.m.) injections of the vaccine on a 4-weekly basis. Subjects in the trial received different doses of the vaccine following at least 30 days of cocaine abstinence. Importantly, participants had to demonstrate a willingness to seek treatment and to participate in the study. This desire to stop may be the key factor of any successful treatment outcome. A dose-related antibody response was mounted in all patients receiving active vaccine, persisting for at least 84 days (press release, Cantab, 15 June 1999).

Results of a phase II study in 9 out-patient cocaine addicts further showed that TA-CD was well tolerated both systemically and locally. Antibody titres were higher than those reported in the phase I trial. The cocaine-specific antibodies persisted during the 12 weeks of monitoring. No cocaine metabolites were detected in urine of 5 out of 8 patients, indicating the absence of cocaine use (press release, Xenova, 9 July 2001). Xenova is currently conducting a phase IIa dose escalation trial involving cocaine addicts in an out-patient treatment programme (PharmaProjects, 16 November 2001).

The Scripps Research Institute vaccine
 The present version of the vaccine from the Scripps Research Institute consists of a modified form of cocaine derivative conjugated with keyhole limpet haemocyanin (KLH). The development is at the preclinical stage in the US. Results with the cocaine conjugate vaccine are promising and indicate that vaccination reduces response to cocaine and brain cocaine levels in rats28.

Nicotine

TA-NIC from Xenova
 Xenova's TA-NIC vaccine is formulated with nicotine conjugated to the carrier protein rCTB and an aluminium adjuvant. Preclinical studies showed that it induced antibodies against nicotine which help to prevent entry of nicotine into the brain. Xenova is currently performing a phase I trial to assess the safety, tolerability and immunogenicity of two different doses of the nicotine conjugate vaccine in smokers and non-smokers (press release, Xenova, 10 September 2001).

NicVAX from Nabi
 The conjugate vaccine from Nabi (NicVAX) is composed of nicotine and a carrier protein to prevent or treat nicotine dependence. In animals, NicVAX at doses up to 350 times the relative intended human dose showed no toxic effects, even when nicotine was administered after the vaccination. The vaccine generated significant antibody titres to nicotine. In rats, antibodies produced by vaccination with NicVAX significantly reduced brain nicotine concentrations following i.v. administration of nicotine29. These antibodies prevented adverse effects like increases in blood pressure or locomotor activation in response to injected nicotine. A phase I/II trial is expected to start in the first half of 2002 (press release, Nabi, 15 November 2001).

General comments on addiction vaccines

The major challenge here will be directly related to the primary objective of these vaccines. Indeed, the induced immune responses should be of sufficient magnitude to neutralize the ‘drugs’ (cocaine, nicotine, etc) in the bloodstream before their passage to the brain and their interaction with neurons. Persistently high levels of circulating antibodies of high affinity are required. Importantly, nicotine reaches the brain in only a few seconds after a cigarette puff, which leaves a very short period for the antibodies to interfere with the acute amounts of nicotine. Therefore, it seems more reasonable to consider this approach as complementary to a global approach of prevention of relapses in subjects who have quit already and are well motivated. Then, the additional help provided by vaccination could make the difference through the absence of a ‘positive’ effect in case of relapse.

On the other hand, cocaine abusers could represent a more difficult population to help than smokers. There may be a high risk that illicit drug users may simply move to other drugs when cocaine is neutralized by an efficacious vaccine. Again, the vaccine should be considered as one means amongst others to help these patients. The effects of vaccination should, therefore, also be compatible with the best developed pharmaceuticals.

These considerations show that we are still far from developing ‘preventive’ vaccines for a general adolescent or pre-adolescent population.


   Vaccination and dental caries
Top
 Abstract
 Introduction
 Contraceptive vaccines
 Vaccination and drug addiction
 Vaccination and dental caries
Conclusions
 Acknowledgements
 References
 
Dental caries is the most common infectious disease affecting humans. The main causative agents are a group of streptococcal species collectively referred to as the mutans streptococci30.

Streptococcus mutans has been identified as the major aetiological agent of human dental caries. The first step in the initiation of infection by this pathogenic bacterium is its attachment to a suitable receptor.

Two groups of proteins from mutans streptococci represent primary candidates for a human caries vaccine: (i) glucosyltransferase enzymes, which synthesize adhesive glucans and allow microbial accumulation; and (ii) cell-surface fibrillar proteins that mediate adherence to the salivary pellicle31.

It is hypothesized that a mucosal vaccine against a combination of S. mutans surface proteins would protect against dental caries by inducing specific salivary immunoglobulin A (IgA) antibodies. These IgAs may reduce bacterial pathogenesis and adhesion to the tooth surface by affecting several adhesins simultaneously.

Vaccination against glucosyltransferase (GTF)

The initiating step in infection by S. mutans is its attachment through glucan-binding proteins to receptors on the tooth surface. The induction of a specific immune response against GTF would prevent glucan production and inhibit the binding of S. mutans to the teeth. Mucosal immunization via the oral and nasal routes results in good salivary IgA responses32.

Several different vaccine preparations of GTF have been tested in animals and are protective against caries33. Following successful results in rats34,35, a phase I trial has been conducted in 80 young men by the Forsyth Institute with peptides from two regions of GTF. The vaccine was administered either orally or dripped on the inside surface of the lips. It was found to be safe and to delay the accumulation of S. mutans in plaques for several months. Clinical studies are planned and a nasal spray vaccine with GTF is under development (Harvard University Gazette, 4 October 2001; Pharmaprojects, 12 November 2001).

Surface proteins

Other proteins like the surface proteins fimbriae36, PAc37, or Ag I/II38 have been tested in animals as potential targets for vaccination. A preclinical trial from the University of Indiana showed that intranasal vaccination of rats with a mixture of S. mutans surface proteins enriched with fimbriae and conjugated with the B-subunit of cholera toxin induced salivary IgA and IgG responses and reduced lesions of enamel39.

Other antigens

Oral active immunization of animals with killed Streptococcus sobrinus40 or recombinant Salmonella expressing surface protein antigen A (Spa A) of S. sobrinus41 resulted in some decrease in caries lesions.

Finally, the hypothesis that caries is associated with a non-protective Th2 immune response could argue in favour of vaccination with heat-killed Mycobacterium vaccae known to induce Th1 type immune responses42.

General comments on caries vaccines

Children may represent the primary target population. Therefore, ‘caries vaccines’ could be relatively close to more classical anti-infectious vaccines. Indeed, infants become mucosally immunocompetent and secrete salivary immunoglobulin A antibodies during the first weeks after birth, whereas mutans streptococci colonize the tooth surfaces at a discrete time period that extends around 26 months of life. Therefore, immunization of infants may establish effective immunity against an ensuing colonization attempts by mutans streptococci. The main question relating to caries vaccines could therefore be the medical risk that represents caries, which is more difficult to estimate than that of more classical infections like polio, tetanus, meningitis, etc where the need to protect children is clear. Nevertheless, we believe that vaccines are of high benefit when unmet needs exist in the treatment of diseases or conditions. Additional health economic considerations must be taken into account. The balance will then be between technical difficulties and costs related to vaccine development on the one hand, and the benefit of such new approaches for society on the other hand. This balance should guide all our vaccine development choices.


   Conclusions
Top
 Abstract
 Introduction
 Contraceptive vaccines
 Vaccination and drug addiction
 Vaccination and dental caries
 Conclusions
Acknowledgements
 References
 
Thanks to dramatic technological improvements, the field of vaccinology can now extend from prophylaxis to therapy, and from infectious diseases to dysimmune disorders and even to non-immune related conditions, including neurological or cardiovascular disorders. We would propose the term ‘chronic disorder vaccines’ for these new fields of application. In the present paper, we focused on ‘life-style vaccines’ defined as vaccines to manage chronic conditions in healthy individuals. Three examples were arbitrarily chosen, which may correspond to that definition. However, one can argue that ‘dental caries vaccines’ are closer to classical anti-infectious prophylaxis, illustrating the difficulties of the definition. In the near future, a better knowledge of the genome and further significant technological progress will most probably allow additional unexpected applications of vaccines.


   Acknowledgements
Top
 Abstract
 Introduction
 Contraceptive vaccines
 Vaccination and drug addiction
 Vaccination and dental caries
 Conclusions
 Acknowledgements
References
 
We thank Melinda Meaders for active contribution to the general introduction, Ulrike Krause for in-depth review of the manuscript and Jean-Paul Prieels for critical discussion. We also thank Maryline Bauthier for secretarial support.


   Footnotes
 
Correspondence to: Dr Philippe Monteyne, GlaxoSmithKline Biologicals, Rue de l'Institut 89, B-1330 Rixensart, Belgium


   References
Top
 Abstract
 Introduction
 Contraceptive vaccines
 Vaccination and drug addiction
 Vaccination and dental caries
 Conclusions
 Acknowledgements
 References
 

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