http://news.bmn.com/hmsbeagle/120/notes/feature7

Abstract

Vaccination is used routinely to protect against infectious disease and is being explored increasingly as a method of protection against tumors. Also, it has been established that vaccination using antigens associated with reproduction can protect against undesired pregnancy. Substantial progress over the past decade suggests that, if the remaining immunological and socioeconomic issues can be resolved, antifertility vaccines could be a valuable, additional method of family planning.

The human population exceeded six billion in October 1999, double the population in 1960. It is growing currently by 77 million people per year (United Nations Population Information Network). Such an alarming rise reflects the fact that, at a global level, 40% of couples of reproductive age do not practice any form of contraception currently [1]. Approximately one half of the one million new pregnancies each day are unintended, and in the United States, 46% of women have had at least one elective abortion by the end of their child-bearing years [2]. There is a clear need for the increased use of contraception and a wider choice of contraceptive options. In addition to humans, reduced fertility is often desirable in animal populations [3,4]. One approach towards additional methods of fertility control is the development of vaccines that elicit an antibody response capable of neutralizing hormones, or sperm or egg antigens that are essential for reproduction (figure 1). It seems probable that this approach will become accepted generally for veterinary use. However, although the efficacy of an antifertility vaccine in humans has been established [5], several issues are currently being addressed before these vaccines can be employed routinely for human family planning.

Reversibility and Safety

In the past, concerns have been raised that antifertility vaccines might produce permanent infertility. However, it has been a general finding that, in the absence of boosting, protection from pregnancy is afforded only over a period of weeks or months, rather than years. Indeed, the generation of longer term immune responses will be a necessary improvement to current antifertility vaccines. To date, human phase I and phase II trials have involved mostly, but not exclusively, human chorionic gonadotropin (hCG)-based vaccines [6,7]. The anti-hCG vaccines have used the ­chain of hCG [7], a heterospecies dimer of human ­chain with sheep ­chain [7,8] or a C­terminal peptide (CTP) from the ­chain [6,9]. Generally, the vaccines have proved to be safe in these trials, but long-term safety of the vaccine over several years in large numbers of people will also need to be established eventually.

The Problem of Low Responders

The only successful human phase II trial carried out to date used the heterospecies dimer [8]; in this study, 80% of vaccinated females produced protective levels of antibody. Unless pre-screening to identify adequate responders is used, a significant improvement in the number of individuals mounting the necessary level of response is required. Indeed, although the U.S. company Zonagen, Inc. entered a collaborative option agreement with Wyeth-Ayerst laboratories in 2000, regarding the development of a human oocyte zona-pellucida-based contraceptive vaccine, the agreement was terminated in September 2001 and Zonagen suspended further research into the vaccine, because of an inability to induce sufficient antibody titers for a contraceptive effect in all of the baboons in the trial. Much more so than for veterinary antifertility vaccines, the human user will need to be sure that the contraceptive vaccine will be effective for them. Promiscuous T-cell epitopes might hold the key.

Is the Vaccine Approach Acceptable?

One issue that has been raised is that the development of nonbarrier methods of contraception is detrimental to the fight against sexually transmitted diseases. Education regarding the use of appropriate methods for individual lifestyles is of paramount importance with all types of contraception. In fact, it might be possible eventually to include additional antigens within the vaccine formulation that would provoke a protective mucosal immune response against organisms causing sexually transmitted diseases. Some antifertility vaccines, including those based upon hCG, act post-fertilization and therefore, are not acceptable to all people. Nonetheless, several currently available methods of contraception, such as intrauterine devices and some forms of hormonal contraception, can act post-fertilization also but are used by large numbers of people. Vaccines that act pre-fertilization would probably be acceptable to most people, but only if a high level of safety and efficacy can be demonstrated convincingly.

The Future of Clinical Trials

Irrespective of the type of vaccine, vaccine development will require substantial sums of money. Governments, nongovernmental organizations, and the pharmaceutical industry will need to be convinced that such an approach is likely to become an acceptable method of birth control. To date, clinical trials have been carried out largely under the auspices of the government of India and, separately, the World Health Organisation (WHO). Currently, the government of India is supporting continuing research, but further clinical trials are not planned until the vaccines have undergone further refinement. The WHO-sponsored program ceased further trials whilst a new version of their CTP vaccine, which now includes a loop peptide from the hCG ­chain also [6], was developed. The relevant program committee is due to meet in the near future to discuss possible clinical trials with the new vaccine.

Concluding Remarks

Although the further refinement of vaccines aimed at controlling fertility is necessary, it would seem probable that an efficacy comparable to that of many of the current family-planning methods will be achievable. More evidence regarding the long-term safety of this approach will only accumulate if extensive clinical trials are carried out. This will require enthusiastic political and commercial commitment to develop such vaccines for general use.

Matt Morrow is a freelance illustrator based in Omaha, Nebraska.

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Abstract

Vaccination is used routinely to protect against infectious disease and is being explored increasingly as a method of protection against tumors. Also, it has been established that vaccination using antigens associated with reproduction can protect against undesired pregnancy. Substantial progress over the past decade suggests that, if the remaining immunological and socioeconomic issues can be resolved, antifertility vaccines could be a valuable, additional method of family planning.

The human population exceeded six billion in October 1999, double the population in 1960. It is growing currently by 77 million people per year (United Nations Population Information Network). Such an alarming rise reflects the fact that, at a global level, 40% of couples of reproductive age do not practice any form of contraception currently [1]. Approximately one half of the one million new pregnancies each day are unintended, and in the United States, 46% of women have had at least one elective abortion by the end of their child-bearing years [2]. There is a clear need for the increased use of contraception and a wider choice of contraceptive options. In addition to humans, reduced fertility is often desirable in animal populations [3,4]. One approach towards additional methods of fertility control is the development of vaccines that elicit an antibody response capable of neutralizing hormones, or sperm or egg antigens that are essential for reproduction (figure 1). It seems probable that this approach will become accepted generally for veterinary use. However, although the efficacy of an antifertility vaccine in humans has been established [5], several issues are currently being addressed before these vaccines can be employed routinely for human family planning.

Reversibility and Safety

In the past, concerns have been raised that antifertility vaccines might produce permanent infertility. However, it has been a general finding that, in the absence of boosting, protection from pregnancy is afforded only over a period of weeks or months, rather than years. Indeed, the generation of longer term immune responses will be a necessary improvement to current antifertility vaccines. To date, human phase I and phase II trials have involved mostly, but not exclusively, human chorionic gonadotropin (hCG)-based vaccines [6,7]. The anti-hCG vaccines have used the ­chain of hCG [7], a heterospecies dimer of human ­chain with sheep ­chain [7,8] or a C­terminal peptide (CTP) from the ­chain [6,9]. Generally, the vaccines have proved to be safe in these trials, but long-term safety of the vaccine over several years in large numbers of people will also need to be established eventually.

The Problem of Low Responders

The only successful human phase II trial carried out to date used the heterospecies dimer [8]; in this study, 80% of vaccinated females produced protective levels of antibody. Unless pre-screening to identify adequate responders is used, a significant improvement in the number of individuals mounting the necessary level of response is required. Indeed, although the U.S. company Zonagen, Inc. entered a collaborative option agreement with Wyeth-Ayerst laboratories in 2000, regarding the development of a human oocyte zona-pellucida-based contraceptive vaccine, the agreement was terminated in September 2001 and Zonagen suspended further research into the vaccine, because of an inability to induce sufficient antibody titers for a contraceptive effect in all of the baboons in the trial. Much more so than for veterinary antifertility vaccines, the human user will need to be sure that the contraceptive vaccine will be effective for them. Promiscuous T-cell epitopes might hold the key.

Is the Vaccine Approach Acceptable?

One issue that has been raised is that the development of nonbarrier methods of contraception is detrimental to the fight against sexually transmitted diseases. Education regarding the use of appropriate methods for individual lifestyles is of paramount importance with all types of contraception. In fact, it might be possible eventually to include additional antigens within the vaccine formulation that would provoke a protective mucosal immune response against organisms causing sexually transmitted diseases. Some antifertility vaccines, including those based upon hCG, act post-fertilization and therefore, are not acceptable to all people. Nonetheless, several currently available methods of contraception, such as intrauterine devices and some forms of hormonal contraception, can act post-fertilization also but are used by large numbers of people. Vaccines that act pre-fertilization would probably be acceptable to most people, but only if a high level of safety and efficacy can be demonstrated convincingly.

The Future of Clinical Trials

Irrespective of the type of vaccine, vaccine development will require substantial sums of money. Governments, nongovernmental organizations, and the pharmaceutical industry will need to be convinced that such an approach is likely to become an acceptable method of birth control. To date, clinical trials have been carried out largely under the auspices of the government of India and, separately, the World Health Organisation (WHO). Currently, the government of India is supporting continuing research, but further clinical trials are not planned until the vaccines have undergone further refinement. The WHO-sponsored program ceased further trials whilst a new version of their CTP vaccine, which now includes a loop peptide from the hCG ­chain also [6], was developed. The relevant program committee is due to meet in the near future to discuss possible clinical trials with the new vaccine.

Concluding Remarks

Although the further refinement of vaccines aimed at controlling fertility is necessary, it would seem probable that an efficacy comparable to that of many of the current family-planning methods will be achievable. More evidence regarding the long-term safety of this approach will only accumulate if extensive clinical trials are carried out. This will require enthusiastic political and commercial commitment to develop such vaccines for general use.

Matt Morrow is a freelance illustrator based in Omaha, Nebraska.

Tell us what you think.

Archives