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[1]SB Fishel, RG Edwards, CJ Evans: Human chorionic gonadotropin secreted by preimplantation embryos cultured in vitro. Science 223, 816-818 (1984)
[2]JP Hearn, AA Gidley-Baird, JK Hodges, PM Summers, GE Webley: Embryonic signals during the peri-implantation period in primates. J Reprod Fertil Suppl 36, 49-58 (1988)
[3]GP Talwar, SK Dubey, M Salahuddin, C Das: Antibody response to Pr-beta-HCG-TT vaccine in human subjects. Contraception 13, 237-243 (1976)
[4]GP Talwar, NC Sharma, SK Dubey, M Salahuddin, C Das, S Ramakrishnan, S Kumar, V Hingorani: Isoimmunization against human chorionic gonadotropin with conjugates of processed β-subunit of the hormone and tetanus toxoid. Proc Nac Acad Sci 73, 218-222 (1976)
[5]I Kharat, NS Nair, K Dhall, H Sawhney, U Krishna, SM Shahani, A Banerjee, S Roy, S Kumar, V Hingorani, O Singh, GP Talwar, S Mokkapati, S Datey, S Gupta, M Roy, BK Singh, LN Gaur, BN Saxena: Analysis of menstrual records of women immunized with anti-hCG vaccines including antibodies partially cross-reactive with hLH. Contraception 41, 293-9 (1990)
[6]S Kumar, NC Sharma, JS Bajaj, GP Talwar, V Hingorani: Clinival profile and toxicology studies on 4 women immunized with Pr-β-hCG-TT. Contraception 13, 252-267 (1976)
[7]I Nath, PD Gupta, UN Bhuyan, GP Talwar: Autopsy report on rhesus monkeys immunized with Pr-β-HCG-TT vaccine. Contraception 13, 213-224 (1976)
[8]RB Thau: Active immunization of rhesus monkeys against beta subunit of ovine luteinizing hormone: evaluation of safety and effectiveness of antigonadotropin vaccine, In: Contraception Research for Today and Nineties. Ed: GP Talwar, New York, Springer-Verlag, 217-230 (1988).
[9]RB Thau, CB Wilson, K Sundaram, D Phillips, T Donelly, NS Halmi, CW Bardin: Long-term immunization against beta subunit of ovine luteinizing hormone has no adverse effect on pituitary functions in rhesus monkeys. Am J Reprod Immunol Microbiol 15, 92-8 (1987)
[10]NR Rose, CL Burek, JP Smith: Safety evalualtion of hCG vaccine in primates: auto antibody production. In: Contraception Research for Today and Nineties. Ed: GP Talwar, New York, Springer-Verlag, 231-239 (1988)
[11]JP Louvet, GT Ross, S Birken, RE Canfield: Absence of neutralizing effect of antisera to the unique structural region of human chorionic gonadotropin. J Clin Endocrinol Metab 39, 1155-1158 (1974)
[12]S Ramakrishnan, C Das, SK Dubey, M Salahuddin, GP Talwar: Immunogenecity of three C-terminal synthetic peptides of beta subunit of human chorionic gonadotropin and properties of the antibodies raised against 45-amino acid C-terminal peptide. J Reprod Immunol 1, 249-261 (1979)
[13]D Sahal, S Ramakrishnan, KSN Iyer, C Das, GP Talwar: Immunological properties of a carboxy-terminal 53-amino acid peptide of the beta subunit of human chorionic gonadotropin. J Reprod Immunol 4, 145-156 (1982)
[14]H Nash, ED Johansson, GP Talwar, J Vasquez, S Segal, E Coutinho, T Luukkainen, K Sundaram: Observations on the antigenicity and clinical effects of a candidate antipregnancy vaccine: beta-subunit of human chorionic gonadotropin linked to tetanus toxoid. Fertil Steril 34, 328-335 (1980)
[15]GP Talwar, O Singh, LV Rao: An improved immunogen for anti-human chorionic gonadotropin vaccine elicited antibodies reactive with a conformation native to the hormone without cross-reaction with human follicle stimulating hormone and human thyroid stimulating hormone. J Reprod Immunol 14, 203-212 (1988)
[16]GP Talwar, V Hingorani, S Kumar, S Roy, A Banerjee, SM Shahani, U Krishna, K Dhall, H Sawhney, NC Sharma, O Singh, A Gaur, LV Rao, K Arunan, BN Saxena, S Mokkapati , S Datey, S Gupta, M Roy, BK Singh, LN Gaur: Phase I clinical trials with three formulations of anti-human chorionic gonadotropin vaccine. Contraception 41, 301-316 (1990)
[17]GP Talwar, O Singh, R Pal, N Chatterjee, P Sahai, K Dhall, J Kaur, SK Das, S Suri, K Buckshee: A vaccine that prevents pregnancy in women. Proc Natl Acad Sci U S A 91, 8532-8536 (1994)
[18]M Singh, SK Das, S Suri, O Singh, GP Talwar: Regain of fertility and normality of progeny born at below protective threshold antibody titres in women immunized with HSD-TT vaccine. Am J Reprod Immunol 39, 395-398 (1998)
[19]A Kaliyaperumal, VS Chauhan, GP Talwar, R Raghupathy: Carrier-induced epitope-specific regulation and its bypass in a protein-protein conjugate, Eur J Immunol 25, 3375-3380 (1995)
[20]A Gaur, K Arunan, O Singh, GP Talwar: Bypass by an alternate carrier of acquired unresponsiveness to hCG upon repeated immunization with tetanus conjugated vaccine. Int Immunol 2, 151–155 (1990)
[21]GP Talwar: An immunotherapeutic vaccine for multibacillary leprosy. Int Rev Immunol 18, 229–249 (1999)
[22]S Purswani, GP Talwar, R Vohra, R Pal, AK Panda, NK Lohiya, JC Gupta: Mycobacterium indicus pranii is a potent immunomodulator for a recombinant vaccine against human chorionic gonadotropin. J Reprod Immunol 91, 24-30 (2011)
[23]S Purswani, GP Talwar: Development of a highly immunogenic recombinant candidate vaccine against human chorionic gonadotropin. Vaccine 29, 2314-2348 (2011)
[24]D Fioretti, S Iurescia, VM Fazio, RM Monica: DNA vaccines: developing new strategies with cancer. J Biomed Biotechnol, Article ID 174378 (2010)
[25]V Pereira, MZ Turk, T Saraiva, C De Castro, B Souza, P Mancha Agresti, F Lima, V Pfeiffer, M Azevedo, C Rocha, D Pontes, V Azevedo, A Miyoshi: DNA vaccines approach: from concepts to applications. World J Vaccines 4, 50–71 (2014)
[26]S Wang, JS Kennedy, K West, DC Montefiori, S Coley, J Lawrence, S Shen, S Green, AL Rothman, FA Ennis, J Arthos, R Pal, P Markham, S Lu: Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers. Vaccine 26, 1098–1110 (2008)
[27]CL Trimble, S Peng, F Kos, P Gravitt, R Viscidi, E Sugar, D Pardoll, TC Wu: A phase I trial of a human papillomavirus DNA vaccine for HPV16 + cervical intraepithelial neoplasia 2/3. Clin Cancer Res 15, 361–367 (2009)
[28]K Okuda, Y Wada, M Shimada: Recent developments in preclinical DNA vaccination. Vaccine 2, 89–106 (2014)
[29]KN Nand, JC Gupta, AK Panda, SK Jain, GP Talwar: Priming with DNA enhances considerably the immunogenicity of hCGβ- LTB vaccine. Am J Reprod Immunol 74, 302-308 (2015)
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Frontiers in Bioscience-Elite (FBE) is published by IMR Press from Volume 13 Issue 2 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.
Current status of a unique vaccine preventing pregnancy
, Kripa N. Nand 1, Jagdish C. Gupta 1, Atmaram H. Bandivdekar 2, Radhey S. Sharma 3, Nirmal K. Lohiya 41 Talwar Research Foundation, New Delhi, India
2 National Institute for Research in Reproductive Health, Mumbai, India
3 Indian Council of Medical Research, New Delhi, India
4 Department of Zoology, University of Rajasthan, Jaipur, India
*Author to whom correspondence should be addressed.
Abstract
The ability of a vaccine linking beta hCG to a carrier to generate antibodies against hCG, its reversibility and safety was established by Phase I clinical trials conducted in India, Finland, Sweden, Chile and Brazil. Employing a hetero-species dimer (beta hCG-αoLH) linked to tetanus toxoid further improved the immunogenicity of the vaccine. Phase II clinical trials showed that anti-hCG titres above 50 ng/ml prevented pregnancy of sexually active fertile women without derangement of ovulation and menstrual regularity. On decline of antibodies, women conceived again to give birth to normal progeny. A genetically engineered vaccine consisting of beta hCG linked to B subunit of heat labile enterotoxin of E. coli has been made. It is expressed as DNA as well as protein. Priming with DNA followed by protein version of the vaccine generates very high titres against hCG in mice. Extensive toxicology studies in 2 species of rodents, and marmosets have shown complete safety of the vaccine. The vaccine is cleared for Clinical trials by the National Review committee on Genetic Manipulation and Drugs Controller General of India.
Keywords
- Contraception
- Fertility control
- Human chorionic gonadotropin
- hCG
- Review
References
- [1] SB Fishel, RG Edwards, CJ Evans: Human chorionic gonadotropin secreted by preimplantation embryos cultured in vitro. Science 223, 816-818 (1984)
- [2] JP Hearn, AA Gidley-Baird, JK Hodges, PM Summers, GE Webley: Embryonic signals during the peri-implantation period in primates. J Reprod Fertil Suppl 36, 49-58 (1988)
- [3] GP Talwar, SK Dubey, M Salahuddin, C Das: Antibody response to Pr-beta-HCG-TT vaccine in human subjects. Contraception 13, 237-243 (1976)
- [4] GP Talwar, NC Sharma, SK Dubey, M Salahuddin, C Das, S Ramakrishnan, S Kumar, V Hingorani: Isoimmunization against human chorionic gonadotropin with conjugates of processed β-subunit of the hormone and tetanus toxoid. Proc Nac Acad Sci 73, 218-222 (1976)
- [5] I Kharat, NS Nair, K Dhall, H Sawhney, U Krishna, SM Shahani, A Banerjee, S Roy, S Kumar, V Hingorani, O Singh, GP Talwar, S Mokkapati, S Datey, S Gupta, M Roy, BK Singh, LN Gaur, BN Saxena: Analysis of menstrual records of women immunized with anti-hCG vaccines including antibodies partially cross-reactive with hLH. Contraception 41, 293-9 (1990)
- [6] S Kumar, NC Sharma, JS Bajaj, GP Talwar, V Hingorani: Clinival profile and toxicology studies on 4 women immunized with Pr-β-hCG-TT. Contraception 13, 252-267 (1976)
- [7] I Nath, PD Gupta, UN Bhuyan, GP Talwar: Autopsy report on rhesus monkeys immunized with Pr-β-HCG-TT vaccine. Contraception 13, 213-224 (1976)
- [8] RB Thau: Active immunization of rhesus monkeys against beta subunit of ovine luteinizing hormone: evaluation of safety and effectiveness of antigonadotropin vaccine, In: Contraception Research for Today and Nineties. Ed: GP Talwar, New York, Springer-Verlag, 217-230 (1988).
- [9] RB Thau, CB Wilson, K Sundaram, D Phillips, T Donelly, NS Halmi, CW Bardin: Long-term immunization against beta subunit of ovine luteinizing hormone has no adverse effect on pituitary functions in rhesus monkeys. Am J Reprod Immunol Microbiol 15, 92-8 (1987)
- [10] NR Rose, CL Burek, JP Smith: Safety evalualtion of hCG vaccine in primates: auto antibody production. In: Contraception Research for Today and Nineties. Ed: GP Talwar, New York, Springer-Verlag, 231-239 (1988)
- [11] JP Louvet, GT Ross, S Birken, RE Canfield: Absence of neutralizing effect of antisera to the unique structural region of human chorionic gonadotropin. J Clin Endocrinol Metab 39, 1155-1158 (1974)
- [12] S Ramakrishnan, C Das, SK Dubey, M Salahuddin, GP Talwar: Immunogenecity of three C-terminal synthetic peptides of beta subunit of human chorionic gonadotropin and properties of the antibodies raised against 45-amino acid C-terminal peptide. J Reprod Immunol 1, 249-261 (1979)
- [13] D Sahal, S Ramakrishnan, KSN Iyer, C Das, GP Talwar: Immunological properties of a carboxy-terminal 53-amino acid peptide of the beta subunit of human chorionic gonadotropin. J Reprod Immunol 4, 145-156 (1982)
- [14] H Nash, ED Johansson, GP Talwar, J Vasquez, S Segal, E Coutinho, T Luukkainen, K Sundaram: Observations on the antigenicity and clinical effects of a candidate antipregnancy vaccine: beta-subunit of human chorionic gonadotropin linked to tetanus toxoid. Fertil Steril 34, 328-335 (1980)
- [15] GP Talwar, O Singh, LV Rao: An improved immunogen for anti-human chorionic gonadotropin vaccine elicited antibodies reactive with a conformation native to the hormone without cross-reaction with human follicle stimulating hormone and human thyroid stimulating hormone. J Reprod Immunol 14, 203-212 (1988)
- [16] GP Talwar, V Hingorani, S Kumar, S Roy, A Banerjee, SM Shahani, U Krishna, K Dhall, H Sawhney, NC Sharma, O Singh, A Gaur, LV Rao, K Arunan, BN Saxena, S Mokkapati , S Datey, S Gupta, M Roy, BK Singh, LN Gaur: Phase I clinical trials with three formulations of anti-human chorionic gonadotropin vaccine. Contraception 41, 301-316 (1990)
- [17] GP Talwar, O Singh, R Pal, N Chatterjee, P Sahai, K Dhall, J Kaur, SK Das, S Suri, K Buckshee: A vaccine that prevents pregnancy in women. Proc Natl Acad Sci U S A 91, 8532-8536 (1994)
- [18] M Singh, SK Das, S Suri, O Singh, GP Talwar: Regain of fertility and normality of progeny born at below protective threshold antibody titres in women immunized with HSD-TT vaccine. Am J Reprod Immunol 39, 395-398 (1998)
- [19] A Kaliyaperumal, VS Chauhan, GP Talwar, R Raghupathy: Carrier-induced epitope-specific regulation and its bypass in a protein-protein conjugate, Eur J Immunol 25, 3375-3380 (1995)
- [20] A Gaur, K Arunan, O Singh, GP Talwar: Bypass by an alternate carrier of acquired unresponsiveness to hCG upon repeated immunization with tetanus conjugated vaccine. Int Immunol 2, 151–155 (1990)
- [21] GP Talwar: An immunotherapeutic vaccine for multibacillary leprosy. Int Rev Immunol 18, 229–249 (1999)
- [22] S Purswani, GP Talwar, R Vohra, R Pal, AK Panda, NK Lohiya, JC Gupta: Mycobacterium indicus pranii is a potent immunomodulator for a recombinant vaccine against human chorionic gonadotropin. J Reprod Immunol 91, 24-30 (2011)
- [23] S Purswani, GP Talwar: Development of a highly immunogenic recombinant candidate vaccine against human chorionic gonadotropin. Vaccine 29, 2314-2348 (2011)
- [24] D Fioretti, S Iurescia, VM Fazio, RM Monica: DNA vaccines: developing new strategies with cancer. J Biomed Biotechnol, Article ID 174378 (2010)
- [25] V Pereira, MZ Turk, T Saraiva, C De Castro, B Souza, P Mancha Agresti, F Lima, V Pfeiffer, M Azevedo, C Rocha, D Pontes, V Azevedo, A Miyoshi: DNA vaccines approach: from concepts to applications. World J Vaccines 4, 50–71 (2014)
- [26] S Wang, JS Kennedy, K West, DC Montefiori, S Coley, J Lawrence, S Shen, S Green, AL Rothman, FA Ennis, J Arthos, R Pal, P Markham, S Lu: Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers. Vaccine 26, 1098–1110 (2008)
- [27] CL Trimble, S Peng, F Kos, P Gravitt, R Viscidi, E Sugar, D Pardoll, TC Wu: A phase I trial of a human papillomavirus DNA vaccine for HPV16 + cervical intraepithelial neoplasia 2/3. Clin Cancer Res 15, 361–367 (2009)
- [28] K Okuda, Y Wada, M Shimada: Recent developments in preclinical DNA vaccination. Vaccine 2, 89–106 (2014)
- [29] KN Nand, JC Gupta, AK Panda, SK Jain, GP Talwar: Priming with DNA enhances considerably the immunogenicity of hCGβ- LTB vaccine. Am J Reprod Immunol 74, 302-308 (2015)