[Frontiers In Bioscience, Elite, 9, 321-332, June 1, 2017]

Current status of a unique vaccine preventing pregnancy

Gursaran P. Talwar1, Kripa N. Nand1, Jagdish C. Gupta1, Atmaram H. Bandivdekar2, Radhey S. Sharma3, Nirmal K. Lohiya4

1Talwar Research Foundation, New Delhi, India, 2National Institute for Research in Reproductive Health, Mumbai, India, 3Indian Council of Medical Research, New Delhi, India, 4Department of Zoology, University of Rajasthan, Jaipur, India


1. Abstract
2. Introduction
3. The initial hCGβ-TT vaccine
3.1. Evaluation of the consequences of partial cross-reactivity with hLH
4. Carboxy terminal peptides (CTPs) of hCGβ as immunogens
5. The Hetero-Species Dimer (HSD-TT/DT) vaccine
5.1. Phase I clinical trials on HSD-TT/DT vaccine
5.2. Phase II efficacy trials
6. Reversibility and regain of fertility
6.1. Normalcy of children born to previously immunized women
7. Revival of the vaccine against hCG
8. Recombinant DNA and protein vaccines
9. Pre-clinical toxicology studies
9.1. In rodents
9.2. In Marmosets
10. Summary
11. Acknowledgements
12. References


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.


1. SB Fishel, RG Edwards, CJ Evans: Human chorionic gonadotropin secreted by preimplantation embryos cultured in vitro. Science 223, 816-818 (1984)
DOI: 10.1126/science.6546453

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)
DOI: 10.1016/0010-7824(76)90037-8

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)
DOI: 10.1073/pnas.73.1.218

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)
DOI: 10.1016/0010-7824(90)90070-C

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)
DOI: 10.1016/0010-7824(76)90039-1

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)
DOI: 10.1016/0010-7824(76)90036-6

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).
DOI: 10.1007/978-1-4612-3746-4_20

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)
DOI: 10.1111/j.1600-0897.1987.tb00163.x

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)
DOI: 10.1007/978-1-4612-3746-4_21

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)
DOI: 10.1210/jcem-39-6-1155

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)
DOI: 10.1016/0165-0378(79)90005-6

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)
DOI: 10.1016/0165-0378(82)90032-8

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)
DOI: 10.1016/S0015-0282(16)45019-3

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)
DOI: 10.1016/0165-0378(88)90020-4

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)
DOI: 10.1016/0010-7824(90)90071-3

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)
DOI: 10.1073/pnas.91.18.8532

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)
DOI: 10.1111/j.1600-0897.1998.tb00376.x

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)
DOI: 10.1002/eji.1830251226

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)
DOI: 10.1093/intimm/2.2.151

21. GP Talwar: An immunotherapeutic vaccine for multibacillary leprosy. Int Rev Immunol 18, 229–249 (1999)
DOI: 10.3109/08830189909043027

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)
DOI: 10.1016/j.jri.2011.06.099

23. S Purswani, GP Talwar: Development of a highly immunogenic recombinant candidate vaccine against human chorionic gonadotropin. Vaccine 29, 2314-2348 (2011)
DOI: 10.1016/j.vaccine.2010.11.069

24. D Fioretti, S Iurescia, VM Fazio, RM Monica: DNA vaccines: developing new strategies with cancer. J Biomed Biotechnol, Article ID 174378 (2010)
DOI: 10.1155/2010/174378

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)
DOI: 10.4236/wjv.2014.42008

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)
DOI: 10.1016/j.vaccine.2007.12.024

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)
DOI: 10.1158/1078-0432.CCR-08-1725

28. K Okuda, Y Wada, M Shimada: Recent developments in preclinical DNA vaccination. Vaccine 2, 89–106 (2014)
DOI: 10.3390/vaccines2010089

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)
DOI: 10.1111/aji.12388

Abbreviations: CTP: Carboxy Terminal Peptide, DCGI (Drugs Controller General of India), DT: Diptheria Toxoid, FSH: Follicle-stimulating Hormone, GLP: Good Laboratory Practice, GMP: Good Manufacturing Practice, hCG: Human Chorionic Gonadotropin, hCGß: ß subunit of Human Chorionic Gonadotropin, hFSH: Human follicle-stimulating Hormone, hGH: Human Growth Hormone, hLH: Human luteinizing hormone, HSD: Hetero-species Dimer, hTSH: Human Thyroid-stimulating Hormone, IAEC: Institutional Animal Ethics Committee, ICCR: International Committee for Contraception Research, IUDs: Intrauterine Devices, LH: Luteinizing Hormone, LTB: Heat-Labile Enterotoxin of E. coli, MIP: Mycobacterium Indicus Pranii, Mw: Mycobacterium w, RCGM (Review Committee on Genetic Manipulation), TSH: Thyroid-stimulating Hormone, TT: Tetanus Toxoid, US FDA: United States Food and Drug Administration, WHO: World Health Organization, α oLH: α subunit of Ovine Luteinizing Hormone , ß-oLH: ß subunit of Ovine Luteinizing Hormone

Key Words: Contraception, Fertility control, Human chorionic gonadotropin, hCG, Review

Send correspondence to: Gursaran P Talwar, The Talwar research Foundation, E-8, Neb Valley, Neb Sarai, New Delhi-110068 India, Tel: 91-011-65022405, E-mail: gptalwar@gmail.com