The studies were undertaken to assess the immunogenicity and safety in infants and older children of a new vaccine-Vi polysaccharide conjugated with Tetanus toxoid protein, developed by Dr. Puneet Garg & his associates at BIO MED(P) ltd, Ghaziabad, INDIA. This new technology has avoided the use of recombinant proteins for conjugation. The vaccine has passed the required safety & immunological parameters in animals. The permission to conduct clinical trial Phase III in human was cleared by the Drugs Controller General (India) after necessary evaluation.
Methods & Materials
Open , multicentric, controlled & comparative study was undertaken. The three consecutive batches of Vi conjugate typhoid vaccine (Peda TyphTM), used for conducting the clinical trial, were found to be of standard quality by Central Drugs Laboratory, Central Research Institute, Kasauli, H.P. of Government of India. The Vi polysaccharide typhoid vaccine manufactured by BIO-MED (P) LTD., was also tested for comparative assessment studies. The study protocols were approved by the ethics committee of eminent medical colleges located in three widely separated zones of India.
Details of three medical colleges where the clinical trials were conducted.
|STUDY CENTRE||CHIEF INVESTIGATOR|
|L.L.R.M Medical College, Meerut, UP.||Dr.S.P.Goel M.D. Professor & Head Department of Pediatrics|
|Dr.Anil Agarwal M.D. Professor of Microbiology & Pathology|
|Gandhi Medical College , Secundrabad ,Andhra Pradesh||Dr.P.Sudershan Reddy M.D., D.C.H. Professor & Head Department of Pediatrics|
|Dr.B.Balaraju M.D., Professor of Medicine & Superintendent Gandhi Medical Hospital|
|Medical College Bhavnagar,Bhavnagar,Gujarat||Dr.M.P. Singh M.D. Professor & Head of the Department of PSM and Superintendent Sir T. General Hospital|
|Dr Alpa N.Parekh M.D., Deptt. of Pediatrics Associate Professor & Head Department of Pediatrics|
Selection of volunteers
The subjects were selected randomly from different economic strata of the society. All children taken in the study were normal, in good health & clinical state.
Group A-Vi conjugate typhoid vaccine (Peda TyphTM)
Peda TyphTM was administered to infants > 12 weeks of age by intramuscular route. 169 volunteers were vaccinated and observed for local and systematic side effects, paired serum samples from 145 volunteers were collected.
Group B-Vi polysaccharide typhoid vaccine
Vaccine was administered to children = 2 years of age by intramuscular route. Thirty seven volunteers were vaccinated and observed for local and systemic side effects, paired serum samples from 29 volunteers were collected.
Evaluation of safety
Local side effects (at the site of injection) : Pain, erythema and inflammation and
Systemic side effects : Fever. diarrhoea, vomiting and any other were recorded 30 minutes, 4 to 6 hours and 48 hours post vaccination. Scaling of adverse reactions was done as following :
Scaling of adverse reactions was done as following :
|Excellent||No local or systemic reactions|
|Good||Local reactions (inflammation)<5 cm in diameter and axillary temperature <38.30 C.|
|Fair||Local reaction (inflammation)>5 cm in diameter and axillary temperature < 38.30C.|
|Bad||Local reaction (inflammation)>5 cm in diameter and axillary temperature > 38.30 C.|
Of the total 169 subjects vaccinated with Peda TyphTM-147 subjects were in category “excellent”, 22 subjects in category “good”. There were no case in “fair” and “bad” categories on the scale of adverse reactions.
There were no serious adverse event leading to premature withdrawal from the study. None of the subjects had inflammation, one subject had erythema at site of injection. Local reactions were confined to mild transient pain which resolved without any sequella.
Three subjects had fever >38.30 C. The temperature rise became normal within 24 hours post vaccination without any medication.
Based on the above data, the principle investigators concluded that Peda TyphTM (Vi Conjugated Typhoid vaccine) was safe & well tolerated in all age groups including infants.
Evaluation of Immunogenicity :
Blood samples(1-2ml) were collected by venipuncture before vaccination on day 0(pre-immune) and 4 weeks after vaccination (post immune). lgG anti Vi antibodies were detemined by ELISA.
ELISA test : (Assay for assessment of immune response in paired serum samples)
ELISA test kit was validated and calibrated as per the guidelines of good laboratory practice.
Serum lgG Vi antibodies were assayed by ELISA and expressed in ELISA units relative to a standard reference. The unitage of the standard reference was assigned by NICHD, NIH, USA.
Preparation of standard reference curve and calculation of lgG antibodies was done by program of ELISA version 2.0, Centers for Disease control , Atlanta(USA).
Biostatistical Analysis : Biostatistical analysis of the clinical trial of Peda TyphTM was done by Dr.R.M. Pandey Ph.D.,FRSS(U.K.),Professor and Head, Department of Bio-Statistics, All India Institute of Medical Sciences ,N.Delhi. Biostatistical analysis proved that Peda TyphTM vaccine is safe and immunogenic. The antibody titers of the sera from 100% of the subjects (from all three centers) showed a four fold or greater rise in antibody titer of each group after immunization .No statistically significant differences were found in male and female children.
Results are graphically presented in figure 2. The lgG anti-Vi antibodies of Peda TyphTM were 97.425 ELISA units in infants and children 3 months to 24 months of age. The geometric mean (95% confidence interval) of all volunteers was 70.32(62.86-78.66).
The Vi conjugate typhoid vaccine (Peda TyphTM) under clinical trial have been found to be highly immunogenic in infants and children less than 2 years of age in which unconjugated Vi polysaccharide typhoid vaccine is known to induce very low or nil immunogenic response.
The efficacy of Vi conjugate typhoid vaccine in clinical trials conducted in Vietnam have been found to be 89% over the 46 months period.
On comparing the data of clinical trial of Vi conjugate typhoid vaccine developed by N.I.H (Published in The New England Journal vol.344 no. 17, 2001 pg.No.1263-1269) with Peda TyphTM manufactured by BIO-MED(P)LTD., it was found that the geometric mean post immune lgG(25-75 percentile) are statistically equivalent.
Immunizations not only prevent mortality and morbidity. They also reduce the expenditure of public and private resources. The latest generation Vi conjugate typhoid vaccine is an effective tool to control the emerging pattern of typhoid fever in children and infants <2 years of age.
The above study has been published in :
Garg P., Garg S., Sharma M.K (2014), Clinical trial of Tetanus Toxoid Conjugated Vi Polysaccharide Typhoid Vaccine in infants and young children, Sharma et al (2014) Biotechnology International 7(4) : 90-100.
Further post licensure studies on Peda TyphTM has been done in SRM Medical college Chennai by Dr. Balaji Chinnasami et al. Dr. Monjori Mitra et.al conducted a large scale Safety Immunogenicity & Efficacy study in Municipal school children in Kolkata (highly endemic area).
The studies have been published in :
- Chinnasami B., Mangayarkarasi V., Prema A., Sadasivam K. & Davis M.J. (2013). Safety and immunogenicity of Salmonella typhi Vi conjugate vaccine (Peda Typh™) is children upto five years. International Journal of Scientific and Research Publication, Volume 3, issue 2, February 2013.
- Chinnasami B., Sadasivam K., Vivekanandhan A., Arunachalam P. & Pasupathy S. (2015). A study on Longevity of Immune Response after vaccination with Salmonella typhi Vi Conjugate Vaccine (Peda Typh™) in children. Journal of Clinical & Diagnostic Research. 2015 May, Vol-9(5).
- Mitra M., Shah N., Ghosh A., et al (2015). Efficacy and Safety of Vi-Tetanus Toxoid Conjugated Typhoid Vaccine (Peda TyphTM) in Indian Children: School Based Cluster Randomized study. Human Vaccine & immunotherapeutics 2016, VoI. 0,No. 0, 1-7
The highlights of the result of the studies are as under :
- Efficacy of Peda Typh has been found to be 100% versus 33 cases of typhoid in control group over a follow up period of 1 year.
- One dose of the vaccine was found to give protective immunity in infants & children . No significant advantage of two doses regimen over one dose was found.”as per Dr. Chinnasami in his study “ A study on Longevity of Immune Response after vaccination with Salmonella typhi Vi Conjugate Vaccine (Peda Typh™) in children.
- Serum analysis of post licensure follow up study at SRM Medical College using Peda Typh™ showed adequate immune response 30 months post vaccination with Single dose – 14 (4.8 – 29.8) µg/ml (which is much greater than earlier seroprotective level 3.52 Elisa unit equivalent to 4.36mcg/ml or current seroprotective level 1.4 µg/ml-2µg/ml).