Immunogenicity and safety of an indigenously manufactured reconstituted pentavalent (DTwP-HBV+Hib) vaccine in comparison with a foreign competitor following primary and booster immunization in Indian children.

OBJECTIVE: An open label, controlled clinical study was conducted in Indian infants aged 6-14 weeks to compare the immunogenicity and safety of a reconstituted pentavalent vaccine (DTwP-HBV+Hib) of Serum Institute of India Ltd (SIIL) with TritanrixHB+Hiberix vaccine of Glaxo Smithkline (GSK). METHODS: Eligible infants were randomized to receive three doses of the study / comparator vaccine. The vaccines were reconstituted prior to administration, by mixing DTwP-HBV (liquid) with the Hib (lyophilized) vaccine. IgG antibody titres were assessed by ELISA at baseline and after one month following the 3-dose primary immunization schedule. Safety was evaluated after each dose. Further, safety and immunogenicity was also evaluated following a booster dose in the same cohort of children (aged between 15-24 months). SETTING: Tertiary-care hospitals in India Important outcome measures: Immunogenicity and safety following a 3-dose primary vaccination series and a booster vaccination. RESULTS: Post-primary immunization, 100% seroprotection was noted for Diphtheria, Tetanus, Hepatitis B and PRP-Hib components in both the vaccine groups. For pertussis, response was 96.1% in SIIL and 95.4% in GSK group. The overall safety profile as well as persistence of antibodies against all vaccine components up to the time of booster immunization was comparable between the SIIL and GSK groups. A marked rise of all antibody concentrations indicated effective priming. The booster dose was safe, well tolerated with a significant increase in antibody concentrations of all the vaccine antigens in both the groups. CONCLUSION: DTwP-HBV+Hib vaccine of SIIL was found to be safe and immunogenic. This Indian vaccine compared well with the licensed vaccine and is a cost-effective alternative for incorporating into the immunization schedule of various countries so as to control worldwide Hepatitis B and Hib infections.

Tumour necrosis factor-alpha and soluble Fas ligand as biomarkers in non-acetaminophen-induced acute liver failure.

OBJECTIVES: Cytokines as prognostic markers in acute liver failure (ALF) have not been evaluated in the Indian subcontinent with hepatitis E as the commonest aetiological agent. We investigated the clinical significance of proinflammatory/apoptotic cytokines soluble Fas ligand (sFasL) and tumour necrosis factor (TNF)-alpha in ALF of specific aetiology. METHODS: A total of 82 cases, 37 ALF and 45 acute hepatitis (AH), and 60 healthy controls were recruited. Serum levels of sFasL and TNF-alpha were determined at admission and death/recovery. RESULTS: Mean sFasL and TNF-alpha serum levels at admission were significantly higher (p < 0.001) in patients with ALF than AH, but no marked difference was observed between ALF-E (expired, n = 23) and ALF-S (survivors, n = 14), although the former had comparatively higher levels. ALF-E had higher than baseline TNF-alpha and sFasL concentrations at death, while in the ALF-S group the samples obtained from the patients as soon as they came out of encephalopathy, showed either lower or similar TNF-alpha and sFasL levels as found at admission. CONCLUSION: The high levels of sFasL and TNF-alpha are associated with ALF. Following the trend of these cytokines can be useful in predicting death and timely referral to a transplant centre.

Safety and immunogenicity of an indigenously developed Haemophilus influenzae type b conjugate vaccine through various phases of clinical trials.

In view of the need for a cost effective Haemophilus influenzae type b (Hib) conjugate vaccine, a lyophilized vaccine as capsular polysaccharide (PRP) conjugated to tetanus toxoid (Sii HibPRO) was indigenously developed by Serum Institute of India Ltd., Pune (SIIL). From 2004-07, this new vaccine underwent a series of clinical studies before its licensure by National Regulatory Authority (NRA). This paper discusses the results obtained during the clinical development of this vaccine. On finding the vaccine to be safe in animal toxicity studies, a Phase I single dose study was carried out to assess the safety profile of Sii HibPRO in healthy adult male volunteers. Subsequently, in Phase III pre-licensure study, immunogenicity and safety of Sii HibPRO was assessed and compared with Hib tetanus conjugate vaccine (Act-HIB) of Aventis, France. Immunogenicity was evaluated based upon serum anti-PRP IgG antibody concentrations by ELISA at prevaccination and one month each after the second and third dose. Safety was evaluated by recording details of adverse events after each dose of the vaccine. Postvaccination after the third dose, there was 100% seroprotection (anti PRP IgG titre >or= 0.15 microg/ml) in both the groups. Long term protection (>or=1 microg/ml) was achieved in 95.2% and 98.06% infants in Sii HibPRO and Act-HIB groups, respectively. At 15 months, prior to booster dose, 30 children in each group were evaluated and all were found to be seroprotected. Post booster, all of them responded with a strong boost response. Safety of Sii HibPRO was re-established in the post marketing surveillance in which 2,739 doses were administered to 1,029 infants, in 23 cities across India.

Clinical and Molecular Risk Factors of Anti-tubercular Therapy Induced Hepatitis.

BACKGROUND: This is a case-control study aimed at evaluating clinical as well as molecular risk factors for occurrence of ATT induced hepatitis in Northern Indian population. METHODS: 100 patients of tuberculosis were recruited from both Outdoor patient department and wards of Lok Nayak Hospital, New Delhi. 40 out of 100 patients who developed ATT induced hepatitis were taken as test group and 60 out of 100 patients who didn't develop liver dysfunction on ATT were taken as controls and studied and compared for clinical factors such as age, gender, nutritional status, HBsAg carrier, chronic hepatitis C and HIV infection. Molecular factors i.e. NAT2 acetylator status, GSTT1 and M1 null mutations were also determined in all of the patients in each group and compared. RESULTS: Mean body weight and serum albumin were significantly lower in the ATT induced hepatitis patients as compared to the control group. No preferential association was observed between age and gender with ATT induced hepatitis. HBsAg carrier (OR-6.5; P = 0.03), HIV infection (OR-5.1; P = 0.01), slow acetylator phenotype (OR-3.85; P = 0.02), GSTM1 null mutation (OR-2.72; P = 0.02) and GSTT1 null mutation (OR-3.12; P = 0.02) were found to be positively co-related to ATT induced hepatitis according to the univariate analysis. HBsAg carrier (OR-23.18; P = 0.01), HIV infection (OR-16.92; P = 0.02), Slow acetylator phenotype (OR-70.90; P = 0.001), GSTM1 null mutation (OR-37.03; P = 0.002) and GSTT1 null mutation (OR-8.19; P = 0.014) were also found to be independently increasing the risk of ATT induced hepatitis using multivariate analysis. CONCLUSION: The present study established a positive co-relation between malnutrition, HBsAg carrier, HIV infection, NAT2 slow acetylators, GSTM1 null mutation, GSTT1 null mutation and ATT induced hepatitis.

Use of VSL[sharp]3 in the treatment of rotavirus diarrhea in children: preliminary results.

UNLABELLED: We conducted a double-blind randomized placebo-controlled study to evaluate efficacy and tolerability of VSL[sharp]3 (CD Pharma India) in the treatment of acute rotavirus diarrhea in children. The patients were randomly assigned to receive 4 days of oral treatment with VSL[sharp]3 probiotic mixture or placebo in addition to usual care for diarrhea. RESULTS: Out of 230 rotavirus-positive acute diarrhea children, 224 children completed the study, (113 in the drug group and 111 in the placebo group). At recruitment on Day 1, there were no significant differences between the 2 groups in terms of frequency of vomiting, mean loose stool frequency, stool consistency, and mean frequency of oral rehydration salts (ORS) and intravenous fluids administered. On Day 2, a lower mean stool frequency and improved stool consistency was noted in the drug group, which achieved statistical significance. This was also reflected in the lower volume of ORS administration in the drug group. Even on Day 3, mean loose stool frequency and frequency of ORS use and frequency of intravenous fluid use was significantly lower in the drug group. The differences in the frequency of loose stools persisted till 8 hours of Day 4. After this, as the placebo group also showed spontaneous improvement the difference between the 2 groups in terms of the overall stools frequency became comparable. However, the overall ORS requirement continued to be significantly lower in the drug group even on Day 4. The overall recovery rates were significantly better in the drug group compared with placebo. No side effects were noted with the use of the probiotic mixture. Use of probiotic mixture VSL[sharp]3 in acute rotavirus diarrhea resulted in earlier recovery and reduced frequency of ORS administration reflecting decreased stool volume losses during diarrhea.

The seroepidemiological study on cytomegalovirus in women of child-bearing age with special reference to pregnancy and maternal-fetal transmission.

We screened 500 women of childbearing age belonging to different socioeconomic class for the presence of IgM antibodies against cytomegalovirus (CMV) infection by ELISA. Among these were 70 pregnant women, positive for CMVspecific IgM antibodies, whose newborns were also tested for the same. IgM positivity was found to be 5.4% (27/500) while 2.2% (11/500) gave equivocal results. There was an increasing trend in IgM positivity with age, decreasing socioeconomic status and increasing parity. Prevalence rate was more in women from rural as compared to those of urban area. Among the pregnant women, in the higher income group, 4 (14.28%) had CMV specific IgM antibodies as compared to 9 (21.43%) of low income. Congenital infection occurred more often (14.28 vs 7.14%) in infants in low income group. Signs and symptoms compatible with acute CMV infection were found in 7.69% (1/13) women and 27.78% (5/18) newborns. Thus the need for screening and protection against this infection is further emphasized.

A phase III, randomized controlled study to assess the safety and immunogenicity of a semi-synthetic diphtheria, tetanus and whole-cell pertussis vaccine in Indian infants.

BACKGROUND: Reactions to DTwP vaccine are well known and are a matter of great concern, much for the development of next generation combination vaccines. To avoid such reactions which occur from foreign compounds, WHO suggested manufacture of DTwP vaccine using semi-synthetic medium. The phase III trial reported here was conducted to assess the immunogenicity, tolerability and safety of a new DTwP vaccine manufactured using semi-synthetic medium for both tetanus and diphtheria toxoids in comparison with the routinely manufactured DTwP vaccine. METHODS: In all, 331 infants aged 6-8 weeks were enrolled, out of which 308 completed the study. The vaccination was done at 6-10-14 weeks following EPI/WHO recommended immunization schedule. Blood samples were collected prior to the administration of first dose and one month after the third dose. RESULTS: Postvaccination, geometric mean titres for each component did not differ significantly amongst the two study groups. Though, the immunogenicity results were comparable between the two vaccines, the incidence of adverse events was comparatively low in semi-synthetic vaccine as against the routine vaccine group for all the three doses. CONCLUSIONS: The semi-synthetic DTwP vaccine was immunogenic and showed a significant lower incidence of local adverse events in comparison to the routine vaccine. This vaccine is now being used in the routine vaccination programme both as a triple antigen (DTwP alone) as well as a combination with Hepatitis B and/or Haemophilus influenzae type b vaccine.

A phase III randomized, controlled study to assess the immunogenicity and tolerability of DTPw-HBV-Hib, a liquid pentavalent vaccine in Indian infants.

Immunogenicity and tolerability of two liquid pentavalent vaccines, Pentavac(®) (new vaccine), and Easyfive(®) (available in the market) was assessed in a multicentre study in India. In all, 484 infants aged 6-8 weeks were enrolled, and their blood samples were assessed prior to the first dose and one month after the third dose. A 100% seroprotection rate was achieved with both vaccines' antigens, except pertussis for which the response was 95% and 96%, respectively, for the two vaccines. A diary-based recording of adverse events showed that the two most common events were pain at the injection site and restricted limb movements and were less frequent (p<0.001) among the recipients of the new vaccine. The new vaccine meets all criteria of childhood vaccination. Its low reactogenicity and low cost are valid reasons to recommend this vaccine for general use.

A phase III randomized, controlled study to assess and compare the immunogenicity and tolerability of single and multi-dose vials of DTwP-Hib, a fully liquid quadravalent vaccine and their comparison with TETRAct-Hib vaccine in Indian infants aged 6-14 weeks.

Both WHO and IAP encourage using combination vaccines, wherever feasible. The phase III trial reported here was conducted to assess and compare the immunogenicity, tolerability and safety of two quadravalent vaccines, Quadrovax(®) (new vaccine), and TETRAct-Hib(®) (available in the market) in a multicentre study, in India. In all, 361 infants aged 6-8 weeks were enrolled, out of which 339 completed the study. The vaccination was done at 6-10-14 weeks following EPI/WHO recommended immunization schedule. Blood samples were collected prior to the administration of first dose and one month after the third dose. Postvaccination, geometric mean titres for each component did not differ significantly between the single dose vial and multi dose vial subgroups and among the two study groups. Adverse events observed were within the range quoted in literature. Quadrovax(®) vaccine manufactured by SIIL was found to be safe, immunogenic and non-inferior to the comparator vaccine. The quadravalent vaccine is best recommended in the second year of life when children receive their booster dose at 15-18 months. It can be given to infants during primary immunization series at 6, 10 and 14 weeks of age when Hepatitis B vaccine is given in a separate arm or to infants at 10 weeks who receive the Hepatitis B vaccine separately following the 0, 6 and 14 weeks or 0, 1 and 6 months schedule.