Background: Rabies is an essentially fatal disease that is preventable with the timely administra... more Background: Rabies is an essentially fatal disease that is preventable with the timely administration of post-exposure prophylaxis (PEP). The high cost of PEP, which includes vaccine and hyperimmune globulin, is an impediment to the goal of preventing rabies in the developing world. Recently a recombinant human IgG 1 anti-rabies monoclonal antibody (SII RMab) has been developed in India to replace serum-derived rabies immunoglobulin. The present study was conducted to demonstrate the safety of SII RMab and to determine the dose resulting in neutralizing serum antibody titers comparable to human rabies immunoglobulin (HRIG) when administered in conjunction with rabies vaccine in a simulated PEP regimen. Methods: This randomized, open label, dose-escalation phase 1 study was conducted in healthy adults at a large tertiary care, referral, public hospital in India. Safety was assessed by active surveillance for adverse events along with standard laboratory evaluations and measurement of anti-drug antibodies (ADA). Anti-rabies antibody levels were measured by rapid fluorescent focus inhibition test (RFFIT) and ELISA. The study duration was 365 days. Findings: SII RMab was well tolerated with similar frequency of local injection site reactions to HRIG. The geometric mean concentrations of rabies neutralizing antibody in the vaccine plus SII RMab 10 IU/kg cohort were comparable to the vaccine plus HRIG 20 IU/kg cohort throughout the 365-day study period; day 14 geometric mean concentrations 23.4 IU/ml (95% CI 14.3, 38.2) vs. 15.3 IU/ml (95% CI 7.72, 30.3; p = NS), respectively. Future post-exposure prophylaxis studies of SII RMab at a dose of 10 IU/kg in conjunction with vaccine are planned.
Immunogenicity and tolerability of two liquid pentavalent vaccines, Pentavac ® (new vaccine), and... more 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.
Immunogenicity and tolerability of two liquid pentavalent vaccines, Pentavac ® (new vaccine), and... more 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.
To address the claim that the Leningrad-Zagreb (L-Z) mumps vaccine strain is causally associated ... more To address the claim that the Leningrad-Zagreb (L-Z) mumps vaccine strain is causally associated with aseptic meningitis, a prospective, post-marketing safety study was conducted with a measles-mumps-rubella vaccine (MMR) (TRESIVACâ; Serum Institute of India Ltd., Pune, India), which uses the L-Z strain as its mumps component in Egypt. In all, 453 119 children (65 423 children aged 16-24 months and 329 211 children aged 5-7 years) received MMR. The control groups which, as a result of local health regulations, were slightly younger than vaccinees, comprised 12 253 and 46 232 children, respectively. Using questionnaires, the parents recorded solicited local, systemic and neurological adverse events for up to 42 days post-vaccination. All data were analysed externally on an intention-to-treat basis by individuals not participating in the study. Local and/or systemic reactions were reported in a small percentage of participants, with pain, fever and parotitis being the most common signs among vaccinees in both age groups. No case of aseptic meningitis, encephalitis, anaphylaxis or convulsions was observed in any participant. Thus, in this series of more than 450 000 Egyptian children, the L-Z mumps vaccine strain in this vaccine did not cause aseptic meningitis. The vaccine is considerably cheaper than Western competitors and a valid alternative to other MMR vaccines.
Both WHO and IAP encourage using combination vaccines, wherever feasible. The phase III trial rep... more 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.
Background. Group A Neisseria meningitidis has been a major cause of bacterial meningitis in the ... more Background. Group A Neisseria meningitidis has been a major cause of bacterial meningitis in the sub-Saharan region of Africa in the meningitis belt. Neisseria meningitidis is an encapsulated pathogen, and antibodies against the capsular polysaccharide are protective. Polysaccharide-protein conjugate vaccines have proven to be highly effective against several different encapsulated bacterial pathogens. Purified polysaccharide vaccines have been used to control group A meningococcal (MenA) epidemics with minimal success. Methods. A monovalent MenA polysaccharide-tetanus toxoid conjugate was therefore developed. This vaccine was developed by scientists working with the Meningitis Vaccine Project, a partnership between PATH and the World Health Organization. Results. A high-efficiency conjugation method was developed in the Laboratory of Bacterial Polysaccharides in the Center for Biologics Evaluation and Research and transferred to the Serum Institute of India, Ltd, which then developed methods for purification of the group A polysaccharide and used its tetanus toxoid as the carrier protein to produce the now-licensed, highly effective MenAfriVac conjugate vaccine. Conclusions. Although many years of application of meningococcal polysaccharide vaccines have had minimal success in preventing meningococcal epidemics in the meningitis belt of Africa, our collaborative efforts to develop a MenA conjugate vaccine yielded a safe and highly effective vaccine.
This study compares the immunogenicity and safety of a single dose of a new meningococcal A conju... more This study compares the immunogenicity and safety of a single dose of a new meningococcal A conjugate vaccine (PsA-TT, MenAfriVac TM , Serum Institute of India Ltd., Pune) against the meningococcal group A component of a licensed quadrivalent meningococcal polysaccharide vaccine (PsACWY, Mencevax ACWY ® , GSK, Belgium) 28 days after vaccination in Indian children. This double-blind, randomized, controlled study included 340 Indian children aged 2-10 years enrolled from August to October 2007; 169 children received a dose of PsA-TT while 171 children received a dose of PsACWY. Intention-to-treat analysis showed that 95.2% of children in PsA-TT group had a ≥4-fold response in serum bactericidal titers (rSBA) 28 days post vaccination as compared to 78.2% in the PsACWY group. A significantly higher rSBA GMT (11,209, 95%CI 9708-12,942) was noted in the PsA-TT group when compared to PsACWY group (2838, 95%CI 2368-3401). Almost all children in both vaccine groups had a ≥4-fold response in group A-specific IgG concentration but the IgG GMC was significantly greater in the PsA-TT group (89.1 g/ml, 95%CI 75.5-105.0) when compared to the PsACWY group (15.3 g/ml, 95%CI 12.3-19.2). Local and systemic reactions during the 4 days after immunization were similar for both vaccine groups except for tenderness (30.2% in PsA-TT group vs 12.3% in PsACWY group). None of the adverse events or serious adverse events was related to the study vaccines. We conclude that MenAfriVac TM is well tolerated and significantly more immunogenic when compared to a licensed polysaccharide vaccine, in 2-to-10-year-old Indian children.
Thermostable vaccines promise to simplify the logistics of vaccine distribution and expand the im... more Thermostable vaccines promise to simplify the logistics of vaccine distribution and expand the immunization coverage. In this study, a pilot-scale spray drying process was developed and used to produce glassy state formulations of a recombinant hepatitis B (HepB) vaccine containing aluminum adjuvant and Neisseria meningitidis A (MenA) protein-polysaccharide conjugate vaccine, representing two common types of subunit vaccines in use today: the spray-dried HepB vaccine formulations were stable for at least 24 months at 37 • C while several MenA vaccine formulations exhibited complete stability at temperatures up to 60 • C. This study demonstrates the feasibility of producing thermostable vaccines with advanced processing and formulation technologies.
<p>An HA1 fragment, H1pHA9, defined by stable breakpoints was designed <i>in silico&l... more <p>An HA1 fragment, H1pHA9, defined by stable breakpoints was designed <i>in silico</i>. (A) Shown in stereoview is the cartoon representation of H1N1 A/California/04/2009 HA trimer (PDB ID: 3LZG). Residues 65–286 comprising H1pHA9 (colored grey) have been mapped onto a monomer (orange) of the crystal structure of H1N1 A/California/04/2009 HA. The rest of the molecule is colored green. The mutations introduced in H1pHA9 are colored red. The receptor binding site residues are colored yellow. (B) The mutated residues (red) in H1pHA9 do not contribute to any of the antigenic sites or the receptor binding site (yellow) on HA. The figures were generated in PyMOL (The PyMOL Molecular Graphics System, version 1.2r2, DeLano Scientific, LLC).</p
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 15, 2015
In 2002, the Meningitis Vaccine Project (MVP) chose the Serum Institute of India, Ltd (SIIL), as ... more In 2002, the Meningitis Vaccine Project (MVP) chose the Serum Institute of India, Ltd (SIIL), as its manufacturing partner to establish a product development partnership (PDP) with the Meningitis Vaccine Project (MVP). MVP was a collaboration between PATH and the World Health Organization (WHO) to develop meningococcal conjugate vaccines for sub-Saharan Africa. From the outset, SIIL recognized that a partnership with MVP carried some risk but also offered important opportunities for accessing new conjugate vaccine technology and know-how. Over 3 years, SIIL successfully accepted technology transfer for the group A meningococcal polysaccharide from SynCo Bio Partners and a conjugation method from the US Food and Drug Administration. SIIL successfully scaled up production of a group A meningococcal conjugate vaccine that used SIIL tetanus toxoid as the carrier protein. Phase 1 studies began in India in 2005, followed by phase 2/3 studies in Africa and India. A regulatory dossier was s...
Background: Rabies is an essentially fatal disease that is preventable with the timely administra... more Background: Rabies is an essentially fatal disease that is preventable with the timely administration of post-exposure prophylaxis (PEP). The high cost of PEP, which includes vaccine and hyperimmune globulin, is an impediment to the goal of preventing rabies in the developing world. Recently a recombinant human IgG 1 anti-rabies monoclonal antibody (SII RMab) has been developed in India to replace serum-derived rabies immunoglobulin. The present study was conducted to demonstrate the safety of SII RMab and to determine the dose resulting in neutralizing serum antibody titers comparable to human rabies immunoglobulin (HRIG) when administered in conjunction with rabies vaccine in a simulated PEP regimen. Methods: This randomized, open label, dose-escalation phase 1 study was conducted in healthy adults at a large tertiary care, referral, public hospital in India. Safety was assessed by active surveillance for adverse events along with standard laboratory evaluations and measurement of anti-drug antibodies (ADA). Anti-rabies antibody levels were measured by rapid fluorescent focus inhibition test (RFFIT) and ELISA. The study duration was 365 days. Findings: SII RMab was well tolerated with similar frequency of local injection site reactions to HRIG. The geometric mean concentrations of rabies neutralizing antibody in the vaccine plus SII RMab 10 IU/kg cohort were comparable to the vaccine plus HRIG 20 IU/kg cohort throughout the 365-day study period; day 14 geometric mean concentrations 23.4 IU/ml (95% CI 14.3, 38.2) vs. 15.3 IU/ml (95% CI 7.72, 30.3; p = NS), respectively. Future post-exposure prophylaxis studies of SII RMab at a dose of 10 IU/kg in conjunction with vaccine are planned.
Immunogenicity and tolerability of two liquid pentavalent vaccines, Pentavac ® (new vaccine), and... more 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.
Immunogenicity and tolerability of two liquid pentavalent vaccines, Pentavac ® (new vaccine), and... more 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.
To address the claim that the Leningrad-Zagreb (L-Z) mumps vaccine strain is causally associated ... more To address the claim that the Leningrad-Zagreb (L-Z) mumps vaccine strain is causally associated with aseptic meningitis, a prospective, post-marketing safety study was conducted with a measles-mumps-rubella vaccine (MMR) (TRESIVACâ; Serum Institute of India Ltd., Pune, India), which uses the L-Z strain as its mumps component in Egypt. In all, 453 119 children (65 423 children aged 16-24 months and 329 211 children aged 5-7 years) received MMR. The control groups which, as a result of local health regulations, were slightly younger than vaccinees, comprised 12 253 and 46 232 children, respectively. Using questionnaires, the parents recorded solicited local, systemic and neurological adverse events for up to 42 days post-vaccination. All data were analysed externally on an intention-to-treat basis by individuals not participating in the study. Local and/or systemic reactions were reported in a small percentage of participants, with pain, fever and parotitis being the most common signs among vaccinees in both age groups. No case of aseptic meningitis, encephalitis, anaphylaxis or convulsions was observed in any participant. Thus, in this series of more than 450 000 Egyptian children, the L-Z mumps vaccine strain in this vaccine did not cause aseptic meningitis. The vaccine is considerably cheaper than Western competitors and a valid alternative to other MMR vaccines.
Both WHO and IAP encourage using combination vaccines, wherever feasible. The phase III trial rep... more 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.
Background. Group A Neisseria meningitidis has been a major cause of bacterial meningitis in the ... more Background. Group A Neisseria meningitidis has been a major cause of bacterial meningitis in the sub-Saharan region of Africa in the meningitis belt. Neisseria meningitidis is an encapsulated pathogen, and antibodies against the capsular polysaccharide are protective. Polysaccharide-protein conjugate vaccines have proven to be highly effective against several different encapsulated bacterial pathogens. Purified polysaccharide vaccines have been used to control group A meningococcal (MenA) epidemics with minimal success. Methods. A monovalent MenA polysaccharide-tetanus toxoid conjugate was therefore developed. This vaccine was developed by scientists working with the Meningitis Vaccine Project, a partnership between PATH and the World Health Organization. Results. A high-efficiency conjugation method was developed in the Laboratory of Bacterial Polysaccharides in the Center for Biologics Evaluation and Research and transferred to the Serum Institute of India, Ltd, which then developed methods for purification of the group A polysaccharide and used its tetanus toxoid as the carrier protein to produce the now-licensed, highly effective MenAfriVac conjugate vaccine. Conclusions. Although many years of application of meningococcal polysaccharide vaccines have had minimal success in preventing meningococcal epidemics in the meningitis belt of Africa, our collaborative efforts to develop a MenA conjugate vaccine yielded a safe and highly effective vaccine.
This study compares the immunogenicity and safety of a single dose of a new meningococcal A conju... more This study compares the immunogenicity and safety of a single dose of a new meningococcal A conjugate vaccine (PsA-TT, MenAfriVac TM , Serum Institute of India Ltd., Pune) against the meningococcal group A component of a licensed quadrivalent meningococcal polysaccharide vaccine (PsACWY, Mencevax ACWY ® , GSK, Belgium) 28 days after vaccination in Indian children. This double-blind, randomized, controlled study included 340 Indian children aged 2-10 years enrolled from August to October 2007; 169 children received a dose of PsA-TT while 171 children received a dose of PsACWY. Intention-to-treat analysis showed that 95.2% of children in PsA-TT group had a ≥4-fold response in serum bactericidal titers (rSBA) 28 days post vaccination as compared to 78.2% in the PsACWY group. A significantly higher rSBA GMT (11,209, 95%CI 9708-12,942) was noted in the PsA-TT group when compared to PsACWY group (2838, 95%CI 2368-3401). Almost all children in both vaccine groups had a ≥4-fold response in group A-specific IgG concentration but the IgG GMC was significantly greater in the PsA-TT group (89.1 g/ml, 95%CI 75.5-105.0) when compared to the PsACWY group (15.3 g/ml, 95%CI 12.3-19.2). Local and systemic reactions during the 4 days after immunization were similar for both vaccine groups except for tenderness (30.2% in PsA-TT group vs 12.3% in PsACWY group). None of the adverse events or serious adverse events was related to the study vaccines. We conclude that MenAfriVac TM is well tolerated and significantly more immunogenic when compared to a licensed polysaccharide vaccine, in 2-to-10-year-old Indian children.
Thermostable vaccines promise to simplify the logistics of vaccine distribution and expand the im... more Thermostable vaccines promise to simplify the logistics of vaccine distribution and expand the immunization coverage. In this study, a pilot-scale spray drying process was developed and used to produce glassy state formulations of a recombinant hepatitis B (HepB) vaccine containing aluminum adjuvant and Neisseria meningitidis A (MenA) protein-polysaccharide conjugate vaccine, representing two common types of subunit vaccines in use today: the spray-dried HepB vaccine formulations were stable for at least 24 months at 37 • C while several MenA vaccine formulations exhibited complete stability at temperatures up to 60 • C. This study demonstrates the feasibility of producing thermostable vaccines with advanced processing and formulation technologies.
<p>An HA1 fragment, H1pHA9, defined by stable breakpoints was designed <i>in silico&l... more <p>An HA1 fragment, H1pHA9, defined by stable breakpoints was designed <i>in silico</i>. (A) Shown in stereoview is the cartoon representation of H1N1 A/California/04/2009 HA trimer (PDB ID: 3LZG). Residues 65–286 comprising H1pHA9 (colored grey) have been mapped onto a monomer (orange) of the crystal structure of H1N1 A/California/04/2009 HA. The rest of the molecule is colored green. The mutations introduced in H1pHA9 are colored red. The receptor binding site residues are colored yellow. (B) The mutated residues (red) in H1pHA9 do not contribute to any of the antigenic sites or the receptor binding site (yellow) on HA. The figures were generated in PyMOL (The PyMOL Molecular Graphics System, version 1.2r2, DeLano Scientific, LLC).</p
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 15, 2015
In 2002, the Meningitis Vaccine Project (MVP) chose the Serum Institute of India, Ltd (SIIL), as ... more In 2002, the Meningitis Vaccine Project (MVP) chose the Serum Institute of India, Ltd (SIIL), as its manufacturing partner to establish a product development partnership (PDP) with the Meningitis Vaccine Project (MVP). MVP was a collaboration between PATH and the World Health Organization (WHO) to develop meningococcal conjugate vaccines for sub-Saharan Africa. From the outset, SIIL recognized that a partnership with MVP carried some risk but also offered important opportunities for accessing new conjugate vaccine technology and know-how. Over 3 years, SIIL successfully accepted technology transfer for the group A meningococcal polysaccharide from SynCo Bio Partners and a conjugation method from the US Food and Drug Administration. SIIL successfully scaled up production of a group A meningococcal conjugate vaccine that used SIIL tetanus toxoid as the carrier protein. Phase 1 studies began in India in 2005, followed by phase 2/3 studies in Africa and India. A regulatory dossier was s...
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