Technical Development of a New Meningococcal Conjugate Vaccine.

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.

Challenges and Opportunities While Developing a Group A Meningococcal Conjugate Vaccine Within a Product Development Partnership: A Manufacturer's Perspective From the Serum Institute of India.

BACKGROUND: 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. METHOD: 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. RESULTS: 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 submitted to the Indian authorities in April 2009 and WHO in September 2009. Export license was granted in December 2009, and WHO prequalification was obtained in June 2010. Vaccine was introduced at public scale in Burkina Faso that December. The group A meningococcal conjugate vaccine was named MenAfriVac, and is the first internationally qualified vaccine developed outside of big pharma. CONCLUSIONS: The project proved to be a sound investment for SIIL and is a concrete example of the potential for PDPs to provide needed products for resource-poor countries.

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.

Mumps outbreaks in Canada and the United States: time for new thinking on mumps vaccines.

Mumps epidemics in Canada and the United States prompted us to review evidence for the effectiveness of 5 different vaccine strains. Early trials with the Jeryl Lynn vaccine strain demonstrated an efficacy of approximately 95%, but in epidemic conditions, the effectiveness has been as low as 62%; this is still considerably better than the effectiveness of another safe strain, Rubini (which has an effectiveness of close to 0% in epidemic conditions). The Urabe vaccine strain has an effectiveness of 54%-87% but is prone to cause aseptic meningitis. Little epidemiological information is available for other vaccines. The Leningrad-Zagreb vaccine strain, which is widely used in developing countries and costs a fraction of what vaccines cost in the developed world, seems to have encouraging results; in 1 study, the effectiveness of this vaccine exceeded 95%. Aseptic meningitis has also been reported in association with this vaccine, but the benign nature of the associated meningitis was shown recently in Croatia. Also, the Leningrad-3 strain seems to be effective but causes less-benign meningitis. No mumps vaccine equals the best vaccines in quality, but the virtually complete safety of some strains may not offset their low effectiveness. Epidemiological data are pivotal in mumps, because serological testing is subject to many interpretation problems.

Safety and pharmacokinetics of a human monoclonal antibody to rabies virus: a randomized, dose-escalation phase 1 study in adults.

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.

Assessment of safety and immunogenicity of two different lots of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b vaccine manufactured using small and large scale manufacturing process.

BACKGROUND: Hib vaccine can be easily incorporated in EPI vaccination schedule as the immunization schedule of Hib is similar to that of DTP vaccine. To meet the global demand of Hib vaccine, SIIL scaled up the Hib conjugate manufacturing process. This study was conducted in Indian infants to assess and compare the immunogenicity and safety of DTwP-HB+Hib (Pentavac(®)) vaccine of SIIL manufactured at large scale with the 'same vaccine' manufactured at a smaller scale. METHODS: 720 infants aged 6-8 weeks were randomized (2:1 ratio) to receive 0.5 ml of Pentavac(®) vaccine from two different lots one produced at scaled up process and the other at a small scale process. Serum samples obtained before and at one month after the 3rd dose of vaccine from both the groups were tested for IgG antibody response by ELISA and compared to assess non-inferiority. RESULTS: Neither immunological interference nor increased reactogenicity was observed in either of the vaccine groups. All infants developed protective antibody titres to diphtheria, tetanus and Hib disease. For hepatitis B antigen, one child from each group remained sero-negative. The response to pertussis was 88% in large scale group vis-à-vis 87% in small scale group. Non-inferiority was concluded for all five components of the vaccine. No serious adverse event was reported in the study. CONCLUSIONS: The scale up vaccine achieved comparable response in terms of the safety and immunogenicity to small scale vaccine and therefore can be easily incorporated in the routine childhood vaccination programme.

Seroprevalence of rubella and immunogenicity following rubella vaccination in adolescent girls in India.

INTRODUCTION: Serologic surveys conducted in different countries indicate that rubella is a worldwide infection. Several such sero surveys conducted in India have also confirmed that 6-47% of women are susceptible to rubella infection. The current study was conducted on 1,329 female adolescents in 12 districts of Maharashtra, India, to assess their serological status in terms of rubella exposure. METHODOLOGY: After enrollment, a pre-vaccination blood sample was collected from the participants followed by rubella vaccination (R-vac). Adverse events were monitored for the next 6-8 weeks, at which time a post-vaccination sample was collected. RESULTS: Pre-vaccination rubella immunity was higher in the urban (80.2%) population compared to the rural (73.1%) population. Following R-vac vaccination, out of 1,159 participants who completed the study, all (100%) in the urban and 99.5% of participants in the rural area developed antibodies against rubella. CONCLUSION: Substantial numbers of women reach childbearing age without immunity against rubella and thus are at a risk of passing the infection to their fetuses, who can then develop subsequent congenital defects leading to congenital rubella syndrome (CRS). An immunization policy recommending vaccination with rubella or rubella containing vaccine is highly desirable to prevent rubella and CRS. 

Immunogenicity of two modern tissue culture rabies vaccines in pre-exposure prophylaxis.

Pre-exposure prophylaxis was given to employees supposed to be involved in rabies vaccine production in India. Prior to availability of the manufacturer's own human diploid cell (HDC) vaccine (Rabivax), immunization was executed with a chick embryo cell (CEC) vaccine (Rabipur). This constellation gave an opportunity to compare retrospectively immunogenicity of these two vaccines. The data was collected by retrospective analysis over more than three years at the clinic of Serum Institute of India Ltd. As per the standard protocol, persons with negative rabies vaccination history receive a dose of 1 ml of rabies vaccine intramuscularly on day 0, 7 and 28, and the virus anti-glycoprotein antibodies are measured one month after the third dose. The antibody levels > or =0.5 IU/ml are considered protective. The CEC and HDC vaccines were used during the analysis period. In all, 43 individuals received the CEC vaccine, 106 the HDC vaccine. The mean age of recipients was 33 years five months (Rabipur) and 30 years three months (Rabivax). All subjects in both groups were males. Five commercial batches of the CEC vaccine (129 doses) and seven batches of the HDC vaccine (318 doses) were used. Ninety-nine percent of the HDC and 93% of the CEC vaccine recipients were protected after the standard three dose schedule. Geometric mean titre was significantly greater for the HDC than CEC vaccine, being 5.05 IU/ml and 2.90 IU/ml, respectively (p = 0.0002). The HDC vaccine showed a good lot-to-lot consistency with respect to GMT both by ANOVA test and Nonparametric ANOVA test. On the other hand, the CEC vaccine demonstrated a variation in titres, when the lots were compared. Three out of four low-responders accepted a booster vaccination, and regardless of whether Rabipur or Rabivax was used, all three responded well one month after the booster. The Indian HDC vaccine compares well with the CEC vaccine in terms of immunogenicity. With HDC vaccines, cost has been an issue. However, since the new HDC vaccine has a comparable cost to the CEC vaccine, it may be possible to use it in large-scale vaccinations.

Mapping antigenic diversity and strain specificity of mumps virus: a bioinformatics approach.

Mumps is an acute infectious disease caused by mumps virus, a member of the family Paramyxoviridae. With the implementation of vaccination programs, mumps infection is under control. However, due to resurgence of mumps epidemics, there is a renewed interest in understanding the antigenic diversity of mumps virus. Hemagglutinin-neuraminidase (HN) is the major surface antigen and is known to elicit neutralizing antibodies. Mutational analysis of HN of wild-type and vaccine strains revealed that the hypervariable positions are distributed over the entire length with no detectable pattern. In the absence of experimentally derived 3D structure data, the structure of HN protein of mumps virus was predicted using homology modeling. Mutations mapped on the predicted structures were found to cluster on one of the surfaces. A predicted conformational epitope encompasses experimentally characterized epitopes suggesting that it is a major site for neutralization. These analyses provide rationale for strain specificity, antigenic diversity and varying efficacy of mumps vaccines.