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The Department of Vaccine Process consists of two programs: 1) the Vaccine Process Development program and 2) the Technical Assistance and Technology Transfer program.
 
Vaccine Process Development Program
 

Rodney Carbis and Hyun Jang checking conditions during a bacterial fermentation run.
 
Background
 
The Vaccine Process Development Program is developing or improving existing vaccine manufacturing technologies to make these technologies available to qualified producers in developing countries. IVI's vaccine development activities to date have centered on the three enteric diseases - cholera, typhoid fever and shigellosis-that are the focus of the Diseases of the Most Impoverished (DOMI) Program. Safe and efficacious licensed vaccines exist for both cholera and typhoid fever, and a number of experimental candidate vaccines are ready to be tested for all three diseases. IVI has also begun a new program to develop pandemic influenza vaccines, particularly against the H5N1 strain that causes avian flu.
 
The Vaccine Process Development Program is supported by the Bill & Melinda Gates Foundation, the Ministry of Education and Human Resources Development of the Republic of Korea, Sartorius AG, and the Swedish International Development Cooperation Agency (SIDA).
 
Goals
 
The goals of the Vaccine Process Development Program are to:
 
  • Develop and improve manufacturing processes for vaccines of interest to IVI (e.g., new-generation vaccines against typhoid, cholera and shigellosis);
  • Demonstrate the consistency of manufacture of these vaccines on a laboratory scale;
  • Assist in the production of vaccine lots and in validating production facilities;
  • Develop assays for in-process control and final lot release;
  • Develop serological assays, if necessary, to assess immunological responses;
  • Conduct clinical trials with vaccine lots used in validation studies.
 
Projects
 
The Cholera Vaccine Program:
 
For the past two years, the Vaccine Process Development group has been assisting the Vietnamese vaccine manufacturer, VaBiotech, to improve the quality of its oral killed whole-cell (WC) cholera vaccine, so that it meets WHO guidelines. This assistance has resulted in the reformulation of the vaccine to remove a toxin producing strain, thus improving the vaccine's safety profile. IVI has also developed two quality control tests specifically to assess the quality and potency of killed whole-cell cholera vaccines-one to demonstrate removal of toxin and the second to quantify LPS antigen. Before IVI's assistance, the Vietnamese vaccine was standardized by optical density, which overestimated the antigen content, resulting in a low dose in certain strains, especially heat-inactivated strains. The new formulation, based on LPS content, effectively increases the dose of certain antigens in the vaccine.
 
The new formulation has been tested in Phase II clinical trials in Son La, Vietnam(see paper in Vaccine) and Kolkata, India. The results indicate that this formulation is superior to the previous vaccine in terms of immunogenicity, having higher vibriocidal antibody responses and rates of seroconversion, and has a very good safety profile. IVI is now in the process of transferring the technology of the reformulated oral cholera vaccine to Shantha Biotechnics in India and BioFarma in Indonesia, through the CHOVI program. As part of this activity, IVI will produce reagents and standards for the toxin and LPS assays and will assist VaBiotech, Shantha, BioFarma, and other manufacturers, as appropriate, in introducing these assays for the routine lot release of this vaccine.
 
The Vi Polysaccharide Typhoid Fever Vaccine Program:
 
IVI is improving and optimizing the existing manufacturing process for the typhoid Vi capsular polysaccharide vaccine. IVI has produced in its laboratories several lots of Vi polysaccharide, using the method developed at Dr. John Robbins laboratory at the US National Institutes of Health (NIH). Quality assessment of the lots, following the WHO requirements for Vi polysaccharide typhoid vaccine, has been conducted at IVI and the more recent lots have been found to comply with these requirements. IVI has used these compliant lots to develop Vi conjugate vaccine, as described in the next section.
 
To improve the recovery of Vi polysaccharide, we have optimized the growth and production of polysaccharide in the fermentation system at IVI. IVI is also conducting experiments to modify the production process and eliminate the phenol extraction step. Preliminary results are encouraging but more work needs to be carried out.
 
In addition, IVI has developed an ELISA to measure antibodies to the Vi CPS vaccine, adapted from Dr. Robbins' laboratory. The assay will be validated at IVI and standard reagents will be produced to support future clinical trials of Vi and Vi-DT (diphtheria toxoid) conjugate typhoid vaccines.
 
The Typhoid Conjugate Vaccine Program:
 
IVI is preparing a second-generation conjugate vaccine that can be effective in younger age groups than the Vi CPS vaccine (which is effective in persons two years and older) and that induces better responses in older recipients. The team has optimized a laboratory-scale preparation of Vi-DT conjugate vaccine, using methods developed by Dr. John Robbins laboratory at the US NIH. Immunogenicity studies of the conjugate vaccine conducted in mice have demonstrated strong anti-Vi antibody responses, far superior to that of the Vi polysaccharide. IVI is developing assays to demonstrate the physical and chemical characteristics of the vaccine. Some of these assays will then be used as lot release assays.
 
The team is also writing standard operating procedures (SOPs) for the conjugation process and the assays used to characterize the vaccine, as an initial step in the process of transferring the technology of the Vi conjugate vaccine to interested producers. As soon as the manufacturing process and the SOPs have been finalized, IVI will then assist with the scale-up of the process at a chosen vaccine manufacturer.
 
The Shigella Vaccine Program:
 
The Vaccine Process Development group has developed a method for purifying ribosomes from Shigella bacteria, using only equipment that is commonly used by developing country vaccine producers. This technology can potentially be used to develop low-cost Shigella vaccines. The production process was initiated with S. flexneri 2a, a strain relatively easy to manipulate under standard laboratory safety conditions. This technology can then be used to produce quality-controlled ribosomal preparations from S. dysenteriae I, using a detoxified mutant as a seed vaccine strain. The goal of this program is to develop an affordable vaccine formulation against S. dysenteriae I, the most fatal form of shigellosis, which often occurs in epidemics. Preliminary safety and immunogenicity studies indicate that the ribosome-based vaccine is safe in mice-based on the lack of weight loss following vaccination-as compared with whole cells, which induced significant weight loss following vaccination. The ribosome-based vaccine also induced very strong serum IgG and IgM responses to O antigen, and boosted IgG levels following a second dose. Dose response curves show that increasing the antigen content results in higher antibody responses, with a plateau beginning to occur at a dose of 10µg.
 
Influenza Vaccine Program:
 
The Vaccine Process Development Program is developing assays for the standardization of influenza vaccine, particularly for the H5N1 strain that causes avian flu. Reagents and standards developed at IVI could be made available to vaccine manufacturers and others, as deemed necessary. In the aim of developing a pandemic influenza virus vaccine, IVI is building a small unit to produce sufficient amounts of egg-derived and cell-derived virions for research purposes. We are also collaborating with Korean research institutions to explore alternative production systems (e.g., mammalian cells, yeasts, phage displays) to produce attenuated viruses, virus-like particles (VLP) and/or influenza antigens (hemagglutinin, neuraminidase, M2 protein).
 
 
 
Technical Assistance and Technology Transfer Program
 

IVI is transferring technology to Bio Farma in Indonesia for cholera and typhoid vaccines.
 
Background
 
Although local producers are becoming increasingly important for the production of vaccines in developing countries, the production and regulatory practices that govern vaccine production are not always optimal in these settings. Thus, developing countries may be reluctant to use vaccines produced in other developing countries unless the manufacturers and their national regulatory authorities (NRAs) are approved by the World Health Organization. The Technical Assistance and Technology Transfer Program therefore provides assistance to upgrade vaccines, manufacturing practices, and regulation in developing countries To help achieve this aim, the IVI participates in the WHO Global Training Network.
 
Another aim of the Technical Assistance and Technology Transfer Program is to successfully transfer vaccine technologies to qualified manufacturers in developing countries, while strictly honoring patent rights. The Program trains staff of partner manufacturers in developing countries in production methods and quality control testing for vaccines of mutual interest. In addition, the Program works with national regulatory authorities to train their staff in appropriate vaccine quality-control and lot release procedures. Training has taken place at the manufacturer's facility, the NRAs, IVI headquarters, and the laboratories of IVI's partner organizations in the industrialized world.
 
The Technical Assistance and Technology Transfer Program is supported by the Bill & Melinda Gates Foundation, the Ministry of Education and Human Resources Development of the Republic of Korea and Sartorius AG.
 
Goals
 
The goals of the Technical Assistance and Technology Transfer Program are to:
 
  • Obtain suitable vaccine technologies that can be transferred to manufacturers in developing countries and review the suitability of these technologies for transfer, while strictly honoring patent rights;
  • Hold discussions with selected vaccine manufacturers and the appropriate national regulatory authorities regarding the introduction of new vaccines;
  • Provide training in production and quality control to partner vaccine producers and national regulatory authorities;
  • Assist with and supervise the production of vaccine lots at partner vaccine producers;
  • Assist in obtaining and/or developing all appropriate documentation required for licensing the new vaccine in the specific country.
 
Projects
 
Technology transfer of oral killed whole-cell cholera vaccine:
 
Following the successful reformulation of the Vietnamese oral inactivated whole-cell cholera vaccine and the successful Phase II trials in Son La, Vietnam and Kolkata, India, the improved vaccine is now ready for transfer to manufacturers in other countries. The vaccine is currently being tested in a large-scale Phase III trial in Kolkata, as the next step in "internationalizing" the vaccine. IVI is transferring the technology of this vaccine to Shantha Biotechnics in India and BioFarma in Indonesia, through the Cholera Vaccine Initiative (CHOVI). Both manufacturers have indicated in discussions a commitment to produce and market the oral cholera vaccine for use in their own countries, as well as to export it for use in other cholera-endemic countries.
 
Technology transfer of the typhoid Vi vaccine:
 
IVI has initiated a program of technology transfer for Vi polysaccharide vaccine to selected manufacturers, with the view of later transfer of conjugate Vi technology. The program will continue to assist other manufacturers with Vi production issues, as needed. The national regulatory authorities will be kept informed of IVI's activities and, where appropriate, will be trained in performing assays for lot release for the vaccines being transferred. Where necessary, IVI will also assist in the preparation of documentation for registration of the vaccines both in the country of manufacture and in other countries where it will be imported.