Viruses vaccine manufacture

An example from virus vaccine manufacture is the titration, prior to inactivation, of the infectivity of the pools of live poliovirus used to make inactivated poliomyelitis vaccine. Adequate infectivity of the virus from the tissue cultures is an indicator of the adequate virus content of the starting material... 

The pharmaceuticals segment (SIC 283) consists of some 1,225 corporations whose primary business is the development, manufacturing, and marketing of medicinal chemicals and botanicals in vitro and other diagnostic substances to diagnose or monitor the state of human or veterinary health bacterial and virus vaccines. 

The last few decades have witnessed the spread of new viruses, most notably HIV/AIDS and, to a much lesser extent, SAKS. The prospect of a bird flu pandemic looms on the horizon. In the event of a pandemic, developed countries may possess only sufficient capacity to produce vaccines for domestic use. To ensure an adequate domestic supply, governments may restrict exports ofvaccines by private manufacturers. Restrictions on export of vaccines would in turn create shortages in other countries, particularly those without ample domestic vaccine capacity. This threat, in spite of the empirical evidence indicating that private enterprises are relatively efficient on average (Lichtenberg, Chapter 7), may justify sponsoring public enterprises for vaccine manufacturing in countries with small domestic markets. 

Plasma-derived hepatitis B virus vaccine is prepared from the plasma of chronic HBsAg carriers, and consists of purified, inactivated 20-nm HBsAg particles adsorbed on to an aluminium adjuvant. The use of a vaccine produced with plasma derived from infected individuals represented a major departure from conventional approaches, and safety testing has therefore been designed to cover all possibilities of risk and to ensure freedom from transmission of residual HBV and other blood-borne agents. Various clinical trials (SEDA-10, 289) (SEDA-11, 289) have confirmed the safety of plasma-derived hepatitis B virus vaccines produced by different manufacturers. Fears that plasma-derived vaccine may transmit AIDS can be considered unfounded. 

Rubella vaccine is a live attenuated virus vaccine. Most of the vaccines currently manufactured outside Japan are produced in human diploid cells and are based either on the RA 27/3 strain (the most widely used) or the Cendehill strain. In Japan, five different vaccine strains (for example TO 336 and MEQ 11) are produced in two different non-human substrates. In China, another vaccine strain (BRD-2) has been developed and produced in human diploid cells. Its antigenicity and reactogenicity are comparable to those of the RA 27/3 strain. 

The finding that the incidences of aseptic meningitis differed after administration of the standard MMR vaccine or Biken MMR vaccine has inevitably raised questions about the consistency of manufacture of the Urabe Am9 mumps virus vaccines. The National Institute of Health found that the biological characteristics of the Urabe Am9 mumps virus contained in the standard MMR vaccine and in the Biken MMR vaccine were different. The Biken Company reported that the mumps vaccine in the standard MMR vaccine was a mixture of two Urabe Am9 mumps vaccine bulks, one identical to that contained in the Biken MMR vaccine and the other produced by a different manufacturing process. 

Cell cultures provide infected fluids that contain little debris and can generally be satisfactorily clarified by filtration. Because most viral vaccines made from cell cultures consist of live attenuated virus, there is no inactivation stage in their manufacture. There are, however, two important exceptions inactivated poliomyelitis virus vaccine is inactivated with dilute formaldehyde or (3-propiolactone and rabies vaccine is inactivated with (3-propiolactone. The preparation of these inactivated vaccines also involves a concentration stage — by adsorption and elution of the virus in the case of poliomyelitis vaccine and by ultrafiltration in the case of rabies vaccine. When processing is complete the bulk materials may be stored until needed for blending into final vaccine. Because of the lability of many viruses, however, it is necessary to store most purified materials at temperatures of —70°C. 

The manufacturers advise that antivirals active against influenza such as oseltamivir and rimantadine should not be given until 2 weeks after the administration of live influenza virus vaccines, and that these vaccines should not be given until 48 hours after stopping the antiviraL This is because of the theoretical concern that these antiviral drugs will inhibit replication of live vaccine virus, and therefore reduce its effect. Note that most influenza vaccines are inactivated (split virion or surface antigen), and that these would not be expected to be affected by antivirals active against influenza. 

Purity requirements depend on the intended use of the biopharmaceutical, dose and risk-benefit ratio. The selection of purification method should consider physicochemical characteristics of the particle to be isolated. For viral particles it is relevant to consider the influence of isoelectric point (pi), surface hydrophobicity, the presence or absence of an envelope, hydrodynamic diameter and lability of virus particles. Viruses should not have their level of infectivity reduced after a purification stage when they are used as vectors, and tests should be carried out to check this. ° During the process of vaccine manufacturing, the production of virus-like particles is dependent on physicochemical parameters such as pH, ionic strength and medium temperature. Type and concentration of chelating agents also seem to affect the protein macrostructure stability and thus should be observed. ... 

What is, perhaps, most disturbing is the assertion by Coulter and Fisher in 1985 that the ADRs from DPT should not have happened. They document that Japan switched to an acellular form of the DPT virus in 1981, which was just as effective in preventing the diseases but had fewer ADRs. Shoemaker reports that In Japan, the Ministry of Health, instead of trying to cover up problems with the vaccines, chose to find a solution." According to Shoemaker, it took almost 20 years for the United States to stop using the whole-cell version of the vaccine, and manufacturers are still distributing the whole-cell version in third-world countries "undoubtedly because it is cheaper to make." ... 

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