Innovative vaccine production technologies: the evolution and value of vaccine production technologies.

This review paper provides an overview of innovative technologies designed to produce bacterial, viral, recombinant subunit, and polysaccharide vaccines, as well as combination vaccines. Advances in this field are illustrated by vaccines against DTP (diphtheria-tetanus-pertussis), influenza, hepatitis B (HepB) and typhoid fever. In addition, technological trends regarding antigens, adjuvants, and preservatives in vaccines are discussed. The progress achieved in vaccine production technologies is especially important for improving the protection of vulnerable populations against infectious diseases. These at-risk groups include infants, the elderly and immunocompromized individuals, as well as people living in developing countries or emerging economies.

Storage at -3 degrees C for 24 h alters the immunogenicity of pertussis vaccines.

The immunogenicity of pertussis antigens in an acellular and a whole-cell triple antigen vaccine used for childhood immunisation was assessed in murine models after storage of vaccines below 0 degree C. Swiss outbred and Balb/c mice received DTPa or DTPw vaccine or placebo. Vaccines were stored at 2-8 degrees C (ideal), or at -3 degrees C for 24 h. Pre and post immunisation IgG responses to pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) were measured using enzyme immunoassays (EIA). In Balb/c mice, responses to pertactin after receiving adversely stored DTPa were significantly reduced (P = 0.005, difference in GMCs 145.9% [24.6-385.4%]). A reduction in GMC to pertactin was also seen in response to adversely stored DTPw (P = 0.190,224.1% [83.8-599.2%]). Outbred mice receiving adversely stored DTPa had lower IgG antibody responses to FHA than those receiving correctly stored vaccine (P = 0.002,522.2% [26.1-2155.6%]). Outbred mice also had a significantly lower response to FHA after administration of DTPw (P = 0.009,14.0% [3.8-51.9%]). Responses to DTPa in both strains generally were greater than those to DTPw. Storage of pertussis vaccines below 0 degree C appears to alter the immunogenicity of PRN and FHA. Further study is required to determine the effects of such storage on vaccine protective efficacy.

Rational approaches to reduce adverse reactions in man to vaccines containing tetanus and diphtheria toxoids.

Adverse reactions to routine vaccines are obstacles to the mass vaccination campaigns. Though the absolute safety of any injectable vaccine cannot be guaranteed, the adverse side effects to vaccines can be minimized by practicing existing scientific knowledge. Adverse side effects to tetanus and diphtheria toxoids have been known for many years and there have been ways to minimize these reactions. These procedures did not get wide acceptance, because the current partially purified tetanus and diphtheria vaccines meet the regulatory requirements and the manufacturers are reluctant to change the established procedures of production due to the amount of work involved in the regulatory issues under the current Good Manufacturing Practices (GMP). Due to the recent epidemic of diphtheria in the independent states of the former Soviet Union, and its potential for spread to other European Countries, vaccination campaigns with tetanus and diphtheria vaccines received a new boost with several international agencies. In this report, we review the causes for adverse reactions to tetanus and diphtheria vaccines and offer practical suggestions for minimizing these reactions. The major issues in minimizing adverse reactions to these vaccines include: (1) purifying the toxins before detoxification as the reactogenic accessory antigens get covalently bound to the toxins during detoxification; (2) either using well-tolerated adjuvants which do not elicit the production of antigenic specific IgE antibodies responsible for adverse reactions or by using non-adjuvanted highly immunogenic polymerized antigens; (3) checking the status of immunity by recently developed rapid serological methods or by the Schick skin-test for diphtheria to avoid allergic or Arthus-type reactions. These approaches are applicable to industrial scales and would result in a pure, less reactogenic and better characterized toxoids antigens which would be more suitable for combined vaccines comprising highly purified acellular pertussis components, polysaccharide-protein conjugates and other antigens.

[A polyvalent complex of Bordetella pertussis antigens as the basis for an acellular pertussis vaccine]. / Polivalentnyi kompleks antigenov Bordetella pertussis kak osnova beskletochnoi kokliushnoi vaktsiny.

The immunogenic and protective properties of acellular pertussis vaccines, prepared on the basis of B. pertussis multicomponent protective complex and the preparation containing only pertussis toxin, were studied. The study revealed that multicomponent preparations containing pertussis toxin (PT), filamentous hemagglutinin, agglutinogens, pertactin and adenylate cyclase possessed more pronounced immunobiological and protective properties in comparison with the monovalent preparation of PT, which was indicative of the expediency of developing acellular pertussis vaccines on the basis of the polyvalent protective complex as minor protective antigens seemed to enhance the protective action of pertussis toxoid, the main protective antigen.

[An acellular pertussis vaccine based on the natural complex of antigens isolated from the supernatant of a synthetic culture medium]. / Beskletochnaia kokliushnaia vaktsina na osnove prirodnogo kompleksa antigenov, vydelennykh iz supernatanta sinteticheskoi sredy kul'tivirovaniia.

A highly effective technology for obtaining a protective antigenic complex, including the main Bordetella pertussis protective antigens (pertussis toxin, filamentous hemagglutinin, agglutinogens, pertactin and adenylate cyclase) and isolated from the supernatant of B. pertussis cultivation medium, has been developed. A new method for the detoxication of antigenic complex which more available to preserve the protective property was suggested. Experimental batches of monovaccine and adsorbed DPT vaccine with the acellular pertussis component, possessing high protective activity and low histamine-sensitizing properties, have been obtained. The stability of protective properties both in liquid and lyophilized acellular pertussis preparations has been noted.

Global DTP manufacturing capacity and capability. Status report: January 1995.

A recently completed survey of 63 manufacturers of diphtheria-tetanus-pertussis (DTP) vaccine and its components in 42 countries shows that there is potentially a large excess installed capacity for DTP production. However, many manufacturers are not producing to capacity, and demand and supply for this vaccine are not matched in individual countries. About half of all countries producing DTP vaccine and its components do not have fully functional national control systems, and some countries are performing none of the critical functions for an effective control of quality. Thus, potential for export of excess capacity is limited. The data collected indicate much homogeneity in the preparation of diphtheria and tetanus toxoids. Nearly all manufacturers use the same seeds and similar purification methods, but there is variability in whether purification is done before or after conversion of toxin to toxoid. About 10% of all manufacturers do not meet WHO-defined standards of purity for these toxoids. There is much more heterogeneity in the pertussis seed strains and the methods of purification used. The formulation of DTP vaccine differs considerably among producers. Potency testing is not being done by the WHO-recommended method by about 50% of manufacturers on lots of diphtheria and tetanus toxoids for release. Testing of irreversibility of conversion of toxin to toxoid, a WHO-specified safety test, is also not being done on each lot of diphtheria toxoid by 15% of manufacturers surveyed nor on each lot of tetanus toxoid vaccine by 30% of manufacturers surveyed. Access to technology to develop new DTP-based combination vaccines will be delayed if these manufacturers cannot ensure consistent high quality vaccine for their target populations. The results and conclusions suggest areas for future activities to strengthen the supply and quality of DTP and DTP-based combination vaccines.

Clinical use of Biken acellular DPT in two-month old infants.

We have examined the antibody titer and side effects in two-month-old infants (1.5-2.5) who received vaccinations of acellular DPT Combined Vaccine Adsorbed "Biken" Lots 22 and 23. We observed high-antibody titers far in excess of prevention levels. No particular increase in side effects was observed in the two-month-old infants, except a normal increase in once-only side effects. The results suggest that this vaccine can protect infants under one year of age, who are especially liable to be affected by this illness.

Safety follow-up in a cohort of Biken acellular DPT vaccine recipients in Japan.

In October 1984 in Sweden, a phase II trial of Biken acellular Pertussis vaccine was started and in 1986, a phase III trial of the same vaccine was begun. During the phase III trial, there were three cases of deaths out of 1,385 of study children at two, four and ten weeks after the second dose of the vaccine, due to severe invasive bacterial infections such as H. influenzae, Pneumococcus, or Meningococcus infection. A number of arguments arose about the results of the Phase III trial. No one can either prove or disprove the association between invasive bacterial infection and administration of acellular pertussis vaccine. The purpose of this paper is to discuss the side effects of Biken acellular DPT vaccine. The pediatricians inquired about the physical status of the children who received Biken acellular DPT vaccine. During the observation period, three out of 940 infants suffered from infectious diseases. One suffered from measles, the other from varicella and the last from mumps. Our retrospective study did not reveal any severe invasive bacterial infection cases cases such as the ones experienced in Sweden.

Clinical trials in the United States and Japan with the Lederle-Takeda and Takeda acellular pertussis-diphtheria-tetanus (APDT) vaccines. The Multicenter APDT Vaccine Study Groups.

The results of the following studies are reported: a longitudinal double blind trial comparing Lederle-Takeda APDT vaccine with Lederle DTP vaccine in two, four and six month old infants; two double blind similar APDT vs DTP trials in 18 month old and four to six year old children; a large longitudinal open trial with APDT in two, four and six month old infants and a household contact efficacy trial with Takeda APDT in Japan. APDT vaccine recipients had a lesser frequency and less severe reactions than whole cell vaccine recipients. Antibody responses to lymphocytosis-promoting factor and agglutinogens were higher in DTP recipients; APDT recipients had a better serologic response to filamentous hemagglutinin. Equivalent 69K protein antibody responses were seen. Vaccine efficacy in the household contact study was 98% (95% CI = 84% to 99%) against classical pertussis and 81% (95 CI = 64% to 90%) if all respiratory illnesses are considered.

Metabolic and hematologic effects and immune complex formation related to pertussis immunization.

Selected metabolic, hematologic, and immunologic functions were evaluated in 3- to 6-mo-old Finnish infants who received whole-cell pertussis-component diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (DTP) vaccine, and in 4- to 6-y-old Los Angeles children who received either a licensed DTP vaccine or an acellular pertussis component DTP vaccine. One d after immunization, there was an increase in total leukocytes and neutrophils and a decrease in lymphocytes in all vaccinees. In 4- to 6-y-old children the leukocytosis and neutrophilia were greater in recipients who received the standard DTP vaccine than in vaccinees who received an acellular pertussis component DTP vaccine. In infants there was an increase in the mean plasma insulin concentration but no change in the glucose concentration 24 h after immunization; no increase in the mean plasma insulin was noted in the 4- to 6-y-old children. Three 4- to 6-y-old vaccinees had higher circulating immune complex concentrations after immunization and two of these children had high clinical reaction scores. The etiology of adverse reactions after DTP immunization is multifactorial. In contrast with findings in animals, our findings do not demonstrate a clinically significant effect due to lymphocytosis-promoting factor on glucose metabolism in vaccinated children. Neutrophilia in vaccinees is probably due to endotoxin, and some reactions may be due to circulating immune complexes.

Preliminary report on household contact studies of the prevention of pertussis in Japanese children by Takeda diphtheria and tetanus toxoids and acellular pertussis vaccine combined.

Acellular pertussis vaccines combined with diphtheria and tetanus toxoids and adsorbed onto an aluminum salt (AcPDT) have been used exclusively in Japan for the immunization of children since 1981. (Interagency Report 2), 1987; Kimura et al. 1), 1985) Immunization of children is initiated at two years of age with a booster dose one year later. Morbidity and mortality rates from pertussis, which had steadily increased since 1975 because of poor acceptance of the whole cell preparation, have declined since widespread use of AcPDT (Kimura, 1985). The apparent efficacy of AcPDT has also been demonstrated by several household contact studies in which rates of pertussis in immunized and unimmunized children exposed to the disease in their own homes were determined. In these studies vaccine efficacy ranged between 78 and 93 percent (Interagency Report). However, there are six different manufacturers of AcPDT in Japan, and their products vary in antigenic constituents. One manufacturer produces AcPDT that contains about 50 percent pertussis toxoid and 50 percent filamentous hemagglutinin (B-type AcPDT). Four manufacturers market vaccines that contain predominantly FHA, approximately 10 percent pertussis toxoid, and approximately one percent agglutinogens (T-type AcPDT). The sixth product comprises pertussis toxoid and FHA in amounts that are intermediate between the B- and T-types. With the exception of one small study (Aoyama, 1988) all of the Japanese studies have considered these AcPDT products as a group, and accordingly product-specific information concerning efficacy is not available.(ABSTRACT TRUNCATED AT 250 WORDS)