A clinical analysis of gelatin allergy and determination of its causal relationship to the previous administration of gelatin-containing acellular pertussis vaccine combined with diphtheria and tetanus toxoids.

BACKGROUND: The number of patients with allergic reactions after administration of gelatin-containing live vaccines is increasingly reported in Japan. These allergic reactions appear to be caused by gelatin allergy. It is still unknown how the patients were sensitized to gelatin. OBJECTIVE: To determine the incidence of gelatin allergy and to identify contributing factors to gelatin allergy, we investigated the following clinical aspects: the development of IgE antibodies to gelatin and the relationship of the patients' past history of acellular pertussis vaccine combined with diphtheria and tetanus toxoid (DTaP) to the development of gelatin allergy. METHODS: We evaluated 366 patient reports, submitted from 1994 to 1997, of adverse reactions after immunization with monovalent measles, mumps, and rubella vaccines containing 0.2% gelatin as stabilizer. On the basis of physician reports, the patients were categorized as to the nature of the adverse reaction. We determined the presence of IgE antibodies to gelatin and obtained past immunization history. RESULTS: The 366 reported patients were categorized as follows: 34 with anaphylaxis, 76 with urticaria, 215 with nonurticarial generalized eruption, and 41 with local reactions only. In 206 patients from whom serum was available, IgE antibodies to gelatin were detected in 25 of 27 (93%) with anaphylaxis, 27 of 48 (56%) with urticaria, and 8 of 90 (9%) with a generalized eruption. None of a group of 41 patients with only local reactions at the injected site and none of a control group of 29 subjects with no adverse reaction had such antibodies. Among 202 patients for whom prior vaccine information was available, all had received DTaP vaccines. Among those for whom the prior DTaP vaccine could be determined to contain gelatin or be free of gelatin, 155 of 158 (98%) subjects had received gelatin-containing DTaP vaccines. This rate is higher than would be expected on the basis of the market share of gelatin-containing (vs gelatin-free) DTaP vaccines (75%). Furthermore, before 1993, when a trivalent measles, mumps, and rubella vaccine (with the same 0.2% gelatin content as the monovalent vaccines) was used and administered before DTaP vaccination, no reports of anaphylaxis to the measles, mumps, and rubella vaccine were received. CONCLUSION: Most anaphylactic reactions and some urticarial reactions to gelatin-containing measles, mumps, and rubella monovalent vaccines are associated with IgE-mediated gelatin allergy. DTaP immunization histories suggest that the gelatin-containing DTaP vaccine may have a causal relationship to the development of this gelatin allergy.

[Intranasal application of inactivated influenza virus vaccines].

Recent concept on the common mucosal immune system gives new direction of influenza vaccine development-mucosal vaccine. Vaccines have to be administered over the mucosal surface (in case of influenza vaccine, intranasal route may be the most suited route) to assure mucosal immunity which is the first hand armament against influenza virus. This article reviews our work on intranasal administration of inactivated influenza virus HA vaccines. Since influenza vaccines are usually given to people who has some degree of immunity due to past infection or immunization, vaccines which have booster effect are preferable. In this context, intranasally administered inactivated influenza HA vaccine was more immunogenic than cold adapted reassortant live influenza virus vaccine, another candidate mucosal influenza virus vaccine, which is now under investigation in the United States.

Adverse events associated with MMR vaccines in Japan.

The largest nationwide active surveillance of four Measles-Mumps-Rubella (MMR) vaccines was conducted in Japan. A total of 1255 pediatricians actively participated in the study, which comprised 8.6% of all members of the Japanese Pediatric Society. The total number of registered recipients of MMR vaccines was 38 203. They were arbitrarily given one of the MMR vaccines produced by three makers (Takeda, Osaka city, Kitasato Minato-ku. Tokyo and Biken Suita city, Japan) or the standard MMR vaccine made of designated strains (Kitasato's measles-AIK-C, Biken's mumps-Urabe Am9 and Takeda's rubella-To336) produced by Takeda, Kitasato and Biken and were observed for 35 days. The rates of virologically confirmed aseptic meningitis per 10,000 recipients were 16.6, 11.6, 3.2 and 0 for the standard MMR, Takeda MMR, Kitasato MMR and Biken MMR vaccines, respectively. The incidence of convulsions between 15 and 35 days was the highest with the standard MMR vaccine and the incidence of fever associated with vomiting occurring between 15 and 35 days (symptoms relevant to aseptic meningitis) were also the highest with the standard MMR vaccine. The incidence of parotid swelling was the lowest with Takeda MMR vaccine. This surveillance revealed that incidences of aseptic meningitis after administration of the standard MMR vaccine and of Biken MMR vaccine were different. This posed questions about the manufacturing consistency of the Urabe Am9 mumps virus vaccines. On the other hand, 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.

[Epidemiology of pertussis and studies on culture positive pertussis cases in Japan].

The number of pertussis patients has decreased steadily in the late 1960s and was extremely small in early 1970s. During 1973-74 the first national survey on pertussis cases confirmed by culture was conducted, when whole cell pertussis vaccine was used. The study revealed that 33.3% of culture positive cases had 2-4 doses of DT combined with whole cell pertussis vaccine. Acellular pertussis vaccine was introduced in 1981 and for the last several years the number of pertussis patients became low for the second time. During 1988-92 exactly the same study was conducted as the previous one. Among 2501 pertussis cases diagnosed clinically 403 were culture positive. Most of the patients were below 1 year of age. Most of the patients were below 1 year of age. Clinical symptoms of those infants were more serious than those of older children. Only 7 out of 403 (1.8%) had a history of 2-4 doses of DT combined with acellular pertussis vaccine. This proved that the acellular pertussis vaccine is by far more effective than the whole cell pertussis vaccine. Serotypes of 377 Bordetella pertussis were identified and 370/377 (98.1%) were serotype 1-3 group.

Immunogenicity and reactogenicity of the component acellular pertussis vaccine produced by a combination of column purified pertussis toxin and filamentous haemagglutinin.

This is the report on a prospective, single blind, comparative study of a component acellular pertussis vaccine produced by a combination of detoxified, column purified pertussis toxin (PT) and filamentous hemagglutinin (FHA) combined with diphtheria and tetanus toxoids (DTcaP) and the traditional acellular pertussis vaccine produced with essentially the same method as described by Sato with DT (DTaP) of the same manufacturer. A total of 616 infants and children received DTcaP and a total of 289 received DTaP. In all age groups for both vaccines values of serum antibodies to PT and FHA after two doses of the vaccines were comparable to those of convalescent sera. Incidences of systemic and local reactions were, in general, not greatly different between DTcaP and DTaP recipients. In Japan the use of traditional acellular vaccines replaced whole cell vaccines in 1981. Protective antigens of Bordetella pertussis have now been specified and thus component vaccines have become theoretically possible. This is the first component vaccine which has been developed in Japan. Several other component vaccines are now under investigation in the world.

Developments in mucosal influenza virus vaccines.

Immunogenicity and efficacy of aerosol inactivated split influenza virus vaccines, which are threefold the strength of the vaccines for parenteral use, and cold-adapted reassortant live influenza virus vaccines were evaluated. Mucosal immune responses were evaluated by quantifying specific IgA antibody of the nasal swab solution, and systemic immune responses were evaluated by determining serum haemagglutination inhibition antibody levels. Efficacy of the aerosol inactivated vaccine was evaluated by a challenge test using live vaccine virus. It was concluded that mucosally administered inactivated influenza virus vaccine stimulated systemic and mucosal immune responses more strongly than live influenza virus vaccine and manifested a much stronger booster effect than live vaccine. Mucosal administration of inactivated influenza virus vaccine was effective in preventing infection by live vaccine virus.

A simple and sensitive ELISA of antibodies to pertussis antigens.

A precise method for quantifying serum antibody levels to antigens of Bordetella pertussis is required to evaluate pertussis vaccines, to diagnose pertussis infections, and to detect transplacentally transmitted maternal antibodies. The purpose of this paper is to report a rapid, sensitive, easy and standardized ELISA method using polystyrene balls for the assay of serum antibodies against pertussis toxin (PT) and filamentous haemagglutinin (FHA), which are protective antigens of B. pertussis. By the polystyrene ball method, a clear-cut difference was observed between values of pre- and postvaccination serum samples while by the conventional plate method those values overlapped. It was concluded that the PS ball method is one of the most sensitive and simple methods for detecting antibodies against PT and FHA.

Local and systemic influenza haemagglutinin-specific antibody responses following aerosol and subcutaneous administration of inactivated split influenza vaccine.

An easily administered and safe vaccine is required to produce the herd immunity necessary to control influenza epidemics worldwide. A commercial quadrivalent inactivated split influenza vaccine was administered intranasally in aerosol form to a group of 46 volunteers; other groups were given the same vaccine subcutaneously and saline intranasally. The results show that mucosal stimulation via intranasal vaccination resulted in a marked increase in local HA-specific IgA antibodies, and that this stimulation was necessary for serum HA-specific IgA responses. Serum HA-specific IgA antibody levels can be used as indicators of local antigenic stimulation, providing a method for evaluating potency and antigenicity in humans of intranasal influenza vaccine. This vaccination route shows much promise for the future.

Enzyme-linked immunosorbent assay of influenza specific IgA antibody in nasal mucus.

An enzyme-linked immunosorbent assay of influenza HA specific IgA antibody in nasal mucus is described. This assay is very sensitive and only a minute quantity of nasal mucus is required.

A comparative trial of the reactogenicity and immunogenicity of Takeda acellular pertussis vaccine combined with tetanus and diphtheria toxoids. Outcome in 3- to 8-month-old infants, 9- to 23-month-old infants and children, and 24- to 30-month-old children.

The reactogenicity and immunogenicity of the Takeda acellular pertussis vaccine combined with tetanus and diphtheria toxoids were compared in 139 infants aged 3 to 8 months, 60 infants and children aged 9 to 23 months, and 99 children aged 24 to 30 months. Good antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), and agglutinogens occurred in all age groups after both the third and fourth doses. After the fourth (booster) dose, the mean antibody values in initially seronegative infants vaccinated at 3 to 8 months of age were as follows: anti-PT, 67.8 enzyme-linked immunosorbent assay units (EU) per milliliter; anti-FHA, 149.5 EU/mL; the agglutinin titer was 125.6. The values in initially seronegative children vaccinated at 24 to 30 months of age were as follows: anti-PT, 92.9 EU/mL; anti-FHA, 251.7 EU/mL; the agglutinin titer was 275.8. Reactions following immunization were minimal. Except for drowsiness after the first dose in infants, there were no clinically significant differences in reactions between infants and older children. The findings in this study coupled with the recent demonstration of efficacy of this vaccine in 2-year-old children supports the recent Japanese recommendation to lower the age of immunization with acellular pertussis vaccine combined with tetanus and diphtheria toxoids to 3 months.

Current epidemiology of pertussis in Japan.

Since the introduction of whole cell pertussis vaccine into general use as part of the routine immunization in 1947 under the Preventive Immunization Law, a steady decrease in reported cases of pertussis was noted until 1974. At that time the number of reported cases reached an all time low and no deaths caused by pertussis were reported. The vaccine (diphtheria-tetanus-whole cell pertussis vaccine) had been given to infants 12 weeks old or older in a 0.5-ml dose by deep subcutaneous injection; three doses were given at intervals of 3 to 8 weeks and the fourth dose (booster) was given 12 to 18 months after the third dose. The immunization was completed with those four doses. Because whole cell vaccine appeared to be associated with severe neurologic illnesses, it was temporarily suspended in 1975. The vaccine was resumed soon thereafter but the age of administration was raised to 24 to 48 months. Under these circumstances acceptance rates of pertussis occurred, reaching a peak in 1979. Although whole cell vaccine was used even after temporary suspension, it was considered to be unacceptable by the public. As a result the acellular pertussis vaccine was developed and has totally replaced whole cell vaccine since 1981. A steady decrease in reported cases of pertussis as well as the number of deaths has been noted since 1979 in accordance with increase in vaccine acceptance rates. The national surveillance system begun in 1981 demonstrated also a steady decrease in the incidence of pertussis during the past 9 years.

Protective efficacy of the Takeda acellular pertussis vaccine combined with diphtheria and tetanus toxoids following household exposure of Japanese children.

The clinical efficacy of an acellular pertussis vaccine containing lymphocytosis-promoting factor, filamentous hemagglutinin, agglutinogens, and the 69-kd outer membrane protein, combined with diphtheria and tetanus toxoids and adsorbed onto an aluminum salt, was assessed in a household contact study. The occurrence of pertussis 7 to 30 days following home exposure among 62 previously vaccinated children was compared with that among 62 unvaccinated children similarly exposed. Classic whooping cough was diagnosed in 43 unimmunized children, and 1 vaccinated child experienced a 5-week illness that was probably pertussis (efficacy, 98%; 95% confidence interval, 84% to 99%). A few children in each group incurred respiratory illnesses that may have represented mild, atypical pertussis; including these as probable pertussis, vaccine efficacy was 81% (95% confidence interval, 64% to 90%). It is concluded that prior immunization with this four-component pertussis vaccine combined with diphtheria and tetanus toxoids is highly efficacious in preventing pertussis.

Developments in pertussis immunisation in Japan.

In Japan acellular pertussis vaccine has totally replaced whole-cell vaccine since 1981. The vaccine is given in combination with diphtheria and tetanus toxoids to children aged 24-48 months; three doses are given with intervals of 3-8 weeks and the fourth dose (booster) is given 12-18 months after the third. There has been a steady decline in cases of pertussis and deaths from the disease since 1979. Comparison of the rates of adverse reactions to whole-cell vaccine in 1973-74 and to acellular vaccine in 1979-80 showed lower rates of fever and of local reactions with the acellular vaccine.

Two doses of measles mumps rubella (MMR) vaccine.

A schedule of two doses of measles mumps rubella vaccine (MMR) at an interval of six weeks was tried in children aged between 12 and 48 months. One hundred percent seroconversion was attained in the measles HI (hemagglutinin inhibition) test, rubella HI test, and mumps ELISA test in both groups of children who received NIH (National Institute of Health, Japan) MMR lot B-30 and Kitasato MMR lot TV-1. The possibility of vaccine failure with one dose of measles vaccine is not negligible [1], and the frequency of vaccine failure increases if three vaccines are combined in the form of MMR. Our observations revealed that a few of the children who had received one dose of MMR remained seronegative with regard to measles HI antibody and rubella HI antibody, and that some of the children remained seronegative with regard to mumps ELISA antibody. A schedule of two doses of MMR was shown to be helpful in reinforcing immunity in children who did not respond satisfactorily to one dose of MMR. We concluded that two doses of MMR are preferable to control measles, mumps and rubella infections.

Serum anti-PT and anti-FHA antibody levels, and agglutinin titers after administration of acellular pertussis vaccines.

Simultaneous evaluation of acellular pertussis vaccines from three manufacturers (Takeda, Biken, and Chiba) was performed. After receiving two doses of acellular pertussis vaccine in the form of DPT (diphtheria pertussis tetanus), both infants and children showed high serum anti-PT (pertussis toxin) and anti-FHA (filamentous hemagglutinin) antibody levels. These levels were equivalent to those observed in children in the convalescent stage of natural pertussis infection. Children who received 2 doses of Biken vaccine showed higher anti-PT and anti-FHA antibody levels than those who received Takeda or Chiba vaccine. Elevation of agglutinin titers was observed in children who received either Takeda or Chiba vaccine.