Feasible improvements in vaccines in the Expanded Programme on Immunization.

Feasible improvements in existing vaccines of the Expanded Programme on Immunization are reviewed. The toxicity of pertussis vaccines can probably be reduced and the immunogenicity increased by recently instituted improvements in purity and selectivity. Candidate vaccines containing inactivated pertussis toxin, with or without other components, are in use in Japan and in controlled trials elsewhere. Inactivated poliovirus vaccines have been improved over the past decade and presently show promise of inducing immunity with as few as two doses administered in infancy. At the same time, improved methods for delivering the oral poliovirus vaccine through mass vaccination campaigns are being increasingly employed throughout the developing world. Major improvements in the measles vaccine will probably come from the development of new stabilizers and the use of vaccines that are immunogenic in the presence of maternal antibody.

PIP: The toxicity of pertussis vaccines can probably be reduced and the immunogenicity increased by recent improvements in purity and selectivity. Inactivated poliovirus vaccines show promise of inducing immunity with 2 doses administered in infancy. The Expanded Program on Immunization (EPI) uses the diphtheria-tetanus-pertussis (DTP) vaccine, poliovirus vaccine, and measles virus vaccine. The incidence of serious toxicity (particularly screaming fits, attacks of pallor, or unusual behavior) and encephalitis is very low. A superior partially purified pertussis vaccine was developed by Sato that contained both the pertussis toxin and filamentous hemagglutinin. With the toxicity of purified-component vaccines reduced, the relevant pertussis antigens can be increased to the point where 2 doses will suffice. The present live oral polioviruses vaccine (OPV) and inactivated poliovirus vaccine (IPV) are prone to thermal instability and a cold chain may be a necessary component of immunization with live poliovirus vaccine in the near future. It was shown that 4th and 5th doses of OPV given at 4-week intervals after the 3rd dose elevated the proportion of infants who developed serum antibody to types 1, 2, and 3 antigen from 69%, 90%, and 76%, respectively, up to 83%, 96%, and 82%. DTP vaccine improved to 2 doses is adequate for initial coverage then full immunization for DPT, poliomyelitis, and measles at 3 and 9 months of age. Vero cells of a heteroploid karyotype and of an indefinite lifespan were used to develop a poliovirus vaccine, as they do not produce tumors in rodents. WHO and the US Food and Drug Administration accepted them as safe as cell substrates for certain purified viral vaccines. Measles virus vaccines also have thermal instability and immunogenicity. Thermal instability was greatly reduced with the introduction of buffered glycerol-sorbitol before lyophilization. Immunogenicity in the presence of maternally derived antibody while indicating successful immunization also indicates susceptibility to measles. In a trial of aerosolized vaccine in Mexican children of different ages using the Edmonston-Zagreb (E-Z) vaccine and the Edmonston-Swartz (E-S) vaccine, successful immunization was high even in 6-month-old infants with the E-Z strain but not with the E-S strain. Both OPV and IPV will continue in general use and improvements will come from more efficient delivery schemes, particularly pulse immunization.

Efficacy and safety of vaccination of marrow transplant recipients with a live attenuated measles, mumps, and rubella vaccine.

Long-term immunity to measles, mumps, and rubella viruses was studied in 57 patients after allogeneic bone marrow transplantation. Among patients who were seropositive at the time of transplant, 51% had retained antibodies to measles, 42% had retained antibodies to mumps, and 76% had retained antibodies to rubella 2 y later. There was no difference in the ability to retain antibodies to these viruses between patients with and those without chronic graft-versus-host disease (GVHD). Twenty seronegative patients without active chronic GVHD or ongoing immunosuppressive treatment were vaccinated with a live attenuated trivalent vaccine against measles, mumps, and rubella. No early or late side effects were detected after the vaccinations. The percentages of patients who seroconverted after vaccination were 77%, 64%, and 75% for measles, mumps, and rubella, respectively. Vaccination of transplant recipients with a live attenuated vaccine against measles, mumps, and rubella is safe and usually effective 2 y after transplant if the patients do not have active chronic GVHD or ongoing immunosuppressive treatment at the time of vaccination.

An anti-plasminogen antibody preparation that inhibits the activation of human plasminogen but enhances the activator activity of the B-chain-streptokinase complex.

An anti-Glu-plasminogen (GLU-PLG) polyclonal antibody antiserum was prepared in the goat, and specific IgG anti-GLU-PLG antibodies were purified by affinity chromatography using a sepharose-GLU-PLG column. In chromogenic assay studies, the anti-GLU-PLG antibody preparation was found to be an effective inhibitor of the activation of PLG, and it produced different inhibition curves with four different PLG activators. 80% inhibition of streptokinase (SK) activation of GLU-PLG occurred with an anti-GLU-PLG antibody/GLU-PLG molar ratio of 1:1, whereas at this ratio only 28% and 36% inhibition of the plasmin-streptokinase (PLN-SK) and the B-chain-streptokinase (B-SK) complexes occurred. At a 1:1 molar ratio of antibody to PLN, no inhibition of PLN activity occurred. When the anti-GLU-PLG antibody preparation was incubated with each PLG activator, an enhancement in the activator activity of the B-SK complex, but not the other activators was observed with mini-plasminogen (MINI-PLG). Enhancement occurred at a molar ratio of 1:1 and reached a peak of 97% enhancement at a molar ratio of 10:1. Enhanced activator activity of the B-SK complex of 49% occurred at a molar ratio of 1:1 when GLU-PLG was the substrate. At higher molar ratios inhibition of activator activity on GLU-PLG was observed, but not on MINI-PLG. These results indicate that there are multiple activator binding sites on PLG, that these four activators all bind differently to GLU-PLG and MINI-PLG, that some antibody populations that are specific for the PLN B-chain can stimulate activator activity, while other antibody populations that are specific for either the PLN A-chain or the B-chain are inhibitory.

[The development and duration of immunity in children vaccinated against measles with the Edmonston-Zagreb vaccine]. / Stvaranje i trajanje imunosti u djece cijepljene protiv ospica vakcinom Edmonston-Zagreb.

After routine measles-rubella-mumps (MRM) vaccine, seroconversion rate for measles heminhibiting (HI) antibodies in a group of 161 children was determined. Of the 154 children who had no HI antibodies in the first serum sample, 153 (99.3%) developed these antibodies in titres greater than or equal to 1:4 and 148 (96.1%) in titres greater than or equal to 1:8 at 6 weeks postvaccination. These results are in concord with the WHO standards. Another study was designed to evaluate persistence of HI antibodies to measles in a group of 123 children who were given MRM vaccine 1-6 years earlier. No significant decrease in HI antibody titers was recorded. It is concluded that immunity acquired through vaccination with the Edmonston-Zagreb measles virus strain in children aged 12 months to 3 years is satisfactory and that it does not decrease at least up to 6 years following vaccination.

[Clinico-immunologic evaluation of a trivalent vaccine against measles, rubella and mumps]. / Valutazione clinico-immunologica di un vaccino trivalente contro morbillo, rosolia e parotite.

Prevention of measles, mumps and rubella can be obtained by a single administration of a trivalent vaccine as it has already been practiced in the U.S.A. since 1970 in the Scandinavian Countries since 1982. The immunological response and the clinical reactions to a new trivalent vaccine (Triviraten-Berna) against measles, mumps, and rubella has been studied in a control group including 41 children (20 females and 21 males) aged from a minimum of 16 months to a maximum of 7 years and 4 months. All the children who resulted not to be immune to the 3 viruses by serologic tests showed a rise in the antibody titer with 100% seroconversion, whereas in those resulting to be already immune to one of the 3 viruses, a persistent antibody titer or an increase was revealed. Neither general nor local clinical reactions were observed. These results suggest that this trivalent vaccine is highly effective, without negative effects and helpful for a mass prevention of such viral diseases.

Immunity and immunization of children against diphtheria in Sweden.

The level of immunity to diphtheria and the effect of vaccination with different doses of diphtheria toxoid was investigated. The 457 study children, 6, 10 and 16 years of age, had as infants received routine primary vaccination with three doses of diphtheria-tetanus-toxoid or diphtheria-tetanus-pertussis vaccine, and the 16 year-olds also had received a booster dose of tetanus with a small dose of diphtheria at the age of ten. Prior to the study booster, 15% of the 6-year-olds had antitoxin levels against diphtheria less than 0.01 IU/ml, the given minimum level for protection. Of the 10-year-olds, 48% had titres less than 0.01 IU/ml, while the corresponding figure for the 16-year-olds was 24%. After a booster injection of 0.1, 0.25 or 0.5 ml of diphtheria-tetanus vaccine, more than 97% of the children showed titre levels greater than or equal to 0.1 IU/ml, while levels of greater than or equal to 1 IU/ml, indicating titres sufficient for long-term protection, were attained by 23-96%. Systemic reactions were few and moderate. Local reactions were of little clinical significance. In a group of 5-years-olds given diphtheria-tetanus primary vaccinations over wider intervals, only 1.4% had antitoxin titres less than 0.01 IU/ml. The results show a need for serologic monitoring of vaccination programmes.

Rapid assessment of the antitetanus immune status of a subject using Dot-ELISA.

We describe a Dot-ELISA system for the rapid, specific and reliable assessment of a subject's antitetanus immune status. The conditions for Dot-ELISA were selected to give positive reactions only for sera with antitetanus antibody titers equal to or higher than 0.06 I.U./ml, considered to represent protection when using "in vitro" methods. This Dot-ELISA method could advantageously be applied to the monitoring of vaccination campaigns, as well as for assessing the antitetanus immune status of the wounded.

[Evaluation of postvaccinal pertussis immunity by using immunoenzyme analysis]. / Otsenka postvaktsinal'nogo protivokokliushnogo immuniteta s pomoshch'iu immunofermentnogo analiza.

The effectiveness of adsorbed DPT vaccine manufactured in the USSR, evaluated by its capacity of inducing the formation of the main classes of immunoglobulins and by the duration of immune response to the acellular complex of protective antigens (pertussis toxin and agglutinogen-2), was studied with the use of modified EIA. Out of 273 children immunized with adsorbed DPT vaccine in the course of this study, 87.2% had IgG-antibodies, 14.1% had IgA-antibodies and 3.2% of the children had IgM-antibodies. The level of immunity in children having received the full course of immunization with adsorbed DPT vaccine was significantly higher in comparison with children given only the primary course of immunization and nonimmunized children of the same age. Antipertussis immunity was found to decrease two years after the completion of the course of immunization with adsorbed DPT vaccine and in children over 5-6 years of age. Adsorbed DPT vaccine prevented the disease, but not infection. The level of postinfection immunity was higher than that of postvaccinal immunity.

Clinical, metabolic, and antibody responses of adult volunteers to an investigational vaccine composed of pertussis toxin inactivated by hydrogen peroxide.

A toxoid vaccine, composed of purified pertussis toxin inactivated with H2O2 (NICHD-Ptxd), was developed on the basis of evidence that serum neutralizing antibodies (antitoxin) would confer immunity to pertussis. In vivo and in vitro assays of NICHD-Ptxd showed only trace or nondetectable levels of pyrogenic, adenosine diphosphate-ribosyltransferase, binding and pharmacologic activities. Nevertheless, about 40% of the antigenicity of pertussis toxin was retained. Adult volunteers were injected, two times 6 weeks apart, with either 10 (n = 21), 50 (n = 25), or 75 (n = 30) micrograms/dose of one lot, Ptx-06, adsorbed onto AI(OH)3. Neither fever nor changes in the levels of leukocytes, lymphocytes, fasting blood glucose, or insulin were observed in the volunteers. The optimal immunizing dose, 50 micrograms, induced levels of antitoxin (geometric mean (GM) 302 U) comparable to those found in eight adults convalescent from pertussis (GM 269 U) and greater than those found in 18-month-old children after their fourth dose of diphtheria and tetanus toxoids and pertussis vaccine (GM 20.0 U, p less than 0.001). These data indicate that NICHD-Ptxd is safe and immunogenic in adults, and they justify its evaluation in infants and children.

Antibody level of New Zealand children immunized with the triple vaccine DTP (diphtheria-tetanus-pertussis).

Enzyme-linked immunosorbent assay (ELISA) tests were used to measure IgG antibody levels in 2638 New Zealand children who had been immunized with the triple vaccine DTP. The percentage of children immune to diphtheria decreased with age. The percentage of children immune to tetanus varied from 67.1 to 55.0%. The percentage of children with measurable antibody to pertussis increased with age. The mean percentages of children with measurable antibody or immunity to one or more DTP components were 34.2% (with 3 components), 34.4% (2 components), and 78.1% (1 component). It appears the immunization strategy for diphtheria and tetanus is satisfactory for herd immunity in New Zealand children. However, the current pertussis strategy may not be providing adequate immunity to 5-year-olds in this country.

Complement-mediated neutralization test for determination of mumps vaccine-induced antibody.

When assessed by a conventional plaque neutralization (NT) test, about one third of recipients of live mumps vaccine were found to have failed to seroconvert, although the majority of them became seropositive by the complement-mediated neutralization (CNT) test. The discrepancy between the conventional NT and CNT was found to result from two factors. First, the predominant production of antibodies to the fusion (F) protein during the early phase of antibody response, and second, a low efficiency of NT of the early antibodies in the absence of complement. These features of antibody response were also seen in natural mumps infection and in experimental infection of monkeys, but were particularly prominent in vaccinees because of the limited extent of antibody response in the latter. The discrepancy between conventional NT and CNT diminished with time after vaccination, after natural infection, and also after experimental infection of monkeys. The CNT test was therefore considered better suited than the conventional NT test for assessment of the outcome of vaccination, at least until 6 to 9 weeks after vaccination. The protective role of the antibody in vivo, which requires the addition of complement for neutralization, was inferred from the observation that the antibody incorporated in the agar overlay significantly reduced the size of plaques formed by mumps virus.

[Effect of histamine on the rosette-forming capacity of T-lymphocytes in immunization with ADPT vaccine and its components]. / Vliianie gistamina na rozetkoobrazuiushchuiu sposobnost' T-limfotsitov pri immunizatsii AKDS-vaktsinoi i ego komponentami.

The results obtained in the study of the influence of histamine on the capacity of T-lymphocytes of guinea pigs immunized with DPT-vaccine and its components for spontaneous rosette formation are presented. Histamine at a concentration of 10(-3) M has been found to inhibit the capacity of blood and splenic lymphocytes of guinea pigs immunized with adsorbed DPT vaccine for spontaneous rosette formation. The inhibitory effect is more pronounced after the immunization of the animals with adsorbed DPT vaccine and Bordetella pertussis suspension.

[Determination of the antigenic activity of diphtheria anatoxin in liquid and sorbed preparations using an erythrocyte diphtheria antigen (anatoxin) diagnostic agent]. / Opredelnie antigennoi aktivnosti difteriinogo anatoksina v zhidkikh i sorbirovannykh preparatakh s pomoshch'iu éritrotsitarnogo difteriinogo antigennogo (anatoksinnogo) diagnostikuma.

On the basis of the experimentally established dependence of the degree of binding of diphtheria toxoid with standard diphtheria antitoxin on the duration of their joint incubation with the maximum binding occurring in 3-4 hours of incubation at 37 degrees C, the method of the in vitro determination of the antigenic activity of diphtheria toxoid in liquid and adsorbed preparations is proposed. The method is based on the principle of double binding with the use of diphtheria antigenic (toxoid) erythrocyte diagnosticum. The antigenic activity of diphtheria toxoid, evaluated by the degree of its maximum binding with diphtheria antitoxin, correlated with its antitoxin-binding activity in animal experiments and did not correlate with its flocculating activity. The antigenic activity of diphtheria toxoid in adsorbed preparations, evaluated by their maximum binding with standard diphtheria antitoxin, was shown to be closely related to the immunogenic potency of these vaccines in animals.

Combined vaccine against measles, mumps, rubella, and varicella.

A combined measles, mumps, rubella, and varicella vaccine produced seroconversions for all four components similar to that found if measles, mumps, and rubella vaccine or live varicella vaccine were given separately. In addition, those exposed to varicella were completely protected or had only a mild rash. Moreover, the reaction rates were not increased if the vaccines were combined. The somewhat lower and delayed serologic response to live varicella vaccine as compared with the combined measles, mumps, rubella, and varicella may have been due to the small amount of varicella vaccine virus used or to its degree of attenuation. Persistence of antibody was observed 1 year postimmunization.

Immunogenicity of specific Bordetella pertussis surface antigens in diphtheria-tetanus-pertussis (DTP) vaccines.

The predominant causative organism of whooping cough in Australia is of a serotype which has normally been associated overseas with unvaccinated communities. Australian DTP vaccines pass the statutory mouse test for Bordetella pertussis potency but this test is now believed to be relatively insensitive to certain factors, especially the major type-specific agglutinogens, which are presumably also important in the human host-parasite relationship. Because endemic B. bronchiseptica infections make some laboratory animals unsatisfactory for testing B. pertussis agglutinin responses, we have developed a test in which young farm sheep were immunized with vaccines. Type-specific agglutinins in their sera were assayed after absorption of non-specific agglutinins by suspensions of selected bordetella strains. Three well-reputed European DTP vaccines and two recent batches of Australian DTP vaccine were tested and compared thus. All evoked significant agglutinin responses to the main agglutinogens.

Serological evaluation of a measles, mumps, and rubella vaccine.

Combined measles, mumps, and rubella vaccination is soon to become available in Britain in the routine immunisation programme. A controlled study was performed in 319 children, aged 13 months, to assess the antibody response and clinical reactions to a new combined measles, mumps, and rubella vaccine in comparison with a single component measles vaccine. In the children who received the combined vaccine, seroconversion was established in 93% for measles, 99% for rubella, and 100% for mumps. In the children who received the single measles vaccine, seroconversion was established in 92% for measles and in none for rubella and mumps. There was no increase in clinical reactions after the measles, mumps, and rubella vaccine compared with the measles vaccine. These results suggest that this combined vaccine would be effective and safe in a British population and give further support for the introduction of the combined measles, mumps, and rubella vaccine to Britain.

Clinical efficacy of a new, enhanced-potency, inactivated poliovirus vaccine.

The 1986-87 outbreak of paralytic poliomyelitis in Senegal, with 676 reported cases, provided an opportunity to evaluate the efficacy of an enhanced-potency inactivated poliovirus vaccine (N-IPV) in the Kolda region, where this vaccine has been used since 1980. 89 cases, confirmed to have poliomyelitis with residual paralysis, were enrolled in a case-control study, up to 5 matched controls being obtained for each case. The clinical efficacy for one dose of N-IPV was 36% (95% confidence interval 0%, 67%) and for two doses was 89% (95% CI 62%, 97%).

Risk of acute non-specific upper respiratory tract infections in healthy men taking dapsone-pyrimethamine for prophylaxis against malaria.

The relative risks of non-specific upper respiratory tract infections were studied in two well matched groups of military recruits to see whether dapsone-pyrimethamine (Maloprim) given as antimalarial prophylaxis was associated with immunosuppression. Mean risks of upper respiratory tract infection were 64% higher in the study group than in the controls, the largest monthly differences being recorded in the months of harder training. These findings were unlikely to have been due solely to harder training in the study group, as concurrently measured sprains (arguably more likely to have been affected) were increased by only 19%. A more likely explanation was some degree of immunosuppression, physical stress possibly having a synergistic effect. These findings suggest that travellers taking dapsone-pyrimethamine as antimalarial prophylaxis may be rendered more susceptible to commoner infections, especially when engaged in increased physical activity.