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Typhoid fever remains an important public health problem in many areas of the world and an effective, non-reactogenic vaccine would be useful to control this disease. An attenuated Salmonella typhi strain (Ty21a), which has shown promise in previous trials, was evaluated in a controlled field trial in Santiago, Chile. In this trial, 82,543 schoolchildren were randomly assigned to receive one or two doses of Ty21a vaccine in enteric-coated capsules or placebo. The enteric-coated vaccine formulation was well tolerated and practical for mass oral immunization. In the first two years of surveillance, 213 cases of bacteriologically-confirmed typhoid fever were found in schoolchildren participating in the trial; annual rates in the placebo group were 139 and 227 per 100,000. Vaccine efficacy in the first two years after vaccination was 59% for two doses and 29% for one dose; no efficacy was found 3-5 years after vaccination. These results indicate that it will be necessary to identify a vaccine formulation and schedule for Ty21a S. typhi that is practical and provides high level protection for greater than 2 years.

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The widely available heat-phenol-inactivated whole cell typhoid vaccine, which provides approximately 65% protection, has limited usefulness because of the adverse reactions it evokes. In contrast, several new typhoid vaccines promise protection without reactogenicity. Attenuated oral vaccine Ty21a has been evaluated in three field trials of efficacy in Santiago, Chile, involving 530,000 schoolchildren. Three doses of Ty21a in an enteric-coated formulation given within one week provided 69% efficacy for at least four years. Fewer doses conferred less protection, while adding a fourth dose significantly enhanced protection; increasing the interval between doses did not improve protection. Large-scale vaccination with Ty21a appeared to cause a herd-immunity effect. Ty21a has reached the stage of being a practical tool for public health. With respect to other vaccines, the safety and immunogenicity of an auxotrophic (Aro-,Pur-) Salmonella typhi mutant (strain 541Ty) has recently been evaluated. Lastly, parenteral purified Vi polysaccharide of S. typhi was safe and immunogenic and provided 64%-72% protection (for at least 17-21 months) in controlled field trials in Nepal and South Africa.

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41 lactating Pakistani women were vaccinated orally with Salmonella typhi vaccine alone or in combination with parenteral Vibrio cholerae whole cell vaccine, in order to study the possible difference in the secretory response after live and inactivated vaccines. The antibody response in saliva, milk and serum was recorded using the enzyme-linked immunosorbent assay, ELISA. All had prevaccination antibody levels against the 2 vaccines. The live S. typhi vaccine gave a serum IgG and IgA response but did not influence the IgM levels. Salivary or milk secretory IgA (SIgA) antibody levels showed both increases and decreases but in most cases remained unchanged. Even if the vaccine was given in enteric coated capsules, the milk and salivary SIgA response was more often decreased than increased, although somewhat higher serum IgG levels were attained with this preparation. Parenteral cholera vaccination enhanced both serum and SIgA milk antibody response. Combination of the 2 vaccines did not have any untoward effect on the antibody response in serum or in secretions against V. cholerae or S. typhi LPS. The results show that an oral vaccine often induces a rather poor, or even negative mucosal antibody response, while a parenteral vaccine provokes a substantial SIgA response in individuals orally primed by natural exposure. This is in agreement with our previous findings with oral and parenteral poliovirus vaccines in this population.

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Pseudomonas aeruginosa toxin A was used to construct conjugate vaccines and potent cytotoxic immunotoxins. Nontoxic, serologically active O polysaccharide derived from P. aeruginosa lipopolysaccharide (LPS) was covalently coupled to toxin A via reductive amination. The conjugate was nontoxic, nonpyrogenic, and had a molecular size of 2 X 10(6). The conjugate vaccine was safe when administered to human volunteers and was capable of evoking an immune response to both LPS and toxin A. Native toxin A was coupled to monoclonal antibodies to the human transferrin receptor and the human interleukin 2 receptor to produce immunotoxins active against receptor-bearing cell lines. Antitumor activity was demonstrated when the immunotoxin directed against the transferrin receptor was administered to nude mice bearing human ovarian tumors.

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Serologically reactive O-polysaccharide from nine serotypes of Pseudomonas aeruginosa were covalently linked to toxin A via reductive amination, with adipic acid dihydrazide serving as a spacer molecule. The conjugates were composed of toxin A/O-polysaccharide ratios ranging from 1.17:1 to 3:1. All possessed an average Mr of greater than 10(6), were devoid of ADP ribosyltransferase activity associated with toxin A, and were nontoxic for mice and guinea pigs. The conjugates were stable from toxic reversion when stored at 37 degrees C for 28 days. The conjugation condition used preserved a substantial proportion of critical epitopes on the toxin A molecule as shown by the ability of toxin A-neutralizing monoclonal antibodies to react with the various conjugates. All nine conjugates were capable of evoking an antitoxin A and an antilipopolysaccharide immunoglobulin G (IgG) response in mice and rabbits. Rabbit antitoxin A IgG was capable of neutralizing the cytotoxic effect of toxin A, whereas mice immunized with any of the conjugates were protected against toxin A intoxication. Rabbit anti-conjugate IgG, when passively transferred to mice, was highly effective at preventing fatal P. aeruginosa burn wound sepsis.

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Lipid A-free polysaccharide (PS) isolated from Pseudomonas aeruginosa immunotype 5 lipopolysaccharide (LPS) was covalently coupled to toxin A via reductive amination. The PS-toxin A conjugate was comprised of 29.8% PS and 70.2% toxin A, possessed a molecular weight of greater than 1 X 10(6), was nontoxic for animals and was nonpyrogenic for rabbits at a dose of 50 micrograms/kg body wt when administered intravenously. The conjugate evoked only mild, transient reactions upon subcutaneous administration to human volunteers. Vaccination engendered immunoglobulin G (IgG) antibody, which neutralized the cytotoxic effect of toxin A and promoted the uptake and killing of P. aeruginosa in the presence of human polymorphonuclear leukocytes. Passively transferred IgG isolated from the serum of immunized donors was far more effective at preventing fatal P. aeruginosa burn wound sepsis than paired preimmunization serum. These studies establish the potential usefulness of such a PS-toxin A conjugate as a vaccine against P. aeruginosa.

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Three doses, given within one week, of Ty21a attenuated Salmonella typhi oral vaccine in an enteric-coated formulation provided 67% efficacy for at least 3 years in a randomised, placebo-controlled field trial involving 109,000 schoolchildren in Santiago, Chile. Increasing the interval between doses to twenty-one days did not enhance protection. Significantly less protection followed administration of vaccine in gelatin capsules with sodium bicarbonate. Ty21a provides the same level of protection as the heat/phenol-inactivated whole cell parenteral vaccine but differs in not causing adverse reactions. Ty21a may now be regarded as a practical public health tool.

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Cell-associated hemagglutinin-negative mutants were derived from cholera enterotoxin-negative Vibrio cholerae JBK70 by Tn5 mutagenesis. One of the mutants identified, SB001, was characterized in greater detail. Its ability to colonize ilea of adult rabbits was determined by feeding approximately 10(8) V. cholerae to each animal. At 17 h after feeding, the numbers of viable vibrios in the ilea were determined. There was a significant, 4 log, decrease in the ability of the hemagglutinin-negative mutant to colonize ileal tissue compared with the parent strain JBK70. In addition, the higher levels of colonization attained by JBK70 and the wild-type parent of JBK70, N16961, were associated with intestinal fluid accumulation and death. Rabbits immunized orally with approximately 10(8) SB001, when challenged 3 weeks later with either homologous biotype and serotype El Tor Inaba N16961 or heterologous Classical Ogawa 395, were protected to the same extent as those animals immunized with either the challenge strain or JBK70. This was evidenced by decreases in both the number of animals showing detectable colonization and the level of colonization achieved. A hemagglutinin-negative mutant of V. cholerae may therefore be of potential use as a live oral vaccine against cholera.

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The rabies antibody content of each of ten lots of human rabies immunoglobulin was titrated by both the mouse neutralization test and the rapid fluorescent focus inhibition test. The two tests did not give comparable results, the antibody titres obtained by the mouse neutralization test being 1.4-9.6 times higher than those obtained by the rapid fluorescent focus inhibition test. This titre difference was associated with a consistently lower antibody response in human volunteers who had received post-exposure rabies vaccine treatment which included the administration of RIG assayed by the RFFIT.

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The ability of serospecific anti-capsular polysaccharide (CPS) antibody to prevent fatal Klebsiella pneumoniae pneumonia was evaluated in a rat lung model. Rats were immunized intramuscularly with 100 micrograms of purified serotype 2 CPS and challenged intrabronchially 14 days later with a serotype 2 strain of K. pneumoniae. Vaccination engendered high levels of serum anti-CPS antibody which afforded significant protection (P less than 0.01) against fatal pneumonia. Immunization promoted clearance of the challenge bacteria from the lungs and prevented bacteremia. Histological examination of lung tissue from infected control animals showed pronounced inflammatory cellular infiltrate in the alveolar spaces, intra- and peribronchial inflammation, and tissue necrosis. In contrast, pathological changes noted in lungs from immunized animals were restricted to infrequent intra- and peribronchial involvement.

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A Pseudomonas aeruginosa polysaccharide-tetanus toxoid (Ttxd) conjugate vaccine was produced. Polysaccharide was derived from lipopolysaccharide (LPS) and covalently linked to Ttxd by using carbodiimide with adipic acid dihydrazide as a spacer molecule. The conjugate possessed a relative molecular weight of greater than 350,000 and was nontoxic and nonpyrogenic. The vaccine bound serospecific monoclonal antibodies with an avidity similar to LPS and reacted with murine and human opsonic antibody. The vaccine was immunogenic in rabbits and mice and elicited IgG antibody to both LPS and Ttxd. The vaccine was safe when parenterally administered to humans and evoked only mild, transient reactions. Mean titers of IgG antibody to LPS rose 19-fold after immunization, with 82% of the volunteers responding with a fourfold or greater rise in titer. IgG antibody to LPS evoked after immunization was opsonic and highly effective at preventing fatal experimental burn wound sepsis due to P. aeruginosa.

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Seven commercial intravenous immune globulin (IVIG) preparations and an experimental hyperimmune globulin (Klebsiella immune-IVIG) were analyzed for antibody levels to Klebsiella capsular polysaccharides, opsonic activity, and protective capacity against Klebsiella. With one exception, all IVIGs reacted immunologically with the various capsular antigens, although titers between the preparations varied considerably. Klebsiella immune-IVIG possessed substantially higher titers (32-fold to 128-fold) than the commercial preparations. Only the hyperimmune globulin was capable of promoting the phagocytosis and killing of six Klebsiella test strains. When prophylactically administered, a commercial IVIG afforded significant protection (P less than 0.01) against fatal experimental Klebsiella sepsis only at a dose of 500 mg/kg. Klebsiella immune-IVIG provided a similar level of protection at a dose of 5 mg/kg. Whereas the commercial IVIG was ineffective when used therapeutically, the hyperimmune globulin was highly protective. Combined antibiotic-immunoglobulin therapy was most effective at reducing mortality.

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The frequencies of capsular serotypes among 703 Klebsiella strains isolated from the blood of hospitalized patients were determined. More than 90% of the isolates were typeable, with 69 of the 77 known serotypes being identified. Serotypes 2, 21, and 55, representing 8.9, 7.8, and 4.8% of all the isolates, respectively, were observed at a frequency significantly higher (P less than 0.05) than that for other capsular serotypes. Approximately 43% of the serotypes appeared at a frequency of less than 0.5%. Differences were found when the seroepidemiology of North American and European isolates was compared. The current findings indicate that a capsular polysaccharide-based vaccine against Klebsiella organisms is feasible and should be multivalent, eliciting antibodies directed against the 25 serotypes which make up approximately 70% of all the bacteremic isolates.

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Polysaccharide (PS) derived from Pseudomonas aeruginosa immunotype 5 lipopolysaccharide was covalently coupled to toxin A by reductive amination with adipic acid dihydrazide as a spacer molecule. The resulting PS-toxin A conjugate was composed of 27.5% PS and 72.5% toxin A. The conjugate was composed of heterogeneous high-molecular-weight species, all of which possessed an Mr greater than 670,000. The conjugate was nontoxic for mice and nonpyrogenic at a dose of 50 micrograms/kg of body weight when intravenously administered to rabbits. Immunization of rabbits with the conjugate evoked both an antilipopolysaccharide immunoglobulin G (IgG) and an anti-toxin A IgG response. Anticonjugate IgG was capable of neutralizing the cytotoxic effect of toxin A. Immunization of mice with the conjugate increased the mean lethal dose from 4.5 X 10(1) P. aeruginosa for control mice to 9.6 X 10(5) P. aeruginosa for vaccinated mice. Similarly, immunization raised the mean lethal dose for toxin A from 0.2 to 4.67 micrograms per mouse.

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A polyvalent Klebsiella vaccine composed of six serotypes of capsular polysaccharides (K2, K3, K10, K21, K30, and K55) was developed and its safety and immunogenicity evaluated in humans. Highly purified capsular antigens were treated in 0.1 N NaOH in 95% ethanol to detoxify trace amounts of contaminating lipopolysaccharide (LPS). The vaccine was nontoxic and nonpyrogenic for animals. A total of 40 individuals received either 25 or 50 micrograms of each represented antigen subcutaneously. Reactions to vaccination, where noted, were transient and mild in nature. An immunizing dose of 50 micrograms of each antigen (300 micrograms total) elicited a fourfold or greater immunoglobulin G (IgG) response to all vaccine antigens in greater than 80% of vaccinees. Generally, the serospecificity of the antibody response was limited to those capsular antigens included in the vaccine. IgG isolated from the serum of vaccinees was found to be highly protective against fatal experimental Klebsiella K2 burn wound sepsis indicating that the functional antibody is elicited following vaccination.

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A new, live attenuated mumps vaccine virus strain for human diploid cells has been developed at the Swiss Serum and Vaccine Institute, Berne. The Rubini virus was derived from a child of the same name possessing typical clinical signs and symptoms of mumps infection. Attenuation of the wild virus was performed by isolation and serial passage in WI-38 human diploid cells, specific pathogen-free hens' eggs and MRC-5 human diploid cells. The attenuated virus has been examined in respect of identity, freedom from adventitious agents and growth potential in MRC-5 cells. Furthermore, it does not evoke any clinical reactions in either baby or adult monkeys. It is characterized by the production in Vero cells of smaller plaques than are elicited by either the Jeryl Lynn or Urabe mumps virus strains. The reactogenicity and immunogenicity of the Rubini virus for man was studied by administering a monovalent vaccine to 13 adult male volunteers and a trivalent human diploid cell Rubini, measles (Edmonston-Zagreb-19 virus strain) and rubella (RA 27/3 virus strain) vaccine to 60 children ranging in age from 15 to 24 months. No reactions were observed. Seroconversion was obtained in 95% of the vaccinees, who developed a mean 50% neutralizing antibody titre of 1:64 after 6-8 weeks. Sensitization to avian and other animal proteins and antibiotics which may follow the use of most of the currently available measles-mumps-rubella vaccines, either single or combined, may be expected to be eliminated when this new vaccine is used. Its use in persons already sensitized to such products should furthermore induce no anaphylactic reactions.

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The further attenuated Enders (FAE) measles vaccine strain and the Edmonston B-Zagreb (EZ) measles vaccine strain were compared. In VERO-cells plaque sizes of FAE varied between 0.5 and 1 mm, those of EZ between 1 and 2 mm in diameter. The lots available in Switzerland during a 2 year period showed virus titers of 10(3.1) to 10(4.0) TCID50 per dose in the one vaccine (FAE) and of 10(3.1) to 10(4.5) TCID50 per dose in the other (EZ). Clinical investigations were performed with FAE and EZ monovalent and trivalent (measles + mumps + rubella) vaccine preparations. The virus titers of the vaccine lots used were 10(3.1) to 10(4.0) TCID50 per dose. The overall seroconversion rates of 96% to 100% indicate that both types of vaccine have comparable immunization properties. Stability tests demonstrated good stability of both the FAE and the EZ vaccines. Thus conservation at 37 degrees C was possible for 2 and 4 weeks, respectively, and at 41 degrees C for 6 and 6 days, respectively, without undue loss of live virus content (less than 1 log 10). Since the EZ vaccine is derived from human diploid cells, it is particularly suitable for the vaccination of persons with a history of allergy to avian proteins.

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