An Haemophilus influenzae type b capsular polysaccharide-protein conjugate has been prepared. The polysaccharide was coupled to the serotype II protein of group B meningococcus through the spacer 6-aminocaproic acid using cyanogen bromide and water soluble carbodiimide. The conjugate can be shown to be reproducible and is stable and highly immunogenic in mice and African green monkeys. Clinical evaluation of this conjugate in children 3 months to 4 years of age showed that it elicited an antibody titer to the polysaccharide moiety greater than 1000 ng/ml in children 8 months of age or older.

Contemporary 14-valent pneumococcal polysaccharide vaccine was first licensed in 1977 in the United States, where about four million doses of vaccine have been distributed to date. The vaccine induces excellent antibody responses in elderly persons as well as in young adults. The antigen content of the vaccine is 50 microgram of each serotype of polysaccharide per dose, and lower titers of antibody are induced when the dose is reduced to 25 or 12.5 microgram of antigen. Adverse reactions are usually mild and consist principally of local erythema and induration at the injection site, with mild fever in a small proportion of subjects. Antibody persists well for at least four years, and it is expected that immunity will last for at least 5 years after vaccination. Local and systemic reactions to the vaccine may be greater when a second dose of vaccine is administered within three years after the initial dose, and this reactivity appears to be due to a Arthus-like response that results from local formation of antigen-antibody complexes. Pneumococcal and influenza vaccines can be injected simultaneously into separate sites without impairment of antibody responses to either vaccine; this feature should facilitate administration of these two vaccines.

Adult persons who were given a pneumococcal polysaccharide vaccine containing 50 μg each of 12 serotypes showed an average 10-fold increase in amount of antibody to the 12 antigens (range 6- to 20-fold) 1 month after vaccination and there was an approximate average 50% decline in antibody 31/2 years later. Children who were 2 to 12 years old at the time of vaccination showed about the same antibody response to the vaccine but this was less persistent and there was about a 55% decline, on the average, after only 21 months, The findings are discussed in the light of need for revaccination and of the nature of antibody responses to polysaccharide antigens.

Current pneumococcal vaccine contains 14 specific capsular polysaccharide antigens, each in 50-γg amount. Reduction of dosage to 25 or 12.5 γg per type gave reduced antibody responses in human subjects for most of the serotypes and these were less than current requirements of the U.S. Food and Drug Administration. Specific antibody following vaccination declines slowly and there was no worthwhile increase in antibody on revaccination 1 to 1.5 years following prior vaccination. Reduction in the dosage of antigen to one-half or one-fourth the 50 γg per antigen amount eliminated the enhanced local and systemic reactions noted previously when the full vaccine amount was given but the time interval between vaccination and revaccination was not long enough to test for the ability of the reduced dose to restimulate antibody production. Pneumococcal and influenza virus vaccines given at the same time into opposite arms showed no important reduction in antibody response to either vaccine and there was no increase in local or systemic reactions compared with that found when the vaccines were given alone.

It has been shown that polyvalent pneumococcal polysaccharide vaccine, now commercially available, is safe, antigenic, and provides protection against pneumonias caused by the pneumococcal serotypes which are present in the vaccine. Early studies also show protection against otitis media caused by these organisms (Mäkelä, 1979). The vaccine is effective in persons with anatomical or functional splenic deficiency but there is a lowered antibody response in immunodepressed patients. Pneumococcal vaccine can be given simultaneously with influenza virus vaccine without significant depression in antibody response to either vaccine and without any increase in reactogenicity. The vaccine contains 14 serotypes that cause approximately 80 per cent of all pneumococcal illnesses, and it shows 80 per cent or greater protective efficacy against pneumonias caused by those serotypes present in the vaccine. Reactions to the vaccine are self-limited and consist generally of mild local and systemic responses. Children of two years of age or older generally respond well to the vaccine; those less than two years of age respond poorly to a majority of the serotypes. It appears that this deficiency may be overcome in part by giving two doses of vaccine at optimally spaced intervals that still remain to be defined. Immunity is expected to last for at least three years at which time booster immunisation might be considered. Reimmunisation at a 12–18 month interval showed no elevation in antibody and there was increased local reaction, apparently due to an ‘Arthus-like’ reaction at the site of injection. This may be overcome by reduced dosage on revaccination but no firm recommendations can be formulated at this time.

Summary Adult persons developed substantial antibody increases against essentially all pneumococcal capsular types following injection of polyvalent pneumococcal vaccine containing 50 μg of each capsular polysaccharide per dose. Revaccination 13 months after the previous immunization did not evoke important further increases in antibodies and there was substantially greater local reaction at the injection site than when the previous dose was given. This finding appeared due to local reaction of antigens with circulating antibodies in the area of injection, since there was a correlation between the measured amount of circulating pneumococcal antibodies and the degree of reaction. Infants less than 2 years of age who were given a half-dose of vaccine generally responded poorly when compared with adults. In studies of 3- to 5-month-old infants, there was some increase _in antibodies when a booster dose of vaccine was given 6 months after the first. Very high level antibody responses against all capsular types were obtained when revaccination was delayed until 2 years of age.

Clinical studies of 12- and 14-valent pneumococcal capsular polysaccha-ride vaccines were carried out among 76 adults and 42 children. All but a small proportion of persons developed significant increases in homologous antibody against all capsular types in the vaccine. Clinical reactions consisted mostly of mild fever and self-limiting local reactions at the injection site, such as commonly seen following administration of killed vaccines. Antibody persisted remarkably well with only slight decline 20 months after the vaccine was given. The vaccine shows great promise for preventing disease and death caused by pneu-mococci and merits wide discretionary application.