The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines.
The development of Haemophilus influenzae type b (Hib) conjugate vaccines has led to the virtual elimination of systemic infections caused by that pathogen, has provided insights into the pathogenesis of and immunity to other capsulated bacteria, and has contributed to the development of new vaccines. Meningitis, a common and serious infection of children, and other infections caused by Hib have been virtually eliminated in countries that have achieved widespread vaccination with Hib conjugates, including the United States, Canada, the United Kingdom, Iceland, Scandinavia, France, and Germany. Hib conjugates have also been shown to be highly effective in developing countries. The principles derived from the use of these vaccines, along with studies of other capsulated pathogens, should allow the rapid inclusion of new polysaccharide-based conjugates into routine vaccination schedules of infants, and should help to realize further reductions in serious systemic infectious diseases.
Natural swine and cattle gamma-IFNs were prepared for trials. One dose of gamma-suiferon contained 1000 IU, that of gamma-boviferon--2000 IU. Three series of researches were carried out to estimate the in vitro and in vivo absorbing activity of phagocytes (monocytes and neutrophiles), their bactericidal ability (on new born pigs and calves, 2 months old animals, sows and cows with calf) and antibodygenesis after immunization of animals by colibacteriosis vaccine. It has been shown in trials that gamma-IFN increased to significant degree (several times, as a rule) the absorbing activity of phagocytes (especially that of monocytes in new-born animals). At the same time bactericidal activity of phagocytes sharply increased--their functional reserve in experimental animals was significantly higher (2-3-times), than in control. Immunization by colinebacteriosis vaccine with additional treatment by homologous gamma-IFN 3-4 times increased antibodygenesis in comparison with control.
OBJECTIVE: To determine the total and functional serogroup C antibody response to a quadrivalent meningococcal polysaccharide vaccine in a group of aboriginal infants, children and adolescents. A secondary objective was to determine their prevalence of meningococcal carriage. DESIGN: Open prospective, before and after intervention study. SUBJECTS: Aboriginal children ages 0.5 to 19.9 years, living in a single Northern community and eligible for a public health immunization campaign conducted in all Manitoba native reserve communities to control a meningococcal serogroup C, electrophoretic type (ET) 15 outbreak. No outbreak cases had occurred in the community at the time of the study. METHODS: Total serogroup C capsular polysaccharide antibody (CPA) and functional bactericidal antibody (BA) responses were measured by enzyme-linked immunosorbent assay and bactericidal assay, respectively. RESULTS: Neisseria meningitidis was recovered from the oropharynx of 13 (5.2%) of 249 aboriginal children including 4 (1.6%) serogroup C isolates, all with the designation C:2a:P1.2,5 ET15. Paired sera from 152 children were available for assay. For CPA the geometric mean concentrations and proportions with > or =2 microg/ml before and after immunization were 0.69, 18% and 12.3, 96%, respectively. A significant increase in serum CPA was achieved by children of all ages, with the greatest response occurring after age 11 years. Among infants or =2 microg/ml. For BA the pre- and post-vaccine geometric mean titers were 1.02 and 45.9. The response was significantly associated with age. BA titers > or =1:8 were present, before and after immunization, respectively, in 0 and 0% of infants or =2-year-olds. CONCLUSION: The age-related total and functional group C meningococcal antibody response after quadrivalent polysaccharide vaccine among aboriginals is similar to that reported for Caucasian children. After age 2 all children made excellent CPA and BA responses. In the younger age groups the BA response was blunted but 82 to 95% achieved CPA titers of > or =2 microg/ml.
In order to determine antibody levels against Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib) in a population of splenectomized subjects, 561 persons in a Danish county, splenectomized between 1984 and 1993 were identified. Two hundred and thirty-five were alive and 149 participated in the study. Each person donated a blood sample for antibody determination by ELISA. Though vaccine coverage among the 149 persons was 91% only 52% had 'protective' levels of pneumococcal antibodies. Despite recommendations for regular follow-up on pneumococcal antibody levels this had only been carried out in 4% of the subjects. Splenectomized subjects who needed pneumococcal revaccination were significantly more likely to have received their initial vaccination less than 14 days before or after splenectomy, as recommended, than those not requiring revaccination. Therefore, the timing of initial pneumococcal vaccination in relation to splenectomy seems to be important. All persons had Hib antibody levels higher than 0.15 microgram/ml and 60% had levels higher than 1 microgram/ml, which are the levels thought to provide short term and long term protection, respectively. In total, 37% of the 149 persons tested had pneumococcal and Hib antibody levels thought to correlate with protection from serious infections.
Results from the serum bactericidal assay (BA) after immunization of human volunteers with the Norwegian serogroup B meningococcal outer membrane vesicle vaccine are surveyed. In the phase II trials with adults we found very high seroconversion rates (greater than 98%) against the vaccine strain in the BA. Details in the antigenic composition of the inoculum used in the BA seem very important as shown here by finding lower bactericidal titres with teenager sera when tested with a variant of the standard inoculum. The present preliminary report corresponds to the presentation given at the Report Meeting on the Norwegian Meningococcal Vaccine Trial, Oslo, 12 September, 1991.
In this introductory presentation, the bacteriology of acute otitis media, sinusitis and orofacial infections is surveyed, and recent data on antibiotic resistance of the most common pathogenic bacteria are reported. In addition, the difference in the immunogenic effect of capsular polysaccharides from pneumococci and Haemophilus influenzae in children of different ages is mentioned. In acute otitis media and sinusitis, pneumococci and H. influenzae are the most common isolates followed in frequency by Branhamella catarrhalis and streptococci group A. It should be emphasized that the average relative risk of otitis media with effusion is much higher in children with viral respiratory infections than in children with nasopharyngeal colonization with pneumococci or H. influenzae. Anaerobic bacteria are the most common causes of odontogenic infections. Penicillin remains the most active of the currently available antibiotics against streptococci group A. Resistance to penicillin of clinical isolates has still not been documented, although resistance may occur to erythromycin and tetracycline. In pneumococci isolates obtained in Sweden, a relative resistance to penicillin occurs in a low percentage. They may also be resistant to erythromycin and tetracycline. The frequency of beta-lactamase producing H. influenzae has been followed nation-wide in Sweden during recent years. The mean frequency varies around 3-4% with local and seasonal peaks up to 12%. The majority of the H. influenzae isolates in Sweden are not fully sensitive to erythromycin, but resistance to chloramphenicol occurs. Most strains (including beta-lactamase producing) are sensitive to co-trimoxazole, cefuroxime, cefotaxime, cefotriaxone and cefaclor. Over 40% of clinical isolates of B. catarrhalis in Sweden produce beta-lactamase.(ABSTRACT TRUNCATED AT 250 WORDS)
The safety and immunogenicity of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) alone, or covalently bound to tetanus toxoid in saline solution (Hib-TT) or adsorbed onto AI(OH)3 (Hib-TT ads), were evaluated after one injection into 18- to 23-month-old healthy children in Sweden. No side reactions were elicited by Hib CPS; side reactions elicited by the two conjugates were similar and comparable to those reported for diphtheria and tetanus toxoids adsorbed. Hib-TT was the most immunogenic of the three vaccines, eliciting about 10-fold higher antibody levels than Hib CPS; of 28 vaccinees, all had greater than 1.0 microgram Ab/mL serum after immunization with Hib-TT. Increases of Hib CPS antibodies within immunoglobulin classes induced by the three vaccines were, in decreasing order, IgG greater than IgM greater than IgA. Within IgG subclasses, rises in IgG1 Hib CPS antibodies were the most frequent, followed by IgG2; some vaccinees with high postimmunization levels also had rises in IgG3 and one in IgG4. Immunization-induced Hib CPS antibodies were bactericidal. Hib-TT also elicited higher levels of tetanus toxoid antibodies than Hib-TT ads; these tetanus toxoid antibodies neutralized tetanus toxin in vivo.
Passive hemagglutination (HA), a bactericidal activity test (BCA), and radioimmunoassay (RIA) were compared in measuring serum antibodies before and after group A meningococcal capsular polysaccharide vaccination of servicemen. The three methods were found satisfactory in demonstrating a response to vaccination in this age group. Of the postimmunization sera, 5% remained without HA and 1% remained without BCA activity; 1% of the postimmunization sera had less than 2 micrograms of antibody per ml as measured by RIA. Approximately 60% of the serum pairs showed a greater than or equal to 32-fold rise in HA titer, a greater than or equal 25-fold rise in BCA titer, or a greater than or equal to 4-fold rise in antibody concentration by RIA. A difference in response to two different vaccine lots was seen with RIA and BCA. Although the calculated correlation between the three methods was good, some individual sera gave discrepant results. These could be shown to be due mainly to one of the following factors: low HA titer was due to lack of the immunoglobulin M and A classes of antibodies, low BCA titer was due to the blocking effect of high immunoglobulin A content, and high BCA titer was due to antibodies directed to bacterial components other than the capsular polysaccharide.
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Protein-based, outer membrane vesicle (OMV) vaccines have previously proven to be efficacious against serogroup B meningococcal disease in Norway and Cuba. Currently, a public health intervention is going on in order to control a serogroup B epidemic in New Zealand. The scale-up and standardization of vaccine production required for controlling the New Zealand epidemic has allowed the establishment of large-scale GMP manufacturing for OMV vaccines. The outcome of this will be licensing of the vaccine in New Zealand and possibly other countries. The availability of licensed OMV vaccines raises the question of whether such vaccines may provide the opportunity to control other outbreaks and epidemics. For instance, such a vaccine could control a localised outbreak of group B meningococci in Normandy, France. "Tailor-made" vaccines, focusing on the sub-capsular antigens may also be considered for use in sub-Saharan Africa for the prevention of the recurrent outbreaks by serogroups A and W135 meningococci. This assumption is based on the epidemiological observation that meningococcal outbreaks in Africa are clonal and are strikingly stable regarding their phenotypic characteristics.