The clinical and immunologic response of Chilean infants to Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine coadministered in the same syringe with diphtheria-tetanus toxoids-pertussis vaccine at two, four and six months of age.

The safety and immunogenicity of a vaccine against Haemophilus influenzae type b consisting of purified polyribosylribitolphosphate conjugated to tetanus toxoid (PRP-T) was evaluated in 278 Chilean infants who were randomly assigned to one of three treatment groups: Group A, PRP-T mixed with diphtheria-tetanus toxoids-pertussis (DTP) vaccine in a single syringe and given as a single inoculation in one arm and placebo in the other arm; Group B, PRP-T given in one arm and DTP in the other arm; Group C, DTP given in one arm and placebo in the other. Infants were immunized at 2, 4 and 6 months of age and examined daily for 4 days after each immunization; serum PRP antibodies were measured at baseline and 2 months after each dose. The only adverse systemic reaction attributable to PRP-T beyond that caused by DTP alone was a 7 to 20% increase in febrile responses in the first 24 hours after the first and second doses of vaccine; the fevers were largely low grade and not accompanied by increased irritability, diminished activity or loss of appetite, compared with the group who received DTP without PRP-T. After the first dose 72% of infants who received PRP-T combined with DTP and 67% who received it in a separate arm attained antibody concentrations greater than or equal to 0.15 micrograms/ml. After two doses of PRP-T, 93 and 95%, respectively, had concentrations greater than or equal to 0.15 microgram/ml and after three doses 100% of infants who received PRP-T had such titers.(ABSTRACT TRUNCATED AT 250 WORDS)

Formulations of single or multiple H. pylori antigens with DC Chol adjuvant induce protection by the systemic route in mice. Optimal prophylactic combinations are different from therapeutic ones.

The ability to induce a protective response against Helicobacter pylori infection has been investigated by systemic immunization of mice with urease formulated with the cationic lipid DC Chol. This compound acts both as a formulating agent and as an adjuvant and induces a balanced Th1/Th2 response shown to be more effective for protection in our previous studies. Urease-DC Chol induced a significant protection in prophylaxis but not in therapeutic immunization. The protection level was between 1.5 and 2 log reduction of bacterial density measured by quantitative culture compared to unimmunized-infected mice. In parallel, the protective efficacy of other H. pylori antigens formulated in a similar way and administered with DC Chol was tested. These antigens were tested alone or in combination in prophylactic and therapeutic regimens. Some combinations of antigens induced a better prophylactic or therapeutic activity than urease alone (0.5-1.5 log further reduction in prophylaxis and therapy respectively, P<0.05). The combinations that induced the best protection were different in prophylaxis and therapy. In conclusion, DC Chol provides a convenient and efficient method to formulate different antigens even when they are present in non-compatible buffers initially. Moreover, the results obtained in protection against H. pylori with such formulations should lead the way to future clinical trials.

[Infectious pathology and antibiotic usage in hospital. Results of a prevalence survey (author's transl)]. / Prévalence de la pathologic infectieuse et de l'antibiothérapie à l'hôpital.

Prevalence surveys of infection and antibiotic usage in hospitals have been performed in U.S.A. on many times, but have never been performed in France. Conducted in a 529 beds hospital, this survey has shown that: - 38% of patients had an infection, - 41% of patients received antimicrobial therapy, - 61% of infections had not a microbiological proof. This prevalence survey is a useful aid for the bearing of the actions of the department of infectious pathology wich supports infection and antibiotherapy in each of their aspects in the whole hospital.

[Antibiotherapy of purulent meningitis in Africa in 1981]. / Antibiothérapie des méningites purulentes en Afrique en 1981.

The place of the different anti-bacterial drugs in the treatment of purulent meningitis must be reconsidered in view of the bacteriological pharmacological and socio-economical data. Sulphonamids have no more interest because of the multiplication of resistant strains in most of the bacterial species. Penicillin G, with a narrow spectrum, keeps good indications (Meningococci and Pneumococci) but its use lacks convenience. With its very broad spectrum of activity, its long half life and its low cost, Chloramphenicol is actually the reference drug well adapted to the particular conditions of Africa. Ampicillins, often too expensive, show a more and limited activity against gram negative pathogens and should be supplied by the Cephalosporins "of the last generation" if not so costly.

Potential and limitations of polysaccharide vaccines in infancy.

Of infections caused by encapsulated bacteria, those due to Haemophilus influenzae b (Hib) are among the most restricted to infancy and require very early immunisation. Hib capsular polysaccharide (CPS) has the most typical T-cell independent profile. The absence of efficacy of this vaccine in infants triggered development of conjugate vaccines which are so effective that there is now no room for plain polysaccharide Hib vaccines. Pneumococcal infections pose similar problems to Hib, but are more complex. The immunogenicity of the different pneumococcal serotypes varies considerably in infancy. Although the current CPS vaccine provides limited protection in infancy, the burden of pneumococcal infection is so high that its use could be reconsidered should conjugate vaccines be available later than expected. Meningococcal infections are less a specific problem for infants. Again, serogroup immunogenicity varies widely. Group B meningococcal CPS is not immunogenic even in adults, Group C behaves as Hib CPS, whereas Group A is immunogenic as early as 6 months of age. Group A CPS may prove of interest for an infant vaccine, especially in epidemic situations. Typhoid fever is uncommon in infancy; Vi CPS is poorly immunogenic in infancy and is, therefore, of limited interest for use as an infant vaccine.

[Epidemiologic features of pneumococcal meningitis in Africa. Clinical and serotypical aspects (author's transl)]. / Epidémiologie des méningites à pneumocoque en Afrique. Aspects cliniques et sérotypiques.

Pneumococcal meningitis, because of their frequency and their severity, are regarded as an important problem of Public Health in Africa. In a great number of African countries, particularly Equatorial and Central Africa, the pneumococcus is the first agent of bacterial meningitis. The annual prevalence is estimated as about 14/100 000 persons. The case fatality rate (on 1 600 cases) is 49,5% ; the annual mortality reaches about 7/100 000 (28 000 annual deaths in Africa). The babies and the old persons are more exposed to the risk, with an annual prevalence of 28,5/100 000 before five years old, and of 16,1/100 000 after sixty years old. The risk is small between five and forty five years old. The risk is very high in patients homozygous for sickle-cell disease. The spread of all detected serotypes, by descending frequency is : 1, 5, 6, 3, 23, 12, 2, 14, 9, 18, 19, 4, 8, 29, 40, others (Danish system of nomenclature). The distribution according to age is indicated by the authors. A vaccine with only 8 serotypes (1, 5, 6, 3, 23, 12, 2, 14) could cover 80% of serotypes in Dakar. For the babies, addition to pneumococcal vaccine with polyribose phosphate of Haemophilus influenzae b, could be useful, because high prevalence of meningitis with this germ before five years old in Africa.

[Diagnostic approach to prolonged fever (apropos of 72 cases)]. / Approche diagnostique des fièvres au long cours (à propos de 72 cas)

A report of 72 case histories of prolonged feven (more than three weeks, diagnosis not obvious on admission). The writers review the frequency of occurrence of the various etiologies. Infections are the most frequent cause (43 cases). A good number of them are easy to diagnose based on clinical exams and routine tests. Others are a great deal more difficult to diagnose, and in particular deep, suppurative foci. Collagen diseases then follow with 10 cases, the diagnosis of which is made by immunology and histology. Cancers are not very numerous (4 cases) and poorly represent the usual breakdown (kidney, lungs, liver, colon, pancreas). There were no cases of involvement of the blood and reticuloendothelial systems. With regard to examination of these patients, the writers discuss the merits of lymphography and laparatomies, and they set limits to therapeutic tests.

Treatment of purulent meningitis with a new cephalosporin-Rocephin (Ro 13-9904). Clinical, bacteriological and pharmacological observations in 24 cases.

In 21 of the 24 cases the diagnosis of purulent meningitis was confirmed by culturing the causal agent and/or by immunological diagnosis. The daily dosage of Rocephin ranged between 15 and 200 mg/kg administered in 2 i.m. injections. A cure was achieved in cases of meningococcal meningitis (1 case with sequelae: blindness in one eye), in 5 out of 6 cases of Haemophilus influenzae meningitis (1 case with severe neuropsychiatric sequelae), in 3 out of 9 cases of pneumococcal meningitis and in 2 out of 4 cases of enterobacterial meningitis. The tolerance was generally excellent. Sterilisation of the cerebrospinal fluid (CSF) was achieved in all 20 cases of meningitis confirmed by culture. The MIC levels are lower than the lowest CSF peak for Rocephin found in this study. The unusual pharmacological behavior of Rocephin makes it possible to achieve and to maintain for a long time highly satisfactory concentration levels in the CSF. These properties of Rocephin should lift the long-standing objections to the use of cephalosporins for the treatment of purulent meningitis.

[Bacteroides fragilis bacteremias: clinical and evolutive features about 33 cases (author's transl)]. / Septicémies à Bacteroides fragilis. Particularités cliniques et évolutives de 33 observations.

The frequency of non soil dwelling anaerobic infections is increasing. The authors report 33 cases of Bacteroides fragilis bacteremias, and study the responsabilities of different factors of prognosis (especially age and underlying conditions). Nitroimidazoles are very active against all Bacteroides fragilis. This therapy is the drug of choice for such infections.

Immunisation with canarypox virus expressing rabies glycoprotein.

Poxviruses have many useful features as vectors for genes that carry immunising antigens from other viruses, such as ease of production and induction of cellular and humoral immunity, but there is concern about the safety of vaccinia virus. We turned to an avian poxvirus (canarypox); this virus undergoes abortive replication in mammalian cells that enables presentation of early gene products to the immune system. Canarypox virus was used as a vector for the rabies glycoprotein G gene. The safety and efficacy of the recombinant (ALVAC-RG; vCP65) were tested in several animal species, then it was subjected to a phase 1 clinical trial. Twenty-five volunteers were randomly assigned to subcutaneous injections of the recombinant (three groups [A, B, and C] received two doses each of 10(3.5), 10(4.5), and 10(5.5) tissue-culture infectious doses50, respectively) or of human diploid cell culture vaccine (HDC; 6.52 international potency units per dose). 28 days after the second dose, all nine ALVAC-RG group-C subjects and two of three group-B subjects had rabies neutralising antibody concentrations of at least 0.5 IU/ml, the level associated with protection in animals. Although the geometric mean titre of these antibodies at that time was lower in group C than in the ten HDC recipients (4.4 [range 0.9-12.5] vs 11.5 [4.7-25.3] IU/ml), a single booster dose at 6 months induced a recall response in volunteers primed with either vaccine. Side-effects associated with ALVAC-RG were mild and of short duration and occurred at similar frequency to those of HDC vaccine. This study has shown the potential of non-replicating poxviruses as vectors for vaccination in human beings. Trials of canarypox-virus recombinants at higher doses and by other routes of administration are needed.

Comparative safety and immunogenicity of an acellular versus whole-cell pertussis component of diphtheria-tetanus-pertussis vaccines in Senegalese infants.

A diphtheria and tetanus toxoid two-component acellular pertussis vaccine (DTaP), consisting of 25 micrograms glutaraldehyde-detoxified pertussis toxin (PT) and 25 micrograms native filamentous hemagglutinin (FHA), was compared with diphtheria and tetanus toxoid whole-cell pertussis vaccine (DTwP) in a randomized, double-blind manner in 286 Senegalese infants inoculated at two, four, and six months of age. In infants receiving DTaP a significantly lower rate of local reactions, crying and fever was observed than in infants receiving DTwP. One month after the third dose, the geometric mean titres for FHA antibodies were higher in the DTaP group, whereas increases in PT antibody titres were higher in the DTwP group. More than 90% of the infants had a fourfold or more increase in antibodies to both PT and FHA with either vaccine. Diphtheria, tetanus, and polio antibody responses were also measured and found to be comparable between the two groups. The results of this pilot study support the implementation of a field trial to compare the protective efficacy of these vaccines against pertussis in the same setting.

Tetravalent (A, C, Y, W 135) meningococcal vaccine in children: immunogenicity and safety.

Tetravalent meningococcal polysaccharide vaccine (groups A, C, Y and W 135) was administered (s.c.) to 26 healthy children, aged three to 13 years old, in order to assess safety and immunogenicity of the vaccine. Side effects were very mild in all children, generally consisting of local soreness for a few hours following injection. A fourfold increase in bactericidal antibody titres was obtained for the four components in 100% of initially seronegative children. This vaccine thus appears as safe and immunogenic in children as it is in adults.

[The prognosis and treatment of pneumococcal meningitis in Africa. 402 cases (author's transl)]. / Pronostic et traitement des méningites à pneumocoque en Afrique. 402 observations.

Over a period of 5 years (1973--1977), 1083 patients were hospitalised in the Infectious Disease Clinic of the Dakar University Hospital Centre with bacteriologically confirmed purulent meningitis. The pneumococcus was responsible in 462 cases (42.6%). Analysis of 402 records showed that 234 patients (58.2% of cases) died, 123 were completely cured (30.6%) whilst there were neurological sequelae in 45 cases (28% of the survivors). The chief factors in poor prognosis were the existence and depth of changes in conscious level, age over 20 years, a CSF cell count of less than 500 per mm3, a CSF protein level greater than 2 g per 1 and I CSF antigen level over 8 microgram per ml. From a therapeutic standpoint, the percentage mortality was similar with chloramphenicol and with penicillin G, but complete cures were statistically more frequent in the patients treated initially with chloramphenicol.

[Bacteriological, pharmacological and clinical comparison between amoxycillin and ceftriaxone in the treatment of 300 purulent meningitis ]. / Comparison bactériologique, pharmacologique et clinique de l'amoxycilline et du ceftriaxone dans 300 méningites purulentes.

Two series of patients suffering purulent meningitis were treated: one (137 patients) with amoxycillin (200 mg/kg/day) by 4 intramuscular injections each day, the other with ceftriaxone (163 patients)/42 mg/Kg/day IM by intramuscular injections each day in the first 23 patients and then only one injection by day in the 140 other patients. Bacteriologically the superiority of CFTRX appears the whole studied strains: MIC of CFTRX are four times lower than those of AMOX for pneumococci, ten times lower for H. influenzae, hundred time lower for meningococci. Amongst the add strains the percentage of resistance to AMOX reaches 64 and only 7 to CFTRX. Pharmacologically, after a same dose of 50mg/kg the peak concentrations in CSF has the same level: CFTRX: 6.8 micrograms/ml, AMOX: 6 micrograms/ml. CSF levels remain efficient for 2 hours with AMOX and for 24 hours with CFTRX. The therapeutic index (mean antibiotic concentration in CSF/mean MIC of the strains) is higher with CFTRX than with AMOX (X 4 for pneumococci, X 15 for H. influenzae, X 100 for meningococci). Clinical results are better with CFTRX than with AMOX in each of the aetiological groups except meningococcal meningitis but the only significative difference concerns pneumococcal meningitis. Clinical tolerance of the two treatments was good. However 2 neonates treated with CFTRX has a severe eczematous erythrodermia and 8 other patients treated with CFTRX had diarrhoea due to elimination of the sensitive flora.

[Epidemiology and prognosis of Haemophilus influenzae meningitis in Africa (901 cases)]. / Epidémiologie et pronostic des méningites a Haemophilus influenzae en Afrique (901 cas).

Haemophilus influenzae meningitis are frequent in Africa in infants between 6 months and two years of age. Type b is observed in 97% of cases. In Dakar, 2% of strains are resistant to ampicillin and 0% to chloramphenicol. Lethality is about 30% and sequellae are very frequent. Prognosis can be predicted by a cotation scale including consciousness, tonus, seizures, nutritional status, delay before treatment and initial bacterial antigen level in CSF.

Acellular pertussis vaccines: evaluation of reversion in a nude mouse model.

An animal model has been developed to assess the safety of acellular pertussis vaccines in terms of reversion to toxicity. Adsorbed pertussis toxoid preparations, alone or combined in a DTP formulation, were administered to nude mice intraperitoneally. In parallel, groups of positive and negative control mice received pertussis toxin and buffer, respectively. The circulating white blood cells of the animals were monitored for 28 days. Mice immunized with glutaraldehyde toxoid preparations did not develop a lymphocytosis during the observation period, whereas mice immunized with an experimental formalin pertussis toxoid vaccine exhibited a high lymphocytosis six days after vaccine administration, demonstrating, in this model, a reversion of the toxoid. The nude mouse model thus appears to reveal the in-vivo reversion of pertussis toxoids and could be included in the quality control panel for the assessment of the safety of acellular pertussis vaccine.