Investigation of different group A immunoassays following one dose of meningococcal group A conjugate vaccine or A/C polysaccharide vaccine in adults.

A double-blind, randomized, controlled phase I study to assess the safety, immunogenicity, and antibody persistence of a new group A conjugate vaccine (PsA-TT) in volunteers aged 18 to 35 years was previously performed. Subjects received one dose of either the PsA-TT conjugate vaccine, meningococcal A/C polysaccharide vaccine (PsA/C), or tetanus toxoid vaccine. The conjugate vaccine was shown to be safe and immunogenic as demonstrated by a standardized group A-specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and by a serum bactericidal antibody (SBA) assay using rabbit complement (rSBA). This report details further analysis of the sera using four additional immunologic assays to investigate the relationship between the different immunoassays. The immunoassays used were an SBA assay that used human complement (hSBA), a group A-specific IgG multiplexed bead assay, and two opsonophagocytic antibody (OPA) assays which used two different methodologies. For each vaccine group, geometric mean concentrations or geometric mean titers were determined for all assays before and 4, 24, and 48 weeks after vaccination. Pearson's correlation coefficients were used to assess the relationship between the six assays using data from all available visits. An excellent correlation was observed between the group A-specific IgG concentrations obtained by ELISA and those obtained by the multiplexed bead assay. hSBA and rSBA titers correlated moderately, although proportions of subjects with putatively protective titers and those demonstrating a > or = 4-fold rise were similar. The two OPA methods correlated weakly and achieved only a low correlation with the other immunoassays. The correlation between hSBA and group A-specific IgG was higher for the PsA-TT group than for the PsA/C group.

Decline of infant and child mortality rates in rural Senegal over a 37-year period (1963-1999).

BACKGROUND: In spite of an improving trend, childhood mortality in rural sub-Saharan Africa remains high and has recently risen in some countries. The factors associated with the long-term decline in childhood mortality are poorly known, due to a lack of data. METHODS: A Senegalese rural population has been under demographic surveillance since 1963. Infant and under-5 mortality rates were calculated for different periods to generate a long-term trend in childhood mortality. Evolution of age and seasonal patterns of mortality were observed. FINDINGS: During the observation period (1963-1999), infant and under-5 mortality rates decreased from 223 per thousand to 80 per thousand and 485 per thousand to 213 per thousand , respectively, with a constant annual rate of decline in the probability of dying since the 1960s (-3.7% and -3.1%, respectively). The age pattern of the under-5 mortality changed drastically, with a large decrease in the death rate between 6 and 24 months of age (from 321 per thousand to 87 per thousand ). This change took place during the 1970s. The seasonal variation, characterized by a greater proportion of deaths during the rainy season, was very marked during the 1960s, then decreased during the 1980s but it has tended to increase again in the 1990s, particularly among children 1-4 years old. CONCLUSION: This study confirms the long-term trend of decrease in child mortality in rural West Africa. Historical knowledge on healthcare developments suggests that immunizations have contributed to the decrease and the change in the age pattern. The re-emergence of malaria seems the most likely explanation for the recent rebound in seasonal variation. Attention to immunization and malaria should continue to be a priority.

Randomised study of the possible adjuvant effect of BCG vaccine on the immunogenicity of diphtheria-tetanus-acellular pertussis vaccine in Senegalese infants.

Following a study in Senegal (1990-1995) in which the relative efficacy of a diphtheria-tetanus-acellular pertussis vaccine (DTaP) was compared with that of a diphtheria-tetanus-whole-cell pertussis vaccine in children given a simultaneous injection of Bacille Calmette-Guérin (BCG) vaccine, this subsequent study was conducted to evaluate the possible adjuvant effect of the BCG vaccine on acellular pertussis vaccine components. A second objective was to compare the immunogenicity of these components when administered in accordance with a 2-4-6-month (spaced) schedule or an accelerated 2-3-4-month schedule. In all, 390 healthy Senegalese infants were randomly divided into three groups of 130 infants. Antibodies to acellular pertussis components were measured in serum samples obtained within 2 days of the first DTaP dose and 1 month after the third dose. BCG vaccine, given simultaneously with the DTaP vaccine, did not influence the immunogenicity of the acellular pertussis vaccine components when compared with separate administration of the two vaccines. Infants immunised according to a 2-4-6-month schedule had a significantly higher immune response than those immunised according to a 2-3-4-month schedule with respect to the response to pertussis toxoid assessed by seroneutralisation on Chinese hamster ovary cells (P<0.0001). These results suggest that BCG and DTaP vaccines can be given simultaneously without interference or enhancement and that more optimal immunogenicity is achieved with an extended than with an accelerated schedule.

Impact of chloroquine resistance on malaria mortality.

Over 12 years, from 1984 to 1995, we conducted a prospective study of overall and malaria specific mortality among three rural populations in the Sahel, savanna and forest areas of Senegal. The emergence of chloroquine resistance has been associated with a dramatic increase in malaria mortality in each of the studied populations. After the emergence of chloroquine resistance, the risk of malaria death among children 0-9 years old in the three populations was multiplied by 2.1, 2.5 and 5.5, respectively. This is the first study to document malaria mortality at the community level in Africa before and after the emergence of chloroquine resistance. Findings suggest that the spread of chloroquine resistance has had a dramatic impact on the level of malaria mortality in most epidemiological contexts in tropical Africa.

Evaluation of an immunoglobulin G enzyme-linked immunosorbent assay for pertussis toxin and filamentous hemagglutinin in diagnosis of pertussis in Senegal.

The enzyme-linked immunosorbent assay is widely employed for the serological diagnosis of pertussis. It is generally concluded that a significant increase in specific immunoglobulin G (IgG) or IgA against the pertussis toxin (PT) or against filamentous hemagglutinin (FHA) in paired sera correlates with Bordetella pertussis infection. However, this type of diagnosis of pertussis has mainly been applied to unvaccinated children, with timely sampling of acute- and convalescent-phase sera. In current practice and in epidemiological studies, such criteria are not always fulfilled. The aim of this study was to analyze the significance of decreases in IgG antibody titers against PT and FHA between paired sera observed in suspected cases of pertussis infection. Serological results from paired sera were available for 460 children experiencing at least 8 days of cough. An anti-PT IgG decrease was observed in 25% of the children, more frequently than the anti-FHA IgG decrease. Fourteen percent of the serologic decreases were observed in children with culture-confirmed infection, and 59% of the decreases were observed in children with confirmation criteria according to World Health Organization recommendations. Most of the decreases were observed when serum samples were collected according to a standard recommended schedule. Serologic decreases were observed more frequently among vaccinated children than among unvaccinated children. This difference, which was highly significant (P < 0.00001), was explained by the different kinetics of the antibody responses between vaccinated and unvaccinated children. The importance of the antibody response for the evaluation of vaccine efficacy, namely a bias toward higher absolute vaccine efficacy when this response is not taken into account, is discussed. This study supports an earlier recommendation that a significant decrease in PT or FHA should be added to the diagnostic criteria for pertussis.

A randomized double-blind trial comparing a two-component acellular to a whole-cell pertussis vaccine in Senegal.

A randomized, double-blind trial comparing a diphtheria-tetanus-acellular pertussis vaccine (DTaP) (pertussis toxoid and filamentous hemagglutinin) with a whole-cell vaccine (DTwP) was conducted. A case-contact study was nested in the trial to estimate absolute efficacy. From 1990 through 1994, 4181 children were randomized to receive one of the vaccines at 2, 4, and 6 months. Severe adverse events were monitored weekly during two visits after vaccination. Fewer serious adverse events were observed after DTaP. Surveillance for cough illnesses persisting more than 7 days, in children under 15 years of age, was made by weekly home visits. Examining physicians, blind to vaccination status, took samples for culture and serologic testing. Pertussis was defined as 21 or more days of cough confirmed by culture, serology, or contact with a culture-confirmed person. Beginning 28 days after the third vaccine dose, the overall ratio of pertussis incidence in the DTaP group relative to the DTwP group (RRac/wc) was 1.54 (95% CI, 1.23-1.93). In children younger than 18 months of age, RRac/wc was 1.16 (95% CI, 0.77-1.73) and 1.76 (95% CI, 1.33-2.33) in children older than 18 months, which suggests a shorter duration of protection with the acellular vaccine (P = 0.090). Absolute efficacy estimates derived from the case-contact study confirmed the lower protection afforded by the acellular vaccine compared with the whole-cell vaccine: 31% (95% CI, 7-49) versus 55% against the protocol case definition, and 85% (95% CI, 66-93) versus 96% for the more severe WHO case definition. Although vaccination with DTaP provided a lower degree of protection than the highly effective DTwP, this difference was less prominent before 18 months of age, the customary age for a fourth dose. The safer DTaP vaccine may prove a valuable substitute for whole-cell vaccines when used in a schedule that includes a booster-dose.

The Senegal pertussis trial: safety and surveillance of adverse reactions.

In the Senegal pertussis trial, common adverse reactions were actively monitored during the pilot phase II study, while the frequency of severe adverse reactions was monitored as a secondary objective within the phase III efficacy trial. Since the trial was conducted in Niakhar, an area in rural West Africa under intensive surveillance, the safety monitoring during the study was incorporated within the general surveillance system. This was a two-step procedure: detection of a potential reaction by a field worker, followed by confirmation report by a physician. The frequency of severe reactions was low among both pertussis vaccine groups, receiving either the two-component acellular vaccine or the whole-cell vaccine currently used in the Senegal Expanded Programme on immunisation. Among severe reactions, only persistent crying was found to be at a significantly higher rate in the whole-cell group. Common adverse reactions were more frequent in the whole-cell group.

Epinephrine absorption following endotracheal administration: effects of hypoxia-induced low pulmonary blood flow.

To investigate the effects of hypoxia-induced decreased pulmonary blood flow on the trans-pulmonary absorption of epinephrine, we measured pulmonary blood flow and arterial plasma tritium counts per minute following endotracheal [3H]epinephrine administration in six chronically instrumented newborn lambs. The lambs were ventilated alternately with room air and with an hypoxic gas mixture sufficient to decrease pulmonary blood flow to approximately 50% of baseline values. Using this model, we found that hypoxia-induced low pulmonary blood flow did not lead to lower concentrations of epinephrine following endotracheal administration, but rather higher concentrations (P < 0.03). In all six lambs, counts per minute of tritium were higher following administration during low pulmonary blood flow. There was a negative correlation between pulmonary blood flow and arterial plasma tritium counts per minute (r = -0.64, P < 0.03). We conclude that trans-pulmonary absorption of epinephrine is not decreased during times of hypoxia-induced low pulmonary blood flow. These data lend support to the clinical practice of intratracheal epinephrine administration during neonatal resuscitation.

Metabolic acidemia with hypoxia attenuates the hemodynamic responses to epinephrine during resuscitation in lambs.

OBJECTIVE: To examine the effects of metabolic acidemia and hypoxia on the hemodynamic responses to epinephrine in an intact neonatal animal model. DESIGN: Multi-experiment, randomized, controlled trial. SETTING: Animal research laboratory of a university hospital. SUBJECTS: Sixteen lambs, ranging in age from 2 to 14 days. INTERVENTIONS: The lambs were chronically catheterized; the ductus arteriosus was ligated; and a pulmonary arterial flow probe was inserted to measure cardiac output, blood pressure (BP), and heart rate. In the first protocol, hemodynamic responses to epinephrine during pure metabolic acidemia or metabolic alkalosis were studied in eight lambs. Each lamb was studied on four different days at a different arterial pH: 6.9, 7.1, 7.4, and 7.6. Ventilation was controlled to maintain PCO2 at 35 to 45 torr (4.66 to 5.99 kPa). Acidemia was induced by the infusion of lactic acid and alkalosis by the infusion of sodium bicarbonate. When the appropriate arterial pH was achieved, 10 micrograms/kg of epinephrine was administered intravenously. In a second protocol, hemodynamic responses to epinephrine during metabolic acidemia or alkalosis plus hypoxia were studied in eight lambs. When the appropriate arterial pH was achieved, hypoxia was induced until cardiac output decreased to 40% of baseline. Epinephrine bolus was given, and after 90 secs, the lambs were resuscitated with oxygen. MEASUREMENTS AND MAIN RESULTS: Epinephrine administered during uncompromised hemodynamics led to hypertension, bradycardia, and decreased cardiac output that were unaffected by arterial pH values between 6.9 and 7.6. Acidemia with hypoxia compromised hemodynamics with decreases in heart rate and cardiac output. Epinephrine administered during this compromised condition did not improve cardiac output, heart rate, or BP before resuscitation with oxygen at any arterial pH studied. Resuscitation with epinephrine and oxygen during hemodynamically compromised states led to increases in heart rate, BP, and cardiac output with significant attenuation of these hemodynamic responses during metabolic acidemia at pH values of 6.9 and 7.1. CONCLUSIONS: During the physiologic conditions associated with neonatal resuscitation, that is, hypoxia with a compromised hemodynamic state, metabolic acidemia significantly attenuates the hemodynamic responses to resuscitation with epinephrine and oxygen. Correction of metabolic acidosis may be warranted in newborn resuscitation.

Effects of graded doses of epinephrine during asphxia-induced bradycardia in newborn lambs.

To study the hemodynamic effects of graded doses of epinephrine (EPI) in a newborn animal model of hemodynamically significant bradycardia, we performed the following study. Ten newborn lambs were chronically instrumented with catheters and flow transducers so that systemic, pulmonary arterial, left atrial and right atrial pressures as well as heart rate, cardiac output and left carotid artery flow could be monitored. During each of five asphyxia induced bradycardia episodes, with cardiac output depressed to approximately 30% of baseline, lambs were given either 0, 1, 10, 50, or 100 micrograms of EPI in a randomized sequence. After 30 s, the lambs were resuscitated with room air ventilation while hemodynamic parameters were monitored. During asphyxia and prior to EPI administration, all hemodynamic parameters were similar. In addition, for the first 30 s following EPI administration, hemodynamic parameters continued to deteriorate in a manner that was not influenced by the dose of EPI administered. During the resuscitation period with resumption of ventilation, systemic blood pressure and coronary perfusion pressure rose higher following 50 and 100 micrograms/kg of EPI than after the smaller doses. Heart rate was highest following the 100 micrograms/kg dose. Stroke volume and cardiac output, however, appeared to be blunted by the 100 micrograms/kg dose of EPI with no differences in carotid flow noted by dose of EPI administered. It appears that doses of EPI greater than 10 micrograms/kg, the dose currently recommended by the American Heart Association, may be beneficial as an adjunct in treatment of hemodynamically significant bradycardia. However, doses as high as 100 micrograms/kg may blunt cardiac output and stroke volume and should be used with caution.

Immunogenicity of Haemophilus influenzae type b conjugate vaccine in allogeneic bone marrow recipients.

A randomized study was conducted in 40 allogeneic marrow recipients to compare the immunogenicity of two Haemophilus influenzae type b (Hib) vaccines (either the Hib capsular polysaccharide [Hib-CPS] or tetanus toxoid-conjugated Hib-CPS [Hib-CPS-T]). A second injection consisted of Hib-CPS-T. Before immunization, 3 patients had serum antibody levels > 1 microgram/mL. After the first injection, the response was better after Hib-CPS-T than after Hib-CPS but lower than in normal subjects; a number of patients lacked any IgG antibody response, especially after Hib-CPS. Of patients who received two injections of Hib-CPS-T, 85% achieved an antibody concentration > or = 1 microgram/mL. Hib-CPS-T induced a response in IgG2-deficient patients whereas Hib-CPS alone did not. IgG antibodies predominantly belonged to the IgG1 subclass. The antibody response was better in patients immunized late after graft. This study shows that Hib-CPS-T is more immunogenic than Hib-CPS in marrow recipients.