Joe P. Bryan

Clinical Manifestations of Plasmodium falciparum Malaria Experimentally Induced by Mosquito Challenge

To determine the characteristics of clinical illness accompanying Plasmodium falciparum infection induced by controlled exposure to infected mosquitoes, records of 118 volunteers participating in studies conducted between 1985 and 1992 were reviewed. One hundred fourteen volunteers (97%) reported at least one symptom attributable to malaria, with fatigue, myalgias or arthralgias, headache, and chills most commonly reported. The median duration of symptoms was 3 days. Fever was recorded in 61% of volunteers; 4 volunteers had temperatures >40 degrees C. Neutropenia and thrombocytopenia were present in 9% and 12% of volunteers, respectively. Despite counts as low as 658/microL (neutrophils) or 73,000/microL (platelets), no secondary infectious or hemorrhagic complications occurred. In all cases, volunteers recovered completely and laboratory values returned to baseline after specific antimalarial therapy. Recrudescence did not occur in any volunteer. In this model, mosquito inoculation of P. falciparum is a reliable, safe, and well-tolerated method of experimental challenge.

Randomized, cross-over, controlled comparison of two inactivated hepatitis A vaccines.

The immunogenicity, tolerability and interchangeability of two hepatitis A vaccines, Vaqta (Merck and Co.) and Havrix (SmithKline) were studied in a randomized, crossover, controlled clinical trial. Vaccine was administered to 201 volunteers at 0 and 26 weeks in one of four vaccine regimens: Havrix-Havrix; Havrix-Vaqta; Vaqta-Havrix or Vaqta-Vaqta. Seroconversion rates (>/=10 mIU/ml) for those whose first dose was Vaqta or Havrix, respectively, were: 41/96 (43%) versus 30/95 (32%) (P=0.15) at 2 weeks and 91/98 (93%) versus 84/97 (87%) (P=0.43) at 4 weeks, and 100% at 26 weeks. Geometric mean concentrations (GMC) of total antibody to hepatitis A virus (anti-HAV) for Vaqta and Havrix were 189 and 114 mIU/ml (P=0.011) at 4 weeks and 234 and 136 mIU/ml (P<0.001) at 26 weeks. At 30 weeks, the GMC after two doses of Havrix was 2612 mIU/ml compared with 5497 after two doses of Vaqta (P<0.001). The GMC in the Havrix-Vaqta group was 5672 mIU/ml compared with 3077 mIU/ml in the Vaqta-Havrix group (P<0.001). Less than half of vaccine recipients reported tenderness or pain. In this study, seroconversion rates of the two vaccines were similar. Vaqta produces significantly higher anti-HAV antibody than Havrix. Crossover immunization is well tolerated and results in high antibody concentrations, especially when Vaqta is the booster dose. The significance of higher anti-HAV antibody concentrations in terms of long-term protection is unknown.

Detection of Immunoglobulin M Antibodies to Hepatitis E Virus by Class Capture Enzyme Immunoassay

ABSTRACT The measurement of antibodies to hepatitis E virus (anti-HEV) has been essential for understanding the epidemiology of hepatitis E. Studies to determine the prevalence of HEV infections require a reliable serologic assay that is sensitive and specific. It is also important to distinguish the acute from the convalescent phase of an infection; this usually requires the detection of the immunoglobulin M (IgM) class of antibody. Few enzyme immunoassays (EIAs) that measure IgM anti-HEV have been described, and most have utilized the sandwich method. The present study describes an EIA that detects IgM anti-HEV by antibody class capture methodology. The assay was validated by using serum and/or plasma panels from experimentally infected nonhuman primates. It was used to demonstrate an anamnestic response and the reappearance of IgM anti-HEV in a chimpanzee experimentally challenged with HEV at two different times 45 months apart. The class capture method was more sensitive than the sandwich EIA when used to test clinical samples from two hepatitis E epidemics in Pakistan; it also had the advantage of distinguishing IgM anti-HEV in the presence of high titers of IgG anti-HEV.

Persistence of antibody to hepatitis B surface antigen after low-dose, intradermal hepatitis B immunization and response to a booster dose

To determine the duration of antibody after low-dose, intradermal (i.d.), plasma-derived hepatitis B vaccination and the response to a booster dose, we studied two classes of medical students who were immunized with 2 micrograms doses i.d. In one class, 73/88 (85%) who had been immunized by skilled personnel at 0, 1 and 6 months, had protective concentrations (greater than or equal to 10 mIU ml-1) of anti-HBs at 20 months after the first dose. Twelve (92%) out of 13 students who received only two doses at 0 and 1 months also had protective concentrations at month 20. At month 27, 11/16 (69%) with antibody less than or equal to 10 mIU ml-1 responded to a fourth dose of 2 micrograms i.d. with protective concentrations of anti-HBs. In the second class, after three doses of vaccine at 0, 1, and 6 months, protective concentrations of anti-HBs were present in 90/93 (97%) at 14 months and in 71/80 (89%) at 25 months. In those who received only two doses, protective concentrations were found in 24/31 (74%) at 14 months and 9/16 (56%) at 25 months. After a booster dose of 2 micrograms i.d. at month 25, anti-HBs concentrations rose from a geometric mean of 78 to 1198 mIU ml-1 in 60 subjects previously immunized with three doses and from 18 to 1054 mIU ml-1 in 16 students previously immunized with only two doses. Overall, 73/76 (96%) of students in the second group had protective concentrations of antibody after the booster dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized comparison of 5 and 10 μg doses of two recombinant hepatitis B vaccines

The high cost of hepatitis B vaccines remains an obstacle to their use. Since the recommended adult dose of Recombivax HB (MSD) is 10 μg and that of Engerix B (SKB) is 20 μg, we sought to determine if 10 μg doses of each vaccine are equally immunogenic. Further, since 5 μg doses of Recombivax are routinely used in those ≤ 29 years of age in the US military, we sought to compare this dose with 5 μg doses of Engerix B. Lower doses of Engerix would result in vaccine cost savings. Methods: members of the Belize Defence Force who were ≥ 18 years of age (median 24) without detectable anti-HBc were randomly assigned to receive Recombivax, 5 or 10 μg, or Engerix, 5 or 10 μg IM at 0, 1, and 6 months. Randomization was weighted toward Engerix. Results: after 3 doses, geometric mean concentrations (GMC) of anti-HBs were highest among those receiving Recombivax 10 μg (n=22) or 5 μg (n=46) with GMC anti-HBs of 744 and 570 mIU ml−1, respectively. Similar propertions in the two groups developed ≥ 10 mIU ml−1 anti-HBs (100 and 98%). Among the 91 people who received Engerix 10 μg, the GMC anti-HBs was 325 mIU ml−1 and 91% developed ≥ 10 mIU ml−1. The 87 people who received Engerix 5 μg had the lowest GMC, 177 mIU ml−1 (p 0.05 compared with other regimens). The proportion attaining ≥ 100 mIU ml−1 was lower in the 5 μg Engerix group (63%) compared with 80% in the 5 μg or 95% in the 10 μg Recombivax groups (p<0.05). Conclusions: Engerix administered in 5 μg doses is less immunogenic than 5 or 10 μg doses of Recombivax. In healthy populations < 30 years of age, regimens of half the recommended adult dose (5 μg of Recombivax or 10 μg of Engerix) are highly immunogenic and may result in significant vaccine cost savings.

A Dose Response Study of Hepatitis A Vaccine in Healthy Adults Who Are ≥30 Years Old and Weigh ≥77 kg

The dose response relationship of 25-, 50-, and 100-U doses of an inactivated hepatitis A vaccine was examined in 358-seronegative volunteers in a 2-dose schedule. The 50-U and 100-U groups had statistically significantly higher seroconversion rates than the 25-U group at weeks 2, 4, 8, and 24. Seroconversion was statistically significantly greater for the 100-U compared with the 25- and 50-U doses 2 weeks after the first injection but was not significantly different by 4 weeks after the first injection in the 50- and 100-U dose groups. After 2 injections, all subjects in all groups seroconverted. The vaccine was well tolerated at all dosage levels.

Hepatitis B vaccine booster dose: Low-dose recombinant hepatitis B vaccines as a booster dose

BACKGROUND The timing and best regimen for a booster dose of hepatitis B vaccine have not been determined. METHODS Two studies were conducted to determine the response to a booster dose of 5 micrograms recombinant hepatitis B vaccine. In the first study, a 5 micrograms (0.5 ml) dose of Recombivax HB was administered intramuscularly 38 months after the initial dose to 71 volunteers. In a second study, we offered a 5 micrograms dose recombinant hepatitis B vaccine, either Recombivax HB (0.5 ml) or Engerix B (0.25 ml), to students who had previously been immunized with three doses of vaccine. RESULTS In the first study, among the 44 persons for whom postbooster sera were available, the geometric mean concentration of anti-hepatitis B surface antigens increased from 42 to 2090 mIU/ml after the 5 micrograms (0.5 ml) dose of Recombivax. In the second study, after a 5 micrograms (0.5 ml) dose of Recombivax, the geometric mean concentration increased from 43 to 990 mIU/ml (n = 48), and in the group that received a 5 micrograms (0.25 ml) dose of Engerix B, the concentration increased from 83 to 2337 mIU/ml (n = 45) (p = 0.18 for postdose concentrations). CONCLUSION A 5 micrograms dose of recombinant vaccine results in an excellent booster response at a cost one fourth to one half that of a full 1 ml dose of vaccine.

Population Density, Poor Sanitation, and Enteric Infections in Nueva Santa Rosa, Guatemala.

Poor sanitation could pose greater risk for enteric pathogen transmission at higher human population densities because of greater potential for pathogens to infect new hosts through environmentally mediated and person-to-person transmission. We hypothesized that incidence and prevalence of diarrhea, enteric protozoans, and soil-transmitted helminth infections would be higher in high-population-density areas compared with low-population-density areas, and that poor sanitation would pose greater risk for these enteric infections at high density compared with low density. We tested our hypotheses using 6 years of clinic-based diarrhea surveillance (2007–2013) including 4,360 geolocated diarrhea cases tested for 13 pathogens and a 2010 cross-sectional survey that measured environmental exposures from 204 households (920 people) and tested 701 stool specimens for enteric parasites. We found that population density was not a key determinant of enteric infection nor a strong effect modifier of risk posed by poor household sanitation in this setting.

Clinical characteristics of hospitalized infants with laboratory-confirmed pertussis in Guatemala

Background Pertussis is an important cause of hospitalization and death in infants too young to be vaccinated (aged <2 months). Limited data on infant pertussis have been reported from Central America. The aim of this study was to characterize acute respiratory illnesses (ARIs) attributable to Bordetella pertussis among infants enrolled in an ongoing surveillance study in Guatemala. Methods As part of a population-based surveillance study in Guatemala, infants aged <2 months who presented with ARI and required hospitalization were enrolled, and nasopharyngeal and oropharyngeal swab specimens were obtained. For this study, these specimens were tested for B pertussis using real-time polymerase chain reaction (PCR). Results Among 301 infants hospitalized with ARI, we found 11 with pertussis confirmed by PCR (pertussis-positive infants). Compared to pertussis-negative infants, pertussis-positive infants had a higher mean admission white blood cell count (20900 vs 12579 cells/μl, respectively; P = .024), absolute lymphocyte count (11517 vs 5591 cells/μl, respectively; P < .001), rate of admission to the intensive care unit (64% vs 35%, respectively; P = .054), and case fatality rate (18% vs 3%, respectively; P = .014). Ten of the 11 pertussis-positive infants had cough at presentation; the majority (80%) of them had a cough duration of <7 days, and only 1 had a cough duration of >14 days. Fever (temperature ≥ 38°C) was documented in nearly half (45%) of the pertussis-positive infants (range, 38.0-38.4°C). Conclusions In this study of infants <2 months of age hospitalized with ARI in Guatemala, pertussis-positive infants had a high rate of intensive care unit admission and a higher case fatality rate than pertussis-negative infants.

Determining gestational age and preterm birth in rural Guatemala: A comparison of methods

Background Preterm birth is the leading cause of death among children <5 years of age. Accurate determination of prematurity is necessary to provide appropriate neonatal care and guide preventive measures. To estimate the most accurate method to identify infants at risk for adverse outcomes, we assessed the validity of two widely available methods—last menstrual period (LMP) and the New Ballard (NB) neonatal assessment—against ultrasound in determining gestational age and preterm birth in highland Guatemala. Methods Pregnant women (n = 188) were recruited with a gestational age <20 weeks and followed until delivery. Ultrasound was performed by trained physicians and LMP was collected during recruitment. NB was performed on infants within 96 hours of birth by trained study nurses. LMP and NB accuracy at determining gestational age and identifying prematurity was assessed by comparing them to ultrasound. Results By ultrasound, infant mean gestational age at birth was 38.3 weeks (SD = 1.6) with 16% born at less than 37 gestation. LMP was more accurate than NB (mean difference of +0.13 weeks for LMP and +0.61 weeks for NB). However, LMP and NB estimates had low agreement with ultrasound-determined gestational age (Lin’s concordance<0.48 for both methods) and preterm birth (κ<0.29 for both methods). By LMP, 18% were judged premature compared with 6% by NB. LMP underestimated gestational age among women presenting later to prenatal care (0.18 weeks for each additional week). Gestational age for preterm infants was overestimated by nearly one week using LMP and nearly two weeks using NB. New Ballard neuromuscular measurements were more predictive of preterm birth than those measuring physical criteria. Conclusion In an indigenous population in highland Guatemala, LMP overestimated prematurity by 2% and NB underestimated prematurity by 10% compared with ultrasound estimates. New, simple and accurate methods are needed to identify preterm birth in resource-limited settings worldwide.