William E. Woodward

Immunization of Man against Falciparum and Vivax Malaria by Use of Attenuated Sporozoites

With strict adherence to ethical guidelines, a volunteer was immunized against sporozoites of Plasmodium falciparum and P. vivax, the antigen consisting of attenuated sporozoites of each species inoculated through bites of mosquitoes X-irradiated at a minimum dosage of 15,000 rads. On one occasion this dosage did not render all P. vivax sporozoites noninfective. Species specificity of antigen and antibody was demonstrated, but within each species a wide geographical diversity of strains proved interchangeably antigenic and susceptible to the antibody. Once immunized, the volunteer was protected for not more than 3 months and 6 months, respectively, from infective P. falciparum and P. vivax sporozoites, the duration of protection being reflected by a positive species-specific circumsporozoite reaction. Studies in this volunteer, and in two others immunized with P. falciparum sporozoites, did not reveal any increase in serum levels of immunoglobulins G and M.

The role of endotoxin during typhoid fever and tularemia in man: IV. The integrity of the endotoxin tolerance mechanisms during infection

Volunteers infected with Salmonella typhosa develop a remarkable hyperreactivity to the pyrogenic and subjective toxic activities of homologous (S. typhos) and heterologous (Pseudomonas) endotoxins. The present studies quantitate this augmented reactivity and demonstrate by three differing approaches that significant tolerance to these endotoxins can be readily induced within the framework of the hyperreactive state. Thus, (a) tolerance induced before illness by repeated daily intravenous injections of the endotoxins remained demonstrable during overt illness, (b) daily intravenous injections of the endotoxins begun during overt illness evoked progressively increasing tolerance, and (c) continuous intravenous infusions of S. typhosa endotoxin during illness rapidly induced a pyrogenic refractory state. Despite unequivocal activation of the endotoxin tolerance mechanisms by any of the above methods, the febrile and toxic course of typhoid fever proceeded unabated. Similarly, in other volunteers with Pasteurella tularensis infection, continuous intravenous infusions of S. typhosa endotoxin evoked initial hyperreactive febrile and subjective toxic responses followed by rapid appearance of a pyrogenic refractory state without modification of the underlying clinical illness. These observations suggest that circulating endotoxin plays no major role in pathogenesis of the sustained fever and toxemia during typhoid fever and tularemia in man. The mechanisms responsible for the systemic hyperreactivity to endotoxin during typhoid fever and tularemia were further investigated. Low grade endotoxemia, nonspecific effects of tissue injury, impaired ability of the reticuloendothelial system to clear circulating endotoxin, and production of cytophilic antibodies capable of sensitizing leukocytes to endotoxin did not appear responsible. Inflammatory reactions to intradermal S. typhosa endotoxin increased significantly during typhoid fever. However, since no such dermal hyperreactivity developed to Pseudomonas endotoxin during typhoid fever nor to S. typhosa endotoxin during tularemia, the systemic hyperreactivity to bacterial endotoxins during typhoid fever and tularemia could not presently be ascribed to enhanced levels of acquired hypersensitivity.

Regimen Simplification to Atazanavir-Ritonavir Alone as Maintenance Antiretroviral Therapy: Final 48-Week Clinical and Virologic Outcomes

BACKGROUND Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/RTV) alone is attractive because of nucleoside reverse-transcriptase inhibitor (NRTI)-sparing benefits, low pill burden, once-daily dosage, and safety. METHODS Subjects with virologic suppression after > or = 48 weeks of initial antiretroviral therapy with 2 NRTIs and a protease inhibitor (PI) were enrolled. Subjects switched to ATV/RTV at entry and discontinued NRTIs after 6 weeks. The primary end point was time to virologic failure (confirmed HIV-1 RNA level > or = 200 copies/mL). Drug resistance at virologic failure was evaluated by standard genotyping and single-genome sequencing (SGS). Residual viremia (1.1-49 copies/mL) was measured by single-copy assay. RESULTS Thirty-four subjects simplified to ATV/RTV alone, of whom 30 (88%) did not experience virologic failure by 48 weeks after simplification. Residual viremia did not change significantly after NRTI discontinuation among those without virologic failure but did increase 4-12 weeks before confirmed virologic failure. No major PI-resistance mutations were identified at virologic failure by standard genotyping or SGS. CONCLUSIONS In this pilot study, simplified maintenance therapy with ATV/RTV alone maintained viral suppression in most subjects through 48 weeks. PI resistance was not detected among subjects experiencing virologic failure. Larger, randomized trials are warranted to further define the efficacy and safety of this strategy.

Volunteer studies of typhoid fever and vaccines.

A series of studies evaluated the efficacy of three categories of typhoid vaccines: killed organisms given parenterally and orally and living attenuated mutants given orally. Vaccinees and unvaccinated controls were challenged with a single strain of virulent Salmonella typhi. Control individuals with prior military service (i.e. mandatory parenteral immunization) were significantly protected compared to non-veterans. Clinical protection of vaccinees was greatest (87%) following oral immunization with a mutant strain lacking epimerase.

Doctor T. E. Woodward's Legacy: From Typhus to Typhoid Fever

Dr. Theodore E. Woodward was one of the early giants of infectious diseases research who set the groundwork for the field. He was the first to evaluate vaccines against typhus, employing volunteers to test the effectiveness of the vaccines. This led to the evaluation of chloramphenicol for the treatment of rickettsial diseases and typhoid fever. Subsequently, he was influential in establishing a unique volunteer unit in Maryland in which a wide range of vaccines were evaluated.

Biohydrogenation of cholesterol as an index of bacterial 7α-dehydroxylase activity

Fecal steroid compositions of 82 human subjects of various ages and diets and gastrointestinal status were examined by gas liquid chromatography. Progressive increases in bacterial activities on both bile acids and neutral sterols were observed with the advance of age in infants and children. The patterns in the 4-year-olds approached those observed in adults. Bacterial activites on fecal steroids were found to be decreased in adult subjects with acute shigellosis and in those challenged by castor oil. In contrast, no significant changes in fecal steroid profiles were observed in the subjects with travellers diarrhea assoicated with toxigenicEscherichia coli. The effects of diarrhea on fecal steroids of infants under 11/2 years were less consistent than those of adults. However, a close relationship was observed between the degree of 7α-dehydroxylation of cholic acid (expressed as the ratio of deoxycholic to the sum of deoxycholic and cholic acids) and the percentage of cholesterol in the feces (r= 0.921, p<0.001). The correlation between the production of lithocholic acid and the percentage cholesterol was also good (r=−0.739, p<0.001). Analysis of neutral steroids may be a good index of intraluminal bile acid metabolism.