Glycoconjugate vaccines provide effective prophylaxis against bacterial infections. To date, however, no commercial vaccine has been available in which the key carbohydrate antigens are produced synthetically. We describe the large-scale synthesis, pharmaceutical development, and clinical evaluation of a conjugate vaccine composed of a synthetic capsular polysaccharide antigen of Haemophilus influenzae type b (Hib). The vaccine was evaluated in clinical trials in Cuba and showed long-term protective antibody titers that compared favorably to licensed products prepared with the Hib polysaccharide extracted from bacteria. This demonstrates that access to synthetic complex carbohydrate-based vaccines is feasible and provides a basis for further development of similar approaches for other human pathogens.

SUMMARY Total protein and deoxyribonucleic acid (DNA) were measured in small-intestinal washings from rats with normal and high rates of DNA (or cell) loss. There was a significant relationship between the loss of these two substances. Preparations of isolated viable epithelial cells contained much less protein in relation to DNA than did the intestinal washings. It was calculated that only 8 to 15 % of the protein lost by washing the rat small intestine arose from the intracellular protein of exfoliated epithelial cells. The rest was derived from extracellular sources.Protein and DNA loss from small-bowel mucosa was measured in six patients. The ratio of protein to DNA was similar to that found in the rats. The mean protein loss from 5 cm of human upper small intestine was 956 ,ug per min or 1.4 g per 24 hours. By calculation, total protein loss from the whole small intestine of man was about 84 g per day, about 10 g coming from within exfoliated cells and the rest arising from extracellular sources. The normal intestine must reabsorb most of this material.The small bowel handles much more protein than the quantity taken by mouth. For instance, in the dog and rat, Nasset and Ju (1961) found that ingested protein was swamped four-or fivefold by endogenous protein. In man it has been estimated that some 45-140 grams of protein are lost into the gut per 24 hours (Spencer, 1960;Wilson, 1962). This large quantity of protein is derived in part from gastrointestinal secretion from saliva, stomach, pancreas, and bile (Spencer, 1960;Nasset, 1964). It has been suggested that exfoliated epithelial cells may be another significant source of endogenous protein (Nasset, 1964;Jefferies, Holman, and Sleisenger, 1962). Wilson (1962) claimed that small intestinal cells in man may account for 25 g of protein per 24 hours and Nasset (1965) calculated that the amount could be as much as 90 g.The small-intestinal mucosa is dynamically the most active epithelial surface in the body, in man losing some 20-50 million cells per minute (Croft, Loehry, Taylor, and Cole, 1968b nucleic acid (DNA) loss (as an estimate of cell loss), and protein loss. To assess the contribution of intracellular protein intestinal epithelial cells were isolated and theirDNA andproteincontentwas measured. Materials and Methods BIOCHEMICAL METHODSDeoxyribonucleic acid was measured by a modified diphenylamine reaction and the values were expressed in ng'atoms DNA-P (Croft and Lubran, 1965 (Loehry, Croft, Singh, and Creamer. 1969). Male albino rats weighing 350-450 g were starved for 24 hours and then anaesthetized. Two pieces of polyvinylchloride tubing were tied respectively into the jejunum at the duodenojejunal flexure and at the terminal ileum. Normal saline was infused via the jejunal tube at measured rates for two to four hours. Fluid was collected from the ileal tube. The rats were killed at the end of the experi-179 on 6 June 2019 by guest. Protected by copyright.

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