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.

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The shoot demography and rhizome growth of Syringodium filiforme Kutz. and Halodule wrightii Aschers. were studied, based on plant dating techniques, to account for their role as pioneer in the succession sequence of Canbbean seagrasses. Results demonstrated that these species are able to develop dense meadows, supporting biomasses in excess of 500 g DW m" They produced more than 2000 g DW m -2 yr-' due to their high leaf (5.0 to 8 5 yr.') and rhizome (2 0 to 3.3 yr-') turnover. Rhizome growth and branch~ng rates were very high, allowing these seagrasses to rapidly occupy the space they colonise. The rapid rhizome turnover involved, however, a high shoot mortality rate and low 11fe expectancy (average shoot life expectancy 100 to 180 d). This implies that, while these pioneer species are able to rapidly occupy the space they colonise, their established shoots cannot occupy that space for a s long a s the more longlived species Thalassia testudinum. We suggest, therefore. that the role of seagrass species a s pioneer or climax species is independent of their capacity to support dense, productive populations, and is closely related to shoot longevity and rhizome turnover.

Polysaccharide-protein conjugates as vaccines have proven to be very effective in preventing Haemophilus influenzae type b infections in industrialized countries. However, cost-effective technologies need to be developed for increasing the availability of anti-H. influenzae type b vaccines in countries from the developing world. Consequently, vaccine production with partially synthetic antigens is a desirable goal for many reasons. They may be rigidly controlled for purity and effectiveness while at the same time being cheap enough that they may be made universally available. We describe here the antigenicity and immunogenicity of several H. influenzae type b synthetic oligosaccharide-protein conjugates in laboratory animals. The serum of H. influenzae type b-immunized animals recognized our synthetic H. influenzae type b antigens to the same extent as the native bacterial capsular polysaccharide. Compared to the anti-H. influenzae type b vaccine employed, these synthetic versions induced similar antibody response patterns in terms of titer, specificity, and functional capacity. The further development of synthetic vaccines will meet urgent needs in the less prosperous parts of the world and remains our major goal.The advent of conjugate vaccines against Haemophilus influenzae type b-associated diseases has opened a new era in vaccinology (15). These vaccines, which demonstrate excellent immunogenicity, safety, and efficacy in infants, have been obtained by conjugating the capsular polysaccharide polyribosylribitolphosphate from H. influenzae type b to carrier proteins (1,3,8,12). They have been particularly useful in preventing infection with H. influenzae type b in high-risk infant populations. In fact, the almost complete disappearance of H. influenzae type b disease in the developed world together with the corresponding reduction in H. influenzae type b pharyngeal carriage testify to the usefulness of these conjugate vaccines.However, it is extremely difficult to accomplish the progress brought by these commercial vaccines in many poor countries because their high cost reduces both their acquisition and their availability. More than 118 million children are without protection, and only Ϸ2% of cases of H. influenzae type b disease are actually prevented worldwide (15).Given this, H. influenzae type b vaccination in developing countries is urgent but limited by cost and the availability of vaccines. The availability of vaccines depends on producing them with improved technologies and making them affordable to even the poorest societies. In 1989, we embarked on a project to produce a new conjugate anti-H. influenzae type b vaccine from a fully synthetic fragment of the capsular polysaccharide. We have now successfully completed the production, preclinical, and clinical development stages for this new vaccine (17). Here we describe the main preclinical studies that have shown the potential of this new vaccine. Several synthetic H. influenzae type b oligosaccharide-protein conjugates were prepared and their immun...

Since 1989, we have been involved in the development of a vaccine against Haemophilus influenzae type b. The new vaccine is based on the conjugation of synthetic oligosaccharides to tetanus toxoid. Our main goals have been (i) to verify the feasibility of using the synthetic antigen and (ii) to search for new production alternatives for this important infant vaccine. Overall, eight trials have already been conducted with adults, children (4 to 5 years old), and infants. We have described herein the details from the first two phase I clinical trials conducted with human adult volunteers under double blind, randomized conditions. The participants each received a single intramuscular injection to evaluate safety and initial immunogenicity. We have found an excellent safety profile and an antibody response similar to the one observed for the control vaccine.