OVERCOMING SCIENTIFIC AND TECHNOLOGICAL BARRIERS

Pneumococcal Vaccines8

Until fairly recently, the state of the art for making vaccines against certain bacterial pathogens, including Hib and S. pneumoniae, relied on the use of capsular polysaccharides. When injected, a purified mixture of different polysaccharides—23 in one commercial pneumococcal product—induces immunity in adults. However, the immunity is of limited duration and produces no immunologic memory. In addition, the vaccine is poorly immunogenic in children. More important in the context of the CVI, polysaccharide vaccines are poorly immunogenic in young infants.

These and other considerations have prompted extensive work on glycoconjugate vaccines, in which the antigenic sugar molecule is linked, or conjugated, to a protein carrier. Generally, the resulting vaccine produces greater and longer-lasting antibody responses, which can be boosted by subsequent carriage or revaccination. When given to a young infant, such preparations can protect against infection. The current generation of Hib vaccines is made with conjugate technology; a number of research groups are working to produce a pneumococcal vaccine based on the same scientific principles (Table 1). In the case of pneumococcus, the research thrust of all of the major manufacturers is to make a product for developed-world markets and the prevention of otitis media, rather than the prevention of ARI in the developing world. However, a few firms are also constructing alternative formulations that include serotypes more prevalent in developing countries.

The particular challenge with the pneumococcal vaccines is that unlike Hib, which is a single-serotype preparation, these formulations must include multiple serotypes to be effective. Although they are administered together, each serotype-specific combination of polysaccharide and carrier protein amounts to a unique vaccine. Because the conjugation process is quite complicated, multiple-serotype conjugate vaccines are expected to be very expensive.

Indeed, cost currently poses a significant barrier to the use of these vaccines in the developing world. For example, it is difficult for a country to justify spending more to immunize its children with a conjugate Hib vaccine than it allocates for the purchase of all seven vaccines called for under the Expanded Programme on Immunization. 9 The rationale for buying Hib vaccine is similarly weakened if that cost is two or four times as much as is spent treating all cases of Hib disease in a given year. Improvements in the efficiency of the

8  

Unless otherwise noted, material in this section is based on presentations by John LaMontagne, Philip Russell, and David Briles.

9  

Otavio Oliva.



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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 OVERCOMING SCIENTIFIC AND TECHNOLOGICAL BARRIERS Pneumococcal Vaccines8 Until fairly recently, the state of the art for making vaccines against certain bacterial pathogens, including Hib and S. pneumoniae, relied on the use of capsular polysaccharides. When injected, a purified mixture of different polysaccharides—23 in one commercial pneumococcal product—induces immunity in adults. However, the immunity is of limited duration and produces no immunologic memory. In addition, the vaccine is poorly immunogenic in children. More important in the context of the CVI, polysaccharide vaccines are poorly immunogenic in young infants. These and other considerations have prompted extensive work on glycoconjugate vaccines, in which the antigenic sugar molecule is linked, or conjugated, to a protein carrier. Generally, the resulting vaccine produces greater and longer-lasting antibody responses, which can be boosted by subsequent carriage or revaccination. When given to a young infant, such preparations can protect against infection. The current generation of Hib vaccines is made with conjugate technology; a number of research groups are working to produce a pneumococcal vaccine based on the same scientific principles (Table 1). In the case of pneumococcus, the research thrust of all of the major manufacturers is to make a product for developed-world markets and the prevention of otitis media, rather than the prevention of ARI in the developing world. However, a few firms are also constructing alternative formulations that include serotypes more prevalent in developing countries. The particular challenge with the pneumococcal vaccines is that unlike Hib, which is a single-serotype preparation, these formulations must include multiple serotypes to be effective. Although they are administered together, each serotype-specific combination of polysaccharide and carrier protein amounts to a unique vaccine. Because the conjugation process is quite complicated, multiple-serotype conjugate vaccines are expected to be very expensive. Indeed, cost currently poses a significant barrier to the use of these vaccines in the developing world. For example, it is difficult for a country to justify spending more to immunize its children with a conjugate Hib vaccine than it allocates for the purchase of all seven vaccines called for under the Expanded Programme on Immunization. 9 The rationale for buying Hib vaccine is similarly weakened if that cost is two or four times as much as is spent treating all cases of Hib disease in a given year. Improvements in the efficiency of the 8   Unless otherwise noted, material in this section is based on presentations by John LaMontagne, Philip Russell, and David Briles. 9   Otavio Oliva.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 TABLE 1 Characteristics of Conjugate Pneumococcal Vaccines Organization Protein Carrier Linker Technology Saccharide Length Vaccine Serotypes in Clinical Trials Phase of Trials Pasteur-Merieux Connaught Tetanus toxoid Diphtheria toxoid Short linker (new technology) — 6, 14, 19, 23 (propose to add 3, 4, 9, and 18) Phase I/II Lederle-Praxis CRM 197 Short linker Short 6, 14, 18, 19, 23 (propose to add 4 and 9 for United States and 1 and 5 for “developing country” formulations) Phase I/II Merck OMP-meningococcus B Bivalent linker Long 4, 6, 9, 14, 18, 19, 23 Phase I/II University of Rochester CRM 197, tetanus toxoid Reductive amination Short 6, 14, 19, 23 (amine) Phase I National Institute of Child Health and Human Development Tetanus toxoid Short linker (6-carbon) Long 6, 12 Phase I Dutch-Nordic Consortium Tetanus toxoid Thioether Variable None (propose to use a 4-valent vaccine similar to Merck’s) None SOURCE: National Institute of Allergy and Infectious Diseases, 1994.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 the conjugation process, however, offer the prospect of a more affordable conjugate and should be pursued.10 There are a number of specific scientific issues that must be considered as conjugate vaccines continue along the development pipeline. For instance, researchers need to determine how many pneumococcal polysaccharide antigens can be incorporated into a single vaccine using the same carrier proteins. They would also like to know what sorts of immunization schedules and routes of immunization will be most practical. Another important question is whether more than one type of protein carrier can be combined into one vaccine for several diseases (for example, Hib glycoconjugate plus S. pneumoniae). In the long term, however, it is the complexity of making pneumococcal conjugates that seems to pose the greatest challenge in the developing-world context. A number of developing nations are now able to make DTP reliably, and some are working collaboratively with developed-world manufacturers to combine this trivalent “platform” vaccine with newer products, such as hepatitis B. However, the DTP vaccine is in flux: a new acellular pertussis component will soon be substituted for the current whole-cell version, and the implications of this change for the D and T components are unclear. As the number of available vaccines increases and the costs of newer formulations rise, donor agencies are less able to provide vaccine. This creates pressure for developing nations to build domestic manufacturing capacity. The movement toward vaccine self-sufficiency (whether through direct purchase of vaccine or indigenious manufacturer) is proceeding despite significant quality control and regulatory concerns. (See page 29.) Developing countries may be reluctant to incorporate pneumococcal conjugates into their immunization programs, given the limited serotype coverage11 of candidate vaccines. The median coverage of two proposed seven-valent pneumococcal vaccines (the Merck and Lederle-Praxis formulations) is below 70 percent in the group of developing-world countries for which data are available.12 Given the mortality and morbidity caused by pneumococcal infection, however, even an incomplete vaccine may have a substantial impact on adverse outcomes. Coverage could be increased through the addition of more serotypes, but this would probably add substantially to the cost of the final product. Each additional serotype adds a diminishing amount of coverage, since rarer serotypes cause a small proportion of overall disease. Vaccine cost might 10   George Siber. 11   “Coverage,” as used here, means the proportion of infections caused by serotypes that are included in a particular vaccine formulation. 12   Pneumococcal Conjugate Vaccines: Report of a Meeting, World Health Organization, Programme for the Control of Acute Respiratory Infections, November 1993.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 be reduced, and vaccine efficacy or immunogenicity enhanced, through improvements in the conjugation process. The obstacles facing the development of conjugate vaccines (Box 1) and their use in less-developed countries suggest to some that alternative strategies need to be considered. Researchers have for a number of years been working on one such approach, common-antigen vaccines, and initial results in animals look promising. Common antigens are “common” because they are identical or very similar across all pneumococcal serotypes and therefore may provide broad protection when used to immunize. Since these antigens theoretically could be produced in bulk via recombinant technology and would not have to be conjugated, they would be considerably cheaper than glycoconjugates. Of the common-antigen candidates, pneumolysin and pneumococcal surface protein A (PspA) have been the most studied. No common-antigen vaccines for pneumococcal disease have yet been tested in humans. Pneumolysin, a cytoplasmic protein, can damage ciliary surfaces of respiratory epithelial cells and cause lesions in the lung that resemble those caused by pneumococcal pneumonia. The protein also can fix complement, which may be one of the ways it acts as a virulence factor. Mice infected with pneumococci that do not make pneumolysin may survive many days longer than mice infected with normal pneumococci. Other studies find that the survival time of mice immunized with pneumolysin and then infected with S. pneumoniae is significantly lengthened compared with infected animals that are not immunized. But even immunized mice remain bacteremic. In contrast, PspA can rid the experimental animals’ bodies of pneumococci. Some strains of mice immunized with PspA are completely protected against death, while others succumb but survive longer than their nonimmunized counterparts. Scientists are working to understand why all animals are not protected equally. Since PspA is both serologically variable and cross-reactive, it is possible a mixture of such proteins will be more immunogenic than a single surface antigen. Despite the limitations of the animal models, some suggest that clinical trials should be initiated to evaluate the potential of common-antigen vaccines. It is hoped a successful common antigen (or combination of antigens) would complement a vaccine ’s glycoconjugate components. Efforts to conjugate common-antigen proteins to capsular polysaccharides have so far not been successful. 13 In any case, studies on common-antigen vaccines should not be conducted in lieu of research to develop glycoconjugate vaccines; both approaches should be vigorously pursued. 13   Jan Poolman.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 BOX 1 Conjugate Technology for the Developing World—Issues and Potential Problems: S. Pneumoniae Vaccines Incomplete serotype coverage Variable immunogenicity Possible limited effectiveness Potential for ecologic replacement High manufacturing costs Quality control challenge Difficult technology transfer Complex delivery (multiple doses/injection) SOURCE: Russell, 1994. Meningococcal Vaccines14 Currently available vaccines against N. meningitides-caused meningitis are far from optimal, particularly with respect to the population most relevant to the CVI: children. The existing polysaccharide vaccines against serogroups A and C—the most prevalent types in the so-called meningitis belt—provide little or no protection in children under 18 months of age. In addition, the duration of protection of a single dose of Group A vaccine is less than 2 years in children 1 to 4 years of age. For these reasons, A/C polysaccharide vaccines are used in all U.S. military personnel, and many thousands of doses are used for epidemic control. Researchers have developed and are testing in humans a meningococcal A/C conjugate vaccine, which they hope will be immunogenic in infants. The capsular polysaccharides of the group B meningococcus, which causes disease primarily outside of the meningitis belt, are poorly immunogenic in adults and children. One possible explanation is the group B polysaccharides’ similarity to sialic acid moieties on human tissue. Therefore, vaccine researchers have focused their efforts on alternative cell-surface antigens. These include the 14   Unless otherwise noted, material in this section is based on presentations by Wendell Zollinger and Carl Frasch.

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The Children’s Vaccine Initiative: Continuing Activities: A Summary of Two Workshops Held September 12–13 and October 25–26, 1994 transferrin-binding proteins, chemically modified group B polysaccharide conjugated to a carrier protein, meningococcal lipopolysaccharides, and the outer membrane proteins (OMPs). Several vaccines based on OMPs have been assessed in clinical trials. Results from the most recent of these studies indicate the vaccines can be as much as 80 percent efficacious in those over 4 years of age. In younger individuals, however, efficacy drops significantly. And in those initially protected, antibody responses are not long lasting, even when a booster dose of vaccine is administered. At least in one study,15 the bulk of the antibodies produced by immunization did not have bactericidal activity, suggesting the antibody response may be directed against the wrong OMP epitopes. Some of these shortcomings might be overcome (Box 2). For example, one step might be to eliminate the class 4 OMP in order to avoid the induction of “blocking” antibody—antibody that may interfere with an otherwise protective immune response. However, recent work by investigators at the Walter Reed Army Institute of Research revealed very little difference in bactericidal titers between vaccines containing class 4 OMP and those without these proteins. More effective adjuvants, such as QS-21 (a plant-derived glucoside) and MPL (monophosphoryl lipid A), and increasing the number of doses to three, might also improve vaccine efficacy. In a Chilean study of a group B vaccine, 16 antibody response among vaccinees continued to increase even after the last dose, suggesting that subsequent natural infection, or carriage, served to enhance the immune response. Researchers may want to evaluate mucosal (intranasal) immunization with native antigens in order to mimic the booster effect seen with natural carriage. One important unresolved question in the design of group B vaccines is whether or not protection is serotype specific.17 An additional concern is that OMP is a complex antigen, containing many proteins, lipopolysaccharides, and even some capsular polysaccharide —all of which may stimulate the production of antibodies. Researchers currently have no way of knowing which antibodies, or combinations of antibodies, are responsible for immunologic protection.18 Scientists for years have set their hopes on a meningococcal vaccine that would provide protection against all three primary serogroups. Given the difficulty in developing an effective group B product and the progress that is being made toward an effective A/C conjugate, however, a wiser strategy might 15   Zollinger, WD, Boslego, J, Moran, E, Gracia, J, Cruz, C, Brandt, B, et al., The Chilean National Committee for Meningococcal Disease: Meningococcal serogroup B vaccine protection trial and follow-up studies in Chile. NIPH Annals 14:211, 1991. 16   See footnote 15. 17   Claire Broome. 18   Helena Makela.