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Appendix A
Selection of Vaccine Candidates for Accelerated Development

JUDGING THE FEASIBILITY OF ACCELERATED VACCINE DEVELOPMENT

The selection of candidates for accelerated vaccine development depends in part on the mechanisms used to promote development. In the broadest sense, accelerated development could refer to any increase in emphasis or funding at any point along the continuum from disease definition and basic research through clinical trials to licensure.

In the early phases of vaccine development, the questions that need to be answered and the methods most appropriate for answering them may be difficult to define. Diverse approaches may be desirable until a scientific consensus emerges on the research directions most likely to be productive. Once the pathways for development have been set, however, the tasks needed to bring the vaccine to licensure are easier to identify and place in a uniform framework.

The National Institute of Allergy and Infectious Diseases’ (NIAID) influence to accelerate development is most likely to be effective in the latter stages of the continuum, probably through the contract mechanism. One of the committee’s first responsibilities was to identify vaccine candidates “ready” for this kind of support. Candidates were included in the ranking exercise described in Chapter 3 if committee members and knowledgeable consultants believed that their successful development was technically possible within 10 years. Candidates excluded from the analysis are described briefly in the supplement to this volume (see Appendix I), or in the committee’s first report (Appendix B, Institute of Medicine, 1985).

The knowledge required to determine the feasibility of accelerated development covers a wide spectrum, from characteristics of the pathogen to the composition of the target population. The latter is important not only for cost-effective vaccine delivery, but also to determine whether there is sufficient motivation to achieve reasonable utilization. No checklist can replace experienced judgment in assessing vaccine feasibility, but it is possible to identify certain factors that generally facilitate vaccine development (although all may not be essential):



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix A Selection of Vaccine Candidates for Accelerated Development JUDGING THE FEASIBILITY OF ACCELERATED VACCINE DEVELOPMENT The selection of candidates for accelerated vaccine development depends in part on the mechanisms used to promote development. In the broadest sense, accelerated development could refer to any increase in emphasis or funding at any point along the continuum from disease definition and basic research through clinical trials to licensure. In the early phases of vaccine development, the questions that need to be answered and the methods most appropriate for answering them may be difficult to define. Diverse approaches may be desirable until a scientific consensus emerges on the research directions most likely to be productive. Once the pathways for development have been set, however, the tasks needed to bring the vaccine to licensure are easier to identify and place in a uniform framework. The National Institute of Allergy and Infectious Diseases’ (NIAID) influence to accelerate development is most likely to be effective in the latter stages of the continuum, probably through the contract mechanism. One of the committee’s first responsibilities was to identify vaccine candidates “ready” for this kind of support. Candidates were included in the ranking exercise described in Chapter 3 if committee members and knowledgeable consultants believed that their successful development was technically possible within 10 years. Candidates excluded from the analysis are described briefly in the supplement to this volume (see Appendix I), or in the committee’s first report (Appendix B, Institute of Medicine, 1985). The knowledge required to determine the feasibility of accelerated development covers a wide spectrum, from characteristics of the pathogen to the composition of the target population. The latter is important not only for cost-effective vaccine delivery, but also to determine whether there is sufficient motivation to achieve reasonable utilization. No checklist can replace experienced judgment in assessing vaccine feasibility, but it is possible to identify certain factors that generally facilitate vaccine development (although all may not be essential):

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries knowledge of clinical signs and symptoms of the disease to allow differentiation from similar syndromes identification of the pathogen and its major characteristics, including strains and serotypes, their infectivity, their virulence, their antigenicity, and the nature of essential immunogens the existence of specific techniques for cultivation of the pathogen identification of nonhuman models of infection knowledge of the human immune response to the pathogen, including the duration and type of response (e.g., serum antibody, mucosal antibody, or cell-mediated immunity) definition of the target population. All aspects of the knowledge base that involve technical feasibility must be reassessed frequently: a vaccine not foreseeable today may become a reality in the future because of one unexpected development in the laboratory. Such developments are especially likely in the fields relevant to vaccine development because modern biotechnology has only begun to be explored. ACCELERATED VACCINE DEVELOPMENT AND BASIC RESEARCH PRIORITIES The criteria for selecting candidates for accelerated vaccine development do not address the general question of which vaccines are most needed in the developing world or its particular regions. For some diseases that impose major burdens, the knowledge base is insufficient to allow consideration of accelerated vaccine development by NIAID. Nevertheless, portions of the analysis described in this report can be applied to these disease problems to gain useful information about long-term goals and potential benefits. The description of disease burden considerations in Chapter 4 may be especially helpful in this regard. The committee hopes that the selection of candidates for accelerated vaccine development will not divert funds from long-term basic research programs. For these programs, the scientific merit of the research proposal should continue to be the dominant criterion for funding. SELECTING CANDIDATES FOR ACCELERATED DEVELOPMENT The committee believed that its major contribution to establishing priorities would be the clear explication of a logical method for this task and that it probably could never satisfy all potential critics with its choice of candidates for assessment. As noted in Chapter 3, if a candidate is omitted from the full assessment, no conclusions should be made regarding its position in the priority rankings relative to the assessed contenders. When the prospects for vaccine control of disease were reasonable, however, the committee tried to include in the full analysis those candidates generally recognized in the developing world and the United States as major disease problems.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries The process involved a number of iterations of selection, review, and revision. At an international workshop in Washington, D.C., on August 1–3, 1984, a draft list of infectious diseases prevalent in the developing world was reviewed and revised. This list was the starting point for candidate selection and is shown in Table A.1. About 40 diseases were chosen from Table A.1 by the workshop participants as major health problems in the developing world. These diseases are listed in Table A.2. Some diseases were included in this list as models because vaccine prospects had been carefully reviewed in the committee’s prior assessment. A working group at the workshop then assessed the state of knowledge on these diseases in three areas: disease mechanisms, protective mechanisms, and protective antigens. A simple scoring system was used (+/++/+++), and on the basis of scores, pathogen/disease entities were assigned to one of three categories: good prospects for the technical feasibility of vaccine development, promising prospects, or insufficient knowledge to evaluate prospects. Based on these judgments, candidates were either included in the full assessment, excluded from it, or subjected to further review by a committee subgroup which consulted with experts on relevant vaccine development efforts. Appendixes D-1 through D-19 describe the prospects for immunizing against the candidate pathogens, and the supplement to this volume describes prospects and knowledge gaps for a range of diseases prevalent in the developing world and for which accelerated development efforts are not feasible or appropriate at this time. For a number of the pathogens considered in the supplement, vaccine development prospects are such that their exclusion from consideration was a difficult decision. Because of rapid technologic advances in the vaccine development field, the state of knowledge and vaccine development prospects for these potential candidates should be regularly reviewed. Table A.3 lists the pathogens for which the vaccine development prospects were reviewed in the committee’s first report. For various reasons, these pathogens were not included as primary contenders in the assessment of vaccine priorities for important diseases in the United States, although some are now included in this analysis. REFERENCE Institute of Medicine. 1985. New Vaccine Development: Establishing Priorities, Volume I. Diseases of Importance in the United States. Washington, D.C.: National Academy Press.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE A.1 Important Diseases in Developing Countries Amebiasis E. histolytica Ancylostomiasis (hookworm disease) N. americanus A. duodenale A. ceylanicum Ascariasis A. lumbricoides Brucellosis B. abortus, biotypes 1–9 B. canis B. melitensis, biotypes 1–3 B. suis, biotypes 1–4 Chlamydial infections (see also trachoma) Chlamydia Cholera V. cholerae Cryptosporidiosis Cryptosporida spp. Cytomegalovirus Dengue fever Immunological types 1–4 Group B togaviruses Dengue hemorrhagic fever Diarrheas, viral Norwalk agent Rotaviruses Diarrheas, bacterial Enteropathic E. coli Enterotoxigenic E. coli C. jejuni Salmonella (nontyphoid) Shigella Herpes simplex virus Herpesvirus varicellae Japanese encephalitis Leishmaniasis, cutaneous Old world, L. tropica New world, L. brasiliensis and L. mexicana Leishmaniasis, visceral L. donovani Leprosy M. leprae Malaria P. vivax P. malariae P. falciparum P. ovale Measles (rubeola) Measles virus Meningitis, aseptic Enteroviruses (picornaviruses) Coxsackie virus group A, types 2, 3, 7, 9 Coxsackie virus group B, types 2–5 Echovirus types 2, 5–7, 9–11, 14, 18, 30 Poliovirus Arboviruses Mumps H. simplex and varicella viruses Adenovirus Meningitis, meningococcal N. meningitidis Mumps Mumps virus, a myxovirus Onchocerciasis (skin disease and river blindness), O. volvulus Respiratory infections, acute bacterial B. pertussis S. pneumoniae M. pneumoniae H. influenzae L. pneumophilia Rift Valley fever Rift Valley fever virus (group B togavirus) Rubella Rubella virus Russian spring-summer encephalitis Group B togavirus Salmonellosis S. typhimurium S. heidelberq S. newport S. infantis S. enteritidis S. st. paul Schistosomiasis S. mansoni S. haematobium S. japonicum S. intercalatum Shigellosis S. dysenteriae, group A S. flexneri, group B S. boydii, group C S. sonnei, group D Streptococcus group A Streptococcus group B Syphilis T. pallidum

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Diarrheas, parasitic E. histolytica G. lamblia Diphtheria C. diphtheriae Dracunculiasis (Guinea worm disease) Eastern equine encephalitis Epstein-Barr virus Filariasis W. bancrofti B. malayi Giardiasis G. lamblia Gonorrhea N. gonorrhoeae Hantaan viruses and related agents Hepatitis A Hepatitis B Hepatitis non-A, non-B Paratyphoid fever S. paratyphi A (S. enteritidis serotype paratyphoid A) S. schottmuelleri (S. paratyphi B, S. enteritidis serotype paratyphoid B) S. paratyphi C (S. hirschfeldii, S. enteritidis serotype paratyphoid C) Plague Y. pestis (P. pestis) Poliomyelitis Poliovirus types 1, 2, 3 Q fever C. burneti (R. burneti) Rabies Rabiesvirus, a rhabdovirus Relapsing fever B. recurrentis Respiratory infections, acute viral Parainfluenza types 1–4 Respiratory syncytial virus Adenovirus, types 1–7, 14, 21 Rhinoviruses Coronaviruses Types of coxsackie virus groups A and B Echoviruses Tetanus C. tetani Trachoma C. trachomatis Trichuriasis T. trichiura (T. trichiurus) Trypanosomiasis, African T. gambiense T. rhodensiense Trypanosomiasis, South American T. cruzi Tuberculosis M. tuberculosis Typhoid S. typhi Typhus Rickettsia West Nile fever West Nile fever virus (group B togavirus)

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE A.2 Potential Candidate Diseases for New or Improved Vaccine Development Amebiasis Ancylostomiasis (hookworm) Ascariasis Brucellosis Chlamydial infections Cholera Dengue fever Diarrheas E. coli Norwalk agent Salmonella (nontyphoid) Shigella Rotavirus Campylobacter Filariasis Giardiasis Gonorrhea Hantaan virus Hemophilus influenzae type B invasive disease Hepatitis A Hepatitis B Influenza virus Japanese encephalitis Leishmaniasis Leprosy Malaria Measles Meningococcal meningitis Onchocerciasis Skin disease River blindness Pertussis Rabies Respiratory infections Parainfluenza Respiratory syncytial virus Adenovirus Streptococcus pneumoniae Hemophilus influenzae Schistosomiasis Streptococcus group A Streptococcus group B Trichuriasis Trypanosomiasis African South American Tuberculosis Typhoid Yellow fever TABLE A.3 Pathogens Not Included as Candidates but Discussed in the Committee’s First Report (Appendix B) Acquired immune deficiency syndrome agent Adenovirus (respiratory disease) Anaerobic bacteria Clostridium botulinum Clostridium difficile Clostridium perfringens Clostridium tetani Chlamydia Epstein-Barr virus Giardia lamblia Hospital acquired infections (gram-negative bacteria) Nontypable Hemophilus influenzae Non-A, non-B hepatitis Histoplasma capsulatum Human papilloma virus Kawasaki disease agent Legionella spp. (Legionnaire’s disease) Mycoplasma pneumoniae Rhinovirus Rickettsia rickettsii (Rocky Mountain spotted fever) Salmonella spp. (nontyphoidal) Staphylococcus aureus Streptococcus mutans Treponema pallidum (syphilis) Treponema-like spirochete of Lyme disease