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Appendix D-1
The Prospects for Immunizing Against Dengue Virus

DISEASE DESCRIPTION

Dengue viruses cause two clinically important syndromes: classical dengue fever and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS).

Dengue fever is an age-dependent syndrome, usually most severe in adolescents and adults. It is an acute, relatively short febrile disease (the mean duration is 5 days) characterized by headache, myalgias, lack of appetite, gastrointestinal disturbance, severe prostration, and a rash (Halstead, 1981a). The severe prostration extends into the convalescent phase and is not proportional to the shortness of the illness. Because of this debilitation and its potential effect on combat readiness, dengue is always high on lists of diseases of military importance.

Dengue hemorrhagic fever/dengue shock syndrome is also age-dependent; it primarily affects children. This acute vascular permeability produces one of the most dramatic syndromes seen in human medicine. Previously healthy children may turn pale and cyanotic, collapse, sometimes pass blood from the mouth or rectum, and expire after a short, stormy course of 6 to 24 hours. Shock is evident first and then hemorrhage, which may not be apparent or occur before death. Reported fatality rates have ranged from as low as 1 percent to a high of 20 to 50 percent (Halstead, 1981a). The disease begins with a febrile phase, often with innocuous upper respiratory symptoms. With the return of a normal temperature, the vascular permeability phase begins. There also appears to be other severe expressions of dengue virus infection such as a syndrome in which severe hemorrhage appears without increased vascular permeability (Halstead, personal communication, 1985).

The committee gratefully acknowledges the efforts of S.B.Halstead, who prepared major portions of this appendix, and the advice and assistance of T.Bektimirov. The committee assumes full responsibility for all judgments and assumptions.



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-1 The Prospects for Immunizing Against Dengue Virus DISEASE DESCRIPTION Dengue viruses cause two clinically important syndromes: classical dengue fever and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Dengue fever is an age-dependent syndrome, usually most severe in adolescents and adults. It is an acute, relatively short febrile disease (the mean duration is 5 days) characterized by headache, myalgias, lack of appetite, gastrointestinal disturbance, severe prostration, and a rash (Halstead, 1981a). The severe prostration extends into the convalescent phase and is not proportional to the shortness of the illness. Because of this debilitation and its potential effect on combat readiness, dengue is always high on lists of diseases of military importance. Dengue hemorrhagic fever/dengue shock syndrome is also age-dependent; it primarily affects children. This acute vascular permeability produces one of the most dramatic syndromes seen in human medicine. Previously healthy children may turn pale and cyanotic, collapse, sometimes pass blood from the mouth or rectum, and expire after a short, stormy course of 6 to 24 hours. Shock is evident first and then hemorrhage, which may not be apparent or occur before death. Reported fatality rates have ranged from as low as 1 percent to a high of 20 to 50 percent (Halstead, 1981a). The disease begins with a febrile phase, often with innocuous upper respiratory symptoms. With the return of a normal temperature, the vascular permeability phase begins. There also appears to be other severe expressions of dengue virus infection such as a syndrome in which severe hemorrhage appears without increased vascular permeability (Halstead, personal communication, 1985). The committee gratefully acknowledges the efforts of S.B.Halstead, who prepared major portions of this appendix, and the advice and assistance of T.Bektimirov. The committee assumes full responsibility for all judgments and assumptions.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Limitations of Existing Vaccines Numerous dengue vaccines have been produced and tested in small numbers of human beings, but vaccines have not yet been made for all four dengue virus types. Early live attenuated vaccines against dengue were made in suckling mouse brain (Hotta, 1957; Sabin and Schlesinger, 1945; Schlesinger et al., 1956; Wisseman et al., 1963), a substrate no longer considered acceptable for human use. Recently, dengue 1, 2, and 4 attenuated viruses, grown in tissue cultures and produced under U.S. Army sponsorship, have been tested in humans. None have all of the attributes thought to be necessary for an acceptable vaccine, and large-scale production is not contemplated. Attenuated dengue 1, 2, 3, and 4 virus strains have been selected at the dengue laboratory, Ramathibodi Hospital, Bangkok. To date, dengue 2 has been tested in 10 human volunteers; the results apparently were successful. All volunteers responded and none developed dengue-like symptoms (Halstead, personal communication, 1985). PATHOGEN DESCRIPTION Dengue viruses are togaviruses of the genus flavivirus and are transmitted by the mosquito vector Aedes aegypti. They are enveloped, single-stranded RNA viruses. There are four distinct antigenic types, dengue types 1, 2, 3, and 4, and several antigenic and biologic subtypes. All dengue serotypes produce the dengue fever syndrome; dengue 2 and possibly dengue 3 and 4 have been implicated as the proximal causes of DHF/DSS (Halstead, 1981b). HOST IMMUNE RESPONSE Infection with a dengue serotype results in life-long immunity to that type. From a single infection, short-lived cross protection against disease produced by a different virus type may persist for 6 to 12 weeks. DHF/DSS may be regarded as a complication of the immune response; certain individuals who experience an initial dengue infection are at risk of developing severe disease following infection with a different virus serotype (Halstead, 1981b). This phenomenon has been documented prospectively; dengue types 1, 3, or 4 infections followed by dengue type 2 produces DSS. The underlying mechanism in DHF/DSS is thought to be as follows. Dengue virus appears to replicate in mononuclear phagocytes. Antibody to one dengue serotype reacts with a second serotype producing immune complexes that attach to and infect mononuclear phagocytes, a phenomenon known as antibody-dependent infection enhancement (Halstead, 1980a). This infection causes the cells to release proteolytic enzymes, thromboplastin, and vascular permeability factors, which in turn lead to hemorrhage and vascular collapse (Halstead, 1983).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries DISTRIBUTION OF DISEASE Geographic Distribution The geographic distribution of dengue infection and disease has increased steadily since World War II, and the virus may be more widely circulating now than at any time in history. Certainly more people are infected annually than at any previous time (Halstead, 1980b). The virus is endemic or enzootic in the warm areas of virtually all tropical countries. The vector, Aedes aegypti, does not thrive at altitudes above 1,000 meters; hence, dengue is a lowland or coastal disease. The virus has the potential to spread to temperate zones during summer months, as in the recent dengue epidemics in Queensland, Australia. Much of the southern United States is receptive to dengue transmission. DHF/DSS is endemic in all tropical Southeast Asian countries. A single large outbreak (116,000 hospitalizations) occurred in Cuba in 1981. Disease Burden Estimates An estimated 1.5 billion persons live in countries with dengue activity (Halstead, 1980b). In dengue endemic areas of tropical Asia, virtually all adults have flavivirus hemagglutination inhibition (HI) antibody, presumably dengue in origin. Therefore, a conservative estimate is that in endemic areas, dengue viruses infect 10 percent of the susceptible population per year. Infections at this rate effectively mean that most adults are immune. If it is estimated that 40 percent of tropical populations are children 15 years and younger (600 million children), then there are about 60 million dengue infections per year. These figures ignore the circulation of multiple types, which will cause an upward revision of the estimate. As shown in Table D-1.1, cases are assumed to occur only in the three younger age groups, with 90 percent in the two youngest groups. All cases fall into acute morbidity categories A, B, and C. Illness usually results in a visit to the physician, drug prescription for symptomatic relief, and treatment at home. Hence, cases of dengue fever are assigned to categories A and B. For all cases in category A, there is likely to be an equal number of asymptomatic infections (22.5 million). In tropical Southeast Asia, DHF/DSS has produced 1.3 million hospitalizations and 23,000 deaths in a 30-year period. DHF/DSS incidence is increasing, with a mean annual incidence for the past 5 years of about 60,000 hospitalizations and 1,500 deaths (Halstead, personal communication, 1985). PROBABLE VACCINE TARGET POPULATION The potential target population for a safe and effective dengue vaccine includes (1) infants and children in DHF/DSS endemic areas and (2) infants and children (and initially adults) in countries with

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-1.1 Disease Burden: Dengue Fever       Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Dengue fever 7,500,000 4 14,500,000 4 500,000 4     B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Dengue fever 4,000,000 5 7,000,000 5 4,000,000 5     C Severe pain, severe short-term impairment, or hospitalization Dengue hemorrhagic fever 20,000 6 40,000 6         D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)     n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)     n.a.   n.a.   n.a.   n.a. F Total impairment     n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility     n.a.   n.a.   n.a.   n.a. H Death   5,000 n.a. 9,900 n.a. 100 n.a.   n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries periodic epidemics of dengue fever. Tourists and military personnel visiting dengue endemic areas would also probably receive the vaccine, but their numbers are small compared to the major populations at risk. Of the estimated 1.5 billion people living in areas endemic for dengue fever and areas that have recently had epidemics, about 38 percent, or 570 million, are under the age of 15 and would require vaccination in the initial years. Assuming a crude birth rate of 32 per 1,000 population, 48 million infants would need vaccination in all subsequent years. There appears to be no insurmountable problem associated with incorporating dengue vaccine into the World Health Organization Expanded Program on Immunization (WHO-EPI) in appropriate areas. Vaccine Preventable Illness* Some cases of DHF occur in children under 1 year of age, most often between 6 and 12 months. For calculations it is assumed, though it is not yet certain, that it will be possible to vaccinate successfully children 6 months of age or younger. The major risk of disease occurs after infancy even in endemic areas. Hence, in DHF/DSS endemic areas, 100 percent of the disease burden could be prevented by a vaccine that was 100 percent effective and that could be successfully administered to the entire target population at an early age. Herd immunity has not been studied in dengue infections, but it is possible that the disease burden could be eliminated even if vaccine coverage were not complete. SUITABILITY FOR VACCINE CONTROL Disease-induced serotype-specific immunity and the age distribution of disease suggest that vaccine prevention is feasible. Alternative Control Measures and Treatments Aedes aegypti control, even eradication, is technically feasible. However, given current financial and organizational constraints, successful mosquito control is not politically feasible. *   Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries PROSPECTS FOR VACCINE DEVELOPMENT The challenge in developing a dengue vaccine is that it must protect against DHF/DSS while not making the population susceptible to DHF/DSS. Such a task poses a most difficult problem to workers in the vaccine development field. Hotta (1957), Sabin and Schlesinger (1945), Schlesinger et al. (1956), and Wisseman et al. (1963) demonstrated the ease and reproducibility of selecting an attenuated live dengue virus vaccine by serial passage in the brains of suckling mice. More recently, dengue attenuation strategies have used clonal selection of viruses grown in tissue culture to pick variants from wild virus populations. These variants (dengue 1, 2, and 4) demonstrated temperature sensitivity, reduced suckling mouse neurovirulence, reduced rhesus monkey viremia, and somewhat lower antibody responses in infected monkeys, attributes thought to indicate attenuation for humans (Bancroft et al., 1984; Eckels et al., 1984; Halstead et al., 1984a,b,c,d). When tested in humans, however, the variants either were overattenuated, yielding unacceptably low seroconversion rate in susceptibles (dengue 2 and 4), or were underattenuated, producing symptoms in human volunteers (dengue 1 and 4). A dengue 2 vaccine serially passaged 50 times in primary dog kidney cells has been shown to be acceptably immunogenic and nonreactogenic in 10 adult volunteers tested in Thailand (Halstead, personal communication, 1985). However, it shares with all other vaccine strains limited growth potential in suitable mammalian cells, and thus the maximum titer of the vaccine probably will be about 105. Any dengue vaccine program must have as major components ongoing epidemiological studies of risk factors, surveillance for DHF/DSS cases among vaccinees, and fundamental immunological studies designed to elucidate the mechanisms of DHF/DSS. A coherent understanding of risk factors is essential for the successful development, testing, and use of dengue vaccines. Current knowledge indicates that use of nonpersisting antigens would be extremely dangerous in situations in which dengue viruses continue to circulate in human populations. The existence of a jungle dengue cycle clearly means that the disappearance of one or more dengue viruses from circulation would be transient. As long as an efficient urban vector is established, dengue transmission must be expected at any time. Unless virological risk factors for dengue shock syndrome can be authoritatively determined for residents of all countries in DHF/DSS endemic areas, a tetravalent vaccine appears to be the best option available. Recent studies from Thailand, however, suggest that only secondary dengue 2 infections in children result in DSS, allowing for the possibility of a monovalent dengue 2 vaccine to protect against severe disease and death (Sangkawibha et al., 1984). Studies in monkeys show that neutralizing antibodies can be developed to all four components of a tetravalent vaccine (Halstead and Palumbo, 1973). The success of the combined measles, mumps, and rubella vaccines demonstrates that multiple live viruses can be inoculated in man without interference.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Strategies for genetic manipulation of RNA viruses comparable to the insertion of DNA segments in vaccinia viruses are only now being developed. Conceivably, cDNA segments could be inserted into DNA vectors, allowing for production of the antigenic proteins or peptides required to induce immunity to all four dengue serotypes. Genetic mapping of the dengue virus genome is under way (National Institute of Allergy and Infectious Diseases, 1985). Other strategies for developing second generation vaccines include (1) engineering dengue vaccines by substituting immunoprotective epitopes into the 17D yellow fever virus and using this virus as a possible vector; (2) experimentation with other vectors, such as bacteria or other viruses; and (3) definition of epitopes that induce the formation of protective rather than enhancing antibodies in a manner similar to that demonstrated for yellow fever (Schlesinger et al., 1985). Among the various vaccine approaches discussed above, the committe chose to evaluate an attenuated live vector virus containing the gene for a broadly cross reacting protective antigen. Such an antigen has yet to be identified; if one does not exist, or its use proves impracticable, then a vector containing a gene for a protective antigen from each of the four dengue virus types will be the preferred approach. Predictions for vaccine development are similar for either strategy. REFERENCES Bancroft, W.H., R.M.Scott, K.H.Eckels, C.H.Hoke, Jr., T.E.Simms, K.D.Jesrani, P.L.Summers, D.R.Dubois, D.Tsoulos, and P.K. Russell. 1984. Dengue virus type 2 vaccine: Reactogenicity and immunogenicity in soldiers. J. Infect. Dis. 149(6):1005–1010. Eckels, K.H., R.M.Scott, W.H.Bancroft, J.Brown, D.R.Dubois, P.L. Summers, P.K.Russell, and S.B.Halstead. 1984. Selection of attenuated dengue 4 viruses by serial passage in primary kidney cells. V. Human response to immunization with a candidate vaccine prepared in fetal rhesus lung cells. Am. J. Trop. Med. Hyg. 33(4):684–689. Halstead, S.B. 1980a. Immunological parameters of togavirus syndromes. Pp. 107–173 in Togaviruses, Biology, Structure Replication, R.W.Schlesinger, ed. New York: Academic Press. Halstead, S.B. 1980b. Dengue hemorrhagic fever—a public health problem and a field for research. Bull. WHO 52:1–21. Halstead, S.B. 1981a. Arboviruses and their diseases, Pacific and Southeast Asia. Pp. 1140–1149 in Textbook of Pediatric Infectious Diseases, R.D.Feigin and J.D.Cherry, eds. Philadelphia: W.B. Saunders. Halstead, S.B. 1981b. The pathogenesis of dengue. Molecular epidemiology in infectious disease. The Alexander D.Langmuir Lecture. Am. J. Epid. 114:632–648.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Halstead, S.B. 1983. Selective primary health care: Strategies for control of disease in the developing world. XI. Dengue. Rev. Infect. Dis. 6(2):251–264. Halstead, S.B. 1985. Personal communication, The Rockefeller Foundation, New York, New York. Halstead, S.B., and N.E.Palumbo. 1973. Studies on the immunization of monkeys against dengue. II. Protection following inoculation of combinations of viruses. Am. J. Trop. Med. Hyg. 22(3):375–381. Halstead, S.B., A.R.Diwan, N.J.Marchette, N.E.Palumbo, and L. Srisukonth. 1984a. Selection of attenuated dengue 4 viruses by serial passage in primary kidney cells. I. Attributes of uncloned virus at different passage levels. Am. J. Trop. Med. Hyg. 33(4):654–665. Halstead, S.B., N.J.Marchette, A.R.Diwan, N.E.Palumbo, and R. Putvatana. 1984b. Selection of attenuated dengue 4 viruses by serial passage in primary kidney cells. II. Attributes of virus cloned at different dog kidney passage levels. Am. J. Trop. Med. Hyg. 33(4):666–671. Halstead, S.B., N.J.Marchette, A.R.Diwan, N.E.Palumbo, R.Putvatana, and L.K.Larsen. 1984c. Selection of attenuated dengue 4 viruses by serial passage in primary kidney cells. III. Reversion to virulence by passage of cloned virus in fetal rhesus lung cells. Am. J. Trop. Med. Hyg. 33(4):672–678. Halstead, S.B., K.H.Eckels, R.Putvatana, L.K.Larsen, and N.J. Marchette. 1984d. Selection of attenuated dengue 4 viruses by serial passage in primary kidney cells. IV. Characterization of a vaccine candidate in fetal rhesus lung cells. Am. J. Trop. Med. Hyg. 33(4):679–683. Hotta, S. 1957. Some immunological properties of dengue virus cultivated in tissue culture. Ann. Trop. Med. Parasitol. 51:249–255. National Institute of Allergy and Infectious Diseases. 1985. Program for Accelerated Development of New Vaccines. Progress Report. Bethesda, Md.: National Institutes of Health. Sabin, A.B., and R.W.Schlesinger. 1945. Production of immunity to dengue with virus modified by propagation in mice. Science 101:640–642. Sangkawibha, N., S.Rojanasuphot, S.Ahandrik, S.Viriyapongse, S. Jatanasen, V.Salitul, B.Phanthumachinda, and S.B.Halstead. 1984. Risk factors in dengue shock syndrome: A prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am. J. Epidemiol. 120(5):653–669. Schlesinger, R.W., I.Gordon, J.W.Frankel, J.N.Winter, P.R.Patterson, and W.R.Dorrance. 1956. Clinical and serological response of man to immunization with attenuated dengue and yellow fever viruses. J. Immunol. 77:352–364. Schlesinger, J.J., Brandriss, M.W., and E.E.Walsh. 1985. Protection against 17D yellow fever encephalitis in mice by passive transfer of monoclonal antibodies to the non-structural glycoproteins gp 48 and by active immunization with gp 48. J. Immunol. 135:2805–2809. Wisseman, C.L., Jr., B.H.Sweet, and E.C.Rosenzweig. 1963. Attenuated living type 1 dengue vaccines. Am. J. Trop. Med. Hyg. 12:620–623.