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Appendix D-12
The Prospects for Immunizing Against Respiratory Syncytial Virus

DISEASE DESCRIPTION

Information on morbidity caused by respiratory syncytial virus (RSV) infection in developing countries is very limited. Much of the available information is contained or referenced in the proceedings of two recent symposia on acute respiratory infections (Clyde and Denny, 1983; Douglas and Kerby-Eaton, 1985). Studies in South America and other regions have identified the virus in association with outbreaks of bronchiolitis and pneumonia. In developed countries, the agent reinfects frequently during childhood, but illness produced by reinfection is generally milder than that associated with the initial infection and rarely causes major problems. A similar pattern probably occurs in developing countries; therefore, a suitable vaccine should be able to reduce the severity of the initial infection.

PATHOGEN DESCRIPTION

RSV is a lipoprotein-enveloped RNA virus of medium size (120–200 nm). The outer envelope contains glycoprotein. The virus is heat labile, which complicates its isolation and study. RSV was long considered by most to be a single serotype, but recent evidence suggests that two serotypes exist (National Institute of Allergy and Infectious Diseases, 1985). Early studies described aberrant strains that were poorly neutralized by postinfectious ferret sera (Coates et al., 1966). Although human convalescent sera did not distinguish these differences, the frequency of such aberrant strains and their contribution to the problem of reinfection has never been entirely explained. Recent studies of the proteins of RSV have produced new information about the surface structure of the virus and the antigens that may be

The committee gratefully acknowledges the efforts of A.S.Monto, who prepared major portions of this appendix, and the advice and assistance of F.W.Denny, W.P.Glezen, and K.McIntosh. 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-12 The Prospects for Immunizing Against Respiratory Syncytial Virus DISEASE DESCRIPTION Information on morbidity caused by respiratory syncytial virus (RSV) infection in developing countries is very limited. Much of the available information is contained or referenced in the proceedings of two recent symposia on acute respiratory infections (Clyde and Denny, 1983; Douglas and Kerby-Eaton, 1985). Studies in South America and other regions have identified the virus in association with outbreaks of bronchiolitis and pneumonia. In developed countries, the agent reinfects frequently during childhood, but illness produced by reinfection is generally milder than that associated with the initial infection and rarely causes major problems. A similar pattern probably occurs in developing countries; therefore, a suitable vaccine should be able to reduce the severity of the initial infection. PATHOGEN DESCRIPTION RSV is a lipoprotein-enveloped RNA virus of medium size (120–200 nm). The outer envelope contains glycoprotein. The virus is heat labile, which complicates its isolation and study. RSV was long considered by most to be a single serotype, but recent evidence suggests that two serotypes exist (National Institute of Allergy and Infectious Diseases, 1985). Early studies described aberrant strains that were poorly neutralized by postinfectious ferret sera (Coates et al., 1966). Although human convalescent sera did not distinguish these differences, the frequency of such aberrant strains and their contribution to the problem of reinfection has never been entirely explained. Recent studies of the proteins of RSV have produced new information about the surface structure of the virus and the antigens that may be The committee gratefully acknowledges the efforts of A.S.Monto, who prepared major portions of this appendix, and the advice and assistance of F.W.Denny, W.P.Glezen, and K.McIntosh. 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 important for vaccine development. There are two major surface glycoproteins. Neither of them has hemagglutinating or neuraminidase activity; however, one of them is probably responsible for fusion of the viral membrane to infected cells and for fusion of an infected cell to neighboring cells (Walsh and Hruska, 1983). This protein, in an unreduced state, has a molecular weight of 66,000–68,000 (Bernstein and Hruska, 1981). Monoclonal antibody that immunoprecipitates this protein neutralizes the virus in vitro, prevents formation of syncytia, and may have some protective effect when administered passively to small animals subsequently inoculated with RSV. The other surface glycoprotein has a molecular weight of 84,000–90,000 and has no known function. Monoclonal antibody to this larger glycoprotein may be neutralizing in the presence of complement. Neither of the glycoproteins has yet been purified. DNA complementary to the RSV genome has been cloned (Collins and Wertz, 1983; Venkatesan et al., 1983), and which of the cloned fragments correspond to the messages for the two surface glycoproteins has been investigated (Collins and Wertz, 1985). The genes coding for the major glycoprotein and fusion protein have apparently now been cloned (National Institute of Allergy and Infectious Diseases, 1985). HOST IMMUNE RESPONSE RSV infection and disease occur in the very young in the presence of maternal IgG, but there is some evidence that infants with high levels of serum antibody are less often infected or severely ill than infants with low levels (Glezen et al., 1981; Parrot et al., 1973). There is also evidence that partial immunity may be conferred by natural infection; adults who have been inoculated with tissue culture grown virus have shown subsequent resistance to reinfection by the same route (Mills et al., 1971). Most studies suggest, however, that RSV infection recurs at yearly or biennial intervals under natural conditions (Beem, 1967; Henderson et al., 1979). Reinfections are frequently less severe than first infections, but this appears to be a function of increasing age more than immunity (Henderson et al., 1979). Reinfections in the same RSV epidemic probably are rare, however. It seems likely that secretory immunity is more important in protection against reinfection than systemic immunity, although this point cannot be made with certainty. DISTRIBUTION OF DISEASE Geographic Distribution The presence of respiratory syncytial viruses as respiratory pathogens is quite uniform worldwide, but the severity and characteristics of disease caused by RSV probably vary. The age of initial acquisition also may vary, although antibody prevalence studies do not show any clear-cut differences between developed and developing countries.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Disease Burden Estimates Examining mortality statistics provides some perspective on the burden of RSV infection in children in developing countries, especially those under age 5. The causes of childhood mortality often change as a country develops. Initially, diarrheal diseases may be the leading cause of death. General development and the implementation of oral rehydration programs may reduce the impact of these diseases and increase the proportion of deaths due to respiratory infections. With further development, mortality from acute respiratory infections also begins to decline. The reasons for these shifts are complex, in part because of the effects of malnutrition and other risk factors. Even with complete mortality statistics it is difficult to establish the role of RSV, because numerous other pathogens also cause respiratory infections in children. Parainfluenza viruses and adenoviruses produce similar symptoms. In addition, bacterial superinfections may occur and can contribute to mortality. The disease burden estimates for RSV are shown in Table D-12.1 and are described in Appendix B. It should be emphasized that these are uncertain estimates because of the lack of data on RSV in developing countries. The association between acute lower respiratory tract illness from respiratory syncytial virus infection and the development of chronic obstructive pulmonary disease remains speculative (Glezen, 1984). No attempt has been made to estimate possible chronic morbidity associated with RSV infection. PROBABLE VACCINE TARGET POPULATION Infants would be the principal target population for an RSV vaccine, because the most severe disease caused by the virus occurs early in the first year of life. This population could be reached through the World Health Organization Expanded Program on Immunization (WHO-EPI). Other possible target populations include the elderly (Garvie and Gray, 1980) and older children with chronic cardiopulmonary disease (e.g., congenital heart disease, bronchopulmonary dysplasia, and asthma). RSV could be severe or fatal for children in this latter group at any age (MacDonald et al., 1982). Delivery of vaccine to pregnant or soon-to-be pregnant women may offer an alternative approach to immunizing young infants, if the latter proves not to be practicable. A vaccine conferring temporary immunity might be acceptable for the major target population because the period of highest vulnerability is so brief (the first year of life).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-12.1 Disease Burden: Respiratory Syncytial Virus     Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description 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 44,604,000 3 3,300,000 3         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 14,868,000 5 1,100,000 5         C Severe pain, severe short-term impairment, or hospitalization 1,486,800 7 110,000 7         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 148,680 n.a. 11,000 n.a.   n.a.   n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Vaccine Preventable Illness* If the distribution of RSV illness in developing countries is similar to that in developed countries, then a large proportion of RSV illness in the first year of life occurs below the age of 6 months. Thus, a vaccine would have to be delivered starting at a very early age. With the glycoprotein vaccine, partial protection would be achieved after the first dose, but full protection probably could not be achieved before age 6 months. An attenuated live vaccine might be expected to provide full protection at an earlier age if it only required a single dose. Because of these considerations, it is judged that only about two-thirds of the burden of RSV would be preventable with a glycoprotein vaccine, and about three-quarters would be preventable with an attenuated vaccine. SUITABILITY FOR VACCINE CONTROL Severe RSV illness occurs in young infants, so vaccine prevention or amelioration of RSV illness will depend on the ability to develop a vaccine that can stimulate immunity at a very early age. Calculations in Chapter 7 are based on the assumption that this will be possible (see Chapter 5). A vaccine that produces immunity of relatively short duration may be acceptable for the reasons discussed above. The feasibility of the alternative strategy—immunizing pregnant women—also needs to be investigated, especially if producing a vaccine immunogenic in young infants proves to be impossible. Alternative Control Measures and Treatments There is no specific treatment for RSV infection that is suitable for widespread use in developing countries. Antibiotic therapy may reduce the problems associated with secondary bacterial infections. In severe cases, supportive care (i.e., hospitalization) may reduce the fatality rate. Aerosolized ribavirin has been found to be useful in some U.S. situations (Hall et al., 1983; Taber et al., 1983). PROSPECTS FOR VACCINE DEVELOPMENT History Early investigators attempted to prevent RSV infection by inoculating susceptible children with a formalin-inactivated, *   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 concentrated, adjuvant-enhanced vaccine. The results of these trials are well known. Vaccinees developed high levels of neutralizing and complement-fixing antibody, but on subsequent exposure to wild RSV, they developed infections that were more severe than those seen in parallel control children (Chin et al., 1969; Fulginiti et al., 1969; Kapikian et al., 1969; Kim et al., 1969). This hyperreactivity has never been satisfactorily explained. The disease was similar to that seen in normal children, but it occurred at an older age and was somewhat more severe. Attempts to make live attenuated vaccines also have met with little success. Early cold-adapted vaccines were too pathogenic for use in young children. Temperature sensitive mutants, while less pathogenic than cold-adapted variants, still produced significant upper and very mild lower respiratory symptoms in vaccinees encountering the virus for the first time (Kim et al., 1973). Moreover, there was evidence that these vaccines did not protect completely (Wright et al., 1976). There is reasonable hope that a subunit vaccine can be developed. This is particularly true if the glycoproteins responsible for protection can be identified and can be made by introducing cloned DNA fragments into appropriate cellular hosts. In light of the experience noted above and that with measles virus, further work is needed to understand the response of the immune system to administration of such antigens by various routes. Other expected difficulties involve growing this virus in large quantities and also purifying it or its proteins. Current Vaccine Development Recent vaccine development has focused primarily on three approaches: live vaccines administered parenterally, live attenuated vaccines administered in the respiratory tract, and investigations of the RSV genome with a view to producing virus antigens by recombinant DNA techniques. A vaccine grown in tissue culture and designed for subcutaneous administration was recently tested in a large number of young children (Belshe et al., 1982). This vaccine failed to protect, although it weakly stimulated antibody to RSV. Attenuated vaccines administered in the respiratory tract have been examined more extensively. The most promising candidates have been members of the temperature-sensitive mutant group developed by Chanock and his associates at the National Institutes of Health (Gharpure et al., 1969). The ts-1 vaccine, while considerably less pathogenic than earlier strains, still induced symptomatic illness, including otitis media and mild bronchitis, in unprimed infants. Attempts have been made to further mutagenize this strain and also to test the more attenuated ts-2 mutant. These attempts have not yet been successful. The prospects for developing vaccines from genetically engineered live strains also are reasonably promising. The genome of RSV has been sequenced and major products identified and cloned, as noted above (Collins and Wertz, 1985). This could lead the way to production of viral antigens by recombinant DNA techniques.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Clinical Trials The major problem anticipated in clinical trials of RSV vaccines is the necessity to examine infants in the first year of life. Live attenuated vaccines that are of sufficiently low pathogenicity to be safe in this group are likely to be minimally infectious in partially immune adult or older pediatric patients. Subunit vaccines administered to the respiratory mucosa may be easier to test, but they hold the definite, albeit small, risk of producing severe atypical disease on subsequent exposure to wild virus. However, as knowledge of the natural illness and natural immunity grows, the likelihood of repeating the experience with the killed parenteral vaccine diminishes. Needs for Further Vaccine Development Successful development of new RSV vaccines will depend on investigations in several areas. Researchers must learn more about natural immunity to RSV infection in infants and adults, and about the possible role of antigenic variants in recurrent RSV infections. Attempts to purify antigens from viruses grown in tissue culture and to produce intact antigens from cloned DNA fragments should be encouraged. REFERENCES Beem, M. 1967. Repeated infections with respiratory syncytial virus. J. Immunol. 98:1115–1122. Belshe, R.B., L.P.Van Voris, and M.A.Mufson. 1982. Parenteral administration of live respiratory syncytial virus vaccine: results of a field trial. J. Infect. Dis. 145(3):311–319. Bernstein, J.M., and R.J.Hruska. 1981. Respiratory syncytial virus proteins: Identification by immunoprecipitation. J.Virol. 38(1):278–285. Chin, J., R.L.Magoffin, L.A.Shearer, J.H.Schieble, and E.H. Lennette. 1969. Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am. J. Epidemiol. 89:449–463. Clyde, W.A., and F.W.Denny, eds. 1983. Workshop on acute respiratory diseases among children of the world. Pediatr. Res. 17:1023–1076. Coates, H.V., D.W.Alling, and R.M.Chanock. 1966. An antigenic analysis of respiratory syncytial virus isolates by a plaque reduction neutralization test. Am. J.Epidemiol. 89:299–313. Collins, P.L., and G.M.Wertz. 1983. cDNA cloning and transcriptional mapping of nine polyadenylylated RNAs encoded by the genome of human respiratory syncytial virus. Proc. Natl. Acad. Sci. 80(11):3208–3212. Collins, P.L., and G.M.Wertz. 1985. Gene products and genome organization of human respiratory syncytial virus. Pp. 297–298 in Vaccines 85. Molecular and Chemical Basis of Resistance to

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Parasitic, Bacterial, and Viral Diseases, R.M.Lerner, R.M.Chanock, and F.Brown, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Douglas, R.M., and E.Kerby-Eaton, eds. 1985. Acute Respiratory Infections in Childhood. Proceedings of an International Workshop, Sydney, Australia, August 1984. Sydney: University of Adelaide. Fulginiti, V.A., J.J.Eller, O.F.Sieber, J.W.Joyner, M.Minamitani, and G.Meiklejohn. 1969. Respiratory virus immunization, I. A field trial of two inactivated respiratory virus vaccines: An aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus infection. Am. J. Epidemiol. 89:435–448. Garvie, D.G., and J.Gray. 1980. Outbreak of respiratory syncytial virus infection in the elderly. Brit. Med. J. 281:1253–1254. Gharpure, M.A., P.F.Wright, and R.M.Chanock. 1969. Temperature-sensitive mutants of respiratory syncytial virus. J.Virol. 3:414–421. Glezen, W.P. 1984. Reactive airway disorders in children: Role of respiratory virus infections. Clin. Chest Med. 5:635–644. Glezen, W.P., A.Paredes, J.E.Allison, L.H.Taber, and A.L.Frank. 1981. Risk of respiratory syncytial virus infection for infants from low-income families in relationship to age, sex, ethnic group, and maternal antibody level. J. Pediatr. 98(5):708–715. Hall, C.B., J.T.McBride, E.E.Walsh, D.M.Bell, C.L.Gala, S.Hildreth, L.G. ten Eyck, and W.J.Hall. 1983. Aerosolized ribavirin treatment of infants with respiratory syncytial virus infection. A randomized double-blind study. N. Engl. J. Med. 308(24):1443–1447. Henderson, F.W., A.M.Collier, Jr., W.A.Clyde, and F.W.Denny. 1979. Respiratory-syncytial virus infection, reinfection and immunity. A prospective, longitudinal study in young children. N. Engl. J. Med. 300(10):530–534. Kapikian, A.Z., R.H.Mitchell, R.M.Chanock, R.A.Shvedoff, and C.E. Stewart. 1969. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am. J. Epidemiol. 89:405–421. Kim, H.W., J.G.Canchola, C.D.Brandt, G.Pyles, R.M.Chanock, K. Jensen, and R.H.Parrott. 1969. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J.Epidemiol. 89:422–434. Kim, H.W., J.O.Arrobio, C.D.Brandt, P.Wright, D.Hodes, R.M. Chanock, and R.H.Parrott. 1973. Safety and antigenicity of temperature sensitive (ts) mutant respiratory syncytial virus (RSV) in infants and children. Pediatrics 52:56–63. MacDonald, N.E., C.B.Hall, S.C.Suffin, C.Alexson, P.J.Harris, and J.A.Manning. 1982. Respiratory syncytial virus infection in infants with congenital heart disease. N. Engl. J. Med. 307(7):397–400. Mills, J., J.E.VanKirk, P.F.Wright, and R.M.Chanock. 1971. Experimental respiratory syncytial virus infection of adults. Possible mechanisms of resistance to infection and illness. J. Immunol. 107:123–130.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries National Institute of Allergy and Infectious Diseases. 1985. Program for Accelerated Development of New Vaccines. Progress Report. Bethesda, Md.: National Institutes of Health. Parrott, R.H., H.W.Kim, J.O.Arrobio, D.S.Hodes, B.R.Murphy, C.D. Brandt, E.Camargo, and R.M.Chanock. 1973. Epidemiology of respiratory syncytial virus infection in Washington, D.C. II. Infection and disease with respect to age, immunologic status, race and sex. Am. J.Epidemiol. 98:289–300. Taber, L.H., V.Knight, B.E.Gilbert, H.W.McClung, S.Z.Wilson, H.J. Norton, J.M.Thurson, W.H.Gordon, R.L.Atmar, and W.R.Schlaudt. 1983. Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics 72(5): 613–618. Venkatesan, S., N.Elango, and R.M.Chanock. 1983. Construction and characterization of cDNA clones for four respiratory syncytial viral genes. Proc. Natl. Acad. Sci. 80(5):1280–1284. Walsh, E.E., and J.Hruska. 1983. Monoclonal antibodies to respiratory syncytial virus proteins. Identification of the fusion protein. J. Virol. 47(1):171–177. Wright, P.F., T.Shinozaki, W.Fleet, S.H.Sell, J.Thompson, and D.T. Karzon. 1976. Evaluation of a live, attenuated respiratory syncytial virus vaccine in infants. J.Pediatr. 88(6):931–936.