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Appendix D-9
The Prospects for Immunizing Against Parainfluenza Viruses

Much of the information available on morbidity and mortality arising from parainfluenza virus infections is contained or referenced in the proceedings of two recent symposia on acute respiratory infections (Clyde and Denny, 1983; Douglas and Kerby-Eaton, 1985).

DISEASE DESCRIPTION

The disease problems caused by the four parainfluenza viruses (PIV) in developing countries have not been well characterized. Most of the specific information comes from developed countries. In the latter, PIV-1 and PIV-2 usually have been associated with croup (laryngotracheal bronchitis), while PIV-3 has been found more frequently with bronchiolitis and pneumonia. These are broad generalizations, however, and symptoms vary widely even on first infection. PIV-4 appears to cause only mild upper respiratory infections and has never been associated with severe disease in young children. The parainfluenza viruses reinfect frequently during childhood, but the diseases associated with reinfections are generally milder than those caused by initial infections.

PATHOGEN DESCRIPTION

The parainfluenza viruses are species in the Paramyxoviridae family. Much information exists about the two surface glycoproteins of paramyxoviruses. One, the HN protein, contains both hemagglutinating and neuraminidase activity (Scheid et al., 1972). These two activities may occupy separate sites on the HN molecule (Portner, 1981). In vitro studies of the other surface glycoprotein have shown that it has the

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-9 The Prospects for Immunizing Against Parainfluenza Viruses Much of the information available on morbidity and mortality arising from parainfluenza virus infections is contained or referenced in the proceedings of two recent symposia on acute respiratory infections (Clyde and Denny, 1983; Douglas and Kerby-Eaton, 1985). DISEASE DESCRIPTION The disease problems caused by the four parainfluenza viruses (PIV) in developing countries have not been well characterized. Most of the specific information comes from developed countries. In the latter, PIV-1 and PIV-2 usually have been associated with croup (laryngotracheal bronchitis), while PIV-3 has been found more frequently with bronchiolitis and pneumonia. These are broad generalizations, however, and symptoms vary widely even on first infection. PIV-4 appears to cause only mild upper respiratory infections and has never been associated with severe disease in young children. The parainfluenza viruses reinfect frequently during childhood, but the diseases associated with reinfections are generally milder than those caused by initial infections. PATHOGEN DESCRIPTION The parainfluenza viruses are species in the Paramyxoviridae family. Much information exists about the two surface glycoproteins of paramyxoviruses. One, the HN protein, contains both hemagglutinating and neuraminidase activity (Scheid et al., 1972). These two activities may occupy separate sites on the HN molecule (Portner, 1981). In vitro studies of the other surface glycoprotein have shown that it has the 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 capacity to fuse membranes and is responsible both for the formation of syncytia and for entry of the virus into the cell (Scheid and Choppin, 1974). Antibody to either glycoprotein is neutralizing, and antibody to the fusion protein also prevents cell-to-cell spread of the virus (Merz et al., 1980). The fusion proteins of measles and mumps viruses, closely related to paramyxoviruses, are antigenically denatured by formalin, and it is possible that early measles and parainfluenza vaccines failed for this reason. HOST IMMUNE RESPONSE Reinfections are common with PIV-1, PIV-2, and PIV-3. They appear to be most frequent with PIV-3 (Chanock et al., 1963). In addition, evidence from volunteer studies in adults suggests that secretory neutralizing antibody correlates better than serum antibody with protection against challenge with PIV-1 (Smith et al., 1966). It is assumed that this rule also holds for PIV-2 and PIV-3, although the assumption has not been proved, and information in children is scanty. Although there is some cross-reactivity between these three PIV types, cross-protection probably does not occur. There does not appear to be any serologic variation within each type. DISTRIBUTION OF DISEASE Geographic Distribution Seroepidemiological studies indicate that the parainfluenza viruses are ubiquitous; even isolated populations have been found to possess antibodies against them. The severity of diseases caused by the viruses and the age of initial infection may vary in different parts of the world, but little information is available on these topics. Croup appears to be less common in the developing world than in developed countries, but the reasons for this situation are not known: it is possible that the PIV infection simply takes a different clinical form. Also, it is unclear to what extent PIV infections play a role in the life-threatening respiratory diseases often seen in children in developing countries. Disease Burden Estimates Examining mortality statistics provides some perspective on the burden of parainfluenza virus 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

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries respiratory infections also begins to decline. The reasons for these shifts are complex, in part because of the effects of malnutrition, environmental pollution, and other risk factors. Even with complete mortality statistics it is difficult to establish the role of the parainfluenza viruses, because numerous other pathogens also cause respiratory infections in children. Respiratory syncytial virus (RSV) and adenoviruses (particularly in the Far East) produce similar symptoms. In addition, bacterial superinfections may occur and can contribute to mortality. The disease burden estimates for parainfluenza virus infection are shown in Table D-9.1, and their derivations are described in Appendix B. It should be emphasized that these estimates are uncertain because of the lack of data on parainfluenza in developing countries. Acute lower respiratory tract illness from parainfluenza virus infection may eventually contribute to chronic obstructive pulmonary disease (Glezen, 1984). However, no attempt has been made to include such a contribution in chronic morbidity estimates. This aspect of the disease burden of the parainfluenza viruses requires periodic reevaluation. PROBABLE VACCINE TARGET POPULATION The most severe illnesses caused by parainfluenza virus infections occur in the first years of life. Hence, the target population would be infants at the earliest feasible age. The simplest design for the use of a PIV vaccine would be to administer it during the first 6 months of life. The aim would be to prevent as much PIV-3 disease as possible and also to reduce PIV-1 and PIV-2 infections, which usually occur later (at least in the United States). It is likely that a subunit vaccine could be incorporated into the World Health Organization Expanded Program on Immunization (WHO-EPI) delivery schedules, possibly in combination with other vaccines that are delivered at an early age, e.g., DTP. Because high levels of passively acquired maternal antibody appear to play a role in protecting infants against parainfluenza viruses during the first year of life (Glezen et al., 1984), a vaccine administered to pregnant women also might be effective. Identification of an appropriate PIV vaccine candidate for pregnant women will require more research on the nature of antibodies induced by PIV infection and the extent to which they cross the placenta. Vaccine Preventable Illness* The vaccine envisaged by the committee would require two early doses and probably additional doses to boost or maintain immunity. In *   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 TABLE D-9.1 Disease Burden: Parainfluenza Viruses     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 58,410,000 3 4,321,500 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 11,682,000 5 864,300 5         C Severe pain, severe short-term impairment, or hospitalization 1,168,200 7 86,430 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 116,820 n.a. 8,643 n.a.   n.a.   n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries the United States, the major portion of illness caused by PIV-1 and PIV-2 occurs after 6 months, but the pattern of PIV-3 illness is similar to that of RSV, involving a considerable amount of severe illness under 6 months of age. The first dose of vaccine probably could be administered at about 6 weeks, with a second dose 2 to 3 months later. Vaccinees would be only partially protected during this period. All cases occurring in older age groups (6 months to 4 years) would be vaccine preventable. Deaths probably would occur predominantly in infants, with a disproportionate number in very young infants who would not be fully protected. Natural immunity is not fully protective or is short-lived, so reinfection does occur, although it is milder. Hence, the vaccine is predicted to reduce the severity of illness rather than totally prevent cases of the disease. Given these considerations, an estimated 80 percent of the total disease burden arising from parainfluenza virus illnesses in the developing world theoretically would be vaccine preventable. SUITABILITY FOR VACCINE CONTROL Diseases caused by parainfluenza viruses types 1 and 2 occur predominantly after 6 months of age in the United States, so an opportunity exists to deliver the vaccine prior to the peak of illness, assuming the distribution is the same in developing countries. A lower proportion of parainfluenza virus type 3 disease could be averted. While reinfection does occur, indicating that natural immunity is not fully protective, it is probable that a vaccine could, at a minimum, avert the more severe disease. Alternative Control Measures and Treatments No specific treatment exists for parainfluenza virus infection that is suitable for widespread use in developing countries. Antibiotic therapy may reduce the problems associated with secondary bacterial infections if they occur. In severe cases, supportive care (i.e., hospitalization) may reduce the fatality rate. Aerosolized ribavirin has been found to be useful in some situations (Gelfand et al., 1983; McIntosh et al., 1984). PROSPECTS FOR VACCINE DEVELOPMENT Prior experience with vaccine development has been limited. Trivalent formalin-inactivated PIV vaccines made in monkey kidney tissue cultures and tested in parallel with the killed RSV vaccine failed to protect against natural infection. Unlike the measles and RSV vaccines (Chanock et al., 1968; Fulginiti et al., 1967), however, the PIV vaccines did not induce paradoxically severe disease due to hypersensitivity (Fulginiti et al., 1969). Thus, there is no evidence

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries that highly antigenic parenterally administered vaccines would be harmful. However, based on the experience with measles virus it would be essential that an immunologically active fusion protein be present in the vaccine. Very little ongoing work is directed toward a PIV vaccine. All early attempts were with high-titer inactivated vaccines; mutant attenuated vaccines have not been examined. Predictions about the chances of successful development of PIV vaccines are difficult to make. Because reinfections with PIV-1 and PIV-2 appear to be less frequent than with PIV-3, it may be that these two serotypes will lend themselves more easily to the production of successful vaccines. However, lack of information about reinfections with PIV-1 and PIV-2 may be more a reflection of their epidemicity at 2-year intervals than of their ability to immunize by natural infection. The possibility that serum antibody to these two serotypes may protect against infection (Parrot et al., 1962) gives some hope that a parenteral vaccine of sufficient antigenicity (particularly with regard to the fusion protein) would be protective. Subunit vaccines may be a rational approach to these problems. it appears likely that these could be developed using either traditional or genetic engineering technology. All three PIV types can be grown in embryonated eggs, which are a possible source of large quantities of inexpensive antigen, which in turn could be purified and used in subunit vaccines. There is some information on the antigenicity of these egg-grown viruses when administered by the respiratory route (Wigley et al., 1970). It would be essential to have the F protein present in the antigenically active form in such a vaccine, that is, not formalin inactivated (Merz et al., 1980). Clinical Trials Clinical trials with PIV vaccines will be affected by several problems. The major target is the infant in the first year of life: potential vaccines would have to undergo extensive testing in adults and older children to demonstrate their safety. Attenuated vaccine viruses probably would replicate poorly in older individuals who are likely to be partially immune, so staged trials in progressively younger subjects would be difficult. Subunit vaccines administered parenterally or by the respiratory route might circumvent these problems to some extent, and this may prove to be a promising direction in PIV vaccine research. Vaccine development will depend on research in several areas. First, vaccines that preserve the antigenicity of the fusion protein need to be tested for their ability to prevent infections by PIV-1 and PIV-2. Second, more information is needed regarding the mechanisms by which small children develop immunity to respiratory viruses (e.g., researchers will need to determine whether vaccines will have to be administered directly to the respiratory mucosa). Third, more emphasis needs to be placed on molecular studies of the three PIV serotypes. The production of cloned cDNA coding for the surface

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries glycoproteins of all three PIV types should be a priority. Finally, detailed information on both the HN and the fusion proteins of all three types should be made available through studies of the glycoproteins themselves, their purification, and their chemistry. Some recent progress toward PIV vaccines has been reported by the National Institute of Allergy and Infectious Diseases (1985). Purified HN and F glycoproteins from PIV 3 have been developed by the University of Alabama as a candidate vaccine. Cold adapted PIV 3 mutants have been developed by investigators at Marshall College of Medicine, and tests in humans are planned. In addition, approaches using purified viral fusion proteins are being investigated (National Institute of Allergy and Infectious Diseases, 1985). REFERENCES Chanock, R.M., R.H.Parrott, K.M.Johnson, A.Z.Kapikian, and J.A. Bell. 1963. Myxoviruses: Parainfluenza. Am. Rev. Respir. Dis. 88(suppl.):152–166. Chanock, R.M., R.H.Parrott, A.Z.Kapikian, H.W.Kim, and C.D.Brandt. 1968. Possible role of immunological factors in the pathogenesis of RS virus lower respiratory tract disease. Perspect. Virol. VI:125–139. Clyde, W.A., and F.W.Denny, eds. 1983. Workshop on acute respiratory diseases among children of the world. Pediatr. Res. 17:1023–1076. Douglas, R.M., and E.Kerby-Eaton, eds. 1985. Acute Respiratory Infections in Childhood. Proceedings of an International Workshop, Sydney, August 1984. Sydney: University of Adelaide. Fulginiti, V.A., J.J.Eller, A.W.Downie, and C.H.Kempe. 1967. Altered reactivity to measles virus: Atypical measles in children previously immunized with inactivated measles virus vaccine. JAMA 202:1075–1080. 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 vaccine. Am. J. Epidemiol. 89:435–448. Gelfand, E.W., D.McCurdy, C.P.Rao, and P.J.Middleton. 1983. Ribavirin treatment of viral pneumonitis in severe combined immunodeficiency disease. Lancet II:732–733. Glezen, W.P. 1984. Reactive airway disorders in children: Role of respiratory virus infections. Clin. Chest Med. 5:635–644. Glezen, W.P., A.L.Frank, L.H.Taber, and J.A.Kasel. 1984. Parainfluenza virus type 3: Seasonality and risk of infection and reinfection in young children. J. Infect. Dis. 150:851–857. McIntosh, K., S.C.Kurachek, L.M.Cairns, J.C.Burns, and B.Goodspeed. 1984. Treatment of respiration infection in an immunodeficient infant with ribavirin aerosol. Am. J. Dis. Child. 138(3):305–308.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Merz, D.C., A.Scheid, and P.W.Choppin. 1980. Importance of antibodies to the fusion glycoprotein of paramyxoviruses in the prevention of spread of infection. J. Exp. Med. 151:275–288. 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., A.J.Vargosko, H.W.Kim, J.A.Bellanti, and R.M. Chanock. 1962. III. Myxoviruses parainfluenza. Am. J. Public Health 52:907–917. Portner, A. 1981. The HN glycoprotein of Sendai virus: Analysis of site(s) involved in hemagglutinating and neuraminidase activities. Virology 115:375–384. Scheid, A., and P.W.Choppin. 1974. Identification of biologicalactivities of paramyxovirus glycoproteins. Activation of cell fusion, hemolysis and infectivity by proteolytic cleavage of an inactive precursor protein of Sendai Virus. Virology 57:475–490. Scheid, A., A.L.Caliguiri, R.W.Compans, and P.W.Choppin. 1972. Isolation of paramyxovirus glycoprotein. Association of both hemagglutinating and neuraminidase activities with the larger SV5 glycoprotein. Virology 50:640–652. Smith, C.B., R.H.Purcell, J.A.Bellanti, and R.M.Chanock. 1966. Protective effect of antibody to parainfluenza type 1 virus. N. Engl. J. Med. 275:1145–1152. Wigley, F.M., M.H.Fruchtman, and R.H.Waldman. 1970. Aerosol immunization of humans with inactivated parainfluenza type 2 vaccine. N. Engl. J. Med. 283:1250–1253.