- Email: [email protected]
Treatment and prevention options for respiratory syncytial virus infections
Treatment and prevention options for respiratory syncytial virus infections Myron J. Levin, MD From the Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Denver Although the therapeutic antiviral agents ribavirin and a m a n t a d i n e ameliorate illness caused by influenza A and respiratory syncytial virus (RSV) in children, these agents are used infrequently b e c a u s e they are not cost-effective. Research currently is directed toward defining the high-risk groups for which these antiviral drugs should be used. Treatment of severe respiratory infection with specific immune globulin, either a l o n e or in c o m b i n a t i o n with antiviral drugs, is another therapeutic a p p r o a c h . Prevention of viral respiratory diseases is preferable b e c a u s e some lung d a m a g e occurs before the beginning of treatment, and d a m a g e resulting from the immune response may continue even after the virus is inhibited. As natural history and animal studies suggest, passive immunization can be a c h i e v e d for neonates through active immunization of the mother during pregnancy. However, this a p p r o a c h is limited by the half-life of the transferred antibodies and the lack of a n t i b o d y in premature infants. Standard immune globulin does not contain sufficient RSV neutralizing a n t i b o d y titer to fully protect against severe RSV illness. Passive immunization with RSV immune globulin in infants and children has been shown to prevent or attenuate RSV in high-risk groups. Active immunization against some respiratory viruses has been a c h i e v e d by administration of inactive virus (or their subunits), recombinant viral antigens, and live attenuated virus. Large trials are under way to determine the safety and immunogenicity of these vaccines for children in whom y o u n g a g e and serious underlying illness are significant barriers to primary immune response. The current research environment is suitable for the d e v e l o p m e n t of an immunization strategy to prevent many of the significant respiratory infections in children. (J PEDIATR1994;124:S22-S7)
In terms of individual morbidity and social costs, respiratory syncytial Virus is the most important viral respiratory pathogen in children, worldwide. A ubiquitous illness, RSV infection occurs in epidemics every year. Individuals can be infected with RSV more than once in childhood, l' 2 Moreover, RSV rivals the influenza viruses as a viral cause of epidemic disease in elderly persons. 3, 4
Reprint requests: Myron J. Levin, MD, Departments of Pediatrics and Medicine, University of Colorado, 4200 E. Ninth Ave., Room 10227, Denver, CO 80262. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/0/53629
$22
TREATMENT
OF C L I N I C A L D I S E A S E
Ribavirin. Ribavirin is a nucleoside analog with good in vitro activity against RSV. 5 Because ribavirin inhibits RSV at multiple sites, 6 presumably at separate stages of viral IVIG RSV RSVIG
Intravenously administered immune globulin Respiratory syncytial virus RSV immune globulin
gene replication, clinical resistance has not been observed. Even in the rare instances when ribavirin was administered for more than 100 days to immunocompromised children, clinical resistance was not seen (Simoes et al.: unpublished data). The initial mechanical problems of delivering this
The Journal of Pediatrics Volume 124, Number 5, Part 2
drug by aerosol, especially to patients with an endotracheal tube in place, were solved, and in February 1993 ribavirin was approved for use with ventilators. Although studies report a statistically significant improvement in some clinical signs of RSV infection and in arterial oxygen saturation after administration of ribavirin, these effects are neither dramatic nor cost-effective for most patients. 7-9 This limitation is striking because the alveolar concentration of ribavirin exceeds the amount required to inhibit RSV in vitro by 100-fold to 500-fold. This may indicate the inability of ribavirin to penetrate to a crucial site of virus replication within the cells. Because the drug is too toxic for systemic administration for RSV disease, research is being concentrated on the identification of patient subsets that are predisposed to severe, prolonged disease and in which a significant antiviral effect would be beneficial. As summarized by the American Academy of Pediatrics, this patient population includes infants and children with underlying immunodeficiency, pulmonary disease, or cardiac disease (especially if pulmonary hypertension is present), pediatric patients hospitalized with severe RSV lower tract disease (partial pressure of oxygen <65 mm Hg or increasing partial pressure of carbon dioxide), and infants <6 weeks of age (especially if born prematurely).9 In addition, recent experience at several centers suggests that the high-risk period for normal infants extends through the first 3 months of life. 10 The value of ribavirin in the treatment of infants with RSV and underlying cardiopulmonary disease was demonstrated by Smith et al. 11 in a well-designed placebocontrolled trial. This trial included infants with RSVinduced respiratory failure, some with cardiopulmonary disease. Early antiviral therapy was associated with a reduction in the mean duration of mechanical ventilation, supplemental oxygen, and hospital stay. However, other well-designed but unpublished studies have failed to confirm these results. Because of the limitations and expense, the current practice in many centers limits ribavirin administration to high-risk patients. Nevertheless, ribavirin is the best modality we now have for RSV treatment. Ribavirin is administered to 18,000 to 20,000 patients in an average year, which is approximately one fourth of the number of patients hospitalized each year with RSV lower respiratory tract infection. Passive immunization therapy Basic principles. The shortcomings of ribavirin therapy have heightened the interest in specific immune therapy. This approach is centered on neutralization of glycoproteins on the surface of the viral envelope. These glycoproteins are essential for RSV to infect cells. The G glycopro-
Levin
S 23
tein is important for physical attachment to the cell; the F glycoprotein stimulates cell fusion, a pathologic feature of RSV infection. The F glycoprotein induces the process necessary for RSV entry into the cell. Although neutralization antibodies against both glycoproteins have been described, human and murine sera or monoclonal antibodies are much more likely to neutralize through the F glycoprotein site than the G glycoprotein site. 12, 13 The F glycoprotein is genetically stable in the two subgroups of RSV (RSV A and RSV B). This is an important difference from influenza A, in which epidemics frequently follow mutations in important neutralization epitopes. In RSV, several neutralization sites defined for the F protein are conserved in isolates spanning a 30-year period. I4 RSV A and RSV B are 50% related in the F glycoprotein and only I% to 5% related in the G glycoprotein. 15 Research has therefore concentrated on antibodies that neutralize at F sites, because of the ease with which anti-F neutralizing antibodies can be obtained and their ability to neutralize both viral subgroups efficiently.13 Intravenous immune globulin treatment. Infusion of purified human immune globulin with high titers of anti-RSV neutralizing antibody is effective in reducing RSV titers in the cotton rat. 16 This concept was tested in infants and children with RSV infection by means of large amounts of intravenously administered conventional immune globulin. Although nasal RSV shedding was reduced, there was only modest clinical improvement and no measurable effect on duration of hospital stay.~7 This study is currently being repeated with an RSV immune globulin prepared from human donor plasma that was selected for high RSV antibody titers (Rodriguez et al.: personal communication). This well-designed trial, now in its third year, includes 90 normal patients and 120 high-risk patients, and should give a definitive evaluation of such therapy. Aerosolized anti-RSV antibody. This unique approach is firmly based on successful animal research in which topically administered (endotracheal tube) immune globulin or aerosolized immune globulin greatly reduced viral titer.18-2o Locally administered immune globulin is equal to or superior to the same product administered parenterally. Relevant to medical cost issues, 100 to 200 times less immune globulin was required for equivalent therapy when administered by aerosol. Moreover, even greater protection would be expected from RSV-specific immune globulin. Administration of immune globulin by aerosol is safe in animals, and is also validated for parainfluenza 3 and adenovirus 5 infections in animals (Hemming et al.: unpublished observations). Unpublished work by the same investigators indicates that simultaneous aerosol administration of triamci-
S 24
Levin
nolone with immune globulin on the fifth day of infection markedly reduces the histologic evidence of RSV bronchiolitis and pneumonia in the rat model. Phase I and II trials of aerosolized immune globulin are beginning in human subjects. An unpublished Swiss study was performed with aerosolized conventional immune globulin in the treatment of hospitalized children with RSV bronchiolitis. Once the sugar and other additives in the immune globulin were adjusted, this therapy was well tolerated and effective. This approach is predicated on the availability of relatively inexpensive ultrasonic devices, capable of generating particles (<2 #m aerodynamic mass median diameter) that can reach small bronchioles and alveoli. Similar to the simultaneous use of corticosteroids and immune globulin, the use of ribavirin with IVIG in animal models has suggested an additive effect. 21 The extensive effort to develop broadly reactive, very-high-titer neutralizing monoclonal antibodies should expedite and enhance immunotherapy by any route. 13 Monoclonal antibodies are active in animal models. 22, 23 The availability of monoelonal antibodies should reduce the volume required for therapy. With the volume required for therapy reduced, intramuscular therapy might be substituted for intravenous therapy; smaller volumes also could be given by aerosol. This may reduce costs and, because fewer individual proteins are administered, reduce reactogenicity. PREVENTION Superiority of preventive strategies. The effects of treatment with ribavirin or IVIG in human beings are modest because significant pulmonary damage is present before symptoms draw attention to the infection, and because lung damage is largely due to the immune response, which continues even after all virus is inhibited. 24 Prevention is also preferable because it is, invariably, a less expensive approach and usually an office-based procedure. Antiviral prophylaxis. An experiment, best described as "early intervention therapy," was undertaken by Groothuis et a l Y in which children with severe bronchopulmonary dysplasia were closely monitored for early symptoms of viral respiratory infection. A random cohort with early symptoms, regardless of the severity of their illness, were treated at home or in the hospital for 3 to 5 days with aerosolized ribavirin. Early ribavirin treatment improved oxygenation and some clinical signs more rapidly in the treated group; however, there was no significant effect on the incidence of moderate-to-severe RSV disease or on duration of hospitalization. Passive immunization. The article in this supplement
The Journal of Pediatrics May 1994
written by Dr. Groothuis describes the success of passive immunization with RSVIG in preventing or attenuating RSV infection in high-risk infants and children. 26 This study proves that humoral immunity is sufficient for limiting damage induced by RSV infection in human beings. Animal studies suggest that this effect is through a cell-independent direct neutralization of virus. 27 Most infants <3 months of age, the high-risk group of healthy children, are not considered candidates for RSVIG therapy. This therapy is reserved for children who have an identified underlying illness that predisposes them to severe RSV infection. Passively acquired maternal anti-RSV antibody favorably influences the severity of RSV infection in early infancy. 2s3° During early infancy, any active immunization strategy is difficult to implement. One possible approach to this problem is maternal immunization, which should significantly increase maternal antibody levels and, secondarily, enhance perinatal levels in children born after 32 weeks of gestation. Early trials of candidate vaccines in postpartum women are under way, but there are many potential problems to be solved before trials of these vaccines can be conducted during pregnancy. Active immunization Formalin-inactivated vaccine. The experience more than 25 years ago with this vaccine has profoundly influenced the pace and design of subsequent attempts to achieve active immunization. A vaccine consisting of alum-precipitated, concentrated, formalin-inactivated R s v significantly increased neutralizing antibody in 50% of RSVnaive vaccinees and increased complement-fixing antibodies in almost all vaccinees. However, not only did the vaccine fail to prevent infection, it increased the severity of the illness in children who subsequently became infected; hospitalization was 15 times more likely in vaccines.31, 32 This phenomenon was reproduced in animal models by means of the original vaccine, obtained from cold storage. 33 Naive animals were vaccinated as in human trials and challenged with the wild type of virus. Analysis of these models offered a multifactorial explanation for the previous untoward vaccine response. One explanation is that the vaccine induced a high titer of antibody that bound to virus, but failed to induce a strong neutralizing response. Therefore RSV grew unchecked in the lungs of the vaccinees. The nonprotective nature of this antibody response to the formalin-inactivated vaccine was demonstrated by passive transfer experiments in animals. A second explanation is that the vaccine stimulated a population of lymphocytes (CD4 +) that infiltrated RSV-infected tissue but were not cytotoxic to the RSV, which resulted in the enhanced
The Journal of Pediatrics Volume 124, Number 5, Part 2
pathologic response. In animals depleted of these cells, the deleterious response was ablated. Regardless of the precise mechanism of this phenomenon, any attempt to pursue an inactivated vaccine strategy in very young infants and children will have to proceed very slowly. Subunit vaccines. Subunit vaccines, consisting of F or G antigens or fusion polypeptides containing both F and G epitopes, have been produced by recombinant DNA techniques. These vaccines have not been tested in human subjects. Other vaccines containing immunoaffinity-purifiedF proteins from RSV-infected tissue culture are under study in healthy children.34-37 Because of the untoward response with the formalin-inactivated vaccine, these studies are limited to infants and children with a prior RSV infection who are at least 18 months of age. Generally, these vaccines stimulate large amounts of binding antibody and lesser amounts of neutralizing antibody, and induce variable degrees of protection. The studies are too small to evaluate protection against significant lower respiratory tract disease. However, it is important that no enhanced disease was observed in vaccinees in whom RSV infection developed. At the same time, some vaccinees did have a febrile, wheezing illness. Because some of these vaccines caused enhanced disease in animal models in some laboratories,3s, 39 there is great uncertainty as to how to introduce these vaccines to previously uninfected infants. Their questionable efficacy in individuals who are already immune creates doubt that they Will be effective in unprimed individuals. Live, attenuated vaccines. In the 1960s and 1970s, Vaccine virus strains were produced by cold adaptation so that they would grow poorly at core body temperature (e.g., in the upper nostrils and lower respiratory tract). Attempts to use these vaccines failed either because they were inadequately attenuated and caused significant symptoms (mostly upper respiratory tract infections or otitis) or because they were too attenuated to replicate sufficiently to induce a good immune response.4°, 41 However, one important finding from these studies was the absence of any enhanced disease after subsequent natural infection. Several pharmaceutical firms and the National Institutes of Health have prepared new live attenuated vaccines. These RSV mutants have additional temperature-sensitive sites to ensure minimal reactogenicity, but they retain their immunogenicity. In primate models, these mutants do not cause disease, do stimulate good or balanced antibody responses, do not revert to the wild type of virus (after 10 days in the monkey), and do render the animals resistant to
Levin
S 25
challenge with wild RSV (B. Murphy: personal communication). Live vaccines apparently stimulate local immunity, as demonstrated by a 4-log suppression in the replication of RSV in the nose of immunized animals. This is probably an important feature for any successful vaccine. By comparison, subunit vaccines stimulate very little local IgA response. THE FUTURE Ribavirin will remain a useful therapy for infections for which no immunologic strategies are devised. RSVIG may have a role in treating RSV infection, alone or in combination with ribavirin, whether administered intravenously or by aerosol. RSVIG will be useful in protecting very young infants and high-risk infants and children in the absence of a vaccine. Maternal immunization may eventually be useful for protecting some of these infants. Although active immunization is the ideal approach, this goal is complicated by concern about the safety of subunit vaccines and their limited efficacy. In addition, it will be difficult to introduce these vaccines to young seronegative infants. Live attenuated vaccines may be the solution, provided that their safety can be established for high-risk children. These vaccines offer the advantage of stimulating local mucosal immunity, and are likely to be more immunogenic than subunit vaccines for very young infants. Active immunization may be difficult, as demonstrated by the failure of natural RSV infection to protect fully against subsequent infection. REFERENCES
1. GlezenWP, Taber LH, Frank AL, Kasal JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;140:530-6. 2. Groothuis JR, Salbenblatt CK, Lauer BA. Severe respiratory syncytial virus infection in older children. Am J Dis Child 1990;144:346-8. 3. Falsey AR, Walsh EE, Betts RF. Serologic evidenceof respiratory syncytial virus infection in nursing home patients. J Infect Dis 1990;162:568-9. 4. Cunningham C, Falsey A, Weiner L, et al. Respiratory syncytial virus (RSV) infection in ambulatory and hospitalized patients -->65 years. Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana, p. 372. 5. McIntosh K. Chemotherapy of respiratory syncytial virus infections. In: Mills J, Corey L, eds. Antiviral chemotherapy: new directionsfor clinical applicationand research. New York: Elsevier, 1986:83-8. 6. Patterson JL, Fernandez-Larsson R. Molecular mechanisms of action of ribavirin. Rev Infect Dis 1990;12:1139-45.
S26
Levin
7. Hall CB, McBride JT, Walsh EE, et al. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection: a randomized double-blind study. N Engl J Med 1983; 308:1443-7. 8. Wald ER, Dashefsky B, Green M, et al. In re ribavirin: a case of premature adjudication? J PEDIATR 1988;112:154-8. 9. Committee on Infectious Diseases, American Academy of Pediatrics. Use of ribavirin in the treatment of respiratory syncytial virus infection. Pediatrics 1993;92:501-3. 10. Gruber W, Edwards K, Reed G, Wright P. Respiratory syncytial virus (RSV) infection in outpatient and inpatient populations: implications for effective intervention. Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana, p. 260. 11. Smith DW, Frankel LR, Mathers LH, et al. A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med 1991;325:24-9. 12. Olmstead RA, Elango N, Prince GA, et al. Expression of the F glycoprotein of respiratory syncytial virus by a recombinant vaccinia virus: comparison of the individual contributions of the F and G glycoproteins to host immunity. Proc Natl Acad Sci USA 1986;83:7462-6. 13. Barbas CF III, Crowe JE Jr, Cababa D, et al. Human monoclonal Fab fragments derived from a combinatorial library bind to respiratory syncytial virus F glycoprotein and neutralize infectivity. Proc Nat1 Acad Sci USA 1992;89: 10164-8. 14. Beeler JA, van Wyke Coelingh K. Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: effect of mutation upon fusion function. J Virol 1989;63:2941-50. 15. Johnson PR, Collins PL. The fusion glycoproteins of human respiratory syncytial virus of subgroups A and B: sequence conservation provides a structural basis for antigenic relatedness. J Gen Virol 1988;69:2623-8. 16. Prince GA, Hemming VG, Horswood RL, Chanock RM. Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in the cotton rat. Virus Res 1985;3:193206. 17. Hemming VG, Rodriguez W, Kim HW, et al. Intravenous immunoglobulin treatment of respiratory syncytial virus infections in infants and young children. Antimicrob Agents Chemother 1987;31:1882-6. 18. Prince GA, Hemming VG, Horswood RL, et al. Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats. J Virol 1987;61:1851-4. 19. Hemming VG, Prince GA, London WT, et al. Topically administered immunoglobulin reduces pulmonary respiratory syncytial virus shedding in owl monkeys. Antimicrob Agents Chemother 1988;32:1269-70. 20. Piazza FM, Johnson SA, Ottolini MG, et al. Immunotherapy of respiratory syncytial virus infection in cotton rats (Sigmodonfulviventer) using IgG in a small-particle aerosol. J Infect Dis 1992;166:1422-4. 21. Gruber WC, Wilson SZ, Throop BJ, Wyde PR. Immunoglobulin administration and ribavirin therapy: efficacy in respiratory syncytial virus infection of the cotton rat. Pediatr Res 1987;21:270-4.
The Journal of Pediatrics May 1994
22. Walsh EE, Shlesinger J J, Brandriss MW. Protection from respiratory syncytial virus infection in cotton rats by passive transfer of monoclonal antibodies. Infect Immun 1984; 43:756-8. 23. Taylor G, Stott E J, Bew M, et al. Monoclonal antibodies protect against respiratory syncytial virus. Lancet 1983;2: 976-8. 24. Aherne W, Bird T, Court SDM, et al. Pathological changes in virus infection of the lower respiratory tract in children. J Clin Pathol 1970;23:7-18. 25. Groothuis JR, Woodin KA, Katz R, et al. Early ribavirin treatment of respiratory syneytial viral infection in high-risk children. J PEDIATR 1990;117:792-8. 26. Groothuis JR, Simoes EAF, Levin M J, et al. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 1993; 329:1524-30. 27. Prince GA, Hemming VG, Horswood RL, et al. Mechanism of antibody-mediated viral clearance in immunotherapy of respiratory syncytial virus infection of cotton rats. J Virol 1990;64:3091-2. 28. Glezen WP, Parades A, Allison JE, et al. 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 1981;98:708-15. 29. Bruhn FW, Yeager AS. Respiratory syncytial virus in early infancy: circulating antibody and the severity of infection. Am J Dis Child 1977;131:145-8. 30. Ward KA, Lamden PR, Olgivie MM, Watt PJ. Antibodies to respiratory syncytial virus peptides and their significance in human infection J Gen Virol 1983;64:1867-76. 31. Kim HW, Canchola JG, Brandt CD, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 1969;89:42234. 32. Fulginiti VA, Eller J J, Sieber OF, et al. 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 1969;89:435-48. 33. Murphy BR, Sotnikov A, Lawrence L, et al. Enhanced pulmonary histopathology is seen in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein following RSV challenge 3 or 6 months after immunization. Vaccine 1990;8:497-502. 34. Tristram DA, Welliver RC, Mohar CK, et al. Immunogenieity and safety of respiratory syncytial virus subunit vaccine in seropositive children 18-36 months old. J Infect Dis 1993; 167:191-5. 35. Tristram DA, Hogerman D, Hildreth S, et al. Respiratory syncyfial-virus specific cell-mediated immune (RSV-CMI) responses following vaccination with purified fusion protein (PFP-2) subunit vaccine. Abstracts of the 33rd Interscience Conference on Anfimicrobial Agents and Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana: 261. 36. Simoes EAF, King SJ, Weinberg A, et al. Immunogenicity and safety of respiratory syncytial (RSV) fusion (F) protein vaccine (PFP-2) in high-risk seropositive children. Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and
The Journal o f Pediatrics Volume 124, Number 5, Part 2
Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana, p. 261. 37. Belshe RB, Anderson EL, Walsh EE. Immunogenicity of purified F glycoprotein of respiratory syncytial virus: clinical and immune responses to subsequent natural infection in children. J Infect Dis 1993;168:1024-9. 38. Connors M, Collins PL, Firestone CY, et al. Cotton rats previously immunized with a chimeric RSV FG glycoprotein develop enhanced pulmonary pathology when infected with RSV, a phenomenon not encountered following immunization with vaccinia-RSV recombinants or RSV. Vaccine 1992;10:47584.
Levin
S27
39. Hildreth S, Speelman D, Walsh E, et al. Subunit purified F protein (PFP) vaccine from respiratory syncytial virus (RSV): lack of vaccine-associated enhanced disease in cotton rats. Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana:347. 40. Wright PF, Belshe RB, Kim HW, et al. Administration of a highly attenuated, live respiratory syncytial virus vaccine to adults and children. Infect Immun 1982;37:397-400. 41. Belshe RB, Van Voris LP, Mufson MA. Parenteral administration of live respiratory syncytial virus vaccine: results of a field trial. J Infect Dis 1982;145:311-9.
In terms of individual morbidity and social costs, respiratory syncytial Virus is the most important viral respiratory pathogen in children, worldwide. A ubiquitous illness, RSV infection occurs in epidemics every year. Individuals can be infected with RSV more than once in childhood, l' 2 Moreover, RSV rivals the influenza viruses as a viral cause of epidemic disease in elderly persons. 3, 4
Reprint requests: Myron J. Levin, MD, Departments of Pediatrics and Medicine, University of Colorado, 4200 E. Ninth Ave., Room 10227, Denver, CO 80262. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/0/53629
$22
TREATMENT
OF C L I N I C A L D I S E A S E
Ribavirin. Ribavirin is a nucleoside analog with good in vitro activity against RSV. 5 Because ribavirin inhibits RSV at multiple sites, 6 presumably at separate stages of viral IVIG RSV RSVIG
Intravenously administered immune globulin Respiratory syncytial virus RSV immune globulin
gene replication, clinical resistance has not been observed. Even in the rare instances when ribavirin was administered for more than 100 days to immunocompromised children, clinical resistance was not seen (Simoes et al.: unpublished data). The initial mechanical problems of delivering this
The Journal of Pediatrics Volume 124, Number 5, Part 2
drug by aerosol, especially to patients with an endotracheal tube in place, were solved, and in February 1993 ribavirin was approved for use with ventilators. Although studies report a statistically significant improvement in some clinical signs of RSV infection and in arterial oxygen saturation after administration of ribavirin, these effects are neither dramatic nor cost-effective for most patients. 7-9 This limitation is striking because the alveolar concentration of ribavirin exceeds the amount required to inhibit RSV in vitro by 100-fold to 500-fold. This may indicate the inability of ribavirin to penetrate to a crucial site of virus replication within the cells. Because the drug is too toxic for systemic administration for RSV disease, research is being concentrated on the identification of patient subsets that are predisposed to severe, prolonged disease and in which a significant antiviral effect would be beneficial. As summarized by the American Academy of Pediatrics, this patient population includes infants and children with underlying immunodeficiency, pulmonary disease, or cardiac disease (especially if pulmonary hypertension is present), pediatric patients hospitalized with severe RSV lower tract disease (partial pressure of oxygen <65 mm Hg or increasing partial pressure of carbon dioxide), and infants <6 weeks of age (especially if born prematurely).9 In addition, recent experience at several centers suggests that the high-risk period for normal infants extends through the first 3 months of life. 10 The value of ribavirin in the treatment of infants with RSV and underlying cardiopulmonary disease was demonstrated by Smith et al. 11 in a well-designed placebocontrolled trial. This trial included infants with RSVinduced respiratory failure, some with cardiopulmonary disease. Early antiviral therapy was associated with a reduction in the mean duration of mechanical ventilation, supplemental oxygen, and hospital stay. However, other well-designed but unpublished studies have failed to confirm these results. Because of the limitations and expense, the current practice in many centers limits ribavirin administration to high-risk patients. Nevertheless, ribavirin is the best modality we now have for RSV treatment. Ribavirin is administered to 18,000 to 20,000 patients in an average year, which is approximately one fourth of the number of patients hospitalized each year with RSV lower respiratory tract infection. Passive immunization therapy Basic principles. The shortcomings of ribavirin therapy have heightened the interest in specific immune therapy. This approach is centered on neutralization of glycoproteins on the surface of the viral envelope. These glycoproteins are essential for RSV to infect cells. The G glycopro-
Levin
S 23
tein is important for physical attachment to the cell; the F glycoprotein stimulates cell fusion, a pathologic feature of RSV infection. The F glycoprotein induces the process necessary for RSV entry into the cell. Although neutralization antibodies against both glycoproteins have been described, human and murine sera or monoclonal antibodies are much more likely to neutralize through the F glycoprotein site than the G glycoprotein site. 12, 13 The F glycoprotein is genetically stable in the two subgroups of RSV (RSV A and RSV B). This is an important difference from influenza A, in which epidemics frequently follow mutations in important neutralization epitopes. In RSV, several neutralization sites defined for the F protein are conserved in isolates spanning a 30-year period. I4 RSV A and RSV B are 50% related in the F glycoprotein and only I% to 5% related in the G glycoprotein. 15 Research has therefore concentrated on antibodies that neutralize at F sites, because of the ease with which anti-F neutralizing antibodies can be obtained and their ability to neutralize both viral subgroups efficiently.13 Intravenous immune globulin treatment. Infusion of purified human immune globulin with high titers of anti-RSV neutralizing antibody is effective in reducing RSV titers in the cotton rat. 16 This concept was tested in infants and children with RSV infection by means of large amounts of intravenously administered conventional immune globulin. Although nasal RSV shedding was reduced, there was only modest clinical improvement and no measurable effect on duration of hospital stay.~7 This study is currently being repeated with an RSV immune globulin prepared from human donor plasma that was selected for high RSV antibody titers (Rodriguez et al.: personal communication). This well-designed trial, now in its third year, includes 90 normal patients and 120 high-risk patients, and should give a definitive evaluation of such therapy. Aerosolized anti-RSV antibody. This unique approach is firmly based on successful animal research in which topically administered (endotracheal tube) immune globulin or aerosolized immune globulin greatly reduced viral titer.18-2o Locally administered immune globulin is equal to or superior to the same product administered parenterally. Relevant to medical cost issues, 100 to 200 times less immune globulin was required for equivalent therapy when administered by aerosol. Moreover, even greater protection would be expected from RSV-specific immune globulin. Administration of immune globulin by aerosol is safe in animals, and is also validated for parainfluenza 3 and adenovirus 5 infections in animals (Hemming et al.: unpublished observations). Unpublished work by the same investigators indicates that simultaneous aerosol administration of triamci-
S 24
Levin
nolone with immune globulin on the fifth day of infection markedly reduces the histologic evidence of RSV bronchiolitis and pneumonia in the rat model. Phase I and II trials of aerosolized immune globulin are beginning in human subjects. An unpublished Swiss study was performed with aerosolized conventional immune globulin in the treatment of hospitalized children with RSV bronchiolitis. Once the sugar and other additives in the immune globulin were adjusted, this therapy was well tolerated and effective. This approach is predicated on the availability of relatively inexpensive ultrasonic devices, capable of generating particles (<2 #m aerodynamic mass median diameter) that can reach small bronchioles and alveoli. Similar to the simultaneous use of corticosteroids and immune globulin, the use of ribavirin with IVIG in animal models has suggested an additive effect. 21 The extensive effort to develop broadly reactive, very-high-titer neutralizing monoclonal antibodies should expedite and enhance immunotherapy by any route. 13 Monoclonal antibodies are active in animal models. 22, 23 The availability of monoelonal antibodies should reduce the volume required for therapy. With the volume required for therapy reduced, intramuscular therapy might be substituted for intravenous therapy; smaller volumes also could be given by aerosol. This may reduce costs and, because fewer individual proteins are administered, reduce reactogenicity. PREVENTION Superiority of preventive strategies. The effects of treatment with ribavirin or IVIG in human beings are modest because significant pulmonary damage is present before symptoms draw attention to the infection, and because lung damage is largely due to the immune response, which continues even after all virus is inhibited. 24 Prevention is also preferable because it is, invariably, a less expensive approach and usually an office-based procedure. Antiviral prophylaxis. An experiment, best described as "early intervention therapy," was undertaken by Groothuis et a l Y in which children with severe bronchopulmonary dysplasia were closely monitored for early symptoms of viral respiratory infection. A random cohort with early symptoms, regardless of the severity of their illness, were treated at home or in the hospital for 3 to 5 days with aerosolized ribavirin. Early ribavirin treatment improved oxygenation and some clinical signs more rapidly in the treated group; however, there was no significant effect on the incidence of moderate-to-severe RSV disease or on duration of hospitalization. Passive immunization. The article in this supplement
The Journal of Pediatrics May 1994
written by Dr. Groothuis describes the success of passive immunization with RSVIG in preventing or attenuating RSV infection in high-risk infants and children. 26 This study proves that humoral immunity is sufficient for limiting damage induced by RSV infection in human beings. Animal studies suggest that this effect is through a cell-independent direct neutralization of virus. 27 Most infants <3 months of age, the high-risk group of healthy children, are not considered candidates for RSVIG therapy. This therapy is reserved for children who have an identified underlying illness that predisposes them to severe RSV infection. Passively acquired maternal anti-RSV antibody favorably influences the severity of RSV infection in early infancy. 2s3° During early infancy, any active immunization strategy is difficult to implement. One possible approach to this problem is maternal immunization, which should significantly increase maternal antibody levels and, secondarily, enhance perinatal levels in children born after 32 weeks of gestation. Early trials of candidate vaccines in postpartum women are under way, but there are many potential problems to be solved before trials of these vaccines can be conducted during pregnancy. Active immunization Formalin-inactivated vaccine. The experience more than 25 years ago with this vaccine has profoundly influenced the pace and design of subsequent attempts to achieve active immunization. A vaccine consisting of alum-precipitated, concentrated, formalin-inactivated R s v significantly increased neutralizing antibody in 50% of RSVnaive vaccinees and increased complement-fixing antibodies in almost all vaccinees. However, not only did the vaccine fail to prevent infection, it increased the severity of the illness in children who subsequently became infected; hospitalization was 15 times more likely in vaccines.31, 32 This phenomenon was reproduced in animal models by means of the original vaccine, obtained from cold storage. 33 Naive animals were vaccinated as in human trials and challenged with the wild type of virus. Analysis of these models offered a multifactorial explanation for the previous untoward vaccine response. One explanation is that the vaccine induced a high titer of antibody that bound to virus, but failed to induce a strong neutralizing response. Therefore RSV grew unchecked in the lungs of the vaccinees. The nonprotective nature of this antibody response to the formalin-inactivated vaccine was demonstrated by passive transfer experiments in animals. A second explanation is that the vaccine stimulated a population of lymphocytes (CD4 +) that infiltrated RSV-infected tissue but were not cytotoxic to the RSV, which resulted in the enhanced
The Journal of Pediatrics Volume 124, Number 5, Part 2
pathologic response. In animals depleted of these cells, the deleterious response was ablated. Regardless of the precise mechanism of this phenomenon, any attempt to pursue an inactivated vaccine strategy in very young infants and children will have to proceed very slowly. Subunit vaccines. Subunit vaccines, consisting of F or G antigens or fusion polypeptides containing both F and G epitopes, have been produced by recombinant DNA techniques. These vaccines have not been tested in human subjects. Other vaccines containing immunoaffinity-purifiedF proteins from RSV-infected tissue culture are under study in healthy children.34-37 Because of the untoward response with the formalin-inactivated vaccine, these studies are limited to infants and children with a prior RSV infection who are at least 18 months of age. Generally, these vaccines stimulate large amounts of binding antibody and lesser amounts of neutralizing antibody, and induce variable degrees of protection. The studies are too small to evaluate protection against significant lower respiratory tract disease. However, it is important that no enhanced disease was observed in vaccinees in whom RSV infection developed. At the same time, some vaccinees did have a febrile, wheezing illness. Because some of these vaccines caused enhanced disease in animal models in some laboratories,3s, 39 there is great uncertainty as to how to introduce these vaccines to previously uninfected infants. Their questionable efficacy in individuals who are already immune creates doubt that they Will be effective in unprimed individuals. Live, attenuated vaccines. In the 1960s and 1970s, Vaccine virus strains were produced by cold adaptation so that they would grow poorly at core body temperature (e.g., in the upper nostrils and lower respiratory tract). Attempts to use these vaccines failed either because they were inadequately attenuated and caused significant symptoms (mostly upper respiratory tract infections or otitis) or because they were too attenuated to replicate sufficiently to induce a good immune response.4°, 41 However, one important finding from these studies was the absence of any enhanced disease after subsequent natural infection. Several pharmaceutical firms and the National Institutes of Health have prepared new live attenuated vaccines. These RSV mutants have additional temperature-sensitive sites to ensure minimal reactogenicity, but they retain their immunogenicity. In primate models, these mutants do not cause disease, do stimulate good or balanced antibody responses, do not revert to the wild type of virus (after 10 days in the monkey), and do render the animals resistant to
Levin
S 25
challenge with wild RSV (B. Murphy: personal communication). Live vaccines apparently stimulate local immunity, as demonstrated by a 4-log suppression in the replication of RSV in the nose of immunized animals. This is probably an important feature for any successful vaccine. By comparison, subunit vaccines stimulate very little local IgA response. THE FUTURE Ribavirin will remain a useful therapy for infections for which no immunologic strategies are devised. RSVIG may have a role in treating RSV infection, alone or in combination with ribavirin, whether administered intravenously or by aerosol. RSVIG will be useful in protecting very young infants and high-risk infants and children in the absence of a vaccine. Maternal immunization may eventually be useful for protecting some of these infants. Although active immunization is the ideal approach, this goal is complicated by concern about the safety of subunit vaccines and their limited efficacy. In addition, it will be difficult to introduce these vaccines to young seronegative infants. Live attenuated vaccines may be the solution, provided that their safety can be established for high-risk children. These vaccines offer the advantage of stimulating local mucosal immunity, and are likely to be more immunogenic than subunit vaccines for very young infants. Active immunization may be difficult, as demonstrated by the failure of natural RSV infection to protect fully against subsequent infection. REFERENCES
1. GlezenWP, Taber LH, Frank AL, Kasal JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;140:530-6. 2. Groothuis JR, Salbenblatt CK, Lauer BA. Severe respiratory syncytial virus infection in older children. Am J Dis Child 1990;144:346-8. 3. Falsey AR, Walsh EE, Betts RF. Serologic evidenceof respiratory syncytial virus infection in nursing home patients. J Infect Dis 1990;162:568-9. 4. Cunningham C, Falsey A, Weiner L, et al. Respiratory syncytial virus (RSV) infection in ambulatory and hospitalized patients -->65 years. Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana, p. 372. 5. McIntosh K. Chemotherapy of respiratory syncytial virus infections. In: Mills J, Corey L, eds. Antiviral chemotherapy: new directionsfor clinical applicationand research. New York: Elsevier, 1986:83-8. 6. Patterson JL, Fernandez-Larsson R. Molecular mechanisms of action of ribavirin. Rev Infect Dis 1990;12:1139-45.
S26
Levin
7. Hall CB, McBride JT, Walsh EE, et al. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection: a randomized double-blind study. N Engl J Med 1983; 308:1443-7. 8. Wald ER, Dashefsky B, Green M, et al. In re ribavirin: a case of premature adjudication? J PEDIATR 1988;112:154-8. 9. Committee on Infectious Diseases, American Academy of Pediatrics. Use of ribavirin in the treatment of respiratory syncytial virus infection. Pediatrics 1993;92:501-3. 10. Gruber W, Edwards K, Reed G, Wright P. Respiratory syncytial virus (RSV) infection in outpatient and inpatient populations: implications for effective intervention. Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana, p. 260. 11. Smith DW, Frankel LR, Mathers LH, et al. A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med 1991;325:24-9. 12. Olmstead RA, Elango N, Prince GA, et al. Expression of the F glycoprotein of respiratory syncytial virus by a recombinant vaccinia virus: comparison of the individual contributions of the F and G glycoproteins to host immunity. Proc Natl Acad Sci USA 1986;83:7462-6. 13. Barbas CF III, Crowe JE Jr, Cababa D, et al. Human monoclonal Fab fragments derived from a combinatorial library bind to respiratory syncytial virus F glycoprotein and neutralize infectivity. Proc Nat1 Acad Sci USA 1992;89: 10164-8. 14. Beeler JA, van Wyke Coelingh K. Neutralization epitopes of the F glycoprotein of respiratory syncytial virus: effect of mutation upon fusion function. J Virol 1989;63:2941-50. 15. Johnson PR, Collins PL. The fusion glycoproteins of human respiratory syncytial virus of subgroups A and B: sequence conservation provides a structural basis for antigenic relatedness. J Gen Virol 1988;69:2623-8. 16. Prince GA, Hemming VG, Horswood RL, Chanock RM. Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in the cotton rat. Virus Res 1985;3:193206. 17. Hemming VG, Rodriguez W, Kim HW, et al. Intravenous immunoglobulin treatment of respiratory syncytial virus infections in infants and young children. Antimicrob Agents Chemother 1987;31:1882-6. 18. Prince GA, Hemming VG, Horswood RL, et al. Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats. J Virol 1987;61:1851-4. 19. Hemming VG, Prince GA, London WT, et al. Topically administered immunoglobulin reduces pulmonary respiratory syncytial virus shedding in owl monkeys. Antimicrob Agents Chemother 1988;32:1269-70. 20. Piazza FM, Johnson SA, Ottolini MG, et al. Immunotherapy of respiratory syncytial virus infection in cotton rats (Sigmodonfulviventer) using IgG in a small-particle aerosol. J Infect Dis 1992;166:1422-4. 21. Gruber WC, Wilson SZ, Throop BJ, Wyde PR. Immunoglobulin administration and ribavirin therapy: efficacy in respiratory syncytial virus infection of the cotton rat. Pediatr Res 1987;21:270-4.
The Journal of Pediatrics May 1994
22. Walsh EE, Shlesinger J J, Brandriss MW. Protection from respiratory syncytial virus infection in cotton rats by passive transfer of monoclonal antibodies. Infect Immun 1984; 43:756-8. 23. Taylor G, Stott E J, Bew M, et al. Monoclonal antibodies protect against respiratory syncytial virus. Lancet 1983;2: 976-8. 24. Aherne W, Bird T, Court SDM, et al. Pathological changes in virus infection of the lower respiratory tract in children. J Clin Pathol 1970;23:7-18. 25. Groothuis JR, Woodin KA, Katz R, et al. Early ribavirin treatment of respiratory syneytial viral infection in high-risk children. J PEDIATR 1990;117:792-8. 26. Groothuis JR, Simoes EAF, Levin M J, et al. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 1993; 329:1524-30. 27. Prince GA, Hemming VG, Horswood RL, et al. Mechanism of antibody-mediated viral clearance in immunotherapy of respiratory syncytial virus infection of cotton rats. J Virol 1990;64:3091-2. 28. Glezen WP, Parades A, Allison JE, et al. 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 1981;98:708-15. 29. Bruhn FW, Yeager AS. Respiratory syncytial virus in early infancy: circulating antibody and the severity of infection. Am J Dis Child 1977;131:145-8. 30. Ward KA, Lamden PR, Olgivie MM, Watt PJ. Antibodies to respiratory syncytial virus peptides and their significance in human infection J Gen Virol 1983;64:1867-76. 31. Kim HW, Canchola JG, Brandt CD, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 1969;89:42234. 32. Fulginiti VA, Eller J J, Sieber OF, et al. 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 1969;89:435-48. 33. Murphy BR, Sotnikov A, Lawrence L, et al. Enhanced pulmonary histopathology is seen in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein following RSV challenge 3 or 6 months after immunization. Vaccine 1990;8:497-502. 34. Tristram DA, Welliver RC, Mohar CK, et al. Immunogenieity and safety of respiratory syncytial virus subunit vaccine in seropositive children 18-36 months old. J Infect Dis 1993; 167:191-5. 35. Tristram DA, Hogerman D, Hildreth S, et al. Respiratory syncyfial-virus specific cell-mediated immune (RSV-CMI) responses following vaccination with purified fusion protein (PFP-2) subunit vaccine. Abstracts of the 33rd Interscience Conference on Anfimicrobial Agents and Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana: 261. 36. Simoes EAF, King SJ, Weinberg A, et al. Immunogenicity and safety of respiratory syncytial (RSV) fusion (F) protein vaccine (PFP-2) in high-risk seropositive children. Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and
The Journal o f Pediatrics Volume 124, Number 5, Part 2
Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana, p. 261. 37. Belshe RB, Anderson EL, Walsh EE. Immunogenicity of purified F glycoprotein of respiratory syncytial virus: clinical and immune responses to subsequent natural infection in children. J Infect Dis 1993;168:1024-9. 38. Connors M, Collins PL, Firestone CY, et al. Cotton rats previously immunized with a chimeric RSV FG glycoprotein develop enhanced pulmonary pathology when infected with RSV, a phenomenon not encountered following immunization with vaccinia-RSV recombinants or RSV. Vaccine 1992;10:47584.
Levin
S27
39. Hildreth S, Speelman D, Walsh E, et al. Subunit purified F protein (PFP) vaccine from respiratory syncytial virus (RSV): lack of vaccine-associated enhanced disease in cotton rats. Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), October 17-20, 1993, New Orleans, Louisiana:347. 40. Wright PF, Belshe RB, Kim HW, et al. Administration of a highly attenuated, live respiratory syncytial virus vaccine to adults and children. Infect Immun 1982;37:397-400. 41. Belshe RB, Van Voris LP, Mufson MA. Parenteral administration of live respiratory syncytial virus vaccine: results of a field trial. J Infect Dis 1982;145:311-9.