Atypical Measles and Enhanced Respiratory Syncytial Virus Disease (ERD) Made Simple


Atypical measles and enhanced respiratory syncytial virus disease (ERD) were serious diseases that resulted from exposure of children immunized with inactivated vaccines against measles virus (MV) and respiratory syncytial virus (RSV) to the respective wild-type agents in the 1960s. Although the clinical manifestations of both illnesses were different, the immune responses elicited and primed for by the vaccines shared important similarities. Both vaccines failed to elicit long-lived protective antibody and to promote cytotoxic T lymphocyte responses. In both cases, postvaccination exposure to wild type virus during community outbreaks was associated with immune complex deposition in affected tissues, vigorous CD4+ T lymphocyte proliferative responses, and a Th2 bias of the immune response. No relapses of atypical measles or ERD were ever reported. In this manuscript, the pathogeneses of both enhanced diseases and the requirements for the generation of protective antibodies against MV and RSV are discussed, to contribute to the development of newer safe and effective vaccines against these important pathogens.


Paramyxoviruses are important agents of diseases in children. Among them, measles virus (MV) and respiratory syncytial virus (RSV) have been recognized for decades as causes of pediatric illnesses associated with significant morbidity (1,2). While a protective live attenuated vaccine against MV (LAV) is available for older infants and children, seroconversion rates are lower in young infants and no vaccine has been licensed against RSV. Protecting young infants against MV and RSV is important. In the 1960s, formalin-inactivated vaccines against these agents were developed and administered to infants and children in the United States (38). The vaccines were not protective, and primed for severe forms of disease in individuals exposed to the respective wild-type viruses (312).

Although the pathogeneses of the enhanced illnesses elicited by MV and RSV have been studied separately for decades, both diseases share important similarities in their mechanisms of illness. In this manuscript, we discuss the similarities and specific differences between atypical measles and enhanced RSV disease (ERD). Understanding the pathogeneses of these vaccine-enhanced diseases is important for the development of safe, newer vaccines against paramyxoviruses.

Measles virus.

MV is responsible for hundreds of thousands of deaths every year in developing countries, despite the availability of a safe and effective LAV (1). The vaccine is immunogenic when administered to infants and young children 9–15 months of age, but seroconversion rates are lower in infants under the age of 9 months due to the presence of interfering transplacentally acquired maternal antibody and the immune immaturity of the host (13,14). In developing countries with high rates of measles, infants are often exposed to the virus before the age of 9 months and represent an important number of the fatalities caused by the virus every year (1). For this reason, expanding vaccine coverage in affected areas and/or developing new immunization strategies for young infants is important if this “window of susceptibility” is to be closed.

In the 1960s, inactivated vaccines against MV were introduced in the United States and Europe (712). The formalin-inactivated MV vaccine (FIMV) licensed in the States was immunogenic, but antibody waned within months to a couple of years (7). Fifteen to sixty percent of immunized children subsequently exposed to wild-type MV during community outbreaks developed a severe form of disease called atypical measles (712). Atypical measles was characterized by high fever, a petechial or morbiliform rash that began on the extremities and a severe pneumonitis (712). Other clinical manifestations, including abdominal pain, eosinophilia and hepatic dysfunction were also described (712). The disease was severe enough to warrant hospitalization in many cases (712). The vaccine was withdrawn in 1967 because of these problems.

Respiratory syncytial virus.

Respiratory syncytial virus (RSV) is the main viral respiratory cause of hospitalization in infants and young children worldwide (2). More than 50% of infants experience an RSV infection during their first seasonal encounter with the virus, and over 90% have become infected by the end of the second season of RSV exposure (2,15). Most of these primary infections are symptomatic and 30–70% of them manifest as lower respiratory illness (LRI) with bronchiolitis and/or pneumonia. Reinfections occur through life and are usually symptomatic, although they do not generally cause LRI in immunocompetent adults and healthy older children (2).

In 1961, a formalin-inactivated vaccine against RSV (FIRSV) was developed using the Bernett strain of RSV passaged in human embryonic kidney cells (×3) and vervet monkey kidney cells (×10) (3). RSV was inactivated by incubation with 0.4% formaldehyde for 72 h and adsorbed to 4 mg/mL of aluminum hydroxide. The vaccine was administered in 1–3 doses to RSV-seronegative and RSV-seropositive infants and children during 1966 (36). Control groups of children received a formalin-inactivated parainfluenza vaccine (35) or no vaccine (6). The vaccine was immunogenic, but elicited mainly nonprotective antibodies. During the winter of 1966–1967, immunized children were exposed to RSV in the community, and those that were seronegative for the virus before vaccination experienced a significant increase in the frequency and severity of LRI and a greater incidence of hospitalization compared with control children (36). The main clinical manifestations in these children included bronchoconstriction and pneumonia (36). Furthermore, two immunized infants died as toddlers as a consequence of subsequent RSV infection (3). Autopsy material showed bronchopneumonia, atelectases, and pneumothoraces (3). Histopathology was reported as a “peribronchiolar monocytic infiltration with some excess in eosinophils” (3). High titers of RSV were recovered from the lungs of the two children (3). No vaccine against RSV has been licensed since.


Atypical measles.

Several hypotheses were advanced to explain the pathogenesis of atypical measles, including a MV-derived delayed type hypersensitivity response and a generalized Arthus reaction (1620). Perhaps the most widely accepted hypothesis early on was that atypical measles resulted from an imbalance in the antibody response to the MV glycoproteins hemagglutinin (HA) and fusion (F) elicited by the inactivated vaccine (21,22). Based on tissue culture experiments with a related paramyxovirus, simian virus 5, it was suggested that low levels of antibody against MV F – following a postulated disruption of the protein during formalin inactivation- allowed extensive spread of the virus via cell-to-cell fusion leading to more severe disease (23).

Enhanced respiratory syncytial virus disease.

The question about the mechanism of illness in ERD has dominated the RSV literature for decades. Given the histopathology described in lung sections from affected children (3), a number of models of ERD have focused on the development of pulmonary eosinophilia and Th2 responses (2427). The eosinophilia has been ascribed –as in the case of atypical measles- to an imbalance in the RSV glycoproteins present in the formalin-inactivated vaccine. A dominant immune response against the RSV attachment protein (G), associated again with the presumptive disruption of the fusion (RSV F) protein during formalin inactivation, was postulated to prime for lung eosinophilia and Th2 bias in affected individuals (2527).


Several similarities are apparent upon examination of the immune manifestations that characterized atypical measles and ERD.

First, both FIMV and FIRSV failed to elicit long-lived protective antibodies in children and– as expected for inactivated vaccines- did not elicit a detectable virus-specific cytotoxic T lymphocyte (CTL) response (38,2831). Early determinations of the neutralizing capacity of sera from children immunized with FIMV using Vero cells suggested that these antibodies were protective against MV. However, the clinical manifestations of children and macaques with atypical measles demonstrated that the abundant anamnestic antibody response observed early after challenge was not protective (28,29) and that transient protection after vaccination was probably explained by steric hindrance of critical epitopes. In ERD, antibodies in mice and humans had high anti-RSV F EIA/anti-RSV neutralization ratios, also suggesting poor protective efficacy (live RSV infections elicit antibody responses of low EIA/neutralization ratios) (46). Furthermore, high titers of RSV were recovered from lung sections of affected children, clearly establishing the lack of protection (3).

Second, exposure to wild type viruses led to strong proliferative CD4+ T lymphocyte responses (32,33) and a Th2 polarization of the immune response in both diseases. In rhesus macaques with atypical measles, this Th2 bias was characterized by early suppression of IL-12 (IL-12) secretion by monocytes, followed by pulmonary eosinophilia and late production of IL-4 (34). In animal models of ERD, pulmonary eosinophilia and production of Th2 cytokines have been frequently reported (3537). In fact, formalin inactivation has also been noted to favor a Th2 bias (38). Yet, it is important to highlight that certain mouse strains, cotton rats, and cattle with ERD present pulmonary infiltrates dominated by neutrophils, and not eosinophils (3941). Furthermore, revision of the autopsy reports and original slides from affected children revealed a clear predominance of neutrophils and macrophages in the lungs accompanied by the occasional presence of eosinophils in smaller bronchioles (these eosinophils somehow gained a disproportionate relevance in the original manuscript) (40).

Third, both mechanisms of illness were associated with immune complex deposition in affected tissue. Rhesus macaques with atypical measles had evidence of immune complex deposition on dermal vessels (28). In addition, individuals immunized with FIMV were subsequently re-immunized with LAV to prevent the development of atypical measles, and had significant local reactions to vaccination (1620), also presenting with deposition of immune complexes around dermal vessels (16). As for ERD, a role for immune complexes was first suspected by authors of the original manuscript given the abundance of nonprotective antibody in sera from infected vaccine recipients and the bibasal distribution of pulmonary infiltrates in affected children (3). More recently, peribronchiolar and perivascular deposition of immune complexes has been demonstrated in the lungs of affected mice (30). Antibody deposition did not result in bronchoconstriction during murine ERD in the absence of complement activation and complement did not elicit bronchoconstriction in the absence of antibodies (30). A similar pattern of immune complex deposition was observed in cotton rats (G. Prince, personal communication). Further, staining of the lungs of children who died of ERD in 1967 demonstrate immune complex-mediated activation of the classic complement cascade, evidenced by peribronchiolar deposition of complement component C4d (30).

Fourth, abundant evidence suggests that the glycoprotein imbalance postulated early on as the explanation for both diseases, and ascribed to formalin disruption of the fusion proteins in MV and RSV, is incorrect. Rhesus macaques developed atypical measles in the presence of fusion-inhibiting antibodies (28), and DNA vaccines encoding only the HA glycoprotein (and therefore not the fusion protein) did not prime for atypical measles (42). In RSV, the G protein was postulated to elicit ERD in the theoretical absence of RSV F. But inoculation of BALB/c mice with a formalin-inactivated recombinant RSV that does not encode the G protein elicited ERD of identical severity as that induced by inactivated wild type virus (42,43). In fact, the G protein – often postulated as an important mediator of ERD pulmonary inflammation - has recently been shown to decrease the degree of pulmonary mononuclear cell infiltration during RSV infection (44,45).

Finally, no child ever experienced atypical measles or ERD twice. In fact, exposure to wild-type virus (or in the case of some of the children immunized with FIMV, administration of LAV) reestablished a normal immune response to subsequent exposures in all immunized individuals (33).


Perhaps, the most pressing question about the pathogeneses of atypical measles and ERD is why antibodies failed to confer protection and how was the problem “corrected” by subsequent exposure to live virus. In other words, what is required of specific antibodies to protect against these agents? The inability of several other nonreplicating MV and RSV vaccines to elicit long-lived protective antibody responses in subsequent experiments (including purified RSV F and G proteins, tween ether-inactivated MV, Baculovirus-expressed RSV F protein, among others) stress that lack of protection in atypical measles and ERD cannot be solely attributed to the poor preservation of specific antigens during formalin inactivation (21,22,4648). Development of aberrant immune manifestations after administration of a tween-ether inactivated MV vaccine to children in Europe (21,22), and the failure of a variety of nonreplicating immunogens against RSV in animal models (4648) illustrate the difficulties of developing protective and safe nonreplicating vaccines against these two agents.

Should FIMV or FIRSV had elicited protective antibody, it is likely that exposure to MV or RSV in the community would not have caused these serious illnesses (7,49). In fact, once antibodies fail to protect, ERD and atypical measles can come in different flavors. Different animal models of these enhanced diseases display a varying predominance of neutrophils, macrophages, or eosinophils in affected tissues that depend on the strain of mouse or the species chosen by the investigators (3541). These findings suggest that a variety of CD4+ T cells primed by vaccination to secrete differing cytokines and/or chemokines may elicit enhanced MV or RSV diseases when exposed to abundant wild type virus in the absence of protective antibody (3541). Furthermore, complement activation through immune complex deposition enhances the CD4+ T lymphocyte response and augments disease severity (50).

As for the requirements for the development of protective antibody responses, and also as a clue to the lack of relapses in both diseases, the avidity of antibody for wild-type virus may be important (29). MV-specific antibody elicited by FIMV was of low avidity (29). Changes in antibody avidity after MV challenge correlated with changes in neutralizing capacity (29). Affinity maturation of antibody following MV exposure established a long-lived protective antibody response (29).

Affinity maturation of antibody may be equally important to protect against RSV. In fact, a role for affinity maturation may help to clarify why none of the children who were RSV-seropositive before immunization with FIRSV developed ERD. It is likely that their preexistent RSV-specific antibodies against wild type RSV were of high affinity (low EIA/neutralization ratio) and “outcompeted” the pathogenic antibodies elicited by the vaccine (3). Similarly, exposure of immunized individuals to wild-type infection (21,22,2830) [or LAV remedial administration (19,20)] elicited antibodies of high affinity that also “outcompeted” the pathogenic humoral response generated earlier on by FIMV or FIRSV, and ensured that no relapse of these diseases ever occurred. These observations suggest that characterization of antibody avidity is an important consideration in evaluating vaccines against these paramyxoviruses.


Atypical measles and ERD were serious diseases that resulted from immunization of children with inactivated vaccines against MV and RSV. Both vaccines failed to elicit protective antibody and, in both cases, postvaccination exposure to wild type virus led to immune complex deposition in affected tissues, vigorous anamnestic CD4+ T lymphocyte proliferative responses, and a Th2 bias of the immune response. No relapses of either illness were ever reported. Although the clinical manifestations of both illnesses were different, and obeyed primarily to the individual tropism of each virus (1,2), the similarities in immune responses elicited and primed for by the vaccines suggest that atypical measles and ERD share a common general mechanism of illness. Furthermore, these diseases resulted from a disproportionate response of a primed immune system exposed to wild-type virus in the absence of protective antibody. These experiences highlight the importance of understanding the requirements for the production of protective antibodies against these agents to develop new safe and effective vaccines to protect young infants.



enhanced respiratory syncytial virus disease


formalin-inactivated vaccine against measles virus


formalin-inactivated vaccine against respiratory syncytial virus


live attenuated vaccine against measles virus


measles virus


respiratory syncytial virus


  1. 1

    Griffin D 2001 Measles Virus. Knipe DM, Howley PM Fields Virology. Lippincott/The Williams and Wilkins Co Philadelphia, PA 1401–1443

    Google Scholar 

  2. 2

    Collins PL, Chanock RM, Murphy BR 2001 Respiratory Syncytial Virus. Knipe, DM, Howley PM Fields Virology. Lippincott/ The Williams and Wilkins Co Philadelphia, PA 1443–1486

    Google Scholar 

  3. 3

    Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, Parrott RH 1969 Respiratory syncytial virus disease in infant despite prior administration on antigenic inactivated vaccine. Am J Epidemiol 89: 422–434

    CAS  Article  Google Scholar 

  4. 4

    Chin J, Magoffin RL, Shearer LA, Schieble JH, Lennette EH 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

    CAS  Article  Google Scholar 

  5. 5

    Fulginiti VA, Eller JJ, Sieber OF, Joyner JW, Minamitani M, Meiklejohn G 1969 Respiratory virus immunization. I. A field trial of two inactivated respiratory virus vaccine; an aqueous trivalent parainfluenza virus vaccine and an alumprecipitated respiratory syncytial virus vaccine. Am J Epidemiol 89: 435–448

    CAS  Article  Google Scholar 

  6. 6

    Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE 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

    CAS  Article  Google Scholar 

  7. 7

    Carter CH, Conway TJ, Cornfeld D, Iezzoni DG, Kempe CH, Moscovici C, Rauh LW, Vignec AJ, Warren J 1962 Serologic response of children to inactivated measles vaccine. JAMA 179: 848–853

    CAS  Article  Google Scholar 

  8. 8

    Guinnee VF, Henderson DA, Casey HL, Wingo ST, Ruthiq DW, Cockburn TA, Vinson TO, Calafiore DC, Wilkenstein W Jr Karzon DT, Rathbun ML, Alexander ER, Peterson DR 1966 Cooperative measles vaccine field trial I. Clinical efficacy. Pediatrics 37: 649–665

    Google Scholar 

  9. 9

    Fulginiti VA, Eller JJ, Downie AW, Kempe CH 1967 Altered reactivity to measles virus: Atypical measles in children previously immunized with inactivated measles virus vaccines. JAMA 202: 1075–1080

    CAS  Article  Google Scholar 

  10. 10

    Martin DB, Weiner LB, Nieburg PI, Blair DC 1979 Atypical measles in adolescents and young adults. Ann Intern Med 90: 877–881

    CAS  Article  Google Scholar 

  11. 11

    Young LW, Smith DI, Glasgow LA 1970 Pneumonia of atypical measles. Residual nodular lesions. Am J Roentgenol Radium Ther Nucl Med 110: 439–448

    CAS  Article  Google Scholar 

  12. 12

    Rauh LW, Schmidt R 1965 Measles immunization with killed virus vaccine. Am J Dis Child 109: 232–237

    CAS  Article  Google Scholar 

  13. 13

    Gans HA, Arvin AM, Galinus J, Logan L, DeHovitz R, Maldonado Y 1998 Deficiency of the humoral immune response to measles vaccine in infants immunized at age 6 months. JAMA 280: 527–532

    CAS  Article  Google Scholar 

  14. 14

    Albrecht P, Ennis FA, Saltzman EJ, Krugman S 1977 Persistence of maternal antibody in infants beyond 12 months: Mechanism of measles vaccine failure. J Pediatr 91: 715–718

    CAS  Article  Google Scholar 

  15. 15

    Glezen WP, Taber LH, Frank AL, Kasel JA 1986 Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 140: 543–546

    CAS  PubMed  Google Scholar 

  16. 16

    Bellanti JA 1971 Biologic significance of the secretory Û. A immunoglobulins. Pediatrics 48: 715–729

    CAS  PubMed  Google Scholar 

  17. 17

    Buser F 1967 Side reaction to measles vaccination suggesting the Arthus phenomenon. N Engl J Med 277: 250–251

    CAS  Article  Google Scholar 

  18. 18

    Lennon RG, Isacson P, Rosales T, Elsea WR, Karzon DT, Winkelstein W Jr 1967 Skin tests with measles and poliomyelitis vaccines in recipients of inactivated measles virus vaccine. Delayed Dermal Hypersensitivity. JAMA 200: 275–280

    CAS  Article  Google Scholar 

  19. 19

    Fulginiti VA, Arthur JH, Pearlman DS, Kempe CH 1968 Altered reactivity to measles virus: Local reactions following attenuated measles virus immunization in children who previously received a combination of inactivated and attenuated vaccines. Am J Dis Child 115: 671–676

    CAS  Article  Google Scholar 

  20. 20

    Scott TF, Bonnanno DE 1967 Reactions to live-measles-virus vaccine in children previously inoculated with killed-virus vaccine. N Engl J Med 277: 248–250

    CAS  Article  Google Scholar 

  21. 21

    Norrby E, Enders-Ruckle G, Ter Meulen V 1975 Difference in the appearance of antibodies to structural components of measles virus after immunization with inactivated and live virus. J Infect Dis 132: 262–269

    CAS  Article  Google Scholar 

  22. 22

    Norrby E, Gollmar Y 1975 Identification of measles virus-specific hemolysis-inhibiting antibodies separate from hemagglutination-inhibiting antibodies. Infect Immun 11: 231–239

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Merz DC, Scheid A, Choppin PW 1980 Importance of antibodies to the fusion glycoprotein of paramyxoviruses in the prevention of spread of infection. J Exp Med 151: 275–288

    CAS  Article  Google Scholar 

  24. 24

    Waris ME, Tsou C, Erdman DD, Zaki SR, Anderson LJ 1996 Respiratory syncytial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induces enhanced pulmonary inflammatory response with a predominant Th2-like cytokine pattern. J Virol 70: 2852–2860

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    De Swart RL, Kuiken T, Timmerman HH, van Amerongen G, Van Den Hoogen BG, Vos HW, Neijens HJ, Andeweg AC, Osterhaus AD 2002 Immunization of macaques with formalin-inactivated respiratory syncytial virus (RSV) induces interleukin-13-associated hypersensitivity to subsequent infection. J Virol 76: 11561–11569

    CAS  Article  Google Scholar 

  26. 26

    Connors M, Giese NA, Kulkarni AB, Firestone CY, Morse HC 3rd Murphy BR 1994 Enhanced pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of interleukin-4 (IL-4) and IL-10. J Virol 68: 5321–5325

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Graham BS, Henderson GS, Tang YW, Lu X, Neuzil KM, Colley DG 1993 Priming immunization determines T-helper cytokine mRNA wxpression patterns in lungs of mice challenged with respiratory syncytial virus. J Immunol 151: 2032–2040

    CAS  PubMed  Google Scholar 

  28. 28

    Polack FP, Auwaerter PG, Lee SH, Nousari HC, Valsamakis A, Leiferman KM, Diwan A, Adams RJ, Griffin DE 1999 Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody. Nat Med 5: 629–634

    CAS  Article  Google Scholar 

  29. 29

    Polack FP, Hoffman SJ, Crujeiras G, Griffin DE 2003 A role for non-protective complement-fixing antibodies with low avidity for measles virus in atypical measles. Nat Med 9: 1209–1213

    CAS  Article  Google Scholar 

  30. 30

    Polack FP, Teng MN, Collins PL, Prince GA, Exner M, Regele H, Lirman DD, Rabold R, Hoffman SJ, Karp CL, Kleeberger SR, Wills-Karp M, Karron RA 2002 A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med 196: 859–865

    CAS  Article  Google Scholar 

  31. 31

    Connors M, Kulkarni AB, Firestone CY, Holmes KL, Morse HC 3rd Sotnikov AV, Murphy BR 1992 Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4+ T cells. J Virol 66: 7444–7451

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Kim HW, Keikin SL, Arrobio J, Brandt CD, Chanock RM, Parrott RH 1976 Cell-mediated immunity to respiratory syncytial virus induced by inactivated vaccine or by infection. Pediatr Res 10: 75–78

    CAS  Article  Google Scholar 

  33. 33

    Krause PJ, Cherry JD, Carney JM, Naiditch MJ, O'Connor K 1980 Measles-specific lymphocyte reactivity and serum antibody in subjects with different measles histories. Am J Dis Child 134: 567–571

    CAS  PubMed  Google Scholar 

  34. 34

    Polack FP, Hoffman SJ, Moss WJ, Griffin DE 2002 Altered synthesis of interleukin-12 and type 1 and type 2 cytokinesin rhesus macaques during measles and atypical measles. J Infect Dis 185: 13–19

    CAS  Article  Google Scholar 

  35. 35

    Hussell T, Baldwin CJ, O'Garra A, Openshaw PJ 1997 CD8+ T-Cells control Th2-driven pathology during pulmonary respiratory syncytial virus infection. Eur J Immunol 27: 3341–3349

    CAS  Article  Google Scholar 

  36. 36

    Srikiatkhachorn A, Braciale TJ 1997 Virus-specific CD8+ lymphocytes downregulate T-helper cell Type 2 cytokine secretion and pulmonary eosinophilia during experimental murine respiratory syncytial virus infection. J Exp Med 186: 421–432

    CAS  Article  Google Scholar 

  37. 37

    Tang YW, Graham BS 1994 Anti-interleukin-4 treatment after immunization modulates cytokine expression, reduces illness and increases cytotoxic T-lymphocyte activity in mice challenged with RSV. J Clin Invest 94: 1953–1958

    CAS  Article  Google Scholar 

  38. 38

    Moghaddam A, Olszewska W, Wang B, Tregoning JS, Helson R, Sattentau QJ, Openshaw PJ 2006 A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines. Nat Med 12: 905–907

    CAS  Article  Google Scholar 

  39. 39

    Srikiatkhachorn A, Chang W, Braciale TJ 1999 Induction of the Th 1 and Th 2 responses by respiratory syncytial virus attachment glycoprotein is epitope ad MHC independent. J Virol 73: 6590–6597

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Prince GA, Curtis SJ, Yim KC, Porter DD 2001 Vaccine-enhanced respiratory syncytial virus disease in cotton rats following immunization with Lot 100 or a newly prepared reference vaccine. J Gen Virol 82: 2881–2888

    CAS  Article  Google Scholar 

  41. 41

    Tang YW, Graham BS 1994 Anti-interleukin-4 treatment after immunization modulates cytokine expression, reduces illness and increases cytotoxic T-lymphocyte activity in mice challenged with RSV. J Clin Invest 94: 1953–1958

    CAS  Article  Google Scholar 

  42. 42

    Polack FP, Lee SH, Permar S, Manyara E, Nousari HG, Jeng Y, Mustafa F, Valsamakis A, Adams RJ, Robinson HL, Griffin DE 2000 Successful DNA immunization against measles: neutralizing antibody against either the hemagglutinin or fusion glycoprotein protects rhesus macaques without evidence of atypical measles. Nat Med 6: 776–781

    CAS  Article  Google Scholar 

  43. 43

    Johnson TR, Varga SM, Braciale TJ, Graham BS 2004 Vbeta14(+) T cells mediate the vaccine-enhanced disease induced by immunization with respiratory syncytial virus (RSV) G glycoprotein but not with formalin-inactivated RSV. J Virol 78: 8753–8760

    CAS  Article  Google Scholar 

  44. 44

    Polack FP, Irusta PM, Hoffman SJ, Schiatti MP, Melendi GA, Delgado MF, Laham FR, Thumar B, Hendry RM, Melero JA, Karron RA, Collins PL, Kleeberger SR 2005 The cysteine-rich region of respiratory syncytial virus attachment protein inhibits innate immunity elicited by the virus and endotoxin. Proc Natl Acad Sci USA 102: 8996–9001

    CAS  Article  Google Scholar 

  45. 45

    Bukreyev A, Serra ME, Laham FR, Melendi GA, Kleeberger SR, Collins PL, Polack FP 2006 The cysteine-rich region and secreted form of the attachment G glycoprotein of respiratory syncytial virus enhance the cytotoxic T-lymphocyte response despite lacking major histocompatibility complex class I-restricted epitopes. J Virol 80: 5854–5861

    CAS  Article  Google Scholar 

  46. 46

    Murphy BR, Walsh EE 1988 Formalin-inactivated respiratory syncytial virus vaccine induces antibodies to the fusion glycoprotein that are deficient in fusion-inhibiting activity. J Clin Microbiol 26: 1595–1597

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Connors M, Collins PL, Firestone CY, Sotnikov AV, Waitze A, Davis AR, Hung PP, Chanock RM, Murphy BR 1992 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 10: 475–484

    CAS  Article  Google Scholar 

  48. 48

    Murphy BR, Sotnikov AV, Lawrence LA, Banks SM, Prince GA 1990 Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3–6 months after immunization. Vaccine 8: 497–502

    CAS  Article  Google Scholar 

  49. 49

    Murphy BR, Sotnikov A, Paradiso PR, Hildreth SW, Jenson AB, Baggs RB, Lawrence L, Zubak JJ, Chanock RM, Beeler JA 1989 Immunization of cotton rats with the fusion (F) and large (G) glycoproteins of respiratory syncytial virus (RSV) protects against RSV challenge without potentiating RSV disease. Vaccine 7: 533–540

    CAS  Article  Google Scholar 

  50. 50

    Melendi GA, Hoffman SJ, Karron RA, Irusta PM, Laham FR, Humbles A, Schofield B, Pan CH, Rabold R, Thumar B, Thumar A, Gerard NP, Mitzner W, Barnum SR, Gerard C, Kleeberger SR, Polack FP 2007 C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression. J Virol 81: 991–999

    CAS  Article  Google Scholar 

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Correspondence to Fernando P Polack.

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This work was supported by AI-054952 to F.P.P.

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Polack, F. Atypical Measles and Enhanced Respiratory Syncytial Virus Disease (ERD) Made Simple. Pediatr Res 62, 111–115 (2007).

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