A formalin-inactivated respiratory syncytial virus vaccine was used to immunize infants in the mid-1960s; when these children later were naturally infected by the virus they developed markedly accentuated disease, and two died. For the present work, a new batch of vaccine was prepared using the original formula. Administration of either the old or new vaccines resulted in enhanced lesions in immunized cotton rats subsequently challenged with live virus, although administration of the vaccine reduced virus replication by 90%. Animals primed with formalin-inactivated virus and challenged developed markedly accentuated lesions of the same type as in animals undergoing primary or secondary infection. In addition, the animals with the vaccine-enhanced disease developed alveolitis and interstitial pneumonitis, which appear to be specific markers for the vaccine enhancement. The newly prepared vaccine appears suitable as a reference standard for studying the mechanism of vaccine-enhanced disease caused by this virus. Additionally, we reviewed the lesions in the lungs of the two humans who died with the vaccine-enhanced disease in 1967, and found that they were similar to, but more severe than those seen in the cotton rats.
AherneW.,
BirdT.,
CourtS. D. M.,
GardnerP. S.,
McQuillinJ.1970; Pathological changes in virus infections of the lower respiratory tract in children. Journal of Clinical Pathology 23:7–18
BembridgeG. P.,
Garcia-BeatoR.,
LopezJ. A.,
MeleroJ. A.,
TaylorG.1998; Subcellular site of expression and route of vaccination influence pulmonary eosinophilia following respiratory syncytial virus challenge in BALB/c mice sensitized to the attachment G protein. Journal of Immunology 161:2473–2480
ChinJ.,
MagoffinR. L.,
ShearerL. A.,
SchiebleJ. H.,
LennetteE. H.1969; Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. American Journal of Epidemiology 89:449–463
FulginitiV. A.,
EllerJ. J.,
DownieA. W.,
KempeC. H.1967; Altered reactivity to measles virus. Atypical measles in children previously immunized with inactivated measles virus vaccines. Journal of the American Medical Association 202:1075–1080
FulginitiV. A.,
EllerJ. J.,
SieberO. F.,
JoynerJ. W.,
MinamitaniM.,
MeiklejohnG.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. American Journal of Epidemiology 89:435–448
GershwinJ. L.,
SchelegleE. S.,
GuntherR. A.,
AndersonM. L.,
WoolumsA. R.,
LarochelleD. R.,
BoyleG. A.,
FriebertshauserK. E.,
SingerR. S.1998; A bovine model of vaccine enhanced respiratory syncytial virus pathophysiology. Vaccine 16:1225–1236
HussellT.,
GeorgiouA.,
SparerT. E.,
MatthewsS.,
PalaP.,
OpenshawP. J. M.1998; Host genetic determinants of vaccine-induced eosinophilia during respiratory syncytial virus infection. Journal of Immunology 161:6215–6222
JohnsonT. R.,
JohnsonJ. E.,
RobertsS. R.,
WertzG. W.,
ParkerR. A.,
GrahamB. S.1998; Priming with secreted glycoprotein G of respiratory syncytial virus (RSV) augments interleukin-5 production and tissue eosinophilia after RSV challenge. Journal of Virology 72:2871–2880
KakukT. J.,
SoikeK.,
BrideauR. J.,
ZayaR. M.,
ColeS. L.,
ZhangJ.-Y.,
RobertsE. D.,
WellsP. A.,
WathenM. W.1993; A human respiratory syncytial virus (RSV) primate model of enhanced pulmonary pathology induced with a formalin-inactivated RSV vaccine but not a recombinant FG subunit vaccine. Journal of Infectious Diseases 167:553–561
KapikianA. Z.,
MitchellR. H.,
ChanockR. M.,
ShvedoffR. A.,
StewartC. E.1969; An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. American Journal of Epidemiology 89:405–421
KimH. W.,
CancholaJ. G.,
BrandtC. D.,
PylesG.,
ChanockR. M.,
JensenK.,
ParrottR. H.1969; Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. American Journal of Epidemiology 89:422–434
McIntoshK.,
FishautJ. M.1980; Immunopathologic mechanisms in lower respiratory tract disease of infants due to respiratory syncytial virus. Progress in Medical Virology 26:94–118
MurphyB. R.,
PrinceG. A.,
LawrenceL. A.,
CroenK. D.,
CollinsP. L.1990; Detection of respiratory syncytial virus (RSV) infected cells by in situ hybridization in the lungs of cotton rats immunized with formalin-inactivated virus or purified RSV F and G glycoprotein subunit vaccine and challenged with RSV. Virus Research 16:153–162
PiedraP. A.,
CamussiG.,
OgraP. L.1989a; Immune response to experimentally induced infection with respiratory syncytial virus: possible role in the development of pulmonary disease. Journal of General Virology 70:325–333
PiedraP. A.,
WydeP. R.,
CastlemanW. L.,
AmbroseM. W.,
JewellA. M.,
SpeelmanD. J.,
HildrethS. W.1993; Enhanced pulmonary pathology associated with the use of formalin-inactivated respiratory syncytial virus vaccine in cotton rats is not a unique viral phenomenon. Vaccine 11:1415–1423
PrinceG. A.,
JensonA. B.,
HorswoodR. L.,
CamargoE.,
ChanockR. M.1978; The pathogenesis of respiratory syncytial virus infection in cotton rats. American Journal of Pathology 93:771–791
PrinceG. A.,
PrieelsJ.-P.,
SlaouiM.,
PorterD. D.1999; Pulmonary lesions in primary respiratory syncytial virus infection, reinfection, and vaccine-enhanced disease in the cotton rat ( Sigmodon hispidus ). Laboratory Investigation 79:1385–1392
PrinceG. A.,
JensonA. B.,
HemmingV. G.,
MurphyB. R.,
WalshE. E.,
HorswoodR. L.,
ChanockR. M.1986; Enhancement of respiratory syncytial virus pulmonary pathology in cotton rats by intramuscular inoculation of formalin-inactivated virus. Journal of Virology 57:721–728
SparerT. E.,
MatthewsS.,
HussellT.,
RaeA. J.,
Garcia-BarrenoB.,
MeleroJ. A.,
OpenshawP. J. M.1998; Eliminating a region of respiratory syncytial virus attachment protein allows induction of protective immunity without vaccine-enhanced lung eosinophilia. Journal of Experimental Medicine 187:1921–1926
TebbeyP. W.,
HagenM.,
HancockG. E.1998; Atypical pulmonary eosinophilia is mediated by a specific amino acid sequence of the attachment (G) protein of respiratory syncytial virus. Journal of Experimental Medicine 188:1967–1972
Vaux-PeretzF.,
ChapsalJ.-M.,
MeignierB.1992; Comparison of the ability of formalin-inactivated respiratory syncytial virus, immunopurified F, G and N proteins and cell lysate to enhance pulmonary changes in Balb/c mice. Vaccine 10:113–118
WarisM. E.,
TsouC.,
ErdmanD. D.,
ZakiS. R.,
AndersonL. J.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. Journal of Virology 70:2852–2860