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. 1999 Apr;73(4):2956-62.
doi: 10.1128/JVI.73.4.2956-2962.1999.

Human antibody responses to mature and immature forms of viral envelope in respiratory syncytial virus infection: significance for subunit vaccines

H Sakurai  1 , R A Williamson, J E Crowe, J A Beeler, P Poignard, R B Bastidas, R M Chanock, D R Burton
Affiliations

Human antibody responses to mature and immature forms of viral envelope in respiratory syncytial virus infection: significance for subunit vaccines

H Sakurai et al. J Virol. 1999 Apr.

Abstract

A number of antibodies generated during human respiratory syncytial virus (RSV) infection have been cloned by the phage library approach. Antibodies reactive with an immunodominant epitope on the F glycoprotein of this virus have a high affinity for affinity-purified F antigen. These antibodies, however, have a much lower affinity for mature F glycoprotein on the surface of infected cells and are nonneutralizing. In contrast, a potent neutralizing antibody has a high affinity for mature F protein but a much lower affinity for purified F protein or F protein in viral lysates. The data indicate that at least two F protein immunogens are produced during natural RSV infection: immature F, found in viral lysates, and mature F, found on infected cells or virions. Binding studies with polyclonal human immunoglobulin G suggest that the antibody responses to the two immunogens are of similar magnitudes. Competitive binding studies suggest that overlap between the responses is relatively limited. A mature envelope with an antigenic configuration different from that of the immature envelope has an evolutionary advantage in that the infecting virus is less subject to neutralization by the humoral response to the immature envelope that inevitably arises following lysis of infected cells. Subunit vaccines may be at a disadvantage because they most often resemble immature envelope molecules and ignore this aspect of viral evasion.

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Figures

FIG. 1
FIG. 1
ELISA reactivity of recombinant Fab fragments RSV19 and CM68 with RSV-infected cell lysates (lysate) and affinity-purified F glycoprotein (APF).
FIG. 2
FIG. 2
Reactivity of recombinant Fab fragments with F protein on the surface of RSV-infected cells, as measured by flow cytometry. The MF of infected cells relative to that measured under the same conditions for uninfected cells was calculated following incubation with each antibody over a range of concentrations.
FIG. 3
FIG. 3
Comparative binding of purified pooled human IgG to different antigenic presentations of F protein. The binding of human IgG (IgGp1) over a range of concentrations to affinity-purified F protein in an ELISA and to F protein as it occurs on the surface of RSV-infected cells was measured (the level of binding to G and SH proteins on the surface of infected cells is much lower than that to F protein; see the text).
FIG. 4
FIG. 4
Competition between human polyclonal IgG and affinity-purified F protein for binding to infected cells. Human IgG was incubated with a range of concentrations of affinity-purified F protein. Binding to cells infected with either A2, B1, or cp-52 virus was measured by flow cytometry. Results are expressed as the percentage of IgG bound in the absence of a competitor.
FIG. 5
FIG. 5
Competition between human polyclonal IgG and Fab fragment RSV19 for binding to infected cells. IgG binding to RSV-infected cells preincubated with a range of concentrations of RSV19 was determined by flow cytometry. Results are expressed as the percentage of IgG bound in the absence of the competing Fab.
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