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. 2017 Nov 22:8:2301.
doi: 10.3389/fmicb.2017.02301. eCollection 2017.

The Complexity of Antibody Responses Elicited against the Respiratory Syncytial Virus Glycoproteins in Hospitalized Children Younger than 2 Years

Alfonsina Trento  1   2 , Rosa Rodríguez-Fernández  3 , María I González-Sánchez  3 , Felipe González-Martínez  3 , Vicente Mas  1   2 , Mónica Vázquez  1   2 , Concepción Palomo  1   2 , José A Melero  1   2
Affiliations

The Complexity of Antibody Responses Elicited against the Respiratory Syncytial Virus Glycoproteins in Hospitalized Children Younger than 2 Years

Alfonsina Trento et al. Front Microbiol. .

Abstract

The influence of age and maternal antibodies on the antibody responses to human respiratory syncytial virus (hRSV) glycoproteins in very young children has been a matter of controversy. Both, immaturity of the immune system at very early age and suppression of the host immune response by high level of maternal antibodies have been claimed to limit the host antibody response to virus infection and to jeopardize the use of hRSV vaccines under development in that age group. Hence, the antibody responses to the two major hRSV glycoproteins (F and G) were evaluated in children younger than 2 years, hospitalized with laboratory confirmed hRSV bronchiolitis. A strong negative correlation was found between the titre of circulating ELISA antibodies directed against either prefusion or postfusion F in the acute phase, but not age, and their fold change at convalescence. These changes correlated also with the level of circulating neutralizing antibodies in sera. As reported in adults, most neutralizing antibodies in a subset of tested sera could not be depleted with postfusion F, suggesting that they were mostly directed against prefusion-specific epitopes. In contrast, a weak negative association was found for group-specific anti-G antibodies in the acute phase and their fold change at convalescence only after correcting for the antigenic group of the infecting virus. In addition, large discrepancies were observed in some individuals between the antibody responses specific for F and G glycoproteins. These results illustrate the complexity of the anti-hRSV antibody responses in children experiencing a primary severe infection and the influence of preexisting maternal antibodies on the host response, factors that should influence hRSV serological studies as well as vaccine development.

Keywords: antibody specificity; bronchiolitis; glycoproteins; immune responses; respiratory syncytial virus infections; viral.

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Figures

FIGURE 1
FIGURE 1
ELISA antibody response against hRSV F and neutralization response. (A) Box-and-whisker plots showing ELISA antibodies titres against Pre-F (gray) and Post-F (red) proteins, in acute (empty boxes), and convalescent (filled boxes) phases of infection. The boxes represent the first and the third quartiles, and the solid horizontal lines within the box represent the mean values. The whiskers represent lowest and highest values. (B) Relationship between individual acute and convalescent ELISA titres against Pre-F and Post-F glycoproteins. (C) Scatterplots comparing acute anti-Pre-F and anti-Post-F antibodies titres vs fold change of antibody titres between acute and convalescent phase. Correlation coefficient R2, slope, and p-value are shown. (D) Scatterplot of individual sera comparing titre fold change for Pre-F protein vs. titre fold change for Post-F protein. (E) Box-and-whisker plots showing hRSV neutralizing antibody titres in acute (empty box) and convalescent (gray box) phases of infection. Neutralization was done as described in Section “Materials and Methods” using the recombinant A2 strain of hRSV that expresses GFP. (F) Scatterplots of individual sera comparing fold changes of ELISA titres for Pre-F and Post-F proteins versus fold change in neutralization titre.
FIGURE 2
FIGURE 2
ELISA and neutralization before and after depletion of antibodies binding to postfusion hRSV F. Antibodies from the indicated serum samples were purified with protein A-Sepharose and processed in parallel with RespiGam for depletion of antibodies binding to postfusion hRSV F, as described (Magro et al., 2012). For each serum sample, the left panel shows the ELISA titration of antibodies binding to Pre-F (red) and Post-F (green) proteins before (fill circles) and after (empty circles) the depletion step and the right panel the neutralization of hRSV either before (fill circles) or after depletion (empty circles) of antibodies binding to postfusion F.
FIGURE 3
FIGURE 3
Antibody response against G protein. (A,D) Box-and-whisker plots showing antibody ELISA titres against homologous and heterologous G protein, in acute (grated pattern box) and convalescent (filled box) phase of infection. The boxes represent the first and the third quartile, and the solid horizontal lines within the box represent the mean values. The whiskers represent the lowest and highest values. Antibody titters against RSV-A G protein are colored in blue and antibody titres against RSV-B G protein are colored in red. (B,E) Relationship between individual acute and convalescent titres against the G glycoprotein. (C,F) Scatterplots comparing acute anti-G antibodies titres vs. fold change at convalescence. Correlation coefficient R2, slope and p-value are shown.
FIGURE 4
FIGURE 4
ELISA antibody responses against F and G glycoproteins in selected individual serum samples. The serum samples are indicated at left with the nomenclature of Supplementary Table S1. The left panels of each serum sample show the ELISA antibody titrations against Pre-F and Post-F fusion proteins. The right panels are the ELISA titrations of antibodies against GA and GB glycoproteins. Axes in each panel are colored red or blue according to the antigenic group (blue, group A and red, group B) of the virus that infected each individual.
FIGURE 5
FIGURE 5
Virus neutralization. Each panel shows the neutralization curves of a set of hRSV group A and B virus by the sera indicated at the top of each panel. Neutralization was performed by the neutralization test described in Section “Materials and Methods”. As controls, serum from an adult volunteer (43-02) and the monoclonal antibody Palivixumab are shown in the two lower right panels.
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