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. 2017 Jan 30;12(1):e0170877.
doi: 10.1371/journal.pone.0170877. eCollection 2017.

Characteristics of RSV-Specific Maternal Antibodies in Plasma of Hospitalized, Acute RSV Patients under Three Months of Age

Jop Jans  1 , Oliver Wicht  1   2 , Ivy Widjaja  3 , Inge M L Ahout  1 , Ronald de Groot  1 , Teun Guichelaar  2 , Willem Luytjes  2 , Marien I de Jonge  1 , Cornelis A M de Haan  3 , Gerben Ferwerda  1
Affiliations

Characteristics of RSV-Specific Maternal Antibodies in Plasma of Hospitalized, Acute RSV Patients under Three Months of Age

Jop Jans et al. PLoS One. .

Abstract

Respiratory syncytial virus (RSV) is the leading cause for respiratory illness that requires hospitalization in infancy. High levels of maternal antibodies can protect against RSV infection. However, RSV-infected infants can suffer from severe disease symptoms even in the presence of high levels of RSV-specific antibodies. This study analyzes several serological characteristics to explore potential deficiencies or surpluses of antibodies that could relate to severe disease symptoms. We compare serum antibodies from hospitalized patients who suffered severe symptoms as well as uninfected infants. Disease severity markers were oxygen therapy, tachypnea, oxygen saturation, admission to the intensive care unit and duration of hospitalization. Antibodies against RSV G protein and a prefusion F epitope correlated with in vitro neutralization. Avidity of RSV-specific IgG antibodies was lower in RSV-infected infants compared to uninfected controls. Severe disease symptoms were unrelated to RSV-specific IgG antibody titers, avidity of RSV-IgG, virus neutralization capacity or titers against pre- and postfusion F or G protein ectodomains and the prefusion F antigenic site Ø. In conclusion, the detailed serological characterization did not indicate dysfunctional or epitope-skewed composition of serum antibodies in hospitalized RSV-infected infants suffering from severe disease symptoms. It remains unclear, whether specific antibody fractions could diminish disease symptoms.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. RSV-specific IgG titer and RSV-IgG avidity do not correlate with disease severity.
RSV-specific IgG levels in plasma of infants was determined by ELISA using virus particles. RSV-IgG avidity was assessed by supplementing NaSCN during ELISA. (A) RSV-specific IgG levels were displayed versus age. (B-C) Median RSV-specific IgG levels (± IQR) were compared between healthy and RSV-infected infants as well as between RSV patients with and without oxygen therapy. (D-E) Median (± IQR) avidity of RSV-IgG in healthy infants was compared to RSV-infected infants or between RSV patients with or without oxygen therapy. Associations were assessed by Spearman correlation test. Statistical analyses employed Mann Whitney U test. (**P<0.01).
Fig 2
Fig 2. RSV neutralization does not correlate with severity of disease.
50% plaque reduction neutralization titers (PRNT) were determined against RSV-X and RSV-X-dG, the latter is lacking the G protein. (A-B) Median (± IQR) PRNT against RSV-X were compared between healthy and RSV-infected infants as well as between RSV patients with and without oxygen therapy. (C-D) Median (± IQR) PRNT against RSV-X-dG were compared between healthy and RSV-infected infants as well as between RSV patients with or without oxygen therapy. (E) The PRNT against RSV-X was divided the PRTN against RSV-X-dG, so that values below 1.0 indicate a contribution of anti-G antibodies to the neutralization. The median (± IQR) ratio was compared between plasma from healthy infants and RSV patients with or without oxygen therapy and all were significantly different from 1.0. Statistical analyses employed Mann Whitney U test for comparison between two groups and Kruskall-Wallis for comparison between more than two groups. (*P<0.05, **P<0.01).
Fig 3
Fig 3. RSV-specific IgG against individual RSV glycoproteins do not correlate with disease severity.
RSV glycoprotein-specific antibody levels were determined by ELISA against recombinant, soluble ectodomains. Median IgG levels (± IQR) were compared between healthy and RSV-infected infants as well as between RSV patients with and without oxygen therapy. Glycoproteins used for ELISA coating were (A-B) RSV G protein, (C-D) prefusion F protein, and (E-F) postfusion F protein. (G-H) The relative abundance of antibodies against prefusion F compared to G protein as well as pre- compared to postfusion F protein were categorized assessed by subtracting their levels. The median (± IQR) difference was compared between plasma from healthy infants and RSV patients with or without oxygen therapy. No significant differences were observed by Mann Whitney U test for comparison between two groups and Kruskall-Wallis for comparison between more than two groups.
Fig 4
Fig 4. RSV-specific IgG against F protein antigenic sites Ø and I not correlate with disease severity.
The abundance of antibodies in human infant plasma that bind to the prefusion F protein antigenic site Ø or the postfusion F protein antigenic site I was determined by competition with site-specific monoclonal antibodies in ELISA. (A-B) Median (± IQR) IgG titer that blocks 25% binding of D25 (site Ø) were compared between healthy and RSV-infected infants as well as between RSV patients with and without oxygen therapy. (C-D) Median (± IQR) IgG titer that blocks 15% binding of 131-2A (site I) were compared between healthy and RSV-infected infants as well as between RSV patients with and without oxygen therapy. No significant differences were observed by Mann Whitney U test.
Fig 5
Fig 5. RSV-specific IgG against prefusion F epitope and G protein correlate with neutralization.
Neutralization titers against RSV-X (PRNT) were compared to IgG levels against (A) postfusion F protein, (B) site I (131-2A competition titer), (C) prefusion F protein, (D) site Ø (D25 competition titer) and (E) G protein. Testing for correlation was performed with Spearman correlation test.
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Grants and funding

GF is supported by the Virgo consortium, funded by the Dutch government project number FES0908, and by the Netherlands Genomics Initiative (NGI) project number 050-060-452. OW and WL are supported by the Strategic Program RIVM (SPR) S112008, Dutch Ministry of Health, Welfare and Sport. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.