Discussion
In the present study no association was found between antibody titer against the RSV N protein measured in cord blood and a protection against RSV VS-LRTI. This result differs from the largest cohort studies that analyzed cord blood titers; these studies, conducted in Denmark, Mali, and on American Indian infants found that a higher concentration of neutralizing antibodies at birth was associated with a lower risk of contracting an RSV LRTI and of being hospitalized for this [14,15,23]. Considering the power of the present study; the sample size is comparable with the study reported by Buchwald et al.(587 infants) [18], and greater than that reported by Eick et al. (372 infants) [16], which both concluded to a protection conferred by neutralizing antibodies (while the study conducted in Alaska [155 infants] and Kenya [90 infants] did not find any association [17,18]). Therefore, only a weak protection might have been missed. In addition, the statistical power was sufficient to detect a robust association between known risk factors of RSV VS-LRTI (parity of the mother and a date of birth in the first part of the epidemic season [29]) and the occurrence of VS-LRTI. For the present study, owing to the lack of data available regarding antibody titers against RSV N protein, there was no determination of number of subjects required; the data provided herein will therefore help for the power calculation in future studies.
It is of note that the mean antibody titers against RSV N protein at birth were lower in premature infants, those with a low birth weight, born to a primiparous mother, and born before the peak of the epidemic. This profile is not surprising; for instance, it is well known that majority of transplacental transfer of IgG occurs during the third trimester of pregnancy, and that preterm newborns have a compromised passive immunity [28–30]. Furthermore, multiparous mothers are likely to have been exposed to RSV, as well as those delivering at the end of the epidemic season. These factors are also known to be risk factors for severe RSV infection [31–33]. The multivariate analysis indicates that this risk is mostly mediated through another pathway that the lack of RSV N antibodies.
The study does have some limitations. The most important is that only patients admitted to the hospital they were born in were considered for the analysis of VS-LRTI, thus any cases visiting elsewhere may have been missed. However, there are few other pediatric emergency departments in the region, the HFME university hospital is the largest pediatric hospital in the area and the only one with an intensive care unit; thus it is likely that most cases of RSV VS-LRTI occurring before 3 months of age were captured from either direct admission or from transfers from other hospitals. Furthermore, detection used ELISA that allows standardization of result but does not quantify neutralizing activity. However, a neutralization assay would not have specifically detect antibodies against N protein which were investigated herein. Finally, the severity of LRTI episodes might have been overestimated; a third of cases (n=12/36) were classified as VS-LRTI only on the “inability to feed” criterion, and patients hospitalized for LRTI were very likely to have enteral nutrition, sometimes for less than twenty-four hours (data not shown ). However it is unlikely to have led to a differential selection according to the antibody titer level, and the classification of all episodes of LRTI according to the WHO standardized severity criteria allows comparison with future studies.
In conclusion, the findings presented herein suggest that transfer of maternal antibodies against the RSV N protein does not provide a significant immune protection early in infancy against RSV VS-LRTI. Maternal vaccination may therefore not be a suitable strategy for an N protein candidate vaccine.
Conflict of interest: none
Financial support: none