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