Kinetics of the neutralizing antibody response to respiratory syncytial virus infections in a birth cohort.

The kinetics of respiratory syncytial virus (RSV) neutralizing antibodies following birth, primary and secondary infections are poorly defined. The aims of the study were to measure and compare neutralizing antibody responses at different time points in a birth cohort followed-up over three RSV epidemics. Rural Kenyan children, recruited at birth between 2002 and 2003, were monitored for RSV infection over three epidemic seasons. Cord and 3-monthly sera, and acute and convalescent sera following RSV infection, were assayed in 28 children by plaque reduction neutralization test (PRNT). Relative to the neutralizing antibody titers of pre-exposure control sera (1.8 log10 PRNT), antibody titers following primary infection were (i) no different in sera collected between 0 and 0.4 months post-infection (1.9 log10 PRNT, P=0.146), (ii) higher in sera collected between 0.5 and 0.9 (2.8 log10 PRNT, P<0.0001), 1.0-1.9 (2.5 log10 PRNT, P<0.0001), and 2.0-2.9 (2.3 log10 PRNT, P<0.001) months post-infection, and (iii) no different in sera collected at between 3.0 and 3.9 months post-infection (2.0 log10 PRNT, P=0.052). The early serum neutralizing response to secondary infection (3.02 log10 PRNT) was significantly greater than the early primary response (1.9 log10 PRNT, P<0.0001). Variation in population-level virus transmission corresponded with changes in the mean cohort-level neutralizing titers. It is concluded that following primary RSV infection the neutralizing antibody response declines to pre-infection levels rapidly (~3 months) which may facilitate repeat infection. The kinetics of the aggregate levels of acquired antibody reflect seasonal RSV occurrence, age, and infection history.

The natural history of respiratory syncytial virus in a birth cohort: the influence of age and previous infection on reinfection and disease.

This study aimed to quantify the effect of age, time since last infection, and infection history on the rate of respiratory syncytial virus infection and the effect of age and infection history on the risk of respiratory syncytial virus disease. A birth cohort of 635 children in Kilifi, Kenya, was monitored for respiratory syncytial virus infections from January 31, 2002, to April 22, 2005. Predictors of infection were examined by Cox regression and disease risk by binomial regression. A total of 598 respiratory syncytial virus infections were identified (411 primary, 187 repeat), with 409 determined by antigen assay and 189 by antibody alone (using a "most pragmatic" serologic definition). The incidence decreased by 70% following a primary infection (adjusted hazard ratio = 0.30, 95% confidence interval: 0.21, 0.42; P < 0.001) and by 59% following a secondary infection (hazard ratio = 0.41, 95% confidence interval: 0.22, 0.73; P = 0.003), for a period lasting 6 months. Relative to the age group <6 months, all ages exhibited a higher incidence of infection. A lower risk of severe disease following infection was independently associated with increasing age (P < 0.001) but not reinfection. In conclusion, observed respiratory syncytial virus incidence was lowest in the first 6 months of life, immunity to reinfection was partial and short lived, and disease risk was age related.

Humoral and cellular immunity to RSV in infants, children and adults.

BACKGROUND: Respiratory syncytial virus (RSV) causes respiratory disease throughout life. Here we report differences in naturally acquired immunity with age and presumed exposure. METHODS: A longitudinal, non-interventional, observational study was performed in healthy adults (20 paediatric healthcare workers and 10 non-healthcare workers), children (10 aged 3-6 years) and infants (5 aged 2-4 months and 20 aged 6-12 months). Blood samples were analysed for RSV-neutralising antibody titre, F/Ga/Gb-specific antibody titres, F-specific IgG/IgA memory B-cell frequencies and T-cell production of IFNγ, IL-4, IL-13 and IL-17. RESULTS: Serum G-specific antibody titres were significantly lower in infants and children than adults. However, serum titres of F-specific and RSV-neutralising antibody and IFNγ-producing T-cell frequencies were low or absent in the infants, but comparable between children and adults. Interestingly, F-specific memory IgA B-cells could not be detected in paediatric samples and in samples from non-healthcare workers, but recordable IgA memory B-cells were found in 9/18 paediatric healthcare workers and 2/8 non-healthcare workers at the end of the RSV season. These responses waned 4-6 months later. By contrast, F-specific IgG memory B-cells were detectable in samples from all adults without significant variation across time points. T-cells producing IL-4, IL-13 and IL-17 responses were not detectable in peripheral blood from a subset of volunteers. CONCLUSIONS: Repeated RSV exposure in early life generates immune responses that are inversely related to frequency of severe disease. Induction of F-specific antibody and cellular immune responses through infant vaccination might help to accelerate the development of protective immune responses at an early age. Clinicaltrials.gov reference NCT01563692 and NCT01640652.