Absence of Association between Cord Specific Antibody Levels and Severe Respiratory Syncytial Virus (RSV) Disease in Early Infants: A Case Control Study from Coastal Kenya

Abstract

Background: The target group for severe respiratory syncytial virus (RSV) disease prevention is infants under 6 months of age. Vaccine boosting of antibody titres in pregnant mothers could protect these young infants from severe respiratory syncytial virus (RSV) associated disease. Quantifying protective levels of RSV-specific maternal antibody at birth would inform vaccine development.

Methods: A case control study nested in a birth cohort (2002-07) was conducted in Kilifi, Kenya; where 30 hospitalised cases of RSV-associated severe disease were matched to 60 controls. Participants had a cord blood and 2 subsequent 3-monthly blood samples assayed for RSV-specific neutralising antibody by the plaque reduction neutralisation test (PRNT). Two sample paired t test and conditional logistic regression were used in analyses of log2PRNT titres.

Results: The mean RSV log2PRNT titre at birth for cases and controls were not significantly different (P = 0.4) and remained so on age-stratification. Cord blood PRNT titres showed considerable overlap between cases and controls. The odds of RSV disease decreased with increase in log2PRNT cord blood titre. There was a 30% reduction in RSV disease per unit increase in log2PRNT titre (<3months age group) but not significant (P = 0.3).

Conclusions: From this study, there is no strong evidence of protection by maternal RSV specific antibodies from severe RSV disease. Cord antibody levels show wide variation with considerable overlap between cases and controls. It is likely that, there are additional factors to specific PRNT antibody levels which determine susceptibility to severe RSV disease. In addition, higher levels of neutralizing antibody beyond the normal range may be required for protection; which it is hoped can be achieved by a maternal RSV vaccine.

Fig 1. A box plot of the mean concentration of cord blood titres of cases and controls by age categories.

Differences in the mean concentration of maternally transferred respiratory syncytial virus (RSV) specific antibodies (log₂PRNT titres) from cord blood samples (with P values shown), between cases and controls at age categories in months of first RSV infection; 1–2 and 3–5. Cases were matched to controls in a ratio of 1:2. P values generated using a two sample paired t-test.

Fig 2. Reverse Cumulative Distribution plots of cord blood titres of cases and controls.

The distribution of concentration of maternally transferred RSV specific antibodies (log₂PRNT titres) from cord blood samples of infants born in Kilifi, Kenya. Grey symbols denote cord titres of cases while black symbols denote cord titres of controls.

Fig 3. Relationship between Odds of RSV disease and the levels of Cord blood antibody titres.

A scatter plot showing the odds of RSV associated hospitalization against maternally transferred RSV specific antibodies (log₂PRNT titres) from cord blood samples of infants (both cases and controls) born in Kilifi, Kenya; 2002–2007. Black symbols denote individual cord titres for all 90 infants.

Fig 4. The estimated rate of decay of RSV specific antibodies from birth to 6 months of life among cases and controls.

The estimated rate of decay of maternally transferred RSV specific antibodies (log₂ transformed PRNT titres) over the first 6 months of life for infants (30 RSV cases and 60 controls) from a birth cohort, Kilifi, Kenya, with best fit linear decay models for samples from cases and controls. Grey symbols denote individual cord titres of cases while black symbols denote individual cord titres of controls.

Fig 5. Dynamics of cord titres by time and transmission intensity.

The Red diamond symbols denote individual cord titres by date of birth for RSV A2 strain, Blue diamond symbols denote individual cord titres by date of birth for RSV A Kilifi local strain, Maroon circle markers denote the mean cord titre by quarter (95% CI denoted by Brown whiskers) for RSV A2 strain, Navy blue circle markers denote the mean cord titre by quarter (95% CI denoted by Green whiskers) for RSV A Kilifi local strain. The Grey vertical bars (RSVA) and Orange vertical bars (RSV B) show the number of RSV IFAT positive paediatric severe or very severe pneumonia admissions to Kilifi County Hospital 2002–2005.