Long-term immunity against yellow fever in children vaccinated during infancy: a longitudinal cohort study

Abstract

SummaryBackgroundA single dose of vaccine against yellow fever is routinely administered to infants aged 9–12 months under the Expanded Programme on Immunization, but the long-term outcome of vaccination in this age group is unknown. We aimed to evaluate the long-term persistence of neutralising antibodies to yellow fever virus following routine vaccination in infancy.MethodsWe did a longitudinal cohort study, using a microneutralisation assay to measure protective antibodies against yellow fever in Malian and Ghanaian children vaccinated around age 9 months and followed up for 4·5 years (Mali), or 2·3 and 6·0 years (Ghana). Healthy children with available day-0 sera, a complete follow-up history, and no record of yellow fever revaccination were included; children seropositive for yellow fever at baseline were excluded. We standardised antibody concentrations with reference to the yellow fever WHO International Standard.FindingsWe included 587 Malian and 436 Ghanaian children vaccinated between June 5, 2009, and Dec 26, 2012. In the Malian group, 296 (50·4%, 95% CI 46·4–54·5) were seropositive (antibody concentration ≥0·5 IU/mL) 4·5 years after vaccination. Among the Ghanaian children, 121 (27·8%, 23·5–32·0) were seropositive after 2·3 years. These results show a large decrease from the proportions of seropositive infants 28 days after vaccination, 96·7% in Mali and 72·7% in Ghana, reported by a previous study of both study populations. The number of seropositive children increased to 188 (43·1%, 95% CI 38·5–47·8) in the Ghanaian group 6·0 years after vaccination, but this result might be confounded by unrecorded revaccination or natural infection with wild yellow fever virus during a 2011–12 outbreak in northern Ghana.InterpretationRapid waning of immunity during the early years after vaccination of 9-month-old infants argues for a revision of the single-dose recommendation for this target population in endemic countries. The short duration of immunity in many vaccinees suggests that booster vaccination is necessary to meet the 80% population immunity threshold for prevention of yellow fever outbreaks.FundingWellcome Trust.

Serological Protection 5–6 Years Post Vaccination Against Yellow Fever in African Infants Vaccinated in Routine Programmes

“…This recent study assessed longevity in children who had received YF vaccine as part of 2 randomized controlled clinical trials. The study similarly demonstrated a drastic decline of YF immunity in children vaccinated as infants even within the ideal clinical trial settings with 50.4% (4.5 years post vaccination) and 43.1% (6 years post vaccination) retaining seropositivity in Mali and Ghana, respectively ( 17 ). These findings may be compounded by several factors including natural disease exposure but in keeping with ours suggest a population of children vulnerable to YF infection several years post vaccination irrespective of setting where vaccine was received.…”

“…The analysis of serum samples from 481 children vaccinated with one dose of YF vaccine in infancy showed that roughly 30% did not have protective antibody concentrations of 0.5 UI/ml ( 17 ) 5–6 years after vaccination. Most of this group had undetectable antibody concentrations (seronegative) and even where detectable, concentrations were below 0.1 IU/mL.…”

“…The concentrations of neutralizing antibodies to YF virus were tested at the Robert Koch Institute in Berlin using a microneutralization assay ( 17 ). Briefly, 100 TCDI50 infectious doses of a YF virus 17-D (Stamaril, Sanofi Pasteur, Val de Reuil, France) were incubated with serial 2-fold dilutions of sera before inoculation into Vero cells cultured in 96-well plates.…”

“…Although neutralizing titres of ≥1:5 or 1:10 ( 17 , 19 ) are considered a surrogate of protection (seroprotection), difference in in assay methods may limit comparability of results from different laboratories. The titres were thus standardized by conversion into antibody concentrations in IU/mL using a WHO international standard (WHO International Standard, NISBC 99/616 reconstituted at 143 IU/ml) to allow for comparability with other available data.…”

“…One previous study by Domingo et al involving children from Ghana and Mali examined longevity of antibody response to YF vaccine in African infants who had received the vaccines according to EPI schedules but as part of large randomized controlled trials (ideal settings). In these circumstances, “real life” factors such as cold chain maintenance and other programmatic limitations are less likely to affect overall outcome given the influence of full time study teams ( 17 ). Generating data on the antibody concentrations to YF several years post vaccination under routine EPI program conditions therefore remains important to inform the WHO guidelines with a view to assess need for booster doses if the only dose of YF vaccine is administered in infancy.…”