Systematic review finds lifelong immunity from a single yellow fever vaccine, with rare cases of breakthrough infections.
Study: Yellow fever breakthrough infections after yellow fever vaccination: a systematic review and meta-analysis. Image Credit: chemical industry/Shutterstock.com
In a recent study published in The Lancet Microbe, researchers summarized evidence on yellow fever breakthrough infections after primary vaccination.
Background
Yellow fever, caused by the yellow fever virus, is an acute febrile and potentially fatal hemorrhagic illness, with an estimated 30,000 annual deaths and case fatality risk of 40% in the symptomatic population.
The virus is transmitted by mosquito vectors of Haemagogus or Aedes genera. Yellow fever is endemic to South America and sub-Saharan Africa.
Preventive measures are paramount since there are no effective treatments. Nevertheless, a live-attenuated vaccine developed in the 1930s is available but is contraindicated for specific populations.
Vaccination as pre-exposure prophylaxis confers effective immunity, with short- and long-term seroprotection rates ranging from 71% to 100% and 48% to 100%, respectively.
The World Health Organization (WHO), revising its position on booster vaccination in 2015, stated that a single dose confers lifelong protection and that revaccination was unnecessary.
However, this matter has since been debated, with studies mainly focused on neutralizing antibodies. Nonetheless, increasing evidence suggests a role for T cell immunity in long-term protection. As such, focusing on humoral responses alone would underestimate effectiveness.
About the study
In the present study, researchers summarized yellow fever breakthrough infections within and after 10 years of primary vaccination. They searched the Global Index Medicus, EMBASE, and Medline for studies reporting symptomatic yellow fever in vaccinated individuals between 1936 and 2023.
Eligible studies were randomized controlled trials, retrospective or prospective cohort studies, outbreak reports, case reports, case series, epidemiological surveys, and cross-sectional surveys.
Cases were considered effectively vaccinated if the vaccine was administered ≥ 30 days before the onset of symptoms and presumedly vaccinated if the time since vaccination was not reported/known.
Further, studies adjudicated moderate or good quality on an adapted Newcastle-Ottawa Scale were included in the meta-analysis.
Data on relevant study characteristics were extracted. Confirmed cases were those diagnosed based on virological testing, while probable cases were those diagnosed based on seroconversion. The primary outcome was the proportion of people vaccinated with a single dose ≥ 30 days before symptom onset among confirmed cases.
Secondary outcomes included the proportions of severe, fatal, and non-severe cases among confirmed cases vaccinated ≥ 30 days before symptom onset.
Further, the primary outcome of the meta-analysis was the pooled proportion of the vaccinated population with proof of vaccination ≥ 30 days before symptom onset among probable and confirmed cases.
Findings
Of over 2,600 records identified through the literature search, 37 were eligible for inclusion. These included 17 retrospective cohort studies, eight cross-sectional studies, four case reports, two case series, and six outbreak reports.
Sixteen studies reported African cases and 24 reported cases from South America. In total, studies reported 40,850 suspected cases (whose diagnosis was based on clinical symptomology).
Suspected cases were often described as those with fever and at least one other symptom or sign suggestive of yellow fever. Thirty-three studies comprised 6,951 laboratory-diagnosed cases; only 537 were effectively vaccinated.
Six studies reported the number of vaccinations; only one individual received a second vaccine dose. The time between vaccination and symptom onset was reported for 21 effectively vaccinated laboratory-diagnosed cases.
Among effectively vaccinated cases, 15 were confirmed, and 24 were probable; diagnosis was inconclusive for the remaining 498 cases.
Vaccination proof was available for nine confirmed cases and all probable cases. Probable cases were more common in people aged ≤ 20 vaccinated in childhood. Two confirmed cases died, and one patient with non-severe illness survived.
Among probable cases, disease severity was reported for nine cases; four had severe disease, and all survived. Five studies were included in the meta-analysis. The pooled proportion of verified yellow fever breakthrough infections was 3% among confirmed and probable cases.
Among laboratory-diagnosed cases, the pooled proportion of effectively and presumedly vaccinated was 15% and 28%, respectively.
Conclusions
Overall, the study identified nine confirmed yellow fever breakthrough infections between 1942 and 2020. Three occurred between three months and three years after the primary vaccination.
No confirmed breakthrough infections occurred in those vaccinated ≥ 10 years ago. One confirmed breakthrough infection was reported in a child vaccinated at 10 months.
Notably, among probable cases, a higher proportion of breakthrough infections occurred among those vaccinated as a child than as an adult. All probable and confirmed cases were Brazilians, and 98% of effectively vaccinated cases were also from Brazil.
Notably, the strict criteria (vaccination proof and virological testing for diagnosis) may have led to an underestimation of breakthrough infections.
In sum, the findings suggest that yellow fever breakthrough infections are rare, especially after 10 years of primary vaccination. This supports the current WHO position that a single vaccination can provide lifelong immunity against symptomatic yellow fever.
Future research should focus on the immunogenicity of vaccination in those vaccinated at younger ages and the incidence of breakthrough infections in these age groups.
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