Yellow Fever Vaccine: No Booster Needed, Study Finds

In a recent study published in The Lancet Microbe, researchers compiled evidence on yellow fever outbreaks following primary immunization.

Background

Yellow fever, caused by the yellow fever virus, is an acute febrile and potentially fatal hemorrhagic infection that kills an estimated 30,000 people each year and has a 40% case fatality rate in the symptomatic population.

The virus is spread by mosquito vectors from the Haemagogus or Aedes genera. Yellow fever is endemic in South America and Sub-Saharan Africa.

Preventive actions are essential because there are no viable treatments. Nonetheless, a live-attenuated vaccine created in the 1930s is available, but it is not suitable for certain populations.

Vaccination as pre-exposure prophylaxis provides effective immunity, with short- and long-term seroprotection rates of 71% to 100% and 48% to 100%, respectively.

The World Health Organization (WHO) revised its opinion on booster immunization in 2015, stating that a single dosage provides lifelong protection and that revaccination is unnecessary.

However, this issue has since been contested, with most studies focusing on neutralizing antibodies. Nonetheless, emerging data suggests that T cell immunity has a role in long-term protection. As a result, concentrating just on humorous replies would underestimate effectiveness.

About the study

In the current study, researchers summarized yellow fever breakout infections within and after 10 years following first vaccination. They searched the Global Index Medicus, EMBASE, and Medline databases for papers published between 1936 and 2023 that reported symptomatic yellow fever in vaccinated people.

Randomized controlled trials, retrospective or prospective cohort studies, epidemic reports, case reports, case series, epidemiological surveys, and cross-sectional studies were all considered eligible.

Cases were considered effectively vaccinated if the vaccine was delivered ≥ 30 days before the onset of symptoms, or presumed vaccinated if the period since vaccination was unknown.

Furthermore, papers with moderate or good quality on an adapted Newcastle-Ottawa Scale were included in the meta-analysis.

Data on the pertinent study features were extracted. Confirmed cases were diagnosed using virological testing, whereas probable cases were diagnosed using seroconversion. The primary outcome was the proportion of confirmed cases who were immunized with a single dose at least 30 days before symptom onset.

Secondary outcomes comprised the proportion of severe, fatal, and non-severe cases among confirmed cases vaccinated at least 30 days before symptom onset.

The meta-analysis aimed to determine the proportion of vaccinated individuals who had proof of vaccination ≥ 30 days prior to symptom onset, including suspected and confirmed cases.

Findings

Of the nearly 2,600 documents found throughout the literature search, 37 were eligible for inclusion. There were 17 retrospective cohort studies, 8 cross-sectional studies, 4 case reports, 2 case series, and 6 outbreak reports.

Sixteen studies documented African cases, whereas 24 recorded occurrences from South America. Overall, studies identified 40,850 suspected cases (diagnosed based on clinical symptoms).

Suspected cases were frequently described as having a fever along with at least one other symptom or indication of yellow fever. Thirty-three studies included 6,951 laboratory-diagnosed cases; only 537 were successfully immunized.

Six studies revealed the number of immunizations, with only one person receiving a second dosage. The time between vaccination and symptom onset was recorded for 21 successfully vaccinated laboratory-diagnosed individuals.

Among the effectively vaccinated cases, 15 were confirmed and 24 were probable; the remaining 498 were inconclusive.

Vaccination documentation was available for nine confirmed instances and all possible cases. Probable instances were more likely in persons aged ≤ 20 who had received childhood vaccinations. Two verified cases died, while one patient with a non-severe disease recovered.

Disease severity was described in nine of the probable cases; four had severe disease and all survived. The meta-analysis includes five studies. The combined proportion of verified yellow fever breakthrough infections among confirmed and probable cases was 3%.
Among laboratory-diagnosed cases, the pooled proportion of successfully and presumedly vaccinated individuals was 15% and 28%, respectively.

Conclusions

The investigation found nine confirmed yellow fever breakthrough cases between 1942 and 2020. Three occurred three months to three years following the primary vaccination.

There were no verified breakthrough infections among those who were vaccinated more than ten years ago. One confirmed breakthrough infection was reported in a 10-month-old vaccinated child.

Notably, among probable cases, a greater proportion of breakthrough infections occurred among those immunized as children than adults. Brazilians accounted for all probable and confirmed cases, as well as 98% of effectively vaccinated cases.

Notably, the stringent criteria (vaccination evidence and virological testing for diagnosis) may have resulted in an underestimate of breakthrough infections.

In conclusion, the findings indicate that yellow fever breakthrough infections are uncommon, particularly after ten years after main immunization. This confirms the current WHO position that a single immunization can offer lifelong protection against symptomatic yellow fever.

Future studies should look into the immunogenicity of vaccination in children and the prevalence of breakthrough infections in these age groups.

For more information: Schnyder JL, Bache BE, Welkers MRA, et al. (2024) Yellow fever breakthrough infections after yellow fever vaccination: a systematic review and meta-analysis. The Lancet Microbe,. doi: 10.1016/j.lanmic.2024.06.004. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00190-3/fulltext