Is a second dose of yellow fever vaccine needed? A systematic review of humoral and cell-mediated immunity after revaccination.

Background: In the context of ongoing debate about whether a single dose of the yellow fever (YF) vaccine provides lifelong protection, addressing key unanswered questions-such as the extent to which revaccination enhances humoral and cell-mediated immune (CMI) responses, and the true duration of immunity-is particularly important for protecting high-risk groups. This systematic review evaluated the immunogenicity of YF revaccination, to support evidence-based vaccination policies.

Methods: A systematic search in electronic databases was conducted to identify relevant studies that evaluated humoral or CMI responses following booster YF vaccination in both adults and children from endemic and non-endemic regions. Interventions included full-dose and fractional-dose YF vaccine boosters.

Results: Twenty-one studies (n = 1821 participants) were included. Revaccination temporarily enhances neutralizing antibody titres, particularly in individuals with low or undetectable baseline immunity. Long-term seropositivity remained high in most cohorts. Individuals with high baseline titres showed limited humoral response, suggesting a limited boosting effect. In terms of CMI, booster generally results in minimal activation of T-cell markers compared to primary vaccination, suggesting that revaccination primarily sustains memory responses rather than inducing new activation. In individuals with low baseline immunity, it restores both T-cell and B-cell functional memories. Memory T-cell subsets remain detectable for over 10 years. Children vaccinated at ≤ 2 years and immunocompromised individuals showed marked benefits from revaccination.

Conclusions: Routine YF revaccination appears unnecessary for most immunocompetent individuals across different age groups given durable protection conferred by a single dose. However, booster doses may benefit specific high-risk groups such as individuals vaccinated at very young ages, those with low baseline immunity or with altered immunocompetence.