Yellow fever

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Epidemiology

Due to non-specific acute febrile illness in its early stage including substantial number of asymptomatic cases, there are limitations to define the true incidence and case fatality rate of YF.

Case definitions

• WHO suggests case definitions to survey YF with suspected case as Any person with acute onset of fever, with jaundice appearing within 14 days of onset of the first symptoms.

World Health Organization. (2022). Yellow Fever Outbreak Toolbox. https://www.who.int/emergencies/outbreak-toolkit/disease-outbreak-toolboxes/yellow-fever-outbreak-toolbox

Epidemiology according to geography

• An estimation of YF endemicity in African continent using generalized linear regression model resulted in 130,000 cases with fever and jaundice or haemorrhage (not confirmed yellow fever cases) including 78,000 deaths in the year of 2013 taking into account of YF vaccination campaign.

Garske, T., van Kerkhove, M. D., Yactayo, S., Ronveaux, O., Lewis, R. F., Staples, J. E., Perea, W., Ferguson, N. M., Burke, D., de La Hoz, F., Grenfell, B., Hansen, P. M., & Hutubessy, R. (2014). Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data. PLoS Medicine, 11(5). https://doi.org/10.1371/journal.pmed.1001638

• A systematic review found incidences of YF across African countries were quite heterogenous (I²=99.4%) as per 100,000 population ranging from <1 in Nigeria to 10,350 in Ghana and failed in quantitative synthesis for meta-analysis.

Nwaiwu, A. U., Musekiwa, A., Tamuzi, J. L., Sambala, E. Z., & Nyasulu, P. S. (2021). The incidence and mortality of yellow fever in Africa: a systematic review and meta-analysis. BMC Infectious Diseases, 21(1), 1–11. https://doi.org/10.1186/s12879-021-06728-x

Epidemiology according to severity and Case fatality rate

• A mathematical estimation using Bayesian model showed probability of asymptomatic infection, mild disease and severe disease as 55%, 33% and 12%, respectively, as well as case fatality rate among severe disease as 47%, but the 11 studies authors collected for the study were highly heterogeneous.

Johansson, M. A., Vasconcelos, P. F. C., & Staples, J. E. (2014). The whole iceberg: Estimating the incidence of yellow fever virus infection from the number of severe cases. Transactions of the Royal Society of Tropical Medicine and Hygiene, 108(8), 482–487. https://doi.org/10.1093/trstmh/tru092

• A systematic review and meta-analysis which synthesized 14 articles concluded that case fatality rate of YF among severe disease is 39% (95%CI 31-47).

Servadio, J. L., Muñoz-Zanzi, C., & Convertino, M. (2021). Estimating case fatality risk of severe Yellow Fever cases: systematic literature review and meta-analysis. BMC Infectious Diseases, 21(1), 1–12. https://doi.org/10.1186/s12879-021-06535-4

transmission

• sylvatic cycle
• savannah cycle only in Africa
• urban cycle
• reason why YF doesn't exist in Asia is unknown

clinical features

• 3-6 days incubation
• infection phase
• remission phase
  • most patients ended with remission phase
• intoxication phase

YF vaccine

Correlates of protection

• Neutralization titer ≥1:10

• Log₁₀ neutralization index (LNI) ≥0.7

YF vaccine and Pregnancy

• Though YF vaccine is generally contraindicated for pregnant women because of theoretical risk for fetus, multiple reports have accordingly proved safety in babies born from mothers accidentally immunized by YF vaccine.

Thomas, R. E., Lorenzetti, D. L., Spragins, W., Jackson, D., & Williamson, T. (2012). The safety of yellow fever vaccine 17D or 17DD in children, pregnant women, HIV+ individuals, and older persons: Systematic review. American Journal of Tropical Medicine and Hygiene, 86(2), 359–372. https://doi.org/10.4269/ajtmh.2012.11-0525

YF vaccine and Thymus disease

• Eidex RB and YF Vaccine Safety Working Group in US-CDC reported potential association between thymus diseases and thymectomy and YEL-AVD. 4 among 23 cases of YEL-AVD reported as of 2004 had history of thymus disease and thymectomy. The authors issued alert to Thymectomy, Thymoma, Myasthenia gravis and DiGeorge syndrome.

Eidex, R. B., & Yellow Fever Vaccine Safety Working Group. (2004). History of thymoma and yellow fever vaccination. In Lancet (Vol. 364, Issue 9438, p. 936). Elsevier B.V. https://doi.org/10.1016/S0140-6736(04)17017-7

YF vaccine and Multiple sclerosis

• In a prospective self-controlled case series study published in 2011 reported that between 1 and 5 weeks after YF immunization ('at risk period') MS patients experienced higher exacerbation rate compared to other periods (rate ratio 12.778; 8.57 episodes per year at risk period vs 0.67 episodes per year at non-risk period).

Farez, M. F., & Correale, J. (2011). Yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis. Archives of Neurology, 68(10), 1267–1271. https://doi.org/10.1001/archneurol.2011.131

• Whereas another retrospective self-controlled cohort published in 2020 reported that during 3 months after YF immunization ('exposure risk period') MS patients did not experienced significant increase of disease exacerbation associated with YF immunization.

Huttner, A., Eperon, G., Lascano, A. M., Roth, S., Schwob, J. M., Siegrist, C. A., & Lalive, P. H. (2020). Risk of MS relapse after yellow fever vaccination: A self-controlled case series. Neurology(R) Neuroimmunology & Neuroinflammation, 7(4), 1–6. https://doi.org/10.1212/NXI.0000000000000726

New vaccine development

• Inactivated YF vaccine has been under development. Phase 1 trial of XRX-001 purified whole-virus, β-propiolactone-inactivated vaccine (cultured in Vero cell, adjuvanted with alumninum hydroxide) investigated 2 separated doses in 21 days apart with antigen of 4.8 μg, 0.48 μg and placebo.

Monath, T. P., Fowler, E., Johnson, C. T., Balser, J., Morin, M. J., Sisti, M., & Trent, D. W. (2011). An Inactivated Cell-Culture Vaccine against Yellow Fever. New England Journal of Medicine, 364(14), 1326–1333. https://doi.org/10.1056/NEJMoa1009303

• Non-replicating viral vector YF vaccine has been under development. Phase 1 trial of YF protein-producing Modified Vaccinia Ankara-Bavarian Nordic virus has been completed but has not been reported in peer-reviewed journals.

NCT02743455 - A Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of MVA-BN Yellow Fever Vaccine With and Without Montanide ISA-720 Adjuvant in 18-45 Year Old Healthy Volunteers. https://classic.clinicaltrials.gov/ct2/show/NCT02743455

• mRNA YF vaccine is under development in mice and macaque models.

Medina-Magües, L. G., Mühe, J., Jasny, E., Medina-Magües, E. S., Roth, N., Lopera-Madrid, J., Salas-Quinchucua, C., Knuese, C., Petsch, B., & Osorio, J. E. (2023). Immunogenicity and protective activity of mRNA vaccine candidates against yellow fever virus in animal models. Npj Vaccines, 8(1). https://doi.org/10.1038/s41541-023-00629-7