Review What Constitutes Protective Immunity Following Yellow Fever Vaccination? Jolynne Mokaya 1,2, * , Derick Kimathi 1,2 , Teresa Lambe 3 and George M. Warimwe 1,2   Citation: Mokaya, J.; Kimathi, D.; Lambe, T.; Warimwe, G.M. What Constitutes Protective Immunity Following Yellow Fever Vaccination? Vaccines 2021, 9, 671. https://doi.org/10.3390/ vaccines9060671 Academic Editors: Steven B. Bradfute and Vasso Apostolopoulos Received: 10 May 2021 Accepted: 16 June 2021 Published: 18 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford OX1 3SU, UK; DKimathi@kemri-wellcome.org (D.K.); george.warimwe@ndm.ox.ac.uk (G.M.W.) 2 KEMRI-Wellcome Trust Research Programme, P.O. Box 230-80108, Kilifi 8010, Kenya 3 The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK; teresa.lambe@ndm.ox.ac.uk * Correspondence: jolynne.mokaya@ndm.ox.ac.uk Abstract: Yellow fever (YF) remains a threat to global health, with an increasing number of major outbreaks in the tropical areas of the world over the recent past. In light of this, the Eliminate Yellow Fever Epidemics Strategy was established with the aim of protecting one billion people at risk of YF through vaccination by the year 2026. The current YF vaccine gives excellent protection, but its use is limited by shortages in supply due to the difficulties in producing the vaccine. There are good grounds for believing that alternative fractional dosing regimens can produce strong protection and overcome the problem of supply shortages as less vaccine is required per person. However, immune responses to these vaccination approaches are yet to be fully understood. In addition, published data on immune responses following YF vaccination have mostly quantified neutralising antibody titers. However, vaccine-induced antibodies can confer immunity through other antibody effector functions beyond neutralisation, and an effective vaccine is also likely to induce strong and persistent memory T cell responses. This review highlights the gaps in knowledge in the characterisation of YF vaccine-induced protective immunity in the absence or presence of neutralising antibodies. The assessment of biophysical antibody characteristics and cell-mediated immunity following YF vaccination could help provide a comprehensive landscape of YF vaccine-induced immunity and a better understanding of correlates of protective immunity. Keywords: yellow fever virus; yellow fever; yellow fever vaccine; humoral immune response; cell-mediated immune response 1. Introduction Yellow fever (YF) is a disease caused by YF virus (YFV) which is known to cause death in about 30–60% of those infected [1,2]. The global annual prevalence of YF infection among humans is estimated at 200,000, with most cases reported in sub-Saharan Africa and South America where it is endemic [3]. Over the past five years, there have been outbreaks of YF in Brazil, Angola, Democratic Republic of Congo and Nigeria, with the risk of further spread to other countries and continents [4]. This global threat led to the establishment of the Eliminate Yellow Fever Epidemics (EYE) Strategy, steered by the World Health Organisation (WHO), United Nations Children’s Fund (UNICEF) and Gavi, the Vaccine Alliance [5]. The EYE strategy aims to protect one billion people against YF through vaccination by the year 2026 [5]. 2. Molecular Biology of YF YFV is a member of the family Flaviviridae and genus Flavivirus. This genus includes other human and veterinary pathogens such as Dengue virus (DENV), Zika virus (ZIKV), tick-borne encephalitis virus (TBEV), West Nile virus (WNV) and Japanese encephalitis virus (JEV) [6]. The mature infectious virion is composed of an outer envelope made of a lipid bilayer derived from host membranes, and studded with dimers of envelop (E) Vaccines 2021, 9, 671. https://doi.org/10.3390/vaccines9060671 https://www.mdpi.com/journal/vaccines