A Systematic, Unbiased Mapping of CD8+ and CD4+ T Cell Epitopes in Yellow Fever Vaccinees.

Examining CD8+ and CD4+ T cell responses after primary Yellow Fever vaccination in a cohort of 210 volunteers, we have identified and tetramer-validated 92 CD8+ and 50 CD4+ T cell epitopes, many inducing strong and prevalent (i.e., immunodominant) T cell responses. Restricted by 40 and 14 HLA-class I and II allotypes, respectively, these responses have wide population coverage and might be of considerable academic, diagnostic and therapeutic interest. The broad coverage of epitopes and HLA overcame the otherwise confounding effects of HLA diversity and non-HLA background providing the first evidence of T cell immunodomination in humans. Also, double-staining of CD4+ T cells with tetramers representing the same HLA-binding core, albeit with different flanking regions, demonstrated an extensive diversification of the specificities of many CD4+ T cell responses. We suggest that this could reduce the risk of pathogen escape, and that multi-tetramer staining is required to reveal the true magnitude and diversity of CD4+ T cell responses. Our T cell epitope discovery approach uses a combination of (1) overlapping peptides representing the entire Yellow Fever virus proteome to search for peptides containing CD4+ and/or CD8+ T cell epitopes, (2) predictors of peptide-HLA binding to suggest epitopes and their restricting HLA allotypes, (3) generation of peptide-HLA tetramers to identify T cell epitopes, and (4) analysis of ex vivo T cell responses to validate the same. This approach is systematic, exhaustive, and can be done in any individual of any HLA haplotype. It is all-inclusive in the sense that it includes all protein antigens and peptide epitopes, and encompasses both CD4+ and CD8+ T cell epitopes. It is efficient and, importantly, reduces the false discovery rate. The unbiased nature of the T cell epitope discovery approach presented here should support the refinement of future peptide-HLA class I and II predictors and tetramer technologies, which eventually should cover all HLA class I and II isotypes. We believe that future investigations of emerging pathogens (e.g., SARS-CoV-2) should include population-wide T cell epitope discovery using blood samples from patients, convalescents and/or long-term survivors, who might all hold important information on T cell epitopes and responses.

Repurposing of the childhood vaccines: could we train the immune system against the SARS-CoV-2.

INTRODUCTION: The COVID-19 pandemic is a globalized health concern caused by a beta-coronavirus named Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Since December 2019, when this outbreak flared in Wuhan, China, COVID-19 cases have been continuously rising all over the world. Due to the emergence of SARS-CoV-2 mutants, subsequent waves are flowing in a faster manner as compared to the primary wave, which is more contagious and causing higher mortality. Recently, India has emerged as the new epicenter of the second wave by mutants of SARS-CoV-2. After almost eighteen months of this outbreak, some COVID-19 dedicated therapeutics and vaccines are available, and a few are under trial, but the situation is still uncontrolled. AREA COVERED: This perspective article covers the repurposing of childhood vaccines like Bacille Calmette-Guerin (BCG), Measles, Mumps, Rubella (MMR), and Oral Polio Vaccine (OPV), which are live attenuated vaccines and have been shown the protective effect through 'trained immunity and 'crossreactivity.' EXPERT OPINION: This perspective article has suggested that combinatorial use of these childhood vaccines might exert a better protective effect along with the available COVID-19 therapeutic and vaccines which could be considered as a preventive option against SARS-CoV-2 infection as well as its subsequent waves.

Vaccine development for emerging infectious diseases.

Examination of the vaccine strategies and technical platforms used for the COVID-19 pandemic in the context of those used for previous emerging and reemerging infectious diseases and pandemics may offer some mutually beneficial lessons. The unprecedented scale and rapidity of dissemination of recent emerging infectious diseases pose new challenges for vaccine developers, regulators, health authorities and political constituencies. Vaccine manufacturing and distribution are complex and challenging. While speed is essential, clinical development to emergency use authorization and licensure, pharmacovigilance of vaccine safety and surveillance of virus variants are also critical. Access to vaccines and vaccination needs to be prioritized in low- and middle-income countries. The combination of these factors will weigh heavily on the ultimate success of efforts to bring the current and any future emerging infectious disease pandemics to a close.

Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.