Hui Chen1,2, Jacob Josiah Santiago Alvarez1,3, Sock Hoon Ng4, Rasmus Nielsen5,6, Weiwei Zhai1,2,7,8,9. 1. Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing. 2. Human Genetics, Genome Institute of Singapore, A*STAR, Singapore. 3. Department of Biological Science, National University of Singapore, Singapore. 4. Defence Medical and Environmental Research Institute, DSO National Labs, Singapore. 5. Department of Integrative Biology, Chinese Academy of Sciences, Kunming. 6. Department of Statistics, University of California-Berkeley, Chinese Academy of Sciences, Kunming. 7. School of Biological Sciences, Nanyang Technological University, Chinese Academy of Sciences, Kunming. 8. National Cancer Center, Singapore, Chinese Academy of Sciences, Kunming. 9. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming.
Abstract
BACKGROUND: As a dominant seasonal influenza virus, H3N2 virus rapidly evolves in humans and is a constant threat to public health. Despite sustained research efforts, the efficacy of H3N2 vaccine has decreased rapidly. Even though antigenic drift and passage adaptation (substitutions accumulated during vaccine production in embryonated eggs) have been implicated in reduced vaccine efficacy (VE), their respective contributions to the phenomenon remain controversial. METHODS: We utilized mutational mapping, a powerful probabilistic method for studying sequence evolution, to analyze patterns of substitutions in different passage conditions for an unprecedented amount of H3N2 hemagglutinin sequences (n = 32 278). RESULTS: We found that passage adaptation in embryonated eggs is driven by repeated convergent evolution over 12 codons. Based on substitution patterns at these sites, we developed a metric, adaptive distance (AD), to quantify the strength of passage adaptation and subsequently identified a strong negative correlation between AD and VE. CONCLUSIONS: The high correlation between AD and VE implies that passage adaptation in embryonated eggs may be a strong contributor to the recent reduction in H3N2 VE. We developed a computational package called MADE (Measuring Adaptive Distance and vaccine Efficacy based on allelic barcodes) to measure the strength of passage adaptation and predict the efficacy of a candidate vaccine strain. Our findings shed light on strategies for reducing Darwinian evolution within the passaging medium in order to potentially restore an effective vaccine program in the future.
BACKGROUND: As a dominant seasonal influenza virus, H3N2 virus rapidly evolves in humans and is a constant threat to public health. Despite sustained research efforts, the efficacy of H3N2 vaccine has decreased rapidly. Even though antigenic drift and passage adaptation (substitutions accumulated during vaccine production in embryonated eggs) have been implicated in reduced vaccine efficacy (VE), their respective contributions to the phenomenon remain controversial. METHODS: We utilized mutational mapping, a powerful probabilistic method for studying sequence evolution, to analyze patterns of substitutions in different passage conditions for an unprecedented amount of H3N2 hemagglutinin sequences (n = 32 278). RESULTS: We found that passage adaptation in embryonated eggs is driven by repeated convergent evolution over 12 codons. Based on substitution patterns at these sites, we developed a metric, adaptive distance (AD), to quantify the strength of passage adaptation and subsequently identified a strong negative correlation between AD and VE. CONCLUSIONS: The high correlation between AD and VE implies that passage adaptation in embryonated eggs may be a strong contributor to the recent reduction in H3N2 VE. We developed a computational package called MADE (Measuring Adaptive Distance and vaccine Efficacy based on allelic barcodes) to measure the strength of passage adaptation and predict the efficacy of a candidate vaccine strain. Our findings shed light on strategies for reducing Darwinian evolution within the passaging medium in order to potentially restore an effective vaccine program in the future.
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