Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin

Lee, Juhye; Eguia, Rachel; Zost, Seth J.; Choudhary, Saket; Wilson, Patrick C.; Bedford, Trevor; Stevens-Ayers, Terry; Boeckh, Michael; Hurt, Aeron C.; Lakdawala, Seema S.; Hensley, Scott E.; Bloom, Jesse D

doi:10.1101/670497

Cited by 35 publications

(63 citation statements)

References 66 publications

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“…Nonetheless, its occurrence in vitro warrants further work to evaluate whether the close-by D614G 20 mutation in SARS-CoV-2 impacts protein stability, conformational changes, infectivity or recognition of a distal epitope. While the possibility of a D614G escape pathway is unknown, mutations in the RBD constitute a likely path to escape antibody recognition, as described for Influenza (34,35). Importantly, we found no mutation in the RBD that was present in more than 1% of SARS-CoV-2 sequences; such rare variants are unlikely to interfere with vaccine efficacy.…”

Section: Indicators Of Viral Evolution Have Been Shown To Be Robust Psupporting

confidence: 65%

“…Branch-lengths for both simulated phylogenies were drawn from the SARS-CoV-2 spike gene phylogeny. Mutational fitness over time was estimated for each phylogeny by extracting 35 branches from each node independently and calculating the peak height of the spectral density profile of the graph Laplacian of each subtree with >4 tips (29). Each phylogeny was downsampled 100 times at 50% and mutational fitness was re-calculated.…”

Section: Sequence Analysismentioning

confidence: 99%

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A SARS-CoV-2 vaccine candidate would likely match all currently circulating strains

Dearlove

Lewitus

Bai

et al. 2020

Preprint

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The magnitude of the COVID-19 pandemic underscores the urgency for a safe and effective vaccine. Here we analyzed SARS-CoV-2 sequence diversity across 5,700 sequences sampled since December 2019. The Spike protein, which is the target immunogen of most vaccine 5 candidates, showed 93 sites with shared polymorphisms; only one of these mutations was found in more than 1% of currently circulating sequences. The minimal diversity found among SARS-CoV-2 sequences can be explained by drift and bottleneck events as the virus spread away from its original epicenter in Wuhan, China. Importantly, there is little evidence that the virus has adapted to its human host since December 2019. Our findings suggest that a single vaccine 10

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Section: Indicators Of Viral Evolution Have Been Shown To Be Robust Psupporting

confidence: 65%

Section: Sequence Analysismentioning

confidence: 99%

A SARS-CoV-2 vaccine candidate would likely match all currently circulating strains

Dearlove

Lewitus

Bai

et al. 2020

Preprint

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“…For both the amino-acid preferences and antibody differential selection, the paper reports the average value of the three experimental replicates. To make the logo plots of the antibody selection in Fig 5B, we used the program dmslogo, version 0.2.3 47 .…”

Section: Methodsmentioning

confidence: 99%

Deep mutational scanning comprehensively maps how Zika envelope protein mutations affect viral growth and antibody escape

Sourisseau

Lawrence

Schwarz

et al. 2019

Preprint

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Functional constraints on viral proteins are often assessed by examining sequence conservation among natural strains, but this approach is relatively ineffective for Zika virus because all known sequences are highly similar. Here we take an alternative approach to map functional constraints on Zika virus’s envelope (E) protein by using deep mutational scanning to measure how all amino-acid mutations to the protein affect viral growth in cell culture. The resulting sequence-function map is consistent with existing knowledge about E protein structure and function, but also provides insight into mutation-level constraints in many regions of the protein that have not been well characterized in prior functional work. In addition, we extend our approach to completely map how mutations affect viral neutralization by two monoclonal antibodies, thereby precisely defining their functional epitopes. Overall, our study provides a valuable resource for understanding the effects of mutations to this important viral protein, and also offers a roadmap for future work to map functional and antigenic selection to Zika virus at high resolution. Importance Zika virus has recently been shown to be associated with severe birth defects. The virus’s E protein mediates its ability to infect cells, and is also the primary target of the antibodies that are elicited by natural infection and vaccines that are being developed against the virus. Therefore, determining the effects of mutations to this protein is important for understanding its function, its susceptibility to vaccine-mediated immunity, and its potential for future evolution. We completely mapped how amino-acid mutations to E protein affected the virus’s ability to grow in cells in the lab and escape from several antibodies. The resulting maps relate changes in the E protein’s sequence to changes in viral function, and therefore provide a valuable complement to existing maps of the physical structure of the protein.

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“…Inoculation selection is limited by the low frequency of new variants in donor hosts, the potentially small mucus bottleneck size v , and the fact that some previously infected hosts might not possess well-matched antibodies due to original antigenic sin (Davenport & Hennessy, 1956), antigenic seniority (Lessler et al, 2012), immune backboosting (Fonville et al, 2014), or other sources of individual-specific variation in antibody production (Lee et al, 2019). These factors combined make new variant onward transmission a rare event.…”

Section: Resultsmentioning

confidence: 99%

Asynchrony between virus diversity and antibody selection limits influenza virus evolution

Morris

Petrova

Rossine

et al. 2020

Preprint

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15Seasonal influenza viruses create a persistent global disease burden by evolving to 16 escape immunity induced by prior infections and vaccinations. New antigenic variants 17 have a substantial selective advantage at the population level, but these variants are 18 rarely selected within-host, even in previously immune individuals. We find that the 19 temporal asynchrony between within-host virus exponential growth and 20 antibody-mediated selection make within-host antigenic adaptation rare. Instead, 21 selection for new antigenic variants acts principally at the point of initial virus 22 inoculation, where small virus populations encounter well-matched mucosal antibodies 23 in previously infected individuals. Selection later in infection is rare. Our results explain 24 how virus antigenic evolution can be highly selective at the global level but nearly 25 neutral within hosts. They also suggest new avenues for improving influenza control. 26 29

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Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin

Cited by 35 publications

References 66 publications

A SARS-CoV-2 vaccine candidate would likely match all currently circulating strains

A SARS-CoV-2 vaccine candidate would likely match all currently circulating strains

Deep mutational scanning comprehensively maps how Zika envelope protein mutations affect viral growth and antibody escape

Asynchrony between virus diversity and antibody selection limits influenza virus evolution

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