A Novel Recombinant Influenza Virus Neuraminidase Vaccine Candidate Stabilized by a Measles Virus Phosphoprotein Tetramerization Domain Provides Robust Protection from Virus Challenge in the Mouse Model

Strohmeier, Shirin; Amanat, Fatima; Zhu, Xueyong; McMahon, Meagan; Deming, Meagan E.; Pasetti, Marcela F.; Neuzil, Kathleen M.; Wilson, Ian A.; Krammer, Florian

doi:10.1128/mbio.02241-21

“…However, it suggests that none of the mutations detected severely attenuated the EMVs. This is different than what has been observed with similar EMVs generated against stalk-binding antibodies where severe attenuation in vivo was detected ( 35 ).…”

Section: Resultscontrasting

confidence: 99%

“…Nevertheless, our findings can already aid in annual vaccine strain selection since they can help to identify amino acid changes in circulating strains that may lead to antigenic drift of the NA. In addition, our findings can also inform the design of NA-based vaccines ( 35 , 36 ). Specifically, they indicate which amino acids are important for interactions with human antibodies.…”

Section: Discussionmentioning

confidence: 78%

Novel Epitopes of the Influenza Virus N1 Neuraminidase Targeted by Human Monoclonal Antibodies

Roubidoux

¹

,

Sano

²

,

McMahon

³

et al. 2022

J Virol

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“…Understanding the biophysical constraints of NA evolution not only provides mechanistic insights into influenza antigenic drift, but also facilitates next-generation immunogen design. Development of NA-based immunogens has largely focused on the tetramerization domain 30 – 32 . In contrast, immunogen designs for other viruses, such as HIV and SARS-CoV-2, mainly focus on introducing mutations to the antigen to increase its stability and expression yield 33 – 37 .…”

Section: Discussionmentioning

confidence: 99%

Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase

Lei

¹

,

Tan

²

,

Garcia

³

et al. 2022

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Neuraminidase (NA) of human influenza H3N2 virus has evolved rapidly and been accumulating mutations for more than half-century. However, biophysical constraints that govern the evolutionary trajectories of NA remain largely elusive. Here, we show that among 70 natural mutations that are present in the NA of a recent human H3N2 strain, >10% are deleterious for an ancestral strain. By mapping the permissive mutations using combinatorial mutagenesis and next-generation sequencing, an extensive epistatic network is revealed. Biophysical and structural analyses further demonstrate that certain epistatic interactions can be explained by non-additive stability effect, which in turn modulates membrane trafficking and enzymatic activity of NA. Additionally, our results suggest that other biophysical mechanisms also contribute to epistasis in NA evolution. Overall, these findings not only provide mechanistic insights into the evolution of human influenza NA and elucidate its sequence-structure-function relationship, but also have important implications for the development of next-generation influenza vaccines.

show abstract

“…Understanding the biophysical constraints of NA evolution not only provides mechanistic insights into influenza antigenic drift, but also facilitates next-generation immunogen design. Development of NA-based immunogens has largely focused on the tetramerization domain (Deng et al, 2021; Gao et al, 2021; Strohmeier et al, 2021). In contrast, immunogen designs for other viruses, such as HIV and SARS-CoV-2, mainly focus on introducing mutations to the antigen to increase its stability and expression yield (Hsieh et al, 2020; Krarup et al, 2015; Pallesen et al, 2017; Sanders and Moore, 2021; Sanders et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase

Lei

¹

,

Tan

²

,

Garcia

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Neuraminidase (NA) of human influenza H3N2 virus has evolved rapidly and been accumulating mutations for more than half-century. However, biophysical constraints that govern the evolutionary trajectories of NA remain largely elusive. Here, we show that among 70 natural mutations that are present in the NA of a recent human H3N2 strain, >10% are deleterious for an ancestral strain. By mapping the permissive mutations using combinatorial mutagenesis and next-generation sequencing, an extensive epistatic network is revealed. Biophysical and structural analyses further demonstrate that certain epistatic interactions can be explained by non-additive stability effect, which in turn modulates membrane trafficking and enzymatic activity of NA. Additionally, our results suggest that other biophysical mechanisms also contribute to epistasis in NA evolution. Overall, these findings not only provide mechanistic insights into the evolution of human influenza NA and elucidate its sequence-structure-function relationship, but also have important implications for the development of next-generation influenza vaccines.

show abstract

A Novel Recombinant Influenza Virus Neuraminidase Vaccine Candidate Stabilized by a Measles Virus Phosphoprotein Tetramerization Domain Provides Robust Protection from Virus Challenge in the Mouse Model

Cited by 38 publications

References 63 publications

Novel Epitopes of the Influenza Virus N1 Neuraminidase Targeted by Human Monoclonal Antibodies

Novel Epitopes of the Influenza Virus N1 Neuraminidase Targeted by Human Monoclonal Antibodies

Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase

Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase

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