scholarly journals Broadly Neutralizing Antibodies for Influenza: Passive Immunotherapy and Intranasal Vaccination

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 424 ◽  
Author(s):  
Mrityunjoy Biswas ◽  
Tatsuya Yamazaki ◽  
Joe Chiba ◽  
Sachiko Akashi-Takamura
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Immunoglobulin A ◽  
Influenza Viruses ◽  
Viral Envelope ◽  
Upper Respiratory Tract ◽  
Broadly Neutralizing Antibodies ◽  
Universal Vaccine ◽  
Passive Immunotherapy

Influenza viruses cause annual epidemics and occasional pandemics. The high diversity of viral envelope proteins permits viruses to escape host immunity. Therefore, the development of a universal vaccine and broadly neutralizing antibodies (bnAbs) is essential for controlling various mutant viruses. Here, we review some potentially valuable bnAbs for influenza; one is a novel passive immunotherapy using a variable domain of heavy chain-only antibody (VHH), and the other is polymeric immunoglobulin A (pIgA) induced by intranasal vaccination. Recently, it was reported that a tetravalent multidomain antibody (MDAb) was developed by genetic fusion of four VHHs, which are bnAbs against the influenza A or B viruses. The transfer of a gene encoding the MDAb–Fc fusion protein provided cross-protection against both influenza A and B viruses in vivo. An intranasal universal influenza vaccine, which can induce neutralizing pIgAs in the upper respiratory tract, is currently undergoing clinical studies. A recent study has revealed that tetrameric IgAs formed in nasal mucosa are more broadly protective against influenza than the monomeric and dimeric forms. These broadly neutralizing antibodies have high potential to control the currently circulating influenza virus.

scholarly journals Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wayne D. Harshbarger ◽  
Derrick Deming ◽  
Gordon J. Lockbaum ◽  
Nattapol Attatippaholkun ◽  
Maliwan Kamkaew ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Critical Role ◽  
Binding Activity ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Influenza A Viruses ◽  
Universal Vaccine ◽  
Structural Details ◽  
Structural Solution

AbstractBroadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined classes provide insights to the bias selection of VH3-30 antibodies and reveals that 3I14 represents a novel structural solution within the VH3-30 repertoire. The structures reported here improve our understanding of cross-group heterosubtypic binding activity, providing the basis for advancing immunogen designs aimed at eliciting a broadly protective response to IAV.

scholarly journals Broadly Neutralizing Anti-Influenza Virus Antibodies: Enhancement of Neutralizing Potency in Polyclonal Mixtures and IgA Backbones

2015 ◽  
Vol 89 (7) ◽  
pp. 3610-3618 ◽  
Author(s):  
Wenqian He ◽  
Caitlin E. Mullarkey ◽  
J. Andrew Duty ◽  
Thomas M. Moran ◽  
Peter Palese ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Virus Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Human Peripheral Blood ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Broadly Neutralizing Antibodies ◽  
Variable Regions

ABSTRACTCurrent influenza virus vaccines rely upon the accurate prediction of circulating virus strains months in advance of the actual influenza season in order to allow time for vaccine manufacture. Unfortunately, mismatches occur frequently, and even when perfect matches are achieved, suboptimal vaccine efficacy leaves several high-risk populations vulnerable to infection. However, the recent discovery of broadly neutralizing antibodies that target the hemagglutinin (HA) stalk domain has renewed hope that the development of “universal” influenza virus vaccines may be within reach. Here, we examine the functions of influenza A virus hemagglutinin stalk-binding antibodies in an endogenous setting, i.e., as polyclonal preparations isolated from human sera. Relative to monoclonal antibodies that bind to the HA head domain, the neutralization potency of monoclonal stalk-binding antibodies was vastly inferiorin vitrobut was enhanced by several orders of magnitude in the polyclonal context. Furthermore, we demonstrated a surprising enhancement in IgA-mediated HA stalk neutralization relative to that achieved by antibodies of IgG isotypes. Mechanistically, this could be explained in two ways. Identical variable regions consistently neutralized virus more potently when in an IgA backbone compared to an IgG backbone. In addition, HA-specific memory B cells isolated from human peripheral blood were more likely to be stalk specific when secreting antibodies of IgA isotypes compared to those secreting IgG. Taken together, our data provide strong evidence that HA stalk-binding antibodies perform optimally when in a polyclonal context and that the targeted elicitation of HA stalk-specific IgA should be an important consideration during “universal” influenza virus vaccine design.IMPORTANCEInfluenza viruses remain one of the most worrisome global public health threats due to their capacity to cause pandemics. While seasonal vaccines fail to protect against the emergence of pandemic strains, a new class of broadly neutralizing antibodies has been recently discovered and may be the key to developing a “universal” influenza virus vaccine. While much has been learned about the biology of these antibodies, most studies have focused only on monoclonal antibodies of IgG subtypes. However, the study of monoclonal antibodies often fails to capture the complexity of antibody functions that occur during natural polyclonal responses. Here, we provide the first detailed analyses of the biological activity of these antibodies in polyclonal contexts, comparing both IgG and IgA isotypes isolated from human donors. The striking differences observed in the functional properties of broadly neutralizing antibodies in polyclonal contexts will be essential for guiding design of “universal” influenza virus vaccines and therapeutics.

scholarly journals Pathogenesis and Transmission of Genetically Diverse Swine-Origin H3N2 Variant Influenza A Viruses from Multiple Lineages Isolated in the United States, 2011–2016

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Xiangjie Sun ◽  
Joanna A. Pulit-Penaloza ◽  
Jessica A. Belser ◽  
Claudia Pappas ◽  
Melissa B. Pearce ◽  
...  
Keyword(s):  
United States ◽  
Respiratory Tract ◽  
Influenza A ◽  
Seasonal Influenza ◽  
The United States ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Pandemic Preparedness

ABSTRACTWhile several swine-origin influenza A H3N2 variant (H3N2v) viruses isolated from humans prior to 2011 have been previously characterized for their virulence and transmissibility in ferrets, the recent genetic and antigenic divergence of H3N2v viruses warrants an updated assessment of their pandemic potential. Here, four contemporary H3N2v viruses isolated during 2011 to 2016 were evaluated for their replicative ability in bothin vitroandin vivoin mammalian models as well as their transmissibility among ferrets. We found that all four H3N2v viruses possessed similar or enhanced replication capacities in a human bronchial epithelium cell line (Calu-3) compared to a human seasonal influenza virus, suggestive of strong fitness in human respiratory tract cells. The majority of H3N2v viruses examined in our study were mildly virulent in mice and capable of replicating in mouse lungs with different degrees of efficiency. In ferrets, all four H3N2v viruses caused moderate morbidity and exhibited comparable titers in the upper respiratory tract, but only 2 of the 4 viruses replicated in the lower respiratory tract in this model. Furthermore, despite efficient transmission among cohoused ferrets, recently isolated H3N2v viruses displayed considerable variance in their ability to transmit by respiratory droplets. The lack of a full understanding of the molecular correlates of virulence and transmission underscores the need for close genotypic and phenotypic monitoring of H3N2v viruses and the importance of continued surveillance to improve pandemic preparedness.IMPORTANCESwine-origin influenza viruses of the H3N2 subtype, with the hemagglutinin (HA) and neuraminidase (NA) derived from historic human seasonal influenza viruses, continue to cross species barriers and cause human infections, posing an indelible threat to public health. To help us better understand the potential risk associated with swine-origin H3N2v viruses that emerged in the United States during the 2011-2016 influenza seasons, we use bothin vitroandin vivomodels to characterize the abilities of these viruses to replicate, cause disease, and transmit in mammalian hosts. The efficient respiratory droplet transmission exhibited by some of the H3N2v viruses in the ferret model combined with the existing evidence of low immunity against such viruses in young children and older adults highlight their pandemic potential. Extensive surveillance and risk assessment of H3N2v viruses should continue to be an essential component of our pandemic preparedness strategy.

First exposure to the pandemic H1N1 virus induced broadly neutralizing antibodies targeting hemagglutinin head epitopes

2021 ◽  
Vol 13 (596) ◽  
pp. eabg4535
Author(s):  
Jenna J. Guthmiller ◽  
Julianna Han ◽  
Lei Li ◽  
Alec W. Freyn ◽  
Sean T. H. Liu ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Neutralizing Antibodies ◽  
Antigenic Site ◽  
Influenza Viruses ◽  
Chain Gene ◽  
Influenza B ◽  
Pandemic H1n1 ◽  
Broadly Neutralizing Antibodies ◽  
Receptor Binding Site

Broadly neutralizing antibodies are critical for protection against both drifted and shifted influenza viruses. Here, we reveal that first exposure to the 2009 pandemic H1N1 influenza virus recalls memory B cells that are specific to the conserved receptor-binding site (RBS) or lateral patch epitopes of the hemagglutinin (HA) head domain. Monoclonal antibodies (mAbs) generated against these epitopes are broadly neutralizing against H1N1 viruses spanning 40 years of viral evolution and provide potent protection in vivo. Lateral patch-targeting antibodies demonstrated near universal binding to H1 viruses, and RBS-binding antibodies commonly cross-reacted with H3N2 viruses and influenza B viruses. Lateral patch-targeting mAbs were restricted to expressing the variable heavy-chain gene VH3-23 with or without the variable kappa-chain gene VK1-33 and often had a Y-x-R motif within the heavy-chain complementarity determining region 3 to make key contacts with HA. Moreover, lateral patch antibodies that used both VH3-23 and VK1-33 maintained neutralizing capability with recent pH1N1 strains that acquired mutations near the lateral patch. RBS-binding mAbs used a diverse repertoire but targeted the RBS epitope similarly and made extensive contacts with the major antigenic site Sb. Together, our data indicate that RBS- and lateral patch-targeting clones are abundant within the human memory B cell pool, and universal vaccine strategies should aim to drive antibodies against both conserved head and stalk epitopes.

scholarly journals Residue 627 of PB2 Is a Determinant of Cold Sensitivity in RNA Replication of Avian Influenza Viruses

2001 ◽  
Vol 75 (11) ◽  
pp. 5398-5404 ◽  
Author(s):  
Pascale Massin ◽  
Sylvie van der Werf ◽  
Nadia Naffakh
Keyword(s):  
Mammalian Cells ◽  
Influenza A ◽  
Cultured Cells ◽  
Rna Replication ◽  
Influenza Viruses ◽  
Cold Sensitivity ◽  
Upper Respiratory Tract ◽  
Avian Viruses ◽  
Human Viruses

ABSTRACT Human influenza A viruses replicate in the upper respiratory tract at a temperature of about 33°C, whereas avian viruses replicate in the intestinal tract at a temperature close to 41°C. In the present study, we analyzed the influence of low temperature (33°C) on RNA replication of avian and human viruses in cultured cells. The kinetics of replication of the NP segment were similar at 33 and 37°C for the human A/Puerto-Rico/8/34 and A/Sydney/5/97 viruses, whereas replication was delayed at 33°C compared to 37°C for the avian A/FPV/Rostock/34 and A/Mallard/NY/6750/78 viruses. Making use of a genetic system for the in vivo reconstitution of functional ribonucleoproteins, we observed that the polymerase complexes derived from avian viruses but not human viruses exhibited cold sensitivity in mammalian cells, which was determined mostly by residue 627 of PB2. Our results suggest that a reduced ability of the polymerase complex of avian viruses to ensure replication of the viral genome at 33°C could contribute to their inability to grow efficiently in humans.

scholarly journals Efficacy of recombinant NP-M1 and NP-M1-CRT DNA vaccines against Influenza A viruses in mice C57/BL6

2021 ◽  
Author(s):  
Hamidreza Attaran ◽  
Wen He ◽  
wei wang
Keyword(s):  
Influenza Virus ◽  
Murine Model ◽  
Mammalian Cells ◽  
Influenza A ◽  
Matrix Protein ◽  
Protective Efficacy ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Universal Vaccine

Effective vaccination against the influenza virus remains a challenge because of antigenic shift and drift in influenza viruses. Conservation is an important feature of the Nucleoprotein (NP)and Matrix protein 1(M1) qualifying them as potential candidates for developing a universal vaccine against the influenza A virus. Carliticulin (CRT), a member of heat shock protein (HSP) family, are conserved and widely distributed in many microorganisms and mammalian cells. In this study, a plasmid vector encoding the NP-M1-CRT sequence was constructed and compared with the NP-M1 sequence with respect to immunogenicity and protective efficacy in a murine model. The potency of the created construct for provoking humoral, cellular immune responses, and its protective immunity against the lethal influenza virus infection were then compared with commercial split vaccine and then evaluated in a murine model system. NP-M1-CRT as a DNA vaccine combined with in vivo electroporation could significantly improve the immunogenicity of constructed vectors. Serological evaluations demonstrated the potency of our approach to provoke strong anti-NP specific antibody responses. Furthermore, our strategy of immunization in prime-boost groups were able to provide protection against lethal viral challenge using H1N1 subtype. The ease of production of these types of vectors and the fact that they would not require annual updating and manufacturing may provide an alternative cost-effective approach to limit the spread of potential pandemic influenza viruses.

scholarly journals A comprehensive influenza reporter virus panel for high-throughput deep profiling of neutralizing antibodies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Adrian Creanga ◽  
Rebecca A. Gillespie ◽  
Brian E. Fisher ◽  
Sarah F. Andrews ◽  
Julia Lederhofer ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Depth Profiling ◽  
Influenza Viruses ◽  
Effective Vaccine ◽  
Viral Gene ◽  
Broadly Neutralizing Antibodies ◽  
Level 2 ◽  
Biosafety Level ◽  
Major Target

AbstractBroadly neutralizing antibodies (bnAbs) have been developed as potential countermeasures for seasonal and pandemic influenza. Deep characterization of these bnAbs and polyclonal sera provides pivotal understanding for influenza immunity and informs effective vaccine design. However, conventional virus neutralization assays require high-containment laboratories and are difficult to standardize and roboticize. Here, we build a panel of engineered influenza viruses carrying a reporter gene to replace an essential viral gene, and develop an assay using the panel for in-depth profiling of neutralizing antibodies. Replication of these viruses is restricted to cells expressing the missing viral gene, allowing it to be manipulated in a biosafety level 2 environment. We generate the neutralization profile of 24 bnAbs using a 55-virus panel encompassing the near-complete diversity of human H1N1 and H3N2, as well as pandemic subtype viruses. Our system offers in-depth profiling of influenza immunity, including the antibodies against the hemagglutinin stem, a major target of universal influenza vaccines.

scholarly journals N-Glycolylneuraminic Acid in Animal Models for Human Influenza A Virus

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 815
Author(s):  
Cindy M. Spruit ◽  
Nikoloz Nemanichvili ◽  
Masatoshi Okamatsu ◽  
Hiromu Takematsu ◽  
Geert-Jan Boons ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Animal Models ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
Sialic Acid Content ◽  
Acetylneuraminic Acid

The first step in influenza virus infection is the binding of hemagglutinin to sialic acid-containing glycans present on the cell surface. Over 50 different sialic acid modifications are known, of which N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the two main species. Animal models with α2,6 linked Neu5Ac in the upper respiratory tract, similar to humans, are preferred to enable and mimic infection with unadapted human influenza A viruses. Animal models that are currently most often used to study human influenza are mice and ferrets. Additionally, guinea pigs, cotton rats, Syrian hamsters, tree shrews, domestic swine, and non-human primates (macaques and marmosets) are discussed. The presence of NeuGc and the distribution of sialic acid linkages in the most commonly used models is summarized and experimentally determined. We also evaluated the role of Neu5Gc in infection using Neu5Gc binding viruses and cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH)-/- knockout mice, which lack Neu5Gc and concluded that Neu5Gc is unlikely to be a decoy receptor. This article provides a base for choosing an appropriate animal model. Although mice are one of the most favored models, they are hardly naturally susceptible to infection with human influenza viruses, possibly because they express mainly α2,3 linked sialic acids with both Neu5Ac and Neu5Gc modifications. We suggest using ferrets, which resemble humans closely in the sialic acid content, both in the linkages and the lack of Neu5Gc, lung organization, susceptibility, and disease pathogenesis.

scholarly journals Evolution and Adaptation of the Avian H7N9 Virus into the Human Host

2020 ◽  
Vol 8 (5) ◽  
pp. 778
Author(s):  
Andrew T. Bisset ◽  
Gerard F. Hoyne
Keyword(s):  
Amino Acid ◽  
Avian Influenza ◽  
Influenza A ◽  
Amino Acid Sequences ◽  
Influenza Viruses ◽  
Amino Acid Substitutions ◽  
Upper Respiratory Tract ◽  
Viral Polymerase ◽  
Evolutionary Changes ◽  
Avian Origin

Influenza viruses arise from animal reservoirs, and have the potential to cause pandemics. In 2013, low pathogenic novel avian influenza A(H7N9) viruses emerged in China, resulting from the reassortment of avian-origin viruses. Following evolutionary changes, highly pathogenic strains of avian influenza A(H7N9) viruses emerged in late 2016. Changes in pathogenicity and virulence of H7N9 viruses have been linked to potential mutations in the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA), as well as the viral polymerase basic protein 2 (PB2). Recognizing that effective viral transmission of the influenza A virus (IAV) between humans requires efficient attachment to the upper respiratory tract and replication through the viral polymerase complex, experimental evidence demonstrates the potential H7N9 has for increased binding affinity and replication, following specific amino acid substitutions in HA and PB2. Additionally, the deletion of extended amino acid sequences in the NA stalk length was shown to produce a significant increase in pathogenicity in mice. Research shows that significant changes in transmissibility, pathogenicity and virulence are possible after one or a few amino acid substitutions. This review aims to summarise key findings from that research. To date, all strains of H7N9 viruses remain restricted to avian reservoirs, with no evidence of sustained human-to-human transmission, although mutations in specific viral proteins reveal the efficacy with which these viruses could evolve into a highly virulent and infectious, human-to-human transmitted virus.

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