scholarly journals Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head

2020 ◽  
Vol 14 (2) ◽  
pp. 149-159
Author(s):  
Yulu Wang ◽  
Dan Hu ◽  
Yanling Wu ◽  
Tianlei Ying
Keyword(s):  
Influenza Virus ◽  
Recent Advances ◽  
Globular Head

scholarly journals Lamprey VLRB response to influenza virus supports universal rules of immunogenicity and antigenicity

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Meghan O Altman ◽  
Jack R Bennink ◽  
Jonathan W Yewdell ◽  
Brantley R Herrin
Keyword(s):  
Influenza Virus ◽  
Animal Models ◽  
Convergent Evolution ◽  
Influenza A ◽  
Organic Molecules ◽  
Protein Antigens ◽  
Antigenic Sites ◽  
Foreign Proteins ◽  
Variable Lymphocyte Receptor ◽  
Globular Head

Immunoglobulins (Igs) are a crown jewel of jawed vertebrate evolution. Through recombination and mutation of small numbers of genes, Igs can specifically recognize a vast variety of natural and man-made organic molecules. Jawless vertebrates evolved a parallel system of humoral immunity, which recognizes antigens not with Ig, but with a structurally unrelated receptor called the variable lymphocyte receptor B (VLRB). We exploited the convergent evolution of Ig and VLRB antibodies (Abs) to investigate if intrinsic chemical features of foreign proteins determine their antigenicity and immunogenicity. Surprisingly, we find lamprey VLRB and mouse Ig responses to influenza A virus are extremely similar. Each focuses ∼80% of the response on hemagglutinin (HA), mainly through recognition of the major antigenic sites in the HA globular head domain. Our findings predict basic conservation of Ab responses to protein antigens, strongly supporting the use of animal models for understanding human Ab responses to viruses and protein immunogens.

scholarly journals Mapping of a Novel H3-Specific Broadly Neutralizing Monoclonal Antibody Targeting the Hemagglutinin Globular Head Isolated from an Elite Influenza Virus-Immunized Donor Exhibiting Serological Breadth

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Yu Qiu ◽  
Svetlana Stegalkina ◽  
Jianxin Zhang ◽  
Ekaterina Boudanova ◽  
Anna Park ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Neutralizing Antibodies ◽  
Vaccine Design ◽  
Binding Pocket ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Human Antibody ◽  
Sialic Acid Binding ◽  
Globular Head

ABSTRACT The discovery of potent and broadly protective influenza virus epitopes could lead to improved vaccines that are resistant to antigenic drift. Here, we describe human antibody C585, isolated from a vaccinee with remarkable serological breadth as measured by hemagglutinin inhibition (HAI). C585 binds and neutralizes multiple H3N2 strains isolated between 1968 and 2016, including strains that emerged up to 4 years after B cells were isolated from the vaccinated donor. The crystal structure of C585 Fab in complex with the HA from A/Switzerland/9715293/2013 (H3N2) shows that the antibody binds to a novel and well-conserved epitope on the globular head of H3 HA and that it differs from other antibodies not only in its epitope but in its binding geometry and hypermutated framework 3 region, thereby explaining its breadth and ability to mediate hemagglutination inhibition across decades of H3N2 strains. The existence of epitopes such as the one elucidated by C585 has implications for rational vaccine design. IMPORTANCE Influenza viruses escape immunity through continuous antigenic changes that occur predominantly on the viral hemagglutinin (HA). Induction of broadly neutralizing antibodies (bnAbs) targeting conserved epitopes following vaccination is a goal of universal influenza vaccines and advantageous in protecting hosts against virus evolution and antigenic drift. To date, most of the discovered bnAbs bind either to conserved sites in the stem region or to the sialic acid-binding pocket. Generally, antibodies targeting the stem region offer broader breadth with low potency, while antibodies targeting the sialic acid-binding pocket cover narrower breadth but usually have higher potency. In this study, we identified a novel neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against a broad range of H3N2 with high potency. This epitope may provide insights for future universal vaccine design.

scholarly journals Properly Folded Bacterially Expressed H1N1 Hemagglutinin Globular Head and Ectodomain Vaccines Protect Ferrets against H1N1 Pandemic Influenza Virus

PLoS ONE ◽  
2010 ◽  
Vol 5 (7) ◽  
pp. e11548 ◽  
Author(s):  
Surender Khurana ◽  
Swati Verma ◽  
Nitin Verma ◽  
Corey J. Crevar ◽  
Donald M. Carter ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Pandemic Influenza ◽  
H1n1 Pandemic ◽  
Globular Head

scholarly journals Protective Immunity Based on the Conserved Hemagglutinin Stalk Domain and Its Prospects for Universal Influenza Vaccine Development

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Madhu Khanna ◽  
Sachin Sharma ◽  
Binod Kumar ◽  
Roopali Rajput
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccine ◽  
Natural Infection ◽  
Influenza Viruses ◽  
Cross Protection ◽  
Influenza B ◽  
Universal Vaccine ◽  
Virus Surface ◽  
Head Domain ◽  
Globular Head

Influenza virus surface glycoprotein hemagglutinin (HA) is an excellent and chief target thatelicitsneutralizing antibodies during vaccination or natural infection. Its HA2 subunit (stem domain) is most conserved as compared to HA1 subunit (globular head domain). Current influenza vaccine relies on globular head domain that provides protection only against the homologous vaccine strains, rarely provides cross-protection against divergent strains, and needs to be updated annually. There is an urge for a truly universal vaccine that provides broad cross-protection against different subtype influenza A viruses along with influenza B viruses and need not be updated annually. Antibodies against the stem domain of hemagglutinin (HA) are able to neutralize a wide spectrum of influenza virus strains and subtypes. These stem-specific antibodies have great potential for the development of universal vaccine against influenza viruses. In this review, we have discussed the stem-specific cross-reactive antibodies and heterosubtypic protection provided by them. We have also discussed their epitope-based DNA vaccine and their future prospects in this scenario.

scholarly journals Unmasking Stem-Specific Neutralizing Epitopes by Abolishing N-Linked Glycosylation Sites of Influenza Virus Hemagglutinin Proteins for Vaccine Design

2016 ◽  
Vol 90 (19) ◽  
pp. 8496-8508 ◽  
Author(s):  
Wen-Chun Liu ◽  
Jia-Tsrong Jan ◽  
Yun-Ju Huang ◽  
Ting-Hsuan Chen ◽  
Suh-Chin Wu
Keyword(s):  
Influenza Virus ◽  
Neutralizing Antibody ◽  
Influenza Vaccines ◽  
Mutant Proteins ◽  
Fusion Inhibition ◽  
Influenza Virus Hemagglutinin ◽  
Glycosylation Sites ◽  
Antibody Titers ◽  
Virus Strains ◽  
Globular Head

ABSTRACTInfluenza virus hemagglutinin (HA) protein consists of two components, i.e., a globular head region and a stem region that are folded within six disulfide bonds, plus several N-linked glycans that produce a homotrimeric complex structure. While N-linked glycosylation sites on the globular head are variable among different strains and different subtypes, N-linked glycosylation sites in the stem region are mostly well conserved among various influenza virus strains. Targeting highly conserved HA stem regions has been proposed as a useful strategy for designing universal influenza vaccines. Since the HA stem region is constituted by an HA1 N-terminal part and a full HA2 part, we expressed a series of recombinant HA mutant proteins with deleted N-linked glycosylation sites in the HA1 stem and HA2 stem regions of H5N1 and pH1N1 viruses. Unmasking N-glycans in the HA2 stem region (H5 N484A and H1 N503A) was found to elicit more potent neutralizing antibody titers against homologous, heterologous, and heterosubtypic viruses. Unmasking the HA2 stem N-glycans of H5HA but not H1HA resulted in more CR6261-like and FI6v3-like antibodies and also correlated with the increase of cell fusion inhibition activity in antisera. Only H5 N484A HA2 stem mutant protein immunization increased the numbers of antibody-secreting cells, germinal center B cells, and memory B cells targeting the stem helix A epitopes in splenocytes. Unmasking the HA2 stem N-glycans of H5HA mutant proteins showed a significantly improvement in the protection against homologous virus challenges but did so to a less degree for the protection against heterosubtypic pH1N1 virus challenges. These results may provide useful information for designing more effective influenza vaccines.IMPORTANCEN-linked glycosylation sites in the stem regions of influenza virus hemagglutinin (HA) proteins are mostly well conserved among various influenza virus strains. Targeting highly conserved HA stem regions has been proposed as a useful strategy for designing universal influenza vaccines. Our studies indicate that unmasking the HA2 stem N-glycans of recombinant HA proteins from H5N1 and pH1N1 viruses induced more potent neutralizing antibody titers against homologous and heterosubtypic viruses. However, only immunization with the H5N1 HA2 stem mutant protein can refocus B antibody responses to the helix A epitope for inducing more CR6261-like/FI6v3-like and fusion inhibition antibodies in antisera, resulting in a significant improvement for the protection against lethal H5N1 virus challenges. These results may provide useful information for designing more effective influenza vaccines.

scholarly journals Hemagglutinin Stalk- and Neuraminidase-Specific Monoclonal Antibodies Protect against Lethal H10N8 Influenza Virus Infection in Mice

2015 ◽  
Vol 90 (2) ◽  
pp. 851-861 ◽  
Author(s):  
Teddy John Wohlbold ◽  
Veronika Chromikova ◽  
Gene S. Tan ◽  
Philip Meade ◽  
Fatima Amanat ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Morbidity And Mortality ◽  
Head Domain ◽  
Group 2 ◽  
Reactive Antibody ◽  
Globular Head

ABSTRACTBetween November 2013 and February 2014, China reported three human cases of H10N8 influenza virus infection in the Jiangxi province, two of which were fatal. Using hybridoma technology, we isolated a panel of H10- and N8-directed monoclonal antibodies (MAbs) and further characterized the binding reactivity of these antibodies (via enzyme-linked immunosorbent assay) to a range of purified virus and recombinant protein substrates. The H10-directed MAbs displayed functional hemagglutination inhibition (HI) and neutralization activity, and the N8-directed antibodies displayed functional neuraminidase inhibition (NI) activity against H10N8. Surprisingly, the HI-reactive H10 antibodies, as well as a previously generated, group 2 hemagglutinin (HA) stalk-reactive antibody, demonstrated NI activity against H10N8 and an H10N7 strain; this phenomenon was absent when virus was treated with detergent, suggesting the anti-HA antibodies inhibited neuraminidase enzymatic activity through steric hindrance. We tested the prophylactic efficacy of one representative H10-reactive, N8-reactive, and group 2 HA stalk-reactive antibodyin vivousing a BALB/c challenge model. All three antibodies were protective at a high dose (5 mg/kg). At a low dose (0.5 mg/kg), only the anti-N8 antibody prevented weight loss. Together, these data suggest that antibody targets other than the globular head domain of the HA may be efficacious in preventing influenza virus-induced morbidity and mortality.IMPORTANCEAvian H10N8 and H10N7 viruses have recently crossed the species barrier, causing morbidity and mortality in humans and other mammals. Although these reports are likely isolated incidents, it is possible that more cases may emerge in future winter seasons, similar to H7N9. Furthermore, regular transmission of avian influenza viruses to humans increases the risk of adaptive mutations and reassortment events, which may result in a novel virus with pandemic potential. Currently, no specific therapeutics or vaccines are available against the H10N8 influenza virus subtype. We generated a panel of H10- and N8-reactive MAbs. Although these antibodies may practically be developed into therapeutic agents, characterizing the protective potential of MAbs that have targets other than the HA globular head domain will provide insight into novel antibody-mediated mechanisms of protection and help to better understand correlates of protection for influenza A virus infection.

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