Preexisting human antibodies neutralize recently emerged H7N9 influenza strains

Dunand, Carole J. Henry; Leon, Paul E.; Kaur, Kaval; Tan, Gene S.; Zheng, Na; Andrews, Sarah; Huang, Min; Qu, Xinyan; Huang, Yunping; Salgado-Ferrer, Marlene; Ho, Irvin Y.; Taylor, William M.; Hai, Rong; Wrammert, Jens; Ahmed, Rafi; García‐Sastre, Adolfo; Palese, Peter; Krammer, Florian; Wilson, Patrick C.

doi:10.1172/jci74374

Cited by 118 publications

(141 citation statements)

References 46 publications

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“…HA stalk-reactive mAbs were identified based on the characteristics described for Figure 2. The 33 HA stalk-binding mAbs included 26 unpublished mAbs generated by our group as well as 7 mAbs published previously by our group or others (7, 12, 15-17) (table S3 and S4). The majority of HA stalk mAbs were crossreactive with Group 1 HAs only, though four were also capable of binding HA from Group 2 viruses (H3N2 and H7N9).…”

Section: Resultsmentioning

confidence: 99%

Immune history profoundly affects broadly protective B cell responses to influenza

et al. 2015

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Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal Abs generated from vaccine-induced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, HA stalk-biased, response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies.

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Section: Resultsmentioning

confidence: 99%

Immune history profoundly affects broadly protective B cell responses to influenza

et al. 2015

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“…There have also been reports on the efficacy of mAb(s) against the HA of A(H7N9) virus infections in the mouse model (Chen et al, 2015; Dunand et al, 2015; Tan et al, 2016; Tharakaraman et al, 2015). Since treatment with 3c10-3, or the above mentioned HA-targeting mAb, alone both prevents and treats influenza virus infection, it seems plausible that an antibody cocktail targeting both influenza HA and NA may be a viable therapeutic approach, or could be administered to at-risk individuals (e.g.…”

Section: Discussionmentioning

confidence: 99%

An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody with prophylactic and therapeutic activity in vivo

et al. 2016

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Zoonotic A(H7N9) avian influenza viruses emerged in China in 2013 and continue to be a threat to human public health, having infected over 800 individuals with a mortality rate approaching 40%. Treatment options for people infected with A(H7N9) include the use of neuraminidase (NA) inhibitors. However, like other influenza viruses, A(H7N9) can become resistant to these drugs. The use of monoclonal antibodies is a rapidly developing strategy for controlling influenza virus infection. Here we generated a murine monoclonal antibody (3c10-3) directed against the NA of A(H7N9) and show that prophylactic systemic administration of 3c10-3 fully protected mice from lethal challenge with wild-type A/Anhui/1/2013 (H7N9). Further, post-infection treatment with a single systemic dose of 3c10-3 at either 24, 48 or 72 h post A(H7N9) challenge resulted in both dose- and time-dependent protection of up to 100% of mice, demonstrating therapeutic potential for 3c10-3. Epitope mapping revealed that 3c10-3 binds near the enzyme active site of NA, and functional characterization showed that 3c10-3 inhibits the enzyme activity of NA and restricts the cell-to-cell spread of the virus in cultured cells. Affinity analysis also revealed that 3c10-3 binds equally well to recombinant NA of wild-type A/Anhui/1/2013 and to a variant NA carrying a R289K mutation known to infer NAI resistance. These results suggest that 3c10-3 has the potential to be used as a therapeutic to treat A(H7N9) infections either as an alternative to, or in combination with, current NA antiviral inhibitors.

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“…To exclude denaturation on the plate due to hydrophobic interactions between protein and plate, the proteins were captured via their hexahistidine tag on Ni-NTA HiSorb plates (Qiagen) and ELISAs were performed as described before [13]. Murine mAbs IB11, 6F12 [9], BD3, GG3 [26] and KB2 [27] and the Fab fragment of human mAb CR6261 [10] bind only to the correctly folded stalk domain and were used to probe for conformational integrity.…”

Section: Methodsmentioning

confidence: 99%

Vaccination with soluble headless hemagglutinin protects mice from challenge with divergent influenza viruses

Wohlbold

Nachbagauer

Margine

et al. 2015

Vaccine

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Current influenza virus vaccines provide solid protection from infection with viruses that are well matched with the vaccine strains. However, they do not protect efficiently against drifted or shifted strains. We developed an antigen based on the conserved stalk domain of the influenza virus hemagglutinin and tested its efficacy as a vaccine in a mouse virus challenge model. Although the antigen lacked the correct conformation of the native stalk domain and was not recognized by a panel of neutralizing stalk-reactive antibodies, it did induce considerable protection against H1N1, H5N1 and H6N1 challenge strains. Protection was enhanced when mice had pre-existing immunity against the stalk domain. Since pre-existing immunity is also present in the human population, we hypothesize that a similar antigen could show efficacy in humans as well.

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Preexisting human antibodies neutralize recently emerged H7N9 influenza strains

Cited by 118 publications

References 46 publications

Immune history profoundly affects broadly protective B cell responses to influenza

Immune history profoundly affects broadly protective B cell responses to influenza

An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody with prophylactic and therapeutic activity in vivo

Vaccination with soluble headless hemagglutinin protects mice from challenge with divergent influenza viruses

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