• Broadly neutralizing antibodies target a hemagglutinin anchor epitope.

      Guthmiller, Jenna J; Han, Julianna; Utset, Henry A; Li, Lei; Lan, Linda Yu-Ling; Henry, Carole; Stamper, Christopher T; McMahon, Meagan; O'Dell, George; Fernández-Quintero, Monica L; et al. (Springer Nature, 2021-12-23)
      Broadly neutralizing antibodies (bnAbs) targeting epitopes of the influenza virus hemagglutinin (HA) have the potential to provide near universal protection against influenza virus infection1. However, viral mutants that escape bnAbs have been reported2,3. The identification of bnAb classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Here, we report a distinct class of bnAbs targeting a discrete membrane-proximal anchor epitope of the HA stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with pandemic-threat H2 and H5 viruses. Antibodies targeting this anchor epitope utilize a highly restricted repertoire, which encodes for two public binding motifs that make extensive contacts with conserved residues in the fusion peptide. Moreover, anchor epitope-targeting B cells are common in the human memory B cell (MBC) repertoire and were recalled in humans by an oil-in-water adjuvanted chimeric HA (cHA) vaccine4,5, a potential universal influenza virus vaccine. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of bnAbs that are widespread in the human MBC pool.
    • Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses

      Guthmiller, Jenna J; Lan, Linda Yu-Ling; Fernández-Quintero, Monica L; Han, Julianna; Utset, Henry A; Bitar, Dalia J; Hamel, Natalie J; Stovicek, Olivia; Li, Lei; Tepora, Micah; et al. (Frontiers Media S.A., 2020-10-22)
      The role of gonadal hormones in neural plasticity remains unclear. This study aimed to examine the effects of naturally fluctuating hormone levels over the menstrual cycle in healthy females. Gray matter, functional connectivity (FC) and white matter changes over the cycle were assessed by using functional magnetic resonance imaging (fMRI), resting state fMRI, and structural MRIs, respectively, and associated with serum gonadal hormone levels. Moreover, electrocutaneous sensitivity was evaluated in 14 women in four phases of their menstrual cycle (menstrual, follicular, ovulatory, and luteal). Electrocutaneous sensitivity was greater during follicular compared to menstrual phase. Additionally, pain unpleasantness was lower in follicular phase than other phases while pain intensity ratings did not change over the cycle. Significant variations in cycle phase effects on gray matter volume were found in the left inferior parietal lobule (IPL) using voxel-based morphometry. Subsequent Freesurfer analysis revealed greater thickness of left IPL during the menstrual phase when compared to other phases. Also, white matter volume fluctuated across phases in left IPL. Blood estradiol was positively correlated with white matter volume both in left parietal cortex and whole cortex. Seed-driven FC between left IPL and right secondary visual cortex was enhanced during ovulatory phase. A seed placed in right IPL revealed enhanced FC between left and right IPL during the ovulatory phase. Additionally, we found that somatosensory cortical gray matter was thinner during follicular compared to menstrual phase. We discuss these results in the context of likely evolutionary pressures selecting for enhanced perceptual sensitivity across modalities specifically during ovulation. © Copyright © 2020 Meeker, Veldhuijzen, Keaser, Gullapalli and Greenspan.
    • A single-shot adenoviral vaccine provides hemagglutinin stalk-mediated protection against heterosubtypic influenza challenge in mice.

      Bliss, Carly M; Freyn, Alec W; Caniels, Tom G; Leyva-Grado, Victor H; Nachbagauer, Raffael; Sun, Weina; Tan, Gene S; Gillespie, Virginia L; McMahon, Meagan; Krammer, Florian; et al. (Elsevier, 2022-01-07)
      Conventional influenza vaccines fail to confer broad protection against diverse influenza A viruses with pandemic potential. Efforts to develop a universal influenza virus vaccine include refocusing immunity towards the highly conserved stalk domain of the influenza virus surface glycoprotein, hemagglutinin (HA). We constructed a non-replicating adenoviral (Ad) vector, encoding a secreted form of H1 HA, to evaluate HA stalk-focused immunity. The Ad5_H1 vaccine was tested in mice for its ability to elicit broad, cross-reactive protection against homologous, heterologous, and heterosubtypic lethal challenge in a single-shot immunization regimen. Ad5_H1 elicited hemagglutination inhibition (HI+) active antibodies (Abs), which conferred 100% sterilizing protection from homologous H1N1 challenge. Furthermore, Ad5_H1 rapidly induced H1-stalk-specific Abs with Fc-mediated effector function activity, in addition to stimulating both CD4+ and CD8+ stalk-specific T cell responses. This phenotype of immunity provided 100% protection from lethal challenge with a head-mismatched, reassortant influenza virus bearing a chimeric HA, cH6/1, in a stalk-mediated manner. Most importantly, 100% protection from mortality following lethal challenge with a heterosubtypic avian influenza virus, H5N1, was observed following a single immunization with Ad5_H1. In conclusion, Ad-based influenza vaccines can elicit significant breadth of protection in naive animals and could be considered for pandemic preparedness and stockpiling.