Prospects for antibody-based universal influenza vaccines in the context of widespread pre-existing immunity

Wheatley, Adam K.; Kent, Stephen J.

doi:10.1586/14760584.2015.1068125

Cited by 16 publications

(17 citation statements)

References 141 publications

(45 reference statements)

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“…It is possible that changes in vaccine technology, including development of a universal vaccine, could fundamentally alter influenza vaccine program options in the coming decade and reduce concerns about repeated vaccination effects [60]. Even in this optimistic scenario, the knowledge gained regarding influenza immune response will be valuable, and it will be critical if inactivated egg-based vaccines continue to be used by vaccination programs in many countries.…”

Section: Five-year Viewmentioning

confidence: 99%

Repeated annual influenza vaccination and vaccine effectiveness: review of evidence

Belongia

Skowronski

McLean

et al. 2017

Expert Review of Vaccines

232

185

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Introduction: Studies in the 1970s and 1980s signaled concern that repeated influenza vaccination could affect vaccine protection. The antigenic distance hypothesis provided a theoretical framework to explain variability in repeat vaccination effects based on antigenic similarity between successive vaccine components and the epidemic strain. Areas covered: A meta-analysis of vaccine effectiveness studies from 2010-11 through 2014-15 shows substantial heterogeneity in repeat vaccination effects within and between seasons and subtypes. When negative effects were observed, they were most pronounced for H3N2, especially in 2014-15 when vaccine components were unchanged and antigenically distinct from the epidemic strain. Studies of repeated vaccination across multiple seasons suggest that vaccine effectiveness may be influenced by more than one prior season. In immunogenicity studies, repeated vaccination blunts the hemagglutinin antibody response, particularly for H3N2. Expert commentary: Substantial heterogeneity in repeated vaccination effects is not surprising given the variation in study populations and seasons, and the variable effects of antigenic distance and immunological landscape in different age groups and populations. Caution is required in the interpretation of pooled results across multiple seasons, since this can mask important variation in repeat vaccination effects between seasons. Multi-season clinical studies are needed to understand repeat vaccination effects and guide recommendations. ARTICLE HISTORY

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Section: Five-year Viewmentioning

confidence: 99%

Repeated annual influenza vaccination and vaccine effectiveness: review of evidence

Belongia

Skowronski

McLean

et al. 2017

Expert Review of Vaccines

232

185

View full text Add to dashboard Cite

show abstract

“…While there is reasonably good understanding of CD8 + T cell ID 1 , far less is known about B cell and antibody (Ab) ID. Indeed, the promise of “universal vaccines” for antigenically variable viruses such as HIV and influenza A virus (IAV) based on targeting conserved regions of viral proteins 2,3 , in large part depends on circumventing the immune system’s marked tendency to focus on variable epitopes 4,5 .…”

mentioning

confidence: 99%

Defining B cell immunodominance to viruses

et al. 2017

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Immunodominance defines the hierarchical immune response to competing antigens in complex immunogens. Little is known regarding B cell and antibody immunodominance despite its importance to immunity to viruses and other pathogens. We show that B cells and serum antibodies from inbred mice demonstrate a reproducible immunodominance hierarchy to the five major antigenic sites in the influenza A virus hemagglutinin globular domain. The hierarchy changes as the immune response progresses and depending on antigen formulation and delivery. Passive antibody transfer and sequential infection experiments demonstrate “original antigenic suppression”, where antibodies suppress memory responses to the priming antigenic site. Our study provides a template for attaining deeper understanding of antibody immunodominance to viruses and other immunogens.

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“…Some of the broadly cross-reactive antibodies and new immunogens will elicit antibodies that do not block virus-receptor interactions and thus are predicted to provide protection via alternative mechanisms, including blocking postentry HA conformational changes and fusion in low pH late endosomes, or Fc-dependent functions such as ADCC, ADCP, and ADCL or virus budding and release. In addition to HA, neuraminidase (NA), M2e, and internal proteins are being targeted for next-generation influenza vaccine candidates and therapeutic antibodies (24,25).…”

Section: Discussionmentioning

confidence: 99%

Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics

Winarski

Tang

Klenow

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Several next-generation (universal) influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these mediate inhibitions of virus replication at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of viral infection or disease. In the current study, two monoclonal antibodies (MAbs) 72/8 and 69/1, enhanced respiratory disease (ERD) in mice following H3N2 virus challenge by demonstrating increased lung pathology and changes in lung cytokine/chemokine levels. MAb 78/2 caused changes in the lung viral loads in a dose-dependent manner. Both MAbs increased HA sensitivity to trypsin cleavage at a higher pH range, suggesting MAb-induced conformational changes. pHrodo-labeled virus particles’ entry and residence time in the endocytic compartment were tracked during infection of Madin-Darby canine kidney (MDCK) cells. Both MAbs reduced H3N2 virus residence time in the endocytic pathway, suggesting faster virus fusion kinetics. Structurally, 78/2 and 69/1 Fabs bound the globular head or base of the head domain of influenza hemagglutinin (HA), respectively, and induced destabilization of the HA stem domain. Together, this study describes Mab-induced destabilization of the influenza HA stem domain, faster kinetics of influenza virus fusion, and ERD in vivo. The in vivo animal model and in vitro assays described could augment preclinical safety evaluation of antibodies and next-generation influenza vaccines that generate antibodies which do not block influenza virus–receptor interaction.

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Prospects for antibody-based universal influenza vaccines in the context of widespread pre-existing immunity

Cited by 16 publications

References 141 publications

Repeated annual influenza vaccination and vaccine effectiveness: review of evidence

Repeated annual influenza vaccination and vaccine effectiveness: review of evidence

Defining B cell immunodominance to viruses

Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics

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