A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial

Nachbagauer, Raffael; Feser, Jodi; Naficy, Abdollah; Bernstein, David I.; Guptill, Jeffrey T.; Walter, Emmanuel B.; Berlanda-Scorza, Franceso; Stadlbauer, Daniel; Wilson, Patrick C.; Aydillo, Teresa; Behzadi, Mohammad Amin; Bhavsar, Disha; Bliss, Carly M.; Capuano, Christina; Carreño, Juan Manuel; Chromikova, Veronika; Claeys, Carine; Coughlan, Lynda; Freyn, Alec W.; Gast, Christopher; Javier, Andres; Jiang, Kaijun; Mariottini, Chiara; McMahon, Meagan; McNeal, Monica; Solórzano, Alicia; Strohmeier, Shirin; Sun, Weina; Wielen, Marie Van der; Innis, Bruce L.; Garcı́a-Sastre, Adolfo; Palese, Peter; Krammer, Florian

doi:10.1038/s41591-020-1118-7

Cited by 246 publications

(281 citation statements)

References 63 publications

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“…Indeed, local IgA responses correlate with protection offered by liveattenuated influenza virus vaccines [46][47][48] . A recent Phase I trial of a chimeric HA universal vaccine candidate reported potent induction of IgA bnAbs after vaccinationfurther highlighting the urgent need to understand how antibodies of this isotype contribute to protection 20,49 . Here, we show that consistent with prior studies, bnAbs are primarily responsible for induction of FcαRIdependent NETosis, likely because these antibodies also promote the reciprocal binding events between IgA:FcαRI and HA:sialic acid described above.…”

Section: Discussionmentioning

confidence: 99%

IgA Potentiates NETosis in Response to Viral Infection

Stacey

Golubeva

Posca

et al. 2021

Preprint

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IgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces. As such, IgA plays a key role in protection against a variety of mucosal pathogens, including viruses. In addition to neutralizing viruses directly, IgA can also stimulate Fc-dependent effector functions via engagement of Fc alpha receptors (FcαRI) expressed on the surface of certain immune effector cells. Neutrophils are the most abundant leukocyte, express FcαRI, and are often the first to respond to sites of injury and infection. Here, we describe a novel function for IgA:virus immune complexes (ICs) during viral infections. We show that IgA:virus ICs potentiate NETosis – the programmed cell death pathway through which neutrophils release neutrophil extracellular traps (NETs). Mechanistically, IgA:virus ICs potentiated a suicidal NETosis pathway via engagement of FcαRI on neutrophils through a toll-like receptor (TLR)-independent, NADPH oxidase complex-dependent pathway. NETs also were capable of trapping and inactivating viruses, consistent with an antiviral function.

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Section: Discussionmentioning

confidence: 99%

IgA Potentiates NETosis in Response to Viral Infection

Stacey

Golubeva

Posca

et al. 2021

Preprint

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“…Such evolutionarily stable epitopes could represent preferred targets for the design of therapeutic interventions against a broad spectrum of sarbecoviruses. In fact, targeting epitopes on the conserved stalk of influenza viruses is a promising strategy for a universal vaccine development (Nachbagauer, et al 2021).…”

Section: Discussionmentioning

confidence: 99%

The evolutionary making of SARS-CoV-2

Iruegas

Dosch

Sikora

et al. 2021

Preprint

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Covid-19 is the most devastating pandemic of the past 100 years. A zoonotic transfer presumably at a wildlife market introduced the causative virus, SARS-CoV-2 (sarbecovirus; beta-coronavirus), to humans in late 2019. Meanwhile, the mechanistic details of the infection process have been largely elucidated, and structural models explain binding of the virial spike to the human cell surface receptor ACE2. Yet, the evolutionary trajectory that gave rise to this pathogen is poorly understood. Here we scan SARS-CoV-2 protein sequences in-silico for innovations along the evolutionary lineage starting with the last common ancestor of coronaviruses. Substantial differences in the sets of proteins encoded by SARS-CoV-2 and viruses outside sarbecovirus, and in their domain architectures, indicate divergent functional demands. By contrast, sarbecoviruses themselves are almost fully conserved at these levels of resolution. However, profiling spike evolution on the sub-domain level using predicted linear epitopes reveals that this protein was gradually reshaped within sarbecovirus. The only epitope that is private to SARS-CoV-2 overlaps with the furin cleavage site. This lends phylogenetic support to the hypothesis that a change in strategy facilitated the zoonotic transfer of SARS-CoV-2 and its success as a human pathogen. Upon furin cleavage, spike switches from a “stealth mode” where immunodominant ACE2 binding epitopes are largely hidden to an “attack mode” where these epitopes are exposed. The resulting reinforcement of ACE2 binding extends the window of opportunity for cell entry. SARS-CoV-2 variants fine-tuning this mode switch will be particularly threatening as they optimize immune evasion.

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“…Notably, Group 1 chimeric HA stalk-focusing immunogens were more recently deployed in a Phase 1 clinical trial (NCT03300050). The data released indicate that prime-boosting with chimeric HA vaccines elicited selective boosting of Group 1 stalk antibodies that were maintained for up to 18 months after immunization [164]. Similarly, sequential immunization of humans with HAs from avian H5N1 or H7N9 strains to which the population is normally antigen-naïve, resulted in memory recall of cross-reactive and broadly neutralizing stalk antibodies encompassing both Group 1 [42,43,165] and Group 1/Group 2 IAVs [68,166].…”

Section: Ha Stalk-based Immunogensmentioning

confidence: 95%

Section: Ha Stalk-based Immunogensmentioning

confidence: 97%

Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for ‘Universal’ Influenza Vaccines

Sangesland

Lingwood

2021

Vaccines

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Influenza virus remains a serious public health burden due to ongoing viral evolution. Vaccination remains the best measure of prophylaxis, yet current seasonal vaccines elicit strain-specific neutralizing responses that favor the hypervariable epitopes on the virus. This necessitates yearly reformulations of seasonal vaccines, which can be limited in efficacy and also shortchange pandemic preparedness. Universal vaccine development aims to overcome these deficits by redirecting antibody responses to functionally conserved sites of viral vulnerability to enable broad coverage. However, this is challenging as such antibodies are largely immunologically silent, both following vaccination and infection. Defining and then overcoming the immunological basis for such subdominant or ‘immuno-recessive’ antibody targeting has thus become an important aspect of universal vaccine development. This, coupled with structure-guided immunogen design, has led to proof-of-concept that it is possible to rationally refocus humoral immunity upon normally ‘unseen’ broadly neutralizing antibody targets on influenza virus.

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A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial

Cited by 246 publications

References 63 publications

IgA Potentiates NETosis in Response to Viral Infection

IgA Potentiates NETosis in Response to Viral Infection

The evolutionary making of SARS-CoV-2

Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for ‘Universal’ Influenza Vaccines

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