Broad and Protective Influenza B Virus Neuraminidase Antibodies in Humans after Vaccination and their Clonal Persistence as Plasma Cells

Abstract

Although most seasonal inactivated influenza vaccines (IIV) contain neuraminidase (NA), the extent and mechanisms of action of protective human NA-specific humoral responses induced by vaccination are poorly resolved. Due to the propensity of influenza virus for antigenic drift and shift and its tendency to elicit predominantly strain-specific antibodies, humanity remains susceptible to waves of new strains of seasonal viruses and is at risk from viruses with pandemic potential for which limited or no immunity may exist. Here we demonstrate that the use of IIV results in increased levels of influenza B virus (IBV) NA-specific serum antibodies. Detailed analysis of the IBV NA B cell response indicates concurrent expansion of IBV NA-specific peripheral blood plasmablasts 7 days after IIV immunization which express monoclonal antibodies with broad and potent antiviral activity against both IBV Victoria and Yamagata lineages and prophylactic and therapeutic activity in mice. These IBV NA-specific B cell clonal lineages persisted in CD138+ long-lived bone marrow plasma cells. These results represent the first demonstration that IIV-induced NA human antibodies can protect and treat influenza virus infection in vivo and suggest that IIV can induce a subset of IBV NA-specific B cells with broad protective potential, a feature that warrants further study for universal influenza vaccine development. IMPORTANCE Influenza virus infections continue to cause substantial morbidity and mortality despite the availability of seasonal vaccines. The extensive genetic variability in seasonal and potentially pandemic influenza strains necessitates new vaccine strategies that can induce universal protection by focusing the immune response on generating protective antibodies against conserved targets such as regions within the influenza neuraminidase protein. We have demonstrated that seasonal immunization stimulates neuraminidase-specific antibodies in humans that are broad and potent in their protection from influenza B virus when tested in mice. These antibodies further persist in the bone marrow, where they are expressed by long-lived antibody-producing cells, referred to here as plasma cells. The significance in our research is the demonstration that seasonal influenza immunization can induce a subset of neuraminidase-specific B cells with broad protective potential, a process that if further studied and enhanced could aid in the development of a universal influenza vaccine.

Rapidin vitroassays for screening neutralizing antibodies and antivirals against SARS-CoV-2

“…The PRMNT assay described here measures the neutralization effect of Abs or the antiviral activity of compounds against SARS-CoV-2 in similar manner to what we have previously described with other viruses, including, among others, influenza (Baker et al, 2015;Bauman et al, 2013;Martinez-Sobrido et al, 2010;Nogales et al, 2019;Nogales, Baker, and Martinez-Sobrido, 2015;Nogales et al, 2018;Nogales et al, 2016;Park et al, 2020a;Piepenbrink et al, 2019;Rodriguez, Nogales, and Martinez-Sobrido, 2017;Yang et al, 2016), mammarenaviruses (Brouillette et al, 2018;Ortiz-Riano et al, 2014;Robinson et al, 2016;Rodrigo, de la Torre, and Martinez-Sobrido, 2011), and Zika virus (Park et al, 2019). Although the assay described here was adapted to 96-well plate format, it can be adjusted to 384-well plate format for HTS of SARS-CoV-2 antivirals and/or NAbs.…”

Neuraminidase antigenic drift of H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding

“…Anti-NA antibodies can prevent or decrease the severity of influenza infection [12][13][14][15]. High titer anti-NA antibodies have been correlated with decrease disease severity and protection in adults [16,17].…”

Functional Characterization and Direct Comparison of Influenza A, B, C, and D NS1 Proteins in vitro and in vivo

“…Moreover, HA and NA glycoproteins are also the major antigenic determinants of IAV and IBV and they are used to further classify them in subtypes (IAV) or lineages (IBV) (Martinez-Sobrido et al, 2018;Blanco-Lobo et al, 2019). IAV have a broad species tropism, infecting multiple avian and mammalian species, including humans (Parrish et al, 2015;Mostafa et al, 2018;Long et al, 2019), while IBV are primarily limited to infect humans (Osterhaus et al, 2000;Chen and Holmes, 2008;Piepenbrink et al, 2019). IAV and IBV are both responsible of seasonal epidemics in the human population and are considered a major public health and economic concern worldwide (Krammer et al, 2015;Raviotta et al, 2017;Federici et al, 2018;Paules et al, 2018).…”