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Seasonal influenza viruses constantly change through antigenic drift and the emergence of pandemic influenza viruses through antigenic shift is unpredictable. Conventional influenza virus vaccines induce strain-specific neutralizing antibodies against the variable immunodominant globular head domain of the viral hemagglutinin protein. This necessitates frequent re-formulation of vaccines and handicaps pandemic preparedness. In this completed, observer-blind, randomized, placebo-controlled phase I trial (NCT03300050), safety and immunogenicity of chimeric hemagglutinin-based vaccines were tested in healthy, 18–39-year-old US adults. The study aimed to test the safety and ability of the vaccines to elicit broadly cross-reactive antibodies against the hemagglutinin stalk domain. Participants were enrolled into five groups to receive vaccinations with live-attenuated followed by AS03-adjuvanted inactivated vaccine ( n  = 20), live-attenuated followed by inactivated vaccine ( n  = 15), twice AS03-adjuvanted inactivated vaccine ( n  = 16) or placebo ( n  = 5, intranasal followed by intramuscular; n  = 10, twice intramuscular) 3 months apart. Vaccination was found to be safe and induced a broad, strong, durable and functional immune response targeting the conserved, immunosubdominant stalk of the hemagglutinin. The results suggest that chimeric hemagglutinins have the potential to be developed as universal vaccines that protect broadly against influenza viruses. New influenza virus vaccines tested in humans elicit broadly cross-reactive antibodies that bind the stalk of the viral hemagglutinin protein and may serve as templates to design a universal influenza vaccine.

Immune responses at the respiratory mucosal interface are critical to prevent respiratory infections but it is unclear to what extent antigen specific mucosal secretory IgA (SIgA) antibodies are induced by mRNA vaccination in humans. Here we analyze paired serum and saliva samples from patients with and without prior coronavirus disease 2019 (COVID-19) at multiple time points pre and post severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. Our results suggest mucosal SIgA responses induced by mRNA vaccination are impacted by pre-existing immunity. Indeed, vaccination induced a minimal mucosal SIgA response in individuals without pre-exposure to SARS-CoV-2 while SIgA induction after vaccination was more efficient in patients with a history of COVID-19. Prior exposure to infectious agents can impact the vaccination induced immune response. Here the authors show prior SARS-CoV-2 infection results in more efficient induction of mucosal SARS-CoV-2 secretory IgA antibody following mRNA vaccination.

A panel of influenza virus-like sequences were recently documented in fish and amphibians. Of these, the Wuhan spiny eel influenza virus (WSEIV) was found to phylogenetically cluster with influenza B viruses as a sister clade. Influenza B viruses have been documented to circulate only in humans, with certain virus isolates found in harbor seals. It is therefore interesting that a similar virus was potentially found in fish. Here we characterize the putative hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins of the WSEIV. Functionally, we show that the WSEIV NA-like protein has sialidase activity comparable to B/Malaysia/2506/2004 influenza B virus NA, making it a bona fide neuraminidase that is sensitive to NA inhibitors. We tested the functionality of the HA by addressing the receptor specificity, stability, preferential airway protease cleavage, and fusogenicity. We show highly specific binding to monosialic ganglioside 2 (GM2) and fusogenicity at a range of different pH conditions. In addition, we found limited antigenic conservation of the WSEIV HA and NA relative to the B/Malaysia/2506/2004 virus HA and NA. In summary, we perform a functional and antigenic characterization of the glycoproteins of WSEIV to assess if it is indeed a bona fide influenza virus potentially circulating in ray-finned fish. The recently identified Wuhan spiny eel influenza virus (WSEIV) sequence is more closely related to influenza B than A viruses. Here, the authors functionally characterize the putative surface glycoproteins of WSEIV and show that its NA-like protein has sialidase activity and its HA-like protein binds monosialic ganglioside 2.

The emergence of highly pathogenic avian influenza A(H5N1) virus in dairy cattle herds across the United States in 2024 caused several human infections. Understanding the risk for spillover infections into humans is crucial for protecting public health. We investigated whether immunity from influenza A(H1N1)pdm09 (pH1N1) virus would provide protection from death and severe clinical disease among ferrets intranasally infected with H5N1 virus from dairy cows from the 2024 outbreak. We observed differential tissue tropism among pH1N1-immune ferrets. pH1N1-immune ferrets also had little H5N1 viral dissemination to organs outside the respiratory tract and much less H5N1 virus in nasal secretions and the respiratory tract than naive ferrets. In addition, ferrets with pH1N1 immunity produced antibodies that cross-reacted with H5N1 neuraminidase protein. Taken together, our results suggest that humans with immunity to human seasonal influenza viruses may experience milder disease from the 2024 influenza A(H5N1) virus strain.

Coronavirus disease 2019 (COVID-19) vaccines have saved millions of lives. However, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged causing large numbers of breakthrough infections. These developments necessitated the rollout of COVID-19 vaccine booster doses. It has been reported that mucosal antibody levels in the upper respiratory tract, especially for secretory IgA (sIgA), correlate with protection from infection with SARS-CoV-2. However, it is still unclear how high levels of mucosal antibodies can be induced. In this study, we measured serum IgG, saliva IgG, and saliva sIgA responses in individuals who received COVID-19 mRNA booster vaccinations or who experienced breakthrough infections. We found that mRNA booster doses could induce robust serum and saliva IgG responses, especially in individuals who had not experienced infections before, but saliva sIgA responses were weak. In contrast, breakthrough infections in individuals who had received the primary mRNA vaccination series induced robust serum and saliva IgG as well as saliva sIgA responses. Individuals who had received a booster dose and then had a breakthrough infection showed low IgG induction in serum and saliva but still responded with robust saliva sIgA induction. These data suggest that upper respiratory tract exposure to antigen is an efficient way of inducing mucosal sIgA while exposure via intramuscular injection is not. Antibodies on mucosal surfaces of the upper respiratory tract have been shown to be important for protection from infection with SARS-CoV-2. Here we investigate the induction of serum IgG, saliva IgG, and saliva sIgA after COVID-19 mRNA booster vaccination or breakthrough infections.

Development of mucosal influenza virus vaccines which protect the site of viral entry is of high importance. Recombinant neuraminidase (NA) has emerged as an antigenically conserved intranasal vaccine candidate, capable of inducing broad cross-protection, but it requires effective mucosal adjuvants. Here, we analyze the immunogenicity and protective efficacy of a mucosal recombinant NA-based influenza virus vaccine adjuvanted with the outer membrane proteins from Neisseria meningitidis complexed with exogenous lipopolysaccharides (LPS) from Shigella flexneri or endogenous LPS from N. meningitidis . We observed increased follicular T-helper and germinal center B-cell population percentages in nasal-associated lymphoid tissue, enhanced IgA and IgG antibody responses, and accumulation of lung-resident memory T cells. The vaccine provided complete protection against homologous and partial protection against a heterologous influenza virus (clade 2.3.4.4b H5N1) challenge. These findings underscore the potential of bacterial membrane-derived adjuvants for developing robust mucosal influenza vaccines.

The ongoing co-circulation of influenza viruses and severe acute respiratory disease coronavirus 2 (SARS-CoV-2) presents significant public health challenges. Vaccination is a pivotal tool to tackle infections and severe disease. Administering both the influenza and coronavirus disease 2019 (COVID-19) vaccines simultaneously could simplify vaccine delivery and is already practice in several countries. In this study, we assessed the protective efficacy and humoral immune responses elicited by concomitant administration of a quadrivalent influenza vaccine (QIV) and the Pfizer-BioNTech mRNA COVID-19 vaccine (BNT162b2) in naïve BALB/c mice. We included three ways of co-administration: a) both vaccines at contralateral limbs, b) both vaccines at ipsilateral limbs and c) admixture of the two vaccines before administration. The last regimen was included since it has been shown that the lipid nanoparticles used for mRNA vaccines can also have an adjuvant effect on protein-based antigens. Notably, co-administration of QIV and COVID-19 mRNA vaccine led to significantly higher hemagglutinin inhibiting (HAI) and binding antibody titers compared to QIV only vaccination, especially in the ipsilateral and admixed groups. Conversely, ipsilateral administration and administration of an admixed vaccine had a slightly negative impact on SARS-CoV-2 binding and neutralization titers. These findings support the hypothesis that the co-administration of QIV and COVID-19 mRNA vaccines can induce robust antibody responses, which are indicative of protective immune responses against both infectious agents. •COVID-19 mRNA-LNP and QIV co-vaccination induced potent humoral immune response.•Admixed and ipsilateral co-vaccination enhanced influenza virus antibody responses.•Concomitant vaccination improved protection against influenza virus and SARS-CoV-2.

The highly pathogenic avian influenza H5N1 virus clade 2.3.4.4b has been spreading globally since 2022, causing mortality and morbidity in domestic and wild birds, as well as in mammals, which underscores its potential to cause a pandemic. Here, we generate a panel of anti-hemagglutinin (HA) human monoclonal antibodies (mAbs) against the H5 protein of clade 2.3.4.4b. To develop human chimeric antibodies, H2L2 Harbor Mice®, which express human immunoglobulin germline genes, were immunized with H5 and N1 recombinant proteins from A/mallard/New York/22-008760-007- original/2022 H5N1 virus. Through hybridoma technology, sixteen fully human mAbs are generated, most of which show cross-reactivity against H5 proteins from different clade 2.3.4.4 virus variants. Fourteen out of the sixteen mAbs neutralize the virus in vitro. The mAbs with the strongest hemagglutination inhibition activity also demonstrate greater neutralizing capacity and show increased protective effects in vivo when administered prophylactically or therapeutically in a murine H5N1 challenge model. Using cryo-electron microscopy, we identify a cross-clonotype conserved motif that bound a hydrophobic groove on the head domain of H5 HA. Akin to mAbs against severe acute respiratory syndrome coronavirus 2 during the coronavirus 2019 pandemic, these mAbs could serve as treatments in case of a widespread H5N1 epidemic or pandemic. Clade 2.3.4.4b highly pathogenic H5N1 is currently causing a panzootic and has the potential to become a pandemic. Here, Peña Alzua and colleagues develop specific monoclonal antibodies against this virus that could be used to prevent or treat human infections.

Mucosal IgA is key in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Several mucosal vaccines are in development, and consistent methodologies assessing mucosal IgA are crucial for evaluation across clinical trials. We compared SARS-CoV-2 ancestral spike-specific IgA and secretory IgA (SIgA) in nasal secretions and saliva from 20 adults enrolled at Danderyd Hospital, Stockholm, Sweden, and 23 adults enrolled at the Icahn School of Medicine at Mount Sinai, New York, USA. Nasal secretions were collected by Nasosorption® and nasal swabs, and saliva by passive drooling, Salivette®, and saliva swabs. Antibody levels were measured in all samples using an electrochemiluminescence assay (ECL) and two enzyme-linked immunosorbent assays (ELISAs). Spike-specific IgA and SIgA levels measured by ECL correlated well with those measured by ELISA across nasal and saliva samples (range 0.42–0.94, p < 0.01), except for saliva collected by saliva swabs yielding lower IgA concentrations and weaker correlations (range − 0.21-0.27). Spike-specific IgA levels also correlated well across collection methods (range 0.7–0.9, p < 0.0001), with a weaker correlation between saliva collected by passive drooling and saliva swab (r = 0.55, p < 0.001). Although antibody levels correlated well between nasal secretions and saliva collected by passive drooling or Salivette® (range 0.64–0.86, p < 0.01), the overall levels were > 3-fold higher in nasal secretions compared to saliva (p < 0.01). This multi-center study demonstrates an overall good comparability between spike-specific IgA and SIgA across assays and collection methods, except for saliva swabs. Our findings suggest that nasal secretions may be preferable due to higher spike-specific IgA levels compared to in saliva.