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Neuraminidase (NA)-specific antibodies contribute to immunity against influenza. While studies have demonstrated increased NA inhibiting (NAI) antibody titers after vaccination with egg-derived inactivated influenza vaccines (eIIV), the response to cell culture-derived (c) IIV has not been reported. An immunogenicity sub-study was performed within a clinical trial comparing the effectiveness of egg, cell, and recombinant hemagglutinin (HA)-derived influenza vaccines during the 2018–2019 and 2019–2020 influenza seasons. NAI and neutralizing antibody titers against the A(H1N1)pdm09 and A(H3N2) components of the vaccines were measured in pre- and post-vaccination sera. Responses to the N1 component of eIIV and cIIV were different in both study years 1 and 2 whereas response rate and antibody titers to the N2 component of egg and cell culture-derived vaccines were similar. For example, 43.5 % of eIIV and no cIIV recipients had four-fold NAI titer increases in year 1. There was a weak positive correlation between responses to N1 and N2 for both vaccine types but no correlation between NAI and HA-specific neutralizing antibody responses. Recombinant HA vaccine that does not contain NA served as a specificity control; NAI antibody titers did not increase in recipients except in two individuals presumed to have subclinical infection. Antibody responses to NA following vaccination with eIIV and cIIV were not the same; although the responses to the N1 and N2 components of eIIV were similar, there were fewer responders to N1 than N2 of cIIV. Studies to determine the impact of NA immunity on influenza vaccine effectiveness are warranted. •Inactivated influenza vaccines manufactured with egg- and cell-propagated viruses induce neuraminidase inhibiting (NAI) antibody responses that are similar for the N2 components but different for the N1 responses.•The rise in NAI titers was independent of responses to hemagglutinin.

Background. A single administration of laninamivir octanoate, a long-acting neuraminidase inhibitor, has been proven to be effective in the treatment of influenza but not for post-exposure prophylaxis. Methods. We conducted a double-blind, multicenter, randomized, placebo-controlled study to determine if a single administration of laninamivir octanoate 40 mg was superior to placebo for post-exposure prophylaxis. Eligible participants who had cohabited with an influenza patient within 48 hours of symptom onset were randomly assigned (1:1:1) to 1 of 3 groups: 40 mg of laninamivir octanoate single administration (LO-40SD), 20 mg of laninamivir octanoate once daily for 2 days (LO-20TD), or placebo. The primary efficacy endpoint was the proportion of participants who developed clinical influenza (defined as influenza virus positive, an axillary temperature >37.5°C, and at least 2 symptoms) over a 10-day period. Results. A total of 803 participants were enrolled, with 801 included in the primary analysis. The proportions of participants with clinical influenza were 4.5% (12/267), 4.5% (13/269), and 12.1% (32/265) in the LO-40SD, LO-20TD, and placebo groups, respectively. A single administration of laninamivir octanoate 40 mg significantly reduced the development of influenza compared with placebo (P = .001). The relative risk reductions compared with the placebo group were 62.8% and 63.1% for the LO-40SD and LO-20TD groups, respectively. The incidence of adverse events in the LO-40SD group was similar to that of the LO-20TD and placebo groups. Conclusions. A single administration of laninamivir octanoate was effective and well tolerated as post-exposure prophylaxis to prevent the development of influenza. Clinical Trials Registration. JapicCTI-142679.

The highly pathogenic avian influenza H5N1 viruses constantly evolve and give rise to novel variants that have caused widespread zoonotic outbreaks and sporadic human infections. Therefore, vaccines capable of eliciting broadly protective antibody responses are desired and under development. We here investigated the magnitude, kinetics and protective efficacy of the multi-faceted humoral immunity induced by vaccination in healthy adult volunteers with a Matrix M adjuvanted virosomal H5N1 vaccine. Vaccinees were given escalating doses of adjuvanted vaccine (1.5μg, 7.5μg, or 30μg), or a non-adjuvanted vaccine (30μg). An evaluation of sera from vaccinees against pseudotyped viruses covering all (sub)clades isolated from human H5N1 infections demonstrated that the adjuvanted vaccines (7.5μg and 30μg) could elicit rapid and robust increases of broadly cross-neutralizing antibodies against all clades. In addition, the adjuvanted vaccines also induced multifaceted antibody responses including hemagglutinin stalk domain specific, neuraminidase inhibiting, and antibody-dependent cellular cytotoxicity inducing antibodies. The lower adjuvanted dose (1.5µg) showed delayed kinetics, whilst the non-adjuvanted vaccine induced overall lower levels of antibody responses. Importantly, we demonstrate that human sera post vaccination with the adjuvanted (30μg) vaccine provided full protection against a lethal homologous virus challenge in mice. Of note, when combining our data from mice and humans we identified the neutralizing and neuraminidase inhibiting antibody titers as correlates of in vivo protection.

Background High hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titers are generally associated with reduced influenza risk. While repeated influenza vaccination reduces seroresponse, vaccine effectiveness is not always reduced. Methods During the 2007-2008 influenza season, a randomized, placebo-controlled trial (FLUVACS) evaluated the efficacies of live-attenuated (LAIV) and inactivated influenza vaccines (IIV) among healthy adults aged 18-49 in Michigan; IIV vaccine efficacy (VE) and LAIV VE against influenza disease were estimated at 68% and 36%. Using the principal stratification/VE moderation framework, we analyzed data from this trial to assess how each VE varied by HAI or NAI responses to vaccination observed for vaccinated individuals and predicted counterfactually for placebo recipients. We also assessed how each VE varied with pre-vaccination/baseline variables including HAI titer, NAI titer, and vaccination history. Results IIV VE appeared to increase with Day 30 post-vaccination HAI titer, albeit not significantly ( p =0.20 and estimated VE 14.4%, 70.5%, and 85.5% at titer below the assay lower quantification limit, 512, and 4096 (maximum)). Moreover, IIV VE increased significantly with Day 30 post-vaccination NAI titer ( p =0.040), with estimated VE zero at titer 10 and 92.2% at highest titer 640. There was no evidence that fold-change in post-vaccination HAI or NAI titer associated with IIV VE ( p =0.76, 0.38). For LAIV, there was no evidence that VE associated with post-vaccination or fold-rise HAI or NAI titers (p-values >0.40). For IIV, VE increased with increasing baseline NAI titer in those previously vaccinated, but VE decreased with increasing baseline NAI titer in those previously unvaccinated. In contrast, for LAIV, VE did not depend on previous vaccination or baseline HAI or NAI titer. Conclusions: Future efficacy trials should measure baseline and post-vaccination antibody titers in both vaccine and control/placebo recipients, enabling analyses to better elucidate correlates of vaccine- and natural-protection. Trial registration: ClinicalTrials.gov NCT00538512. October 1, 2007.

Neuraminidase inhibitors (NAIs) complement influenza virus infection management by helping to clear virus, alleviate symptoms, and reduce transmission. In a previous randomised study, we examined the effect of 4 NAIs on virus clearance and influenza symptoms in Japanese paediatric patients. In this second analysis, we examined the effects of NAI treatment on antibody responses and virus clearance, and the relationships between antibody responses and patients’ infection histories (previous infection; asymptomatic infection via household members of same virus type/subtype; vaccination), and between infection histories and viral kinetics. Haemagglutination inhibition (HI) antibody responses produced HI titres ≥40 by Day 14 of NAI treatment, in parallel with virus clearance (trend test P  = 0.001). Comparing patients with and without influenza infection histories (directly or asymptomatic infection via household members) showed that infection history had a marked positive effect on HI antibody responses in patients vaccinated before the current influenza season (before enrolment). Current virus clearance was significantly faster in patients previously infected with the same virus type/subtype than in those not previously infected, and clearance pattern depended on the NAI. Assessment of anti-influenza effects of antiviral drugs and vaccines should consider virus and antibody dynamics in response to vaccination and natural infection histories.

Yearly immunization with inactivated vaccines is the main strategy for the prevention of influenza. 1 When substantial antigenic drift occurs after the formulation of a vaccine — as happened, for instance, during the 1997–1998 season, when the A/Sydney/5/97 variant of the H3N2 subtype circulated — large outbreaks may occur, particularly among institutionalized patients at high risk for infection. 2 Influenza B virus may also cause such outbreaks. 3 , 4 The recent cluster of human cases of H5N1-subtype influenza in Hong Kong is another reminder of the continuing threat of pandemic influenza. 5 – 7 In the event of the rapid spread of a new influenzavirus, . . .

Influenza affects approximately 1 billion individuals each year resulting in between 290,000 and 650,000 deaths. Young children and immunocompromised individuals are at a particularly high risk of severe illness attributable to influenza and these are also the groups of individuals in which reduced susceptibility to neuraminidase inhibitors is most frequently seen. High levels of resistance emerged with previous adamantane therapy for influenza A and despite no longer being used to treat influenza and therefore lack of selection pressure, high levels of adamantane resistance continue to persist in currently circulating influenza A strains. Resistance to neuraminidase inhibitors has remained at low levels to date and the majority of resistance is seen in influenza A H1N1 pdm09 infected immunocompromised individuals receiving oseltamivir but is also seen less frequently with influenza A H3N2 and B. Rarely, resistance is also seen in the immunocompetent. There is evidence to suggest that these resistant strains (particularly H1N1 pdm09) are able to maintain their replicative fitness and transmissibility, although there is no clear evidence that being infected with a resistant strain is associated with a worse clinical outcome. Should neuraminidase inhibitor resistance become more problematic in the future, there are a small number of alternative novel agents within the anti-influenza armoury with different mechanisms of action to neuraminidase inhibitors and therefore potentially effective against neuraminidase inhibitor resistant strains. Limited data from use of novel agents such as baloxavir marboxil and favipiravir, does however show that resistance variants can also emerge in the presence of these drugs.

Volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) virus and treated with the neuraminidase (NA) inhibitor oseltamivir were monitored for the emergence of drugresistant variants. Two (4%) of 54 resistant viruses were detected by NA inhibition assay among last-day isolates recovered from 54 drug recipients. They bore a substitution His274Tyr in the NA. Hemagglutinin (HA) variants detected in the placebo group differed from the eggadapted inoculum virus by virtue of amino acid substitutions at residues 137, 225, or both. These variants had a higher affinity for Neu5Ac(α2–6)Gal-containing receptors, which are characteristic of human respiratory epithelium, than for Neu5Ac(α2–3)Gal-containing receptors, which are typical of chicken egg allantoic membrane. Although appearing to be more sensitive to oseltamivir in humans, the variants with increased affinity for Neu5Ac(α2–6)Gal receptors were less sensitive than the Neu5Ac(α2–3)Gal-binding variants in Madin-Darby canine kidney cells. Thus, HA affinity for receptors is an essential feature of influenza virus susceptibility to NA inhibitors, both in cell culture and in humans.

Background. Laboratory correlates of influenza vaccine protection can best be identified by examining people who are infected despite vaccination. While the importance of antibody to viral hemagglutinin (HA) has long been recognized, the level of protection contributed independently by antibody to viral neuraminidase (NA) has not been determined. Methods. Sera from a controlled trial of the efficacies of inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) were tested by hemagglutination inhibition (HAI) assay, microneutralization (MN) assay, and a newly standardized lectin-based neuraminidase inhibition (NAI) assay. Results. The NAI assay detected a vaccine response in 37% of IIV recipients, compared with 77% and 67% of participants in whom responses were detected by the HAI and MN assays, respectively. For LAIV recipients, the NAI, HAI, and MN assays detected responses in 6%, 21%, and 17%, respectively. In IIV recipients, as NAI assay titers rose, the frequency of infection fell, similar to patterns seen with HAI and MN assays. HAI and MN assay titers were highly correlated, but NAI assay titers exhibited less of a correlation. Analyses suggested an independent role for NAI antibody in protection, which was similar in the IIV, LAIV, and placebo groups. Conclusions. While NAI antibody is not produced to a large extent in response to current IIV, it appears to have an independent role in protection. As new influenza vaccines are developed, NA content should be considered. Clinical Trials Registration. NCT00538512.

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift 1 and suboptimal immune responses 2 . Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses. The neuraminidase-targeting monoclonal antibody FNI9 potently inhibits the enzymatic activity of influenza A and B viruses via receptor mimicry.