Pre-existing Antineuraminidase Antibodies Are Associated With Shortened Duration of Influenza A(H1N1)pdm Virus Shedding and Illness in Naturally Infected Adults

Abstract

Background Influenza causes a substantial burden worldwide, and current seasonal influenza vaccine has suboptimal effectiveness. To develop better, more broadly protective vaccines, a more thorough understanding is needed of how antibodies that target the influenza virus surface antigens, hemagglutinin (HA) (including head and stalk regions) and neuraminidase (NA), impact influenza illness and virus transmission. Methods We used a case-ascertained, community-based study of household influenza virus transmission set in Managua, Nicaragua. Using data from 170 reverse transcriptase–polymerase chain reaction (RT-PCR)–confirmed influenza virus A(H1N1)pdm infections and 45 household members with serologically confirmed infection, we examined the association of pre-existing NA, hemagglutination inhibiting, and HA stalk antibody levels and influenza viral shedding and disease duration using accelerated failure time models. Results Among RT-PCR–confirmed infections in adults, pre-existing anti-NA antibody levels ≥40 were associated with a 69% (95% confidence interval [CI], 34–85%) shortened shedding duration (mean, 1.0 vs 3.2 days). Neuraminidase antibody levels ≥80 were associated with further shortened shedding and significantly shortened symptom duration (influenza-like illness, 82%; 95% CI, 39–95%). Among RT-PCR–confirmed infections in children, hemagglutination inhibition titers ≥1:20 were associated with a 32% (95% CI, 13–47%) shortened shedding duration (mean, 3.9 vs 6.0 days). Conclusions Our results suggest that anti-NA antibodies play a large role in reducing influenza illness duration in adults and may impact transmission, most clearly among adults. Neuraminidase should be considered as an additional target in next-generation influenza virus vaccine development. We found that antibodies against neuraminidase were associated with significantly shortened viral shedding, and among adults they were also associated with shortened symptom duration. These results support neuraminidase as a potential target of next-generation influenza virus vaccines.

Divergent evolutionary trajectories of influenza B viruses underlie their contemporaneous epidemic activity

“…However, less attention is paid to the antigenicity of the NA, and it is not known if human anti-NA antibodies arising from novel Yamagata strains broadly cross-react with older viruses. Increasing awareness of the importance of influenza virus NA immunity has prompted recent efforts to understand the protective effect of anti-NA immunity in animal models; studies have shown that the anti-NA antibodies can significantly reduce virus titers and shedding of influenza B viruses (27) and lower the duration of illness in influenza A/H1N1 virus (28). Crucially, anti-NA antibodies can broadly cross-react against H1N1 and H3N2 subtype viruses, but current influenza vaccines cannot induce an efficient NA response (29).…”

Meeting report and review: Immunological assays and correlates of protection for next‐generation influenza vaccines

“…22,23 Anti-NA enzyme-linked immunosorbent assays (ELISAs), which do not suffer from this shortcoming, have recently been used to show a negative correlation between anti-NA titers and virus shedding in humans in a cohort study. 24 In the same cohort, anti-HA stalk antibodies have been shown to be an independent correlate of protection against both infection as well as symptomatic disease. 14 Cross reactive CD4+ and CD8+ cells have also been identified as correlates of protection in human challenge and cohort studies.…”

“…Of note, anti‐HA stalk antibodies can interfere with H6NX‐based NI assays which have to be taken into account in their interpretation . Anti‐NA enzyme‐linked immunosorbent assays (ELISAs), which do not suffer from this shortcoming, have recently been used to show a negative correlation between anti‐NA titers and virus shedding in humans in a cohort study . In the same cohort, anti‐HA stalk antibodies have been shown to be an independent correlate of protection against both infection as well as symptomatic disease .…”

“…Virus neutralization (VN) assay 18,19 Serum neuraminidase inhibition (NI) antibody titers Enzyme-Linked Lectin assay (ELLA) 9,10 Serum anti-neuraminidase binding antibody ELISA 14,24 HA stalk-specific antibodies ELISA 14…”

Broadly Protective Strategies Against Influenza Viruses: Universal Vaccines and Therapeutics

“…In addition, NA antibodies have been shown to be protective in both chickens and humans (Murphy et al, 1972;Clements et al, 1986;Webster et al, 1988). In humans, antibodies against NA have been associated with decreased viral shedding and shortened duration of symptoms (Maier et al, 2019). Recent studies have highlighted the importance of examining neuraminidase inhibition titers as well as hemagglutinin inhibition titers as a measure of influenza disease severity, suggesting that NA-based protection should be an important consideration when developing new influenza vaccines (Monto et al, 2015;Memoli et al, 2016).…”