Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies

Chen, Yao-Qing; Wohlbold, Teddy John; Zheng, Nai Ying; Huang, Min; Huang, Yunping; Neu, Karlynn E.; Lee, Jiwon; Wan, Hongquan; Rojas, Karla Thatcher; Kirkpatrick, Ericka; Henry, Carole; Palm, Anna; Stamper, Christopher T.; Lan, Linda Yu Ling; Topham, David J.; Treanor, John J.; Wrammert, Jens; Ahmed, Rafi; Eichelberger, Maryna C.; Georgiou, George; Krammer, Florian; Wilson, Patrick C.

doi:10.1016/j.cell.2018.03.030

Cited by 308 publications

(361 citation statements)

References 53 publications

Supporting

Mentioning

348

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with 277 previous studies that have directly observed a neuraminidase directed antibody response following 278 vaccination [23,27]. Given the lack of protection demonstrated and questions about the quality of 279 vaccine induced neuraminidase antibody [28], it is clear that more work needs to be done to understand 280 antigenic drift of the neuraminidase, and how and when anti-neuraminidase antibodies mediate 281 protection. 282…”

Section: Discussion 234supporting

confidence: 79%

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

Levine

Martin

Petrie

et al. 2018

Preprint

View full text Add to dashboard Cite

BackgroundThe 2017-2018 US influenza season was severe with low vaccine effectiveness. Circulating A(H3N2) viruses from multiple genetic groups were antigenically similar to cell-grown vaccine strains. However, most influenza vaccines are egg-propagated.MethodsSerum was collected shortly after illness onset from 15 PCR confirmed A(H3N2) infected cases and 15 uninfected (controls) hospitalized adults enrolled in an influenza vaccine effectiveness study.Geometric mean titers against egg- and cell-grown A/Hong Kong/4801/2014 A(H3N2) vaccine strains and representative circulating viruses (including A/Washington/16/2017) were determined by microneutralization (MN) assays. Independent effects of strain-specific titers on susceptibility were estimated by logistic regression.ResultsMN titers against egg-A/Hong Kong were significantly higher among those who were vaccinated (MN GMT: 173 vs 41; P = 0.01). However, antibody titers to cell-grown viruses were much lower in all individuals (P>0.05) regardless of vaccination. In unadjusted models, a 2-fold increase in MN titers against egg-A/Hong Kong was not significantly protective against infection (29% reduction; p=0.09), but a similar increase in cell-A/Washington titer (3C.2a2) was protective (60% reduction; p=0.02). A similar increase in egg-A/Hong Kong titer was not significantly associated with odds of infection when adjusting for MN titers against A/Washington (15% reduction; P=0.61). A 54% reduction of odds of infection was observed with a 2-fold increase in A/Washington (not significant; P=0.07), adjusted for egg-A/Hong Kong titer.ConclusionAlthough individuals vaccinated in 2017-2018 had high antibody titers against the egg-adapted vaccine strain, antibody responses to cell-grown circulating viruses may not be sufficient to provide protection, likely due to egg-adaptation in the vaccine.

show abstract

Section: Discussion 234supporting

confidence: 79%

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

Levine

Martin

Petrie

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Antibodies are correlates of protection in the majority of currently licensed vaccines and have been shown to also convey protection against HIV, malaria and influenza [44][45][46]. However, for several reasons including quickly mutating antigens and the parallel display of multiple epitopes, these diseases still evade efficient vaccination.…”

Section: Manipulating Gc Selection Processesmentioning

confidence: 99%

Calculating germinal centre reactions

Buchauer

Wardemann

2019

Current Opinion in Systems Biology

View full text Add to dashboard Cite

Germinal centres are anatomically defined lymphoid organ structures that mediate B cell affinity maturation and affect the quality of humoral immune responses. Mathematical models based on differential equations or agent-based simulations have been widely used to deepen our understanding of the cellular and molecular processes characterizing these complex dynamic systems. Along with experimental studies, these tools have provided insights into the spatio-temporal behavior of B cells in germinal center reactions and the mechanisms underlying their clonal selection and cellular differentiation. More recently, mathematical models have been used to define key parameters that influence the quality of humoral vaccine responses such as vaccine composition and vaccination schedule. These studies generated testable predictions for the design of optimized immunization strategies.Graphical Abstract -Basic structure and applications of germinal centre simulations.

show abstract

“…Antibodies measured by the HI assay are an established correlate of protection for influenza virus infection [10,20,21]. Neutralizing antibodies against the dominant surface proteins, hemagglutinin (HA) and neuraminidase (NA), can target different sites on them, and the specificity of the antibody response appears to change with immune history and age [22,23,24,25,26]. HI assays measure antibodies to HA but not NA, and they disproportionately measure anti-HA antibodies that attach near the receptor binding site toward the top of the HA globular domain.…”

Section: Homosubtypic Protection Correlates Better With Anti-ha Antibmentioning

confidence: 99%

Age-specific differences in the dynamics of protective immunity to influenza

Ranjeva

Subramanian

Fang

et al. 2018

Preprint

View full text Add to dashboard Cite

Influenza A viruses evolve rapidly to escape host immunity, such that individuals can be infected multiple times with the same subtype. The form and duration of protective immunity after each influenza infection are poorly understood. Here, we quantify the dynamics of protective immunity against influenza A virus infections by fitting individual-level mechanistic models to longitudinal serology from children and adults in a household cohort study. We find that most protection in children is explained by antibody titers measured by the hemagglutination inhibition (HI) assay. In contrast, in adults, HI antibody titers explain a smaller fraction of protection. Protection against circulating strains wanes to approximately 50% of peak levels 3.5-7 years after infection in both age groups, and wanes faster against influenza A(H3N2) than A(H1N1)pdm09. Protection against H3N2 lasts longer in adults than in children. Our results suggest that the focus of influenza antibody responses changes over time from the highly mutable hemagglutinin head to other epitopes, consistent with the immunological theory of original antigenic sin, and that this change of focus might affect protection. Additionally, we estimate that imprinting, or primary infection with a subtype of one phylogenetic group, has little to no effect on the risk of non-medically attended influenza infections in adults. We also find no evidence of long-term cross-protection between subtypes. This work underscores the need for longitudinal data on multiple components of the immune response to better understand the development of immunity and differences in susceptibility within populations.

show abstract

Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies

Cited by 308 publications

References 53 publications

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

Calculating germinal centre reactions

Age-specific differences in the dynamics of protective immunity to influenza

Contact Info

Product

Resources

About