Immunity toward H1N1 influenza hemagglutinin of historical and contemporary strains suggests protection and vaccine failure

Huang, Stephen S. H.; Lin, Zhen; Banner, David W.; Leόn, Alberto J.; Paquette, Stéphane G.; Rubin, Barry B.; Rubino, Salvatore; Guan, Yi; Kelvin, David J.; Kelvin, Alyson A.

doi:10.1038/srep01698

Cited by 21 publications

(44 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ferrets closely mimic the clinical manifestations of influenza infection in humans as shown previously (Banner and Kelvin, 2012; Belser et al, 2011; Huang et al, 2011; Huang et al, 2013; Rowe et al, 2010). Naïve adult (4-6 months old) and aged (≥ 4 years old) male ferrets were placed into groups for either homologous or heterologous H1N1 sequential infection studies.…”

Section: Resultssupporting

confidence: 80%

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

et al. 2014

Self Cite

View full text Add to dashboard Cite

The major burden of influenza morbidity resides within the elderly population. The challenge managing influenza-associated illness in the elderly is the decline of immune function, where mechanisms leading to immunological senescence have not been elucidated. To better represent the immune environment, we investigated clinical morbidity and immune function during sequential homologous and heterologous H1N1 influenza infection in an aged ferret model. Our findings demonstrated experimentally that aged ferrets had significant morbidity during monosubtypic heterologous 2° challenge with significant weight loss and respiratory symptoms. Furthermore, increased clinical morbidity was associated with slower and shorter hemagglutinin antibody generation and attenuated type 1 T-cell gene responses in peripheral blood. These results revealed dampened immune activation during sequential influenza infection in aged ferrets. With the presence of an aged model, dissecting clinical morbidity, viral dynamics and immune response during influenza infection will aid the development of future prophylactics such as age specific influenza vaccines.

show abstract

Section: Resultssupporting

confidence: 80%

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…All groups lost a moderate amount of weight following infection. At nadir, all groups had lost between 5 and 10% of their original weight similar to our previous findings with this virus [26]. All groups had a temperature increase peaking Day 2 pi.…”

Section: Milder Clinical Disease Was Observed In the Preimmune-vaccinsupporting

confidence: 86%

“…Considering the USSR/77 infection and Cal/09 reinfection, this combination represents a monosubtypic heterologous reinfection. Importantly, these viruses do not produce cross-reacting HAI antibodies when infected into the naïve ferret model as we have previously shown [26]. The protein alignment in the highly variable region of HA (135-295aa), which belongs to the HA-RBD area, has only 59% homology between Cal/09 and USSR/77 [26] and this combination of preimmune exposure and challenge virus infection represents conditions plausible for the immune history of people alive today.…”

Section: Methodsmentioning

confidence: 64%

“…To establish preimmunity, adult ferrets were infected (imprinted) with a sublethal dose of the historical seasonal H1N1 A/USSR/90/1977 (USSR/77) Day 0 of the study. USSR/77 was chosen as the imprinting virus since it was a previously circulating human influenza virus that would have significantly impacted the immune history of many people alive today [26]. Furthermore, USSR/77 is a virus that re-emerged in the 1970s and is antigenically divergent compared to our proposed contemporary challenge virus [14].…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Influenza preimmunity increases vaccination efficacy by influencing antibody longevity, neutralization activity, and epitope specificity

Francis

McNeil

King

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Influenza virus infections are a recurrent public health problem causing millions of hospitalizations each year despite vaccination efforts. The well-known yearly cycling of influenza viruses is the result of the reciprocal and coevolutionary relationship between the host and virus. Together, from the frequent infections and yearly vaccinations humans build a complex immune history over their lifetimes. Despite the prominence of immune history, vaccines are rarely evaluated in the imprinted (preimmune) host. We developed a ferret model for this purpose where ferrets were imprinted with a sublethal dose of the historical seasonal H1N1 strain A/USSR/90/1977 (USSR/77). A +60 day recovery period was given to build immune memory prior to vaccination with a split virion QIV vaccine. To evaluate protection, the ferrets were challenged with a 2009 H1N1 pandemic virus matching the vaccine antigens. The preimmune-vaccinated ferrets did not experience significant disease during challenge while the naïve-vaccinated group were the most severe. Hemagglutination inhibition (HAI) assays showed that preimmune ferrets had a faster and longer antibody response post vaccination for all vaccine antigens compared to minimal HAI responses in the naïve-vaccinated group. To investigate the immune mechanisms leading to disease protection in the preimmune ferrets, we performed microneutralization and isotype ELISA assays. Microneutralization suggested preimmune ferrets developed antibodies that were more functional for virus neutralization. Antibody isotype profiling indicated that virus specific antibodies in the preimmune-vaccinated ferrets was dominated by the IgG isotype suggesting B cell maturity and possible plasticity in a pre-existing B cell. Surprisingly, the naïve-vaccinated ferrets developed a more severe disease with less virus neutralization suggesting improper immunological processing of vaccine antigens. Together, these results showed the preimmune host had greater responses to vaccination, and the predominant IgG virus specific antibodies suggested a flexible long-lived B cell response. These results are important and should be considered for vaccine design.AUTHOR SUMMARYThe influenza virus is a significant threat to human health and the economy despite large-scale vaccination efforts. The low effectiveness of the seasonal influenza vaccine is attributed to the frequently mutating virus enabling people to have several influenza virus infections throughout their lifetimes. As people are susceptible to multiple infections, they build a complex immune history. Despite this, vaccines are often not evaluated in animals with an immune history. Here we developed a ferret model that had previously been infected with a historical influenza virus to evaluate vaccine responses to current vaccines. Ferrets were infected with a sublethal does of a historical virus, A/USSR/90/1977, to develop a preimmune background. Preimmune ferrets were vaccinated with the Sanofi quadrivalent influenza vaccine and the antibody responses were investigated after vaccination. Our results showed that preimmune ferrets had a stronger antibody response following vaccination and the antibodies developed were older and better at neutralizing influenza virus at a virus challenge. Clinically, preimmune-vaccinated ferrets developed a milder disease during challenge compared to naïve-vaccinated ferrets. This work indicates that the host responses to vaccination are dependent on the host background and that influenza vaccine development and evaluation should take host influenza background into account.

show abstract

“…surprising given that these strains are antigenically similar [24,25]. However, we note a weaker correlation between these strains in older subjects who would have been 'primed' by 1956 A(H1N1) or a similar virus [2] compared to the younger age groups.…”

Section: Discussionmentioning

confidence: 89%

Immunity against influenza A(H1N1) infections is determined by age at the time of initial strain circulation

et al. 2016

View full text Add to dashboard Cite

SUMMARYWe explored age-dependent patterns in haemagglutination inhibition (HI) titre to seasonal [1956 A(H1N1), 1977 A(H1N1), 2007 A(H1N1)] and pandemic [A(H1N1)pdm09] influenza strains using serological data collected from an adult French influenza cohort. Subjects were recruited by their general practitioners from 2008 to 2009 and followed until 2010. We explored age-related differences between strain-specific HI titres using 1053 serological samples collected over the study period from 398 unvaccinated subjects. HI titres against the tested seasonal and pandemic strains were determined using the HI technique. Geometric mean titres (GMTs) were estimated using regression models for interval-censored data. Generalized additive mixed models were fit to log-transformed HI estimates to study the relationship between HI titre and age (age at inclusion and/or age at initial strain circulation). GMT against one strain was consistently highest in the birth cohort exposed to that strain during childhood, with peak titres observed in subjects aged 7-8 years at the time of initial strain circulation. Our results complete previous findings on influenza A(H3N2) strains and identify a strain-dependent relationship between HI titre and age at initial strain circulation.

show abstract

Immunity toward H1N1 influenza hemagglutinin of historical and contemporary strains suggests protection and vaccine failure

Cited by 21 publications

References 52 publications

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

Influenza preimmunity increases vaccination efficacy by influencing antibody longevity, neutralization activity, and epitope specificity

Immunity against influenza A(H1N1) infections is determined by age at the time of initial strain circulation

Contact Info

Product

Resources

About