Sequential Seasonal H1N1 Influenza Virus Infections Protect Ferrets against Novel 2009 H1N1 Influenza Virus

Abstract

d Individuals <60 years of age had the lowest incidence of infection, with ϳ25% of these people having preexisting, cross-reactive antibodies to novel 2009 H1N1 influenza. Many people >60 years old also had preexisting antibodies to novel H1N1. These observations are puzzling because the seasonal H1N1 viruses circulating during the last 60 years were not antigenically similar to novel H1N1. We therefore hypothesized that a sequence of exposures to antigenically different seasonal H1N1 viruses can elicit an antibody response that protects against novel 2009 H1N1. Ferrets were preinfected with seasonal H1N1 viruses and assessed for cross-reactive antibodies to novel H1N1. Serum from infected ferrets was assayed for cross-reactivity to both seasonal and novel 2009 H1N1 strains. These results were compared to those of ferrets that were sequentially infected with H1N1 viruses isolated prior to 1957 or more-recently isolated viruses. Following seroconversion, ferrets were challenged with novel H1N1 influenza virus and assessed for viral titers in the nasal wash, morbidity, and mortality. There was no hemagglutination inhibition (HAI) cross-reactivity in ferrets infected with any single seasonal H1N1 influenza viruses, with limited protection to challenge. However, sequential H1N1 influenza infections reduced the incidence of disease and elicited cross-reactive antibodies to novel H1N1 isolates. The amount and duration of virus shedding and the frequency of transmission following novel H1N1 challenge were reduced. Exposure to multiple seasonal H1N1 influenza viruses, and not to any single H1N1 influenza virus, elicits a breadth of antibodies that neutralize novel H1N1 even though the host was never exposed to the novel H1N1 influenza viruses.

Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

“…We recently showed that of the individuals .45 y of age with undetectable HI titers to A(H1N1) pdm09, nearly all (28/31, 90%) had ADCC-mediating Abs to the A(H1N1)pdm09 virus prior to the 2009 pandemic (44). Numerous animal studies showed that infection with seasonal H1N1 viruses, particularly with H1N1 viruses circulating pre-1960, can provide a level of protection from severe A (H1N1)pdm09 virus infection (21,(60)(61)(62)(63). In studies in which Nabs against A(H1N1)pdm09 could not be detected, the levels of nonneutralizing binding Abs correlated closely with protection from severe A(H1N1)pdm09 infection (12,61).…”

EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens

“…When comparing maximal amino acid distances between AMA1 and influenza H1 HA (Figures 2 and 3), it is evident that influenza HA is more variable than AMA1 [41,[43][44][45]. Huber et al have shown that a prime with DNA followed by a live-attenuated virus boost with a mixture of three H3N2 viruses (Hong Kong 1968, Victoria 1975, and Leningrad 1986) covers 20 years of antigenic drift in mice [43].…”

“…Huber et al have shown that a prime with DNA followed by a live-attenuated virus boost with a mixture of three H3N2 viruses (Hong Kong 1968, Victoria 1975, and Leningrad 1986) covers 20 years of antigenic drift in mice [43]. Carter et al show that sequential infection in ferrets with three seasonal H1N1 strains (either historical or modern) confers protection against H1N1pdm challenge (not contained in infection series) [41]. Moreover, a mixture of sera obtained after infection with single viruses neutralized H1N1pdm, while none of the separate sera had neutralizing activity [41].…”

“…Carter et al show that sequential infection in ferrets with three seasonal H1N1 strains (either historical or modern) confers protection against H1N1pdm challenge (not contained in infection series) [41]. Moreover, a mixture of sera obtained after infection with single viruses neutralized H1N1pdm, while none of the separate sera had neutralizing activity [41]. A genetic distance map for H1N1 viruses is shown in Figure 3, and the variants used by [44].…”

“…Sanofi's recently licensed Dengvaxia (CYD-TDV), a tetravalent live-attenuated virus vaccine expressing the pre-membrane (prM) and E proteins of the four dengue serotypes on [41] are shown as + signs, blue = historical H1N1, red = modern H1N1 and green = H1N1pdm challenge strain. Gridlines indicate 5 amino acid differences.…”