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Sequential seasonal H1N1 influenza virus infections protect ferrets against novel 2009 H1N1 influenza virus.

ABSTRACT: Individuals <60 years of age had the lowest incidence of infection, with ~25% 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.

SUBMITTER: Carter DM

PROVIDER: S-EPMC3554183 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Sequential seasonal H1N1 influenza virus infections protect ferrets against novel 2009 H1N1 influenza virus.

Carter Donald M DM Bloom Chalise E CE Nascimento Eduardo J M EJ Marques Ernesto T A ET Craigo Jodi K JK Cherry Joshua L JL Lipman David J DJ Ross Ted M TM

Journal of virology 20121031 3

Individuals <60 years of age had the lowest incidence of infection, with ~25% 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 ...[more]

PMID: 23115287

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Project description:The neuraminidase (NA) inhibitor oseltamivir offers an important immediate option for the control of influenza, and its clinical use has increased substantially during the recent H1N1 pandemic. In view of the high prevalence of oseltamivir-resistant seasonal H1N1 influenza viruses in 2007-2008, there is an urgent need to characterize the transmissibility and fitness of oseltamivir-resistant H1N1/2009 viruses, although resistant variants have been isolated at a low rate. Here we studied the transmissibility of a closely matched pair of pandemic H1N1/2009 clinical isolates, one oseltamivir-sensitive and one resistant, in the ferret model. The resistant H275Y mutant was derived from a patient on oseltamivir prophylaxis and was the first oseltamivir-resistant isolate of the pandemic virus. Full genome sequencing revealed that the pair of viruses differed only at NA amino acid position 275. We found that the oseltamivir-resistant H1N1/2009 virus was not transmitted efficiently in ferrets via respiratory droplets (0/2), while it retained efficient transmission via direct contact (2/2). The sensitive H1N1/2009 virus was efficiently transmitted via both routes (2/2 and 1/2, respectively). The wild-type H1N1/2009 and the resistant mutant appeared to cause a similar disease course in ferrets without apparent attenuation of clinical signs. We compared viral fitness within the host by co-infecting a ferret with oseltamivir-sensitive and -resistant H1N1/2009 viruses and found that the resistant virus showed less growth capability (fitness). The NA of the resistant virus showed reduced substrate-binding affinity and catalytic activity in vitro and delayed initial growth in MDCK and MDCK-SIAT1 cells. These findings may in part explain its less efficient transmission. The fact that the oseltamivir-resistant H1N1/2009 virus retained efficient transmission through direct contact underlines the necessity of continuous monitoring of drug resistance and characterization of possible evolving viral proteins during the pandemic.

Project description:BackgroundDuring the 2009 influenza pandemic both seasonal and 2009 pandemic vaccines were recommended. We conducted a randomized trial of monovalent 2009-H1N1 vaccine and seasonal trivalent inactivated influenza vaccine (IIV3) given sequentially or concurrently to adults.MethodsAdults randomized to 4 study groups and stratified by age (18-64 and ≥65 years) received 1 dose of seasonal IIV3 or placebo and 2 doses of 2009-H1N1 vaccine or placebo in one of 4 combinations, i.e., H1N1+Placebo/H1N1+Placebo/IIV3 (HP/HP/V3), H1N1+IIV3/H1N1+Placebo/Placebo (HV3/HP/P), H1N1+Placebo/H1N1+IIV3/Placebo (HP/HV3/P), and IIV3+Placebo/H1N1+Placebo/H1N1 (V3P/HP/H). Intramuscular injections were given three times at 21 day intervals. Sera for antibody assays were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored.ResultsEight hundred-five (805) adults were enrolled. All combinations of vaccines were safe and well tolerated. In general, one dose of 2009-H1N1 and one dose of IIV3, regardless of sequence or concurrency of administration, were immunogenic in adults. There were no significant differences in geometric mean titers (GMT) or the proportions of subjects with ≥4-fold rise in antibody responses and titers ≥40 for any vaccine group or between age strata for 2009-H1N1 after the first or second dose, although the vaccine sequence affected the titers to the IIV3 antigens. Hemagglutination inhibition antibody (HAI) GMTs against 2009-H1N1 for the combined age strata 21 days after the first 2009-H1N1 dose were 190.4, 182.1, 232.9 and 157.5 for HP/HP/V3, HV3/HP/P, HP/HV3/P and V3P/HP/H, respectively. While IIV3 GMTs were adequate they were generally lower than the 2009-H1N1 GMTs. In a subset of subjects, there was good correlation between HAI and microneutralization (MN) titers (Spearman's correlation coefficient 0.92).ConclusionsAll vaccine combinations were generally well tolerated. Immune responses to one dose of 2009-H1N1 were adequate regardless of the sequence of vaccination in all age groups, but the sequence affected titers to IIV3 antigens.

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Sequential seasonal H1N1 influenza virus infections protect ferrets against novel 2009 H1N1 influenza virus.

Publications

Sequential seasonal H1N1 influenza virus infections protect ferrets against novel 2009 H1N1 influenza virus.

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