Complex Patterns of Human Antisera Reactivity to Novel 2009 H1N1 and Historical H1N1 Influenza Strains

Carter, Donald M.; Lu, Hongzhou; Bloom, Chalise E.; Crevar, Corey J.; Cherry, Joshua L.; Lipman, David J.; Ross, Ted M.

doi:10.1371/journal.pone.0039435

Cited by 11 publications

(11 citation statements)

References 26 publications

(43 reference statements)

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“…All studies were performed in immunologically naive mice that had no preexisting immunity to influenza, and the observed vaccine-induced immune responses were always consistently broad. Most humans have a varied and extensive repertoire of preexisting memory B cells with circulating antibodies that recognize previous H1N1 strains (32)(33)(34). The current trivalent influenza virus (IIV) has a single H1N1 strain that can recall some, but not all, B cell memory responses.…”

Section: Discussionmentioning

confidence: 99%

Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses

Carter

Darby

Lefoley

et al. 2016

J Virol

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170

180

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One of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates. IMPORTANCEUniversal influenza vaccine approaches have the potential to be paradigm shifting for the influenza vaccine field, with the goal of replacing the current standard of care with broadly cross-protective vaccines. We have used COBRA technology to develop an HA head-based strategy that elicits antibodies against many H1 strains that have undergone genetic drift and has potential as a "subtype universal" vaccine. Nine HA COBRA candidates were developed, and these vaccines were used alone, in cocktails or in prime-boost combinations. The most effective regimens elicited the broadest hemagglutination inhibition (HAI) response against a panel of H1N1 viruses isolated over the past 100 years. This is the first report describing a COBRA-based HA vaccine strategy that elicits a broadly reactive response against seasonal and pandemic H1N1 isolates. Influenza vaccine efficacy is constantly undermined by antigenic variation in the circulating viral strains, particularly in the hemagglutinin (HA) and neuraminidase (NA) proteins. Current influenza vaccination strategies rely on changing the HA and NA components of the annual human influenza vaccine to ensure that they antigenically match circulating influenza strains (1, 2). Developing an influenza vaccine that is capable of providing broad and long-lasting protective antibody responses r...

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Section: Discussionmentioning

confidence: 99%

Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses

Carter

Darby

Lefoley

et al. 2016

J Virol

Self Cite

170

180

View full text Add to dashboard Cite

show abstract

“…However, preexisting immunity was not limited to those old enough to have been infected with the 1918 virus or similar viruses of that era. Rather, people born much later, when the circulating H1N1 strains were antigenically distinct from the 1918 virus due to decades of antigenic drift, also had preexisting immunity to novel H1N1 (6). Furthermore, the reactivities of human sera toward the 1918 virus and the 2009 virus are not very strongly correlated (17), suggesting a significant antigenic difference between these two viruses.…”

Section: Discussionmentioning

confidence: 99%

“…This immunity was not uncommon in cohorts born decades after 1918, by which time significant antigenic drift had affected circulating viruses (6). Furthermore, although reactivity of human sera to the 2009 virus correlates with reactivity to the 1918 virus, this correlation is not extraordinarily strong (6).…”

mentioning

confidence: 99%

“…Serological studies revealed that many older and middle-aged adults possessed antibodies that reacted with the novel H1N1 virus prior to the pandemic (6,7). This preexisting humoral immunity was somewhat surprising because of the differences between the hemagglutinin of the novel H1N1 and those of H1N1 viruses that have circulated in human populations since 1918 (6).…”

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confidence: 99%

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

Carter

Bloom

Nascimento

et al. 2013

J Virol

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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.

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“…49,50 As predicted, the proportion of children achieving HAI titers ≥1:40 on day 8 increased with age, but the magnitude of seroprotective titers in the middle (31%) and oldest (84%) strata was unexpected given the degree of divergence of the A(H1N1)pdm09 virus HA sequence from the strains that have circulated during the past two decades. Serologic cross-reactivity between the influenza A(H1N1)pdm09 virus and seasonal H1N1 strains that would not be considered antigenically close has been observed, 51 but the mechanism and competence of these responses remains elusive. Another example of the potential for previous exposure to influenza antigen to shape the antibody response to later exposures may be the observation in our study and elsewhere that immune responses were significantly diminished in individuals who previously received 2008-2009 seasonal influenza vaccine.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Immune Responses to Inactivated Influenza A(H1N1)pdm09 Vaccine in Children

Kotloff

Halasa

Harrison

et al. 2014

Pediatric Infectious Disease Journal

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Background As the influenza AH1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years. Methods Children received two doses of approximately 15 μg or 30 μg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition (HAI) titers were measured on days 0 (pre-vaccination), 8, 21, 29, and 42. Results A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 μg dosage elicited a seroprotective HAI (≥1:40) in 20%, 47%, and 93% of children in the 6-35 month, 3-9 year, and 10-17 year age strata 21 days after dose 1 and in 78%, 82%, and 98% of children 21 days after dose 2, respectively. The 30 μg vaccine dosage induced similar responses. Conclusions The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 μg dose induced seroprotective antibody responses in most 10-17 year olds, younger children required 2 doses, even when receiving dosages 4-6 fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics.

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Complex Patterns of Human Antisera Reactivity to Novel 2009 H1N1 and Historical H1N1 Influenza Strains

Cited by 11 publications

References 26 publications

Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses

Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses

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

Clinical and Immune Responses to Inactivated Influenza A(H1N1)pdm09 Vaccine in Children

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