Influence of pre-existing hemagglutination inhibition titers against historical influenza strains on antibody response to inactivated trivalent influenza vaccine in adults 50–80 years of age

Ross, Ted M.; Lin, Chyongchiou J.; Nowalk, Mary Patricia; Huang, Hsin Hui; Spencer, Sarah; Shay, David K.; Sambhara, Suryaprakash; Sundaram, Maria E.; Friedrich, Thomas C.; Sauereisen, Sandy; Bloom, Chalise E.; Zimmerman, Richard K.

doi:10.4161/hv.28313

Cited by 21 publications

(21 citation statements)

References 28 publications

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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

172

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

172

180

View full text Add to dashboard Cite

show abstract

“…Additionally, targeting influenza A vaccines to a naive pool of IGHV3-30 B cells that provide strong initial binding energy through their BCR H/L CDR3 motifs may prove useful. These vaccine approaches may have the advantage of preventing the memory B cell loss that is further compounded by HA antigen induced expansion of abundant anti-head memory B cell clones 47 48 . A different strategy may be to inhibit the mammalian target of rapamycin (mTOR) pathway which has been reported to modify the nAb repertoire and increase the frequency of Abs potentially cross-reactive to conserved stem epitopes 49 50 .…”

Section: Discussionmentioning

confidence: 99%

A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve

Zhang

Sheehan

et al. 2016

Nat Commun

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Understanding the natural evolution and structural changes involved in broadly neutralizing antibody (bnAb) development holds great promise for improving the design of prophylactic influenza vaccines. Here we report an haemagglutinin (HA) stem-directed bnAb, 3I14, isolated from human memory B cells, that utilizes a heavy chain encoded by the IGHV3-30 germline gene. MAb 3I14 binds and neutralizes groups 1 and 2 influenza A viruses and protects mice from lethal challenge. Analysis of VH and VL germline back-mutants reveals binding to H3 and H1 but not H5, which supports the critical role of somatic hypermutation in broadening the bnAb response. Moreover, a single VLD94N mutation improves the affinity of 3I14 to H5 by nearly 10-fold. These data provide evidence that memory B cell evolution can expand the HA subtype specificity. Our results further suggest that establishing an optimized memory B cell pool should be an aim of ‘universal' influenza vaccine strategies.

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“…We examined factors that may contribute to levels of cross-protective antibodies to drifted viruses postvaccination. An individual's antibody repertoire accumulated from past priming history to influenza viruses can shape the responses to current influenza vaccination ( 33 , 34 ). Preexisting antibody titers to the influenza A(H3N2) vaccine component were correlated with cross-reactive neutralizing antibodies to the drifted A(H3N2) viruses prior to vaccination.…”

Section: Discussionmentioning

confidence: 99%

Neutralizing Antibody Responses to Antigenically Drifted Influenza A(H3N2) Viruses among Children and Adolescents following 2014-2015 Inactivated and Live Attenuated Influenza Vaccination

Levine

Martin

Gross

et al. 2016

Clin Vaccine Immunol

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Human influenza A(H3N2) viruses that predominated during the moderately severe 2014-2015 influenza season differed antigenically from the vaccine component, resulting in reduced vaccine effectiveness (VE). To examine antibody responses to 2014-2015 inactivated influenza vaccine (IIV) and live-attenuated influenza vaccine (LAIV) among children and adolescents, we collected sera before and after vaccination from 150 children aged 3 to 17 years enrolled at health care facilities. Hemagglutination inhibition (HI) assays were used to assess the antibody responses to vaccine strains. We evaluated cross-reactive antibody responses against two representative A(H3N2) viruses that had antigenically drifted from the A(H3N2) vaccine component using microneutralization (MN) assays. Postvaccination antibody titers to drifted A(H3N2) viruses were higher following receipt of IIV (MN geometric mean titers [GMTs], 63 to 68; 38 to 45% achieved seroconversion) versus LAIV (MN GMT, 22; only 3 to 5% achieved seroconversion). In 9- to 17-year-olds, the highest MN titers were observed among IIV-vaccinated individuals who had received LAIV in the previous season. Among all IIV recipients aged 3 to 17 years, the strongest predictor of antibody responses to the drifted viruses was the prevaccination titers to the vaccine strain. The results of our study suggest that in an antigenically drifted influenza season, vaccination still induced cross-reactive antibody responses to drifted circulating A(H3N2) viruses, although higher antibody titers may be required for protection. Antibody responses to drifted A(H3N2) viruses following vaccination were influenced by multiple factors, including vaccine type and preexisting immunity from prior exposure.

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Influence of pre-existing hemagglutination inhibition titers against historical influenza strains on antibody response to inactivated trivalent influenza vaccine in adults 50–80 years of age

Abstract: Seroprotective titers after influenza vaccination increased as the number of responses to historical strains increased.

Cited by 21 publications

References 28 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

A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve

Neutralizing Antibody Responses to Antigenically Drifted Influenza A(H3N2) Viruses among Children and Adolescents following 2014-2015 Inactivated and Live Attenuated Influenza Vaccination

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