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Boosted Influenza-Specific T Cell Responses after H5N1 Pandemic Live Attenuated Influenza Virus Vaccination.

ABSTRACT: In a phase I clinical trial, a H5N1 pandemic live attenuated influenza virus (pLAIV) VN2004 vaccine bearing avian influenza H5N1 hemagglutinin (HA) and NA genes on the A/Ann Arbor cold-adapted vaccine backbone displayed very restricted replication. We evaluated T cell responses to H5N1 pLAIV vaccination and assessed pre-existing T cell responses to determine whether they were associated with restricted replication of the H5N1 pLAIV.ELISPOT assays were performed using pools of overlapping peptides spanning the entire H5N1 proteome and the HA proteins of relevant seasonal H1N1 and H3N2 viruses. We tested stored peripheral blood mononuclear cells (PBMCs) from 21 study subjects who received two doses of the H5N1 pLAIV. The PBMCs were collected 1?day before and 7?days after the first and second pLAIV vaccine doses, respectively.T cell responses to conserved internal proteins M and NP were significantly boosted by vaccination (p?=?0.036). In addition, H5N1 pLAIV appeared to preferentially stimulate and boost pre-existing seasonal influenza virus HA-specific T cell responses that showed low cross-reactivity with the H5 HA. We confirmed this observation by T cell cloning and identified a novel HA-specific epitope. However, we did not find any evidence that pre-existing T cells prevented pLAIV replication and take.We found that cross-reactive T cell responses could be boosted by pLAIV regardless of the induction of antibody. The impact of the "original antigenic sin" phenomenon in a subset of volunteers, with preferential expansion of seasonal influenza-specific but not H5N1-specific T cell responses merits further investigation.

SUBMITTER: Peng Y

PROVIDER: S-EPMC4451682 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Boosted Influenza-Specific T Cell Responses after H5N1 Pandemic Live Attenuated Influenza Virus Vaccination.

Peng YanChun Y Wang Beibei B Talaat Kawsar K Karron Ruth R Powell Timothy J TJ Zeng Hui H Dong Danning D Luke Catherine J CJ McMichael Andrew A Subbarao Kanta K Dong Tao T

Frontiers in immunology 20150602

<h4>Background</h4>In a phase I clinical trial, a H5N1 pandemic live attenuated influenza virus (pLAIV) VN2004 vaccine bearing avian influenza H5N1 hemagglutinin (HA) and NA genes on the A/Ann Arbor cold-adapted vaccine backbone displayed very restricted replication. We evaluated T cell responses to H5N1 pLAIV vaccination and assessed pre-existing T cell responses to determine whether they were associated with restricted replication of the H5N1 pLAIV.<h4>Method</h4>ELISPOT assays were performed ...[more]

PMID: 26082783

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Project description:BACKGROUND:Development of live attenuated influenza vaccines (LAIV) against avian viruses with pandemic potential is an important public health strategy. METHODS AND FINDINGS:We performed open-label trials to evaluate the safety, infectivity, and immunogenicity of H5N1 VN 2004 AA ca and H5N1 HK 2003 AA ca. Each of these vaccines contains a modified H5 hemagglutinin and unmodified N1 neuraminidase from the respective wild-type (wt) parent virus and the six internal protein gene segments of the A/Ann Arbor/6/60 cold-adapted (ca) master donor virus. The H5N1 VN 2004 AA ca vaccine virus was evaluated at dosages of 10(6.7) TCID(50) and 10(7.5) TCID(50), and the H5N1 HK 2003 AA ca vaccine was evaluated at a dosage of 10(7.5) TCID(50). Two doses were administered intranasally to healthy adults in isolation at 4-8 week intervals. Vaccine safety was assessed through daily examinations and infectivity was assessed by viral culture and by realtime reverse transcription-polymerase chain reaction testing of nasal wash (NW) specimens. Immunogenicity was assessed by measuring hemagglutination-inhibition (HI) antibodies, neutralizing antibodies, and IgG or IgA antibodies to recombinant (r)H5 VN 2004 hemagglutinin (HA) in serum or NW. Fifty-nine participants were enrolled: 21 received 10(6.7) TCID(50) and 21 received 10(7.5) TCID(50) of H5N1 VN 2004 AA ca and 17 received H5N1 HK 2003 AA ca. Shedding of vaccine virus was minimal, as were HI and neutralizing antibody responses. Fifty-two percent of recipients of 10(7.5) TCID(50) of H5N1 VN 2004 AA ca developed a serum IgA response to rH5 VN 2004 HA. CONCLUSIONS:The live attenuated H5N1 VN 2004 and HK 2003 AA ca vaccines bearing avian H5 HA antigens were very restricted in replication and were more attenuated than seasonal LAIV bearing human H1, H3 or B HA antigens. The H5N1 AA ca LAIV elicited serum ELISA antibody but not HI or neutralizing antibody responses in healthy adults. (ClinicalTrials.gov Identifiers: NCT00347672 and NCT00488046).

Project description:During the past decade, a number of H5 subtype influenza vaccines have been developed and tested in clinical trials, but most of them induced poor serum antibody responses prompting the evaluation of novel vaccination approaches. One of the most promising ones is a "prime-boost" strategy, which could result in the induction of prompt and robust immune responses to a booster influenza vaccine following priming with homologous or heterologous vaccine strains. In our study we evaluated immunogenicity of an adjuvanted A(H5N1) inactivated influenza vaccine (IIV) in healthy adult subjects who received A(H5N2) live attenuated influenza vaccine (LAIV) 1.5 years earlier and compared this with a group of naïve subjects. We found that priming with A(H5N2) LAIV induced a long-lasting B-cell immunological memory against influenza A(H5N1) virus, which was brought on by more prompt and vigorous antibody production to a single dose of A(H5N1) IIV in the primed group, compared to the naïve controls. Thus, by day 28 after the first booster dose, the hemagglutination inhibition and neutralizing (MN) antibody titer rises were 17.2 and 30.8 in the primed group, compared to 2.3 and 8.0 in the control group, respectively. The majority (79%) of the primed individuals achieved seroprotective MN antibody titers at 7 days after the first dose of the IIV. All LAIV-primed volunteers had MN titers ? 1:40 by Day 28 after one dose of IIV, whereas only 58% subjects from the naïve control group developed similar immune responses at this time point. The second A(H5N1) IIV dose did not increase the immune response in the LAIV-primed group, whereas 2 doses of IIV were required for naïve volunteers to develop significant immune responses. These findings were of special significance since Russian-based LAIV technology has been licensed to WHO, through whom the vaccine has been provided to vaccine manufacturers in India, China and Thailand - countries particularly vulnerable to a pandemic influenza. The results of our study will be useful to inform the development of vaccination strategies in these countries in the event of a pandemic.

Project description:BackgroundSome studies have found a higher frequency of fever with trivalent live attenuated influenza vaccine (LAIV) than with inactivated influenza vaccine (IIV), but quadrivalent LAIV has not been assessed. Understanding fever is important for safety reviews and for parents and providers. In addition, there have been only a limited number of studies in which text messaging was used for vaccine adverse-event (AE) surveillance.MethodsWe conducted a prospective observational study in 3 community clinics in New York City to assess post-influenza vaccination fever in 24- to 59-month-olds during the 2013-2014 season. Enrolled families of children who received quadrivalent LAIV (LAIV4) or IIV (trivalent IIV3 or quadrivalent IIV4) replied to text messages that assessed their temperature on vaccination night and the next 10 nights (days 0 to 10); missing data were collected via telephone and a diary. We compared frequencies of fever (temperature ≥ 100.4°F) according to vaccine group on days 0 to 2 and 3 to 10 by using χ2 and multivariate log-binomial regression adjusted for age, previous influenza vaccination, and vaccine coadministration. We also assessed outcomes using all sources versus only text messages.ResultsMost (84.1% [n = 540]) eligible parents enrolled. Fever frequencies on days 0 to 2 did not differ between LAIV4 and any IIV (3.8% vs 5.7%, respectively; adjusted relative risk [aRR] [95% confidence interval], 0.60 [0.25-1.46]), between LAIV4 and IIV4 (4.2% vs 7.1%, respectively; aRR, 0.58 [0.19-1.72]), or between IIV4 and IIV3 (7.1% vs 6.0%, respectively; aRR, 1.02 [0.30-3.46]). The findings were similar when all data sources versus text-message data alone were used. There were no significant differences on days 3 to 10.ConclusionsPostvaccination fever frequencies were low overall and did not differ according to influenza vaccine type during the 2013-2014 influenza season. The similarity of results when data were limited to text messages lends support to its use for surveillance of vaccine adverse events.

Dataset Information

Boosted Influenza-Specific T Cell Responses after H5N1 Pandemic Live Attenuated Influenza Virus Vaccination.

Publications

Boosted Influenza-Specific T Cell Responses after H5N1 Pandemic Live Attenuated Influenza Virus Vaccination.

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