Evaluation of in vitro cross-reactivity to avian H5N1 and pandemic H1N1 2009 influenza following prime boost regimens of seasonal influenza vaccination in healthy human subjects: a randomised trial

Delia Bethell, David Saunders, Anan Jongkaewwattana, Jarin Kramyu, Arunee Thitithayanont, Suwimon Wiboon-ut, Kosol Yongvanitchit, Amporn Limsalakpetch, Utaiwan Kum-Arb, Nichapat Uthaimongkol, Jean Michel Garcia, Ans E Timmermans, Malik Peiris, Stephen Thomas, Anneke Engering, Richard G Jarman, Duangrat Mongkolsirichaikul, Carl Mason, Nuanpan Khemnu, Stuart D Tyner, Mark M Fukuda, Douglas S Walsh, Sathit Pichyangkul, Delia Bethell, David Saunders, Anan Jongkaewwattana, Jarin Kramyu, Arunee Thitithayanont, Suwimon Wiboon-ut, Kosol Yongvanitchit, Amporn Limsalakpetch, Utaiwan Kum-Arb, Nichapat Uthaimongkol, Jean Michel Garcia, Ans E Timmermans, Malik Peiris, Stephen Thomas, Anneke Engering, Richard G Jarman, Duangrat Mongkolsirichaikul, Carl Mason, Nuanpan Khemnu, Stuart D Tyner, Mark M Fukuda, Douglas S Walsh, Sathit Pichyangkul

Abstract

Introduction: Recent studies have demonstrated that inactivated seasonal influenza vaccines (IIV) may elicit production of heterosubtypic antibodies, which can neutralize avian H5N1 virus in a small proportion of subjects. We hypothesized that prime boost regimens of live and inactivated trivalent seasonal influenza vaccines (LAIV and IIV) would enhance production of heterosubtypic immunity and provide evidence of cross-protection against other influenza viruses.

Methods: In an open-label study, 26 adult volunteers were randomized to receive one of four vaccine regimens containing two doses of 2009-10 seasonal influenza vaccines administered 8 (±1) weeks apart: 2 doses of LAIV; 2 doses of IIV; LAIV then IIV; IIV then LAIV. Humoral immunity assays for avian H5N1, 2009 pandemic H1N1 (pH1N1), and seasonal vaccine strains were performed on blood collected pre-vaccine and 2 and 4 weeks later. The percentage of cytokine-producing T-cells was compared with baseline 14 days after each dose.

Results: Subjects receiving IIV had prompt serological responses to vaccine strains. Two subjects receiving heterologous prime boost regimens had enhanced haemagglutination inhibition (HI) and neutralization (NT) titres against pH1N1, and one subject against avian H5N1; all three had pre-existing cross-reactive antibodies detected at baseline. Significantly elevated titres to H5N1 and pH1N1 by neuraminidase inhibition (NI) assay were observed following LAIV-IIV administration. Both vaccines elicited cross-reactive CD4+ T-cell responses to nucleoprotein of avian H5N1 and pH1N1. All regimens were safe and well tolerated.

Conclusion: Neither homologous nor heterologous prime boost immunization enhanced serum HI and NT titres to 2009 pH1N1 or avian H5N1 compared to single dose vaccine. However heterologous prime-boost vaccination did lead to in vitro evidence of cross-reactivity by NI; the significance of this finding is unclear. These data support the strategy of administering single dose trivalent seasonal influenza vaccine at the outset of an influenza pandemic while a specific vaccine is being developed.

Trial registration: ClinicalTrials.gov NCT01044095.

Conflict of interest statement

Competing Interests: The authors declare they have no competing interests. This study was supported by MedImmune, which also provided FluMist Seasonal Trivalent Live Attenuated Intranasal Vaccine for use in the trial. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. There are no patents, products in development or marketed products to declare.

Figures

Figure 1. CONSORT (2010) flow diagram.
Figure 1. CONSORT (2010) flow diagram.
Figure 2. Individual and geometric mean serum…
Figure 2. Individual and geometric mean serum haemagglutination inhibition assay, H5pp assay and serum neuraminidase inhibition assay results against avian H5N1 virus in 26 healthy human volunteers measured at baseline and two weeks following each dose of prime boost seasonal influenza vaccination (2 doses administered 8 weeks apart).
Figure 3. Individual and geometric mean serum…
Figure 3. Individual and geometric mean serum haemagglutination inhibition assay, microneutralization assay and serum neuraminidase inhibition assay results against pandemic H1N1 2009 virus in 26 healthy human volunteers measured at baseline and two weeks following each dose of prime boost seasonal influenza vaccination (2 doses administered 8 weeks apart).
Figure 4. Individual and geometric mean peripheral…
Figure 4. Individual and geometric mean peripheral blood CD4+ T-cell responses measured at baseline, two weeks after dose 1 and two weeks after dose 2, by study group: (A) against vaccine antigens in IIV, (B) against nucleoprotein H5N1, and (C) against nucleoprotein pH1N1 2009.

References

    1. World Health Organization (2013) Cumulative number of confirmed human cases of avian influenza a(H5N1) reported to WHO. Geneva.Accessed 25 February 2013.
    1. Cox RJ, Brokstad K, Ogra P (2004) Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines. Scand J Immunol 59: 1–15.
    1. Carter NJ, Curran MP (2011) Live attenuated influenza vaccine (FluMist(R); Fluenz): a review of its use in the prevention of seasonal influenza in children and adults. Drugs 71: 1591–1622.
    1. Ambrose CS, Walker RE, Connor EM (2006) Live attenuated influenza vaccine in children. Semin Pediatr Infect Dis 17: 206–212.
    1. Verrier F, Burda S, Belshe R, Duliege AM, Excler JL, et al. (2000) A human immunodeficiency virus prime-boost immunization regimen in humans induces antibodies that show interclade cross-reactivity and neutralize several X4-, R5-, and dualtropic clade B and C primary isolates. J Virol 74: 10025–10033.
    1. McConkey SJ, Reece WH, Moorthy VS, Webster D, Dunachie S, et al. (2003) Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nat Med 9: 729–735.
    1. Gomez CE, Najera JL, Domingo-Gil E, Ochoa-Callejero L, Gonzalez-Aseguinolaza G, et al. (2007) Virus distribution of the attenuated MVA and NYVAC poxvirus strains in mice. J Gen Virol 88: 2473–2478.
    1. Wei CJ, Boyington JC, McTamney PM, Kong WP, Pearce MB, et al. (2010) Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science 329: 1060–1064.
    1. Garcia JM, Lagarde N, Ma ES, de Jong MD, Peiris JS (2010) Optimization and evaluation of an influenza A (H5) pseudotyped lentiviral particle-based serological assay. J Clin Virol 47: 29–33.
    1. Grandea AG, Olsen OA, Cox TC, Renshaw M, Hammond PW, et al. (2010) Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses. Proc Natl Acad Sci U S A 107: 12658–12663.
    1. Lambre CR, Terzidis H, Greffard A, Webster RG (1990) Measurement of anti-influenza neuraminidase antibody using a peroxidase-linked lectin and microtitre plates coated with natural substrates. J Immunol Methods 135: 49–57.
    1. Yewdell JW, Bennink JR, Smith GL, Moss B (1985) Influenza A virus nucleoprotein is a major target antigen for cross-reactive anti-influenza A virus cytotoxic T lymphocytes. Proc Natl Acad Sci U S A 82: 1785–1789.
    1. Browne RH (1995) On the use of a pilot sample for sample size determination. Stat Med 14: 1933–1940.
    1. Lancaster GA, Dodd S, Williamson PR (2004) Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract 10: 307–312.
    1. Stephenson I BR, Nicholson KG, Podda A, Wood JM, Zambon MC, et al. (2005) Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 191: 1210–1215.
    1. Lin JZJ, Dong X, Fang H, Chen J, Su N, et al. (2006) Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 368: 991–997.
    1. Nicholson KG CA, Podda A, Stephensen I, Wood J, Ypema E, et al. (2001) Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 357: 1937–1943.
    1. Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 340: c332.
    1. Gioia C, Castilletti C, Tempestilli M, Piacentini P, Bordi L, et al. (2008) Cross-subtype immunity against avian influenza in persons recently vaccinated for influenza. Emerg Infect Dis 14: 121–128.
    1. Corti D, Langedijk JP, Hinz A, Seaman MS, Vanzetta F, et al. (2010) Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One 5: e8805.
    1. Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, et al. (2011) Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208: 181–193.
    1. Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, et al. (2011) Systems biology of vaccination for seasonal influenza in humans. Nat Immunol 12: 786–795.
    1. Onodera T, Takahashi Y, Yokoi Y, Ato M, Kodama Y, et al. (2012) Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection. Proc Natl Acad Sci U S A 109: 2485–2490.
    1. Murphy BR, Kasel JA, Chanock RM (1972) Association of serum anti-neuraminidase antibody with resistance to influenza in man. N Engl J Med 286: 1329–1332.
    1. Monto AS, Kendal AP (1973) Effect of neuraminidase antibody on Hong Kong influenza. Lancet 1: 623–625.
    1. Neuzil KM JL, Nelson J, Klimov A, Cox N, Bridges CB, et al. (2006) Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5-8-year-old children. J Infect Dis 194: 1032–1039.
    1. Greenbaum JA, Kotturi MF, Kim Y, Oseroff C, Vaughan K, et al. (2009) Pre-existing immunity against swine-origin H1N1 influenza viruses in the general human population. Proc Natl Acad Sci U S A 106: 20365–20370.
    1. Lee LY, Ha do LA, Simmons C, de Jong MD, Chau NV, et al. (2008) Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest 118: 3478–3490.
    1. Ge X, Tan V, Bollyky PL, Standifer NE, James EA, et al. (2010) Assessment of seasonal influenza A virus-specific CD4 T-cell responses to 2009 pandemic H1N1 swine-origin influenza A virus. J Virol 84: 3312–3319.
    1. Yap KL, Ada GL (1978) Cytotoxic T cells in the lungs of mice infected with an influenza A virus. Scand J Immunol 7: 73–80.
    1. Webster RG, Askonas BA (1980) Cross-protection and cross-reactive cytotoxic T cells induced by influenza virus vaccines in mice. Eur J Immunol 10: 396–401.
    1. Guo H, Santiago F, Lambert K, Takimoto T, Topham DJ (2011) T cell-mediated protection against lethal 2009 pandemic H1N1 influenza virus infection in a mouse model. J Virol 85: 448–455.
    1. Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, et al. (2012) Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med 18: 274–280.
    1. Eick AA, Wang Z, Hughes H, Ford SM, Tobler SK (2009) Comparison of the trivalent live attenuated vs. inactivated influenza vaccines among U.S. military service members. Vaccine 27: 3568–3575.
    1. Wang Z, Tobler S, Roayaei J, Eick A (2009) Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses among US military personnel. JAMA 301: 945–953.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner