DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomised clinical trials

Julie E Ledgerwood, Chih-Jen Wei, Zonghui Hu, Ingelise J Gordon, Mary E Enama, Cynthia S Hendel, Patrick M McTamney, Melissa B Pearce, Hadi M Yassine, Jeffrey C Boyington, Robert Bailer, Terrence M Tumpey, Richard A Koup, John R Mascola, Gary J Nabel, Barney S Graham, VRC 306 Study Team, Sarah Hubka, LaSonji Holman, Laura Novik, Pamela Costner, Kathy Zephir, Floreliz Mendoza, Jamie Saunders, Brenda Larkin, Diane Johnson, Nina Berkowitz, Brandon Wilson, Sandra Sitar, Olga Vasilenko, Yesenia Merino, Joseph Casazza, Trishna Goswami, Raymond Cruz, Niraj Desai, Sheryl Young, Uzma Sarwar, Charla Andrews, Phillip Gomez, Becky Sheets, Judy Stein, Galina Yamshchikov, Hope Decederfelt, Judith Starling, LaChonne Stanford, Rhonda Washington-Lewis, Kathy Rhone, Hanne Andersen, Phyllis Zaia, Julie E Ledgerwood, Chih-Jen Wei, Zonghui Hu, Ingelise J Gordon, Mary E Enama, Cynthia S Hendel, Patrick M McTamney, Melissa B Pearce, Hadi M Yassine, Jeffrey C Boyington, Robert Bailer, Terrence M Tumpey, Richard A Koup, John R Mascola, Gary J Nabel, Barney S Graham, VRC 306 Study Team, Sarah Hubka, LaSonji Holman, Laura Novik, Pamela Costner, Kathy Zephir, Floreliz Mendoza, Jamie Saunders, Brenda Larkin, Diane Johnson, Nina Berkowitz, Brandon Wilson, Sandra Sitar, Olga Vasilenko, Yesenia Merino, Joseph Casazza, Trishna Goswami, Raymond Cruz, Niraj Desai, Sheryl Young, Uzma Sarwar, Charla Andrews, Phillip Gomez, Becky Sheets, Judy Stein, Galina Yamshchikov, Hope Decederfelt, Judith Starling, LaChonne Stanford, Rhonda Washington-Lewis, Kathy Rhone, Hanne Andersen, Phyllis Zaia

Abstract

Background: Because the general population is largely naive to H5N1 influenza, antibodies generated to H5 allow analysis of novel influenza vaccines independent of background immunity from previous infection. We assessed the safety and immunogenicity of DNA encoding H5 as a priming vaccine to improve antibody responses to inactivated influenza vaccination.

Methods: In VRC 306 and VRC 310, two sequentially enrolled phase 1, open-label, randomised clinical trials, healthy adults (age 18-60 years) were randomly assigned to receive intramuscular H5 DNA (4 mg) at day 0 or twice, at day 0 and week 4, followed by H5N1 monovalent inactivated vaccine (MIV; 90 μg) at 4 or 24 weeks, and compared with a two-dose regimen of H5N1 MIV with either a 4 or 24 week interval. Antibody responses were assessed by haemagglutination inhibition (HAI), ELISA, neutralisation (ID(80)), and immunoassays for stem-directed antibodies. T cell responses were assessed by intracellular cytokine staining. After enrolment, investigators and individuals were not masked to group assignment. VRC 306 and VRC 310 are registered with ClinicalTrials.gov, numbers NCT00776711 and NCT01086657, respectively.

Findings: In VRC 306, 60 individuals were randomly assigned to the four groups (15 in each) and 59 received the vaccinations. In VRC 310, of the 21 individuals enrolled, 20 received the vaccinations (nine received a two-dose regimen of H5N1 MIV and 11 received H5 DNA at day 0 followed by H5N1 MIV at week 24). H5 DNA priming was safe and enhanced H5-specific antibody titres following an H5N1 MIV boost, especially when the interval between DNA prime and MIV boost was extended to 24 weeks. In the two studies, DNA priming with a 24-week MIV boost interval induced protective HAI titres in 21 (81%) of 26 of individuals, with an increase in geometric mean titre (GMT) of more than four times that of individuals given the MIV-MIV regimen at 4 or 24 weeks (GMT 103-206 vs GMT 27-33). Additionally, neutralising antibodies directed to the conserved stem region of H5 were induced by this prime-boost regimen in several individuals. No vaccine-related serious adverse events were recorded.

Interpretation: DNA priming 24 weeks in advance of influenza vaccine boosting increased the magnitude of protective antibody responses (HAI) and in some cases induced haemagglutinin-stem-specific neutralising antibodies. A DNA-MIV vaccine regimen could enhance the efficacy of H5 or other influenza vaccines and shows that anti-stem antibodies can be elicited by vaccination in man.

Funding: National Institutes of Health.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile for VRC 306 (A) and VRC 310 (B)
Figure 2
Figure 2
Effect of prime boost immunisation on induction of homologous H5-specific antibodies HAI=haemagglutination inhibition assays. Mean titres with standard error of the mean are shown at 2–4 weeks after boost for groups 1–4 and A and B. VRC 306 group 1 received H5N1 MIV at day 0 and week 4. Group 2 received H5 DNA at day 0 followed by H5N1 MIV at week 4. Group 3 received H5 DNA at day 0 followed by H5N1 MIV at week 24. Group 4 received H5 DNA at day 0 and week 4 followed by H5N1 MIV at week 24 (A, B, C). VRC 310 group A received H5N1 MIV at day 0 and week 24 and group B received H5 DNA at day 0 followed by H5N1 MIV at week 24 (D, E, F): (A, D) HAI titres, (B, E) ELISA, and (C, F) neutralisation (ID80).
Figure 3
Figure 3
Induction of stem-specific cross-neutralising antibodies after vaccination mAb=monoclonal antibody. WT=wild-type. (A) Three representative individuals are shown for neutralisation of A/Indonesia/05/2005 (H5N1). (B) Neutralisation of heterlogous virus, A/mallard/Pennsylvania/12180/1984 (1984 Penn H5N2), is shown for three representative individuals. (C) Neutralisation of heterologous virus, A/Hong Kong/1074/1999 (1999 HK H9N2), is shown for two representative individuals.
Figure 4
Figure 4
Analysis of the H5 HAI mean reciprocal antibody titre in relation to the boost interval (VRC 306 and VRC 310) Antibody titres are shown with standard error of the mean. Response at 2–4 weeks after boost is shown for every regimen across both trials. Individuals were dosed at 4-week (A) or 24-week (B) boost intervals. Reference line represents protective HAI titre (1:40).

References

    1. WHO . Influenza (seasonal) fact sheet. World Health Organization; Geneva, Switzerland: 2009.
    1. Luke C, Subbarao K. Vaccines for pandemic influenza. Emerg Infect Dis. 2006;12:66–72.
    1. Bastien N, Antonishyn NA, Brandt K. Human infection with a triple-reassortant swine influenza A(H1N1) virus containing the hemagglutinin and neuraminidase genes of seasonal influenza virus. J Infect Dis. 2010;201:1178–1182.
    1. Garten RJ, Davis CT, Russell CA. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science. 2009;325:197–201.
    1. Shinde V, Bridges CB, Uyeki TM. Triple-reassortant swine influenza A (H1) in humans in the United States, 2005–2009. N Engl J Med. 2009;360:2616–2625.
    1. Belshe RB. The origins of pandemic influenza—lessons from the 1918 virus. N Engl J Med. 2005;353:2209–2211.
    1. WHO Confirmed human cases of avian influenza A(H5N1) 2011. (accessed Aug 14, 2011).
    1. Whittle JR, Zhang R, Khurana S. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci USA. 2011;108:14216–14221.
    1. Knossow M, Skehel JJ. Variation and infectivity neutralization in influenza. Immunology. 2006;119:1–7.
    1. Potter CW, Oxford JS. Determinants of immunity to influenza infection in man. Br Med Bull. 1979;35:69–75.
    1. Ekiert DC, Bhabha G, Elsliger MA. Antibody recognition of a highly conserved influenza virus epitope. Science. 2009;324:246–251.
    1. Sui J, Hwang WC, Perez S. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol. 2009;16:265–273.
    1. Okuno Y, Isegawa Y, Sasao F, Ueda S. A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains. J Virol. 1993;67:2552–2558.
    1. Corti D, Suguitan AL, Jr, Pinna D. Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J Clin Invest. 2010;120:1663–1673.
    1. Kashyap AK, Steel J, Oner AF. Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies. Proc Natl Acad Sci USA. 2008;105:5986–5991.
    1. Wei CJ, Boyington JC, McTamney PM. Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science. 2010;329:1060–1064.
    1. Graham BS, Koup RA, Roederer M. Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 DNA candidate vaccine. J Infect Dis. 2006;194:1650–1660.
    1. Martin JE, Sullivan NJ, Enama ME. A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol. 2006;13:1267–1277.
    1. Treanor JJ, Campbell JD, Zangwill KM, Rowe T, Wolff M. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med. 2006;354:1343–1351.
    1. Wei C-J, Boyington JC, Dai K. Cross-neutralization of 1918 and 2009 influenza viruses: role of glycans in viral evolution and vaccine design. Sci Transl Med. 2010;2:24ra1.
    1. Stephenson I, Wood JM, Nicholson KG, Charlett A, Zambon MC. Detection of anti-H5 responses in human sera by HI using horse erythrocytes following MF59-adjuvanted influenza A/Duck/Singapore/97 vaccine. Virus Res. 2004;103:91–95.
    1. Catanzaro AT, Koup RA, Roederer M. Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector. J Infect Dis. 2006;194:1638–1649.
    1. Catanzaro AT, Roederer M, Koup RA. Phase I clinical evaluation of a six-plasmid multiclade HIV-1 DNA candidate vaccine. Vaccine. 2007;25:4085–4092.
    1. Ledgerwood JE, Graham BS. DNA vaccines: a safe and efficient platform technology for responding to emerging infectious diseases. Hum Vaccin. 2009;5:623–626.
    1. Ledgerwood JE, Pierson TC, Hubka SA. A West Nile virus DNA vaccine utilizing a modified promoter induces neutralizing antibody in younger and older healthy adults in a phase I clinical trial. J Infect Dis. 2011;203:1396–1404.
    1. Martin JE, Louder MK, Holman LA. A SARS DNA vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a phase I clinical trial. Vaccine. 2008;26:6338–6343.
    1. Martin JE, Pierson TC, Hubka S. A West Nile virus DNA vaccine induces neutralizing antibody in healthy adults during a phase 1 clinical trial. J Infect Dis. 2007;196:1732–1740.
    1. Tavel JA, Martin JE, Kelly GG. Safety and immunogenicity of a gag-pol candidate HIV-1 DNA vaccine administered by a needle-free device in HIV-1-seronegative subjects. J Acquir Immune Defic Syndr. 2007;44:601–605.
    1. Jaoko W, Karita E, Kayitenkore K. Safety and immunogenicity study of multiclade HIV-1 adenoviral vector vaccine alone or as boost following a multiclade HIV-1 DNA vaccine in Africa. PLoS One. 2010;5:e12873.
    1. Kibuuka H, Kimutai R, Maboko L. A phase 1/2 study of a multiclade HIV-1 DNA plasmid prime and recombinant adenovirus serotype 5 boost vaccine in HIV-uninfected east Africans (RV 172) J Infect Dis. 2010;201:600–607.
    1. Sui J, Sheehan J, Hwang WC. Wide prevalence of heterosubtypic broadly neutralizing human anti-influenza a antibodies. Clin Infect Dis. 2011;52:1003–1009.
    1. Martin J, Pierson T, Louder M, Nabel G, Graham B. DNA vaccines developed for emerging infectious diseases induce neutralizing antibody and cellular immune responses in healthy adults. Keystone Symposia Viral Immunity (A5); Keystone; Colorado: Jan 20–25, 2008. Abstract 248.
    1. Belshe RB, Frey SE, Graham I. Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant. J Infect Dis. 2011;203:666–673.
    1. Wu L, Kong WP, Nabel GJ. Enhanced breadth of CD4 T-cell immunity by DNA prime and adenovirus boost immunization to human immunodeficiency virus env and gag immunogens. J Virol. 2005;79:8024–8031.
    1. Suguitan AL, Jr, Cheng X, Wang W, Wang S, Jin H, Lu S. Influenza H5 hemagglutinin DNA primes the antibody response elicited by the live attenuated influenza a/vietnam/1203/2004 vaccine in ferrets. PLoS One. 2011;6:e21942.
    1. Wang S, Parker C, Taaffe J, Solorzano A, Garcia-Sastre A, Lu S. Heterologous HA DNA vaccine prime-inactivated influenza vaccine boost is more effective than using DNA or inactivated vaccine alone in eliciting antibody responses against H1 or H3 serotype influenza viruses. Vaccine. 2008;26:3626–3633.
Uncited reference
    1. Yang ZY, Wei CJ, Kong WP. Immunization by avian H5 influenza hemagglutinin mutants with altered receptor binding specificity. Science. 2007;317:825–828.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit