Hyperimmune intravenous immunoglobulin containing high titers of pandemic H1N1 hemagglutinin and neuraminidase antibodies provides dose-dependent protection against lethal virus challenge in SCID mice

Virology Journal

Thomas R Kreil¹  P Noel Barrett³  Hartmut J Ehrlich²  Donald A Baker⁴  John K McVey⁴  Daniel Portsmouth³  Maria R Farcet¹  M Keith Howard³  Richard Fritz³  Astrid Kerschbaum³  Walter Wodal³  Christine Hohenadl³ 

[1] Global Pathogen Safety, Baxter BioScience, Benatzkygasse 2-6, 1221 Vienna, Austria;Global R&D, Baxter BioScience, 1220 Vienna, Austria;Vaccine R&D, Baxter BioScience, Orth/Donau, Austria;Global Quality, Baxter BioScience, Deerfield, Illinois, USA

关键词: Hemagglutinin;    Neuraminidase;    Neutralizing antibody;    Passive transfer;    Intravenous immunoglobulin;    Influenza;    IVIG;    H1N1;   

Others  :  806169
DOI  :  10.1186/1743-422X-11-70

 received in 2014-01-24, accepted in 2014-04-07,  发布年份 2014

【 摘 要 】

Background

Convalescent plasma and fractionated immunoglobulins have been suggested as prophylactic or therapeutic interventions during an influenza pandemic.

Findings

Intravenous immunoglobulin (IVIG) preparations manufactured from human plasma collected before the 2009 H1N1 influenza pandemic, and post-pandemic hyperimmune (H)-IVIG preparations were characterized with respect to hemagglutination inhibition (HI), microneutralization (MN) and neuraminidase-inhibiting (NAi) antibody titers against pandemic H1N1 (pH1N1) and seasonal H1N1 (sH1N1) viruses. The protective efficacy of the IVIG and H-IVIG preparations was evaluated in a SCID mouse challenge model.

Substantial levels of HI, MN and NAi antibodies against pH1N1 (GMTs 1:45, 1:204 and 1: 727, respectively) and sH1N1 (GMTs 1:688, 1:4,946 and 1:312, respectively) were present in pre-pandemic IVIG preparations. In post-pandemic H-IVIG preparations, HI, MN and NAi antibody GMTs against pH1N1 were 1:1,280, 1:11,404 and 1:2,488 (28-, 56- and 3.4-fold enriched), respectively, compared to pre-pandemic IVIG preparations (p < 0.001). Post-pandemic H-IVIG (HI titer 1:1,280) provided complete protection from lethality of SCID mice against pH1N1 challenge (100% of mice survived for 29 days post-challenge). Pre-pandemic IVIG (HI titer 1:70) did not provide significant protection against pH1N1 challenge (50% of mice survived 29 days post-challenge compared to 40% survival in the buffer control group). There was a highly significant correlation between circulating in vivo HI and MN antibody titers and survival (p < 0001).

Conclusion

The substantial enrichment of HA- and NA-specific antibodies in H-IVIG and the efficacious protection of SCID mice against challenge with pH1N1 suggests H-IVIG as a promising intervention against pandemic influenza for immunocompromised patients and other risk groups.

【 授权许可】

   
2014 Hohenadl et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Luke TC, Casadevall A, Watowich SJ, Hoffman SL, Beigel JH, Burgess TH: Hark back: passive immunotherapy for influenza and other serious infections. Crit Care Med 2010, 38:e66-e73.
• [2]Keller MA, Stiehm ER: Passive immunity in prevention and treatment of infectious diseases. Clin Microbiol Rev 2000, 13:602-614.
• [3]World Health Organization: WHO Blood Regulators Network - Position Paper on collection and Use of Convalescent Plasma or Serum as an Element in Pandemic Influenza Planning. Geneva, Switzerland: WHO; 2009:1-4. http://www.who.int/bloodproducts/brn/BRNPosition-ConvPlasma10July09.pdf webcite
• [4]Leider JP, Brunker PA, Ness PM: Convalescent transfusion for pandemic influenza: preparing blood banks for a new plasma product? Transfusion 2010, 50:1384-1398.
• [5]Friesen RH, Koudstaal W, Koldijk MH, Weverling GJ, Brakenhoff JP, Lenting PJ, Stittelaar KJ, Osterhaus AD, Kompier R, Goudsmit J: New class of monoclonal antibodies against severe influenza: prophylactic and therapeutic efficacy in ferrets. PLoS One 2010, 5:e9106.
• [6]Nguyen HH, Tumpey TM, Park HJ, Byun YH, Tran LD, Nguyen VD, Kilgore PE, Czerkinsky C, Katz JM, Seong BL, Song JM, Kim YB, Do HT, Nguyen T, Nguyen CV: Prophylactic and therapeutic efficacy of avian antibodies against influenza virus H5N1 and H1N1 in mice. PLoS One 2010, 5:e10152.
• [7]Prabhu N, Prabakaran M, Hongliang Q, He F, Ho HT, Qiang J, Goutama M, Lim AP, Hanson BJ, Kwang J: Prophylactic and therapeutic efficacy of a chimeric monoclonal antibody specific for H5 haemagglutinin against lethal H5N1 influenza. Antivir Ther 2009, 14:911-921.
• [8]Simmons CP, Bernasconi NL, Suguitan AL, Mills K, Ward JM, Chau NV, Hien TT, Sallusto F, Ha DQ, Farrar J, De J, Lanzavecchia A, Subbarao K: Prophylactic and therapeutic efficacy of human monoclonal antibodies against H5N1 influenza. PLoS Med 2007, 4:e178.
• [9]Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, Liu R, Watt CL, Chan WM, Lai KY, Koo CK, Buckley T, Chow FL, Wong KK, Chan HS, Ching CK, Tang BS, Lau CC, Li IW, Liu SH, Chan KH, Lin CK, Yuen KY: Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 2011, 52:447-456.
• [10]Hung IF, To KK, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CC, Liu SH, Chan KH, Lin CK, Yuen KY: Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest 2013, 144:464-473.
• [11]Kreil TR, Mc Vey JK, Lei LS, Camacho L, Wodal W, Kerschbaum A, Segura E, Vandamme E, Gavit P, Ehrlich HJ, Barrett PN, Baker DA: Preparation of commercial quantities of a hyperimmune human intravenous immunoglobulin preparation against an emerging infectious disease: the example of pandemic H1N1 influenza. Transfusion 2012, 52:803-809.
• [12]Poelsler G, Berting A, Kindermann J, Spruth M, Hammerle T, Teschner W, Schwarz HP, Kreil TR: A new liquid intravenous immunoglobulin with three dedicated virus reduction steps: virus and prion reduction capacity. Vox Sang 2008, 94:184-192.
• [13]Teschner W, Butterweck HA, Auer W, Muchitsch EM, Weber A, Liu SL, Wah PS, Schwarz HP: A new liquid, intravenous immunoglobulin product (IGIV 10%) highly purified by a state-of-the-art process. Vox Sang 2007, 92:42-55.
• [14]Fritz R, Sabarth N, Kiermayr S, Hohenadl C, Howard MK, Ilk R, Kistner O, Ehrlich HJ, Barrett PN, Kreil TR: A vero cell-derived whole-virus H5N1 vaccine effectively induces neuraminidase-inhibiting antibodies. J Infect Dis 2012, 205:28-34.
• [15]Kistner O, Crowe BA, Wodal W, Kerschbaum A, Savidis-Dacho H, Sabarth N, Falkner FG, Mayerhofer I, Mundt W, Reiter M, Grillberger L, Tauer C, Graninger M, Sachslehner A, Schwendinger M, Bruhl P, Kreil TR, Ehrlich HJ, Barrett PN: A whole virus pandemic influenza H1N1 vaccine is highly immunogenic and protective in active immunization and passive protection mouse models. PLoS One 2010, 5:e9349.
• [16]Broberg E, Nicoll A, Mato-Gauci A: Seroprevalence to influenza A(H1N1) 2009 virus–where are we? Clin Vaccine Immunol 2011, 18:1205-1212.
• [17]Marcelin G, DuBois R, Rubrum A, Russell CJ, McElhaney JE, Webby RJ: A contributing role for anti-neuraminidase antibodies on immunity to pandemic H1N1 2009 influenza A virus. PLoS One 2011, 6:e26335.
• [18]Belser JA, Wadford DA, Pappas C, Gustin KM, Maines TR, Pearce MB, Zeng H, Swayne DE, Pantin-Jackwood M, Katz JM, Tumpey TM: Pathogenesis of pandemic influenza A (H1N1) and triple-reassortant swine influenza A (H1) viruses in mice. J Virol 2010, 84:4194-4203.
• [19]Kalthoff D, Grund C, Harder TC, Lange E, Vahlenkamp TW, Mettenleiter TC, Beer M: Limited susceptibility of chickens, turkeys, and mice to pandemic (H1N1) 2009 virus. Emerg Infect Dis 2010, 16:703-705.
• [20]Li GM, Chiu C, Wrammert J, McCausland M, Andrews SF, Zheng NY, Lee JH, Huang M, Qu X, Edupuganti S, Mulligan M, Das SR, Yewdell JW, Mehta AK, Wilson PC, Ahmed R: Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells. Proc Natl Acad Sci U S A 2012, 109:9047-9052.
• [21]Miller MS, Tsibane T, Krammer F, Hai R, Rahmat S, Basler CF, Palese P: 1976 and, H1N1 influenza virus vaccines boost anti-hemagglutinin stalk antibodies in humans. J Infect Dis 2009, 2013(207):98-105.
• [22]Qiu C, Huang Y, Wang Q, Tian D, Zhang W, Hu Y, Yuan Z, Zhang X, Xu J: Boosting heterosubtypic neutralization antibodies in recipients of 2009 pandemic H1N1 influenza vaccine. Clin Infect Dis 2012, 54:17-24.
• [23]Sangster MY, Baer J, Santiago FW, Fitzgerald T, Ilyushina NA, Sundararajan A, Henn AD, Krammer F, Yang H, Luke CJ, Zand MS, Wright PF, Treanor JJ, Topham DJ, Subbarao K: B cell response and hemagglutinin stalk-reactive antibody production in different age cohorts following 2009 H1N1 influenza virus vaccination. Clin Vaccine Immunol 2009, 2013(20):867-876.
• [24]Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI, Mehta A, Razavi B, Del RC, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O'Donnell CD, Yewdell JW, Subbarao K, Marasco WA, Mulligan MJ, Compans R, Ahmed R, Wilson PC: Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 2011, 208:181-193.