Correspondence
Antigenically Distinct MF59-Adjuvanted Vaccine to Boost Immunity to H5N1
N Engl J Med 2008; 359:1631-1633October 9, 2008
- Article
To the Editor:
Antigenically distinct avian influenza A (H5N1) viruses are widely dispersed.1 Clade 1 H5N1 viruses previously predominated in Indochina. Indonesian, Eurasian, and African viruses are clustered in a clade 2 group, with antigenically distinct sublineages. Clade 0 viruses caused influenza outbreaks in Hong Kong in 1997 but have not been isolated since then. To reduce shortfalls in vaccine supply at the onset of the next pandemic, advance stockpiling of vaccine has been suggested. Because of antigenic evolution of H5N1, current vaccines may be suboptimally matched to the actual pandemic virus. Proactive priming may induce immune memory, allowing low-dose vaccination to induce rapid cross-protection when needed.
We report on an open-label study conducted from June through August 2007 at Leicester Royal Infirmary, Leicester, United Kingdom (for details, see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). Two 7.5-μg doses of MF59-adjuvanted, surface-antigen vaccine against clade 1 A/Vietnam/1194/2004 (NIBRG-14) (Novartis) were administered by intramuscular injection 21 days apart to subjects who had been vaccinated (primed) with clade 0 H5 vaccine at least 6 years earlier. All primed subjects had received two doses of either MF59-adjuvanted or nonadjuvanted (plain) A/duck/Singapore/97 (H5N3) vaccine containing 7.5 to 30 μg of hemagglutinin in studies conducted between 1999 and 2001.2-4 Some subjects had also received a booster dose 16 months after primary immunization.3 Antibody responses were detected with the use of neutralizing and hemagglutination-inhibition assays performed at the U.K. Health Protection Agency, with homologous clade 1 NIBRG-14 and heterologous clade 2.2 NIBRG-23 vaccine reference strains and by hemagglutination-inhibition assay at the Centers for Disease Control and Prevention with wild-type A/Vietnam/1194/2004 (clade 1), A/Indonesia/5/2005 (clade 2.1), A/Anhui/1/2005 (clade 2.3), and A/Turkey/15/2006 (clade 2.2) viruses (see the Supplementary Appendix for details).
Twenty-four subjects had received two or three doses of either plain or MF59-adjuvanted H5N3 vaccine, with subjects equally divided between the two groups. Thirty subjects were unprimed. Vaccines had acceptable side-effect profiles, and no serious vaccine-related adverse events were recorded. Serum samples were obtained immediately before each of the two doses of vaccine was administered (on days 0 and 21) and on days 7, 14, and 42 after vaccination.
On each post-vaccination day, and with each assay, geometric mean titers of antibodies to NIBRG-14 and NIBRG-23 were significantly higher among the primed subjects than among the unprimed subjects (P<0.001 for all comparisons, except on day 42 for NIBRG-14 on hemagglutination-inhibition assay). From day 14 onward, and for each assay, titers of antibodies to both viruses were significantly higher in the MF59-primed group than in the plain-primed group (P<0.05 for all comparisons). The highest titers were observed on day 14 in the MF59-primed group, with geometric mean titers of antibodies to NIBRG-14 and NIBRG-23 of 1:378 and 1:347, respectively, on hemagglutination-inhibition assay and of 1:1754 and 1:2128, respectively, on neutralizing assay (Figure 1Figure 1
Titers of Antibodies to NIBRG-14 and NIBRG-23 and Reverse Cumulative Distribution Curves on Day 7 after One Dose of Vaccine. and the Supplementary Appendix). No relation between the post-vaccination titer and the number of previous doses of H5N3 vaccine or their antigen content was observed. By day 7, at least 80% of MF59-primed subjects had titers of at least 1:40 for all wild-type viruses tested on hemagglutination-inhibition assay.Modeling of pandemic spread shows that the maximum reduction in viral transmission is achieved by the induction of a response within 2 weeks after the outbreak of the pandemic.5 Because two doses of the vaccine are required, rapid vaccine deployment will be challenging. Our findings indicate that priming subjects with H5 antigen induces a rapidly mobilized, long-lasting immune memory after the administration of low-dose, antigenically distinct vaccine. Given the protective titers detected by day 7, the effect of MF59 adjuvant is striking. Consideration could be given to a proactive vaccine-priming strategy, particularly among those at high risk for pandemic influenza such as health care workers, so that cross-clade antibodies could be rapidly generated after single vaccination or after exposure to the pandemic virus.
Iain Stephenson, M.A., F.R.C.P.
Karl G. Nicholson, F.R.C.Path., F.R.C.P.
University Hospitals Leicester, Leicester LE1 5WW, United Kingdom
iain.stephenson@uhl-tr. nhs. uk Katja Hoschler, Ph.D.
Maria C. Zambon, Ph.D.
Health Protection Agency, Colindale NW9 5HT, United KingdomKathy Hancock, Ph.D.
Joshua DeVos, M.P.H.
Jacqueline M. Katz, Ph.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333Michaela Praus
Angelika Banzhoff, M.D.
Novartis Vaccine, 35041 Marburg, GermanyDr. Stephenson reports receiving consulting and lecture fees and grant support from Hoffmann–La Roche and Novartis; Dr. Nicholson, receiving consulting and lecture fees from GlaxoSmithKline and Novartis; Dr. Zambon, receiving grant support from CSL, Sanofi-Pasteur, Baxter, and Novartis; Dr. Hancock, receiving grant support from Juvaris BioTherapeutics and the Biomedical Advanced Research and Development Authority; Dr. Katz, receiving grant support from NexBio and Nobilon; and Ms. Praus and Dr. Banzhoff, being employees of Novartis. No other potential conflict of interest relevant to this letter was reported.
5 References1
Chen H ,Smith GJ ,Li KS , et al. Establishment of multiple sublineages of H5N1 influenza virus in Asia: implications for pandemic control. Proc Natl Acad Sci U S A 2006;103:2845-2850
CrossRef | Web of Science | Medline2
Nicholson KG ,Colegate AE ,Podda A , et al. 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 2001;357:1937-1943
CrossRef | Web of Science | Medline3
Stephenson I ,Nicholson KG ,Colegate A , et al. Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 A/Duck/Singapore/97 vaccine in a primed human population. Vaccine 2003;21:1687-1693
CrossRef | Web of Science | Medline4
Stephenson I ,Zambon MC ,Rudin A , et al. Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers. J Virol 2006;80:4962-4970
CrossRef | Web of Science | Medline5
Ferguson NM ,Cummings DAT ,Fraser C ,Cajka JC ,Cooley PC ,Burke DS . Strategies for mitigating an influenza pandemic. Nature 2006;442:448-452
CrossRef | Web of Science | Medline
- Citing Articles (41)
Citing Articles
1
Roberto Gasparini, Daniela Amicizia, Piero Luigi Lai, Donatella Panatto. (2012) Aflunov ® : a prepandemic influenza vaccine. Expert Review of Vaccines 11:2, 145-157
CrossRef2
Timo Vesikari, Aino Forstén, Karl-Heinz Herbinger, Giovanni Della Cioppa, Jenny Beygo, Astrid Borkowski, Nicola Groth, Mariaviviana Bennati, Frank von Sonnenburg. (2011) Safety and immunogenicity of an MF59®-adjuvanted A/H5N1 pre-pandemic influenza vaccine in adults and the elderly. Vaccine
CrossRef3
Giovanni Della Cioppa, Timo Vesikari, Etienne Sokal, Kelly Lindert, Uwe Nicolay. (2011) Trivalent and quadrivalent MF59®-adjuvanted influenza vaccine in young children: A dose- and schedule-finding study. Vaccine 29:47, 8696-8704
CrossRef4
George Risi, Louise Frenette, Joanne M. Langley, Ping Li, Dennis Riff, Eric Sheldon, David W. Vaughn, Louis Fries. (2011) Immunological priming induced by a two-dose series of H5N1 influenza antigen, administered alone or in combination with two different formulations of AS03 adjuvant in adults: Results of a randomised single heterologous booster dose study at 15 months. Vaccine 29:37, 6408-6418
CrossRef5
Philippe Moris, Robbert Most, Isabel Leroux-Roels, Frédéric Clement, Mamadou Dramé, Emmanuel Hanon, Geert G. Leroux-Roels, Marcelle Mechelen. (2011) H5N1 Influenza Vaccine Formulated with AS03A Induces Strong Cross-Reactive and Polyfunctional CD4 T-Cell Responses. Journal of Clinical Immunology 31:3, 443-454
CrossRef6
S. Khurana, N. Verma, J. W. Yewdell, A. K. Hilbert, F. Castellino, M. Lattanzi, G. Del Giudice, R. Rappuoli, H. Golding. (2011) MF59 Adjuvant Enhances Diversity and Affinity of Antibody-Mediated Immune Response to Pandemic Influenza Vaccines. Science Translational Medicine 3:85, 85ra48-85ra48
CrossRef7
Derek T O’Hagan, Rino Rappuoli, Ennio De Gregorio, Theodore Tsai, Giuseppe Del Giudice. (2011) MF59 adjuvant: the best insurance against influenza strain diversity. Expert Review of Vaccines 10:4, 447-462
CrossRef8
Antu K Dey, Indresh K Srivastava. (2011) Novel adjuvants and delivery systems for enhancing immune responses induced by immunogens. Expert Review of Vaccines 10:2, 227-251
CrossRef9
A. Schuchat, B. P. Bell, S. C. Redd. (2011) The Science behind Preparing and Responding to Pandemic Influenza: The Lessons and Limits of Science. Clinical Infectious Diseases 52:Supplement 1, S8-S12
CrossRef10
Philip R. Dormitzer, Grazia Galli, Flora Castellino, Hana Golding, Surender Khurana, Giuseppe Del Giudice, Rino Rappuoli. (2011) Influenza vaccine immunology. Immunological Reviews 239:1, 167-177
CrossRef11
Theodore F. TSAI. (2011) MF59® Adjuvanted Seasonal and Pandemic Influenza Vaccines. YAKUGAKU ZASSHI 131:12, 1733-1741
CrossRef12
Jiri Beran, Ibrahim A. Abdel-Messih, Jolana Raupachova, Lenka Hobzova, Elena Fragapane. (2010) A phase III, randomized, open-label study to assess the tolerability and immunogenicity of an H5N1 influenza vaccine administered to healthy adults with a 1-, 2-, 3-, or 6-week interval between first and second doses. Clinical Therapeutics 32:13, 2186-2197
CrossRef13
Penghui Yang, Chong Tang, Deyan Luo, Zhongpeng Zhan, Li Xing, Yueqiang Duan, Weihong Jia, Daxin Peng, Xiufan Liu, Xiliang Wang. (2010) Cross-clade protection against HPAI H5N1 influenza virus challenge in BALB/c mice intranasally administered adjuvant-combined influenza vaccine. Veterinary Microbiology 146:1-2, 17-23
CrossRef14
Geert Leroux-Roels. (2010) Unmet needs in modern vaccinology. Vaccine 28, C25-C36
CrossRef15
Yuji Yasuda, Ryoya Komatsu, Kenji Matsushita, Taketsugu Minami, Yutaka Suehiro, Hiroshi Sawata, Noriko Nakura, Ralf K. Jaeger, Maria Lattanzi. (2010) Comparison of half and full doses of an MF59-adjuvanted cell culture-derived A/H1N1v vaccine in Japanese children. Advances in Therapy 27:7, 444-457
CrossRef16
Filippo Ansaldi, Marta Zancolli, Paolo Durando, Emanuele Montomoli, Laura Sticchi, Giuseppe Del Giudice, Giancarlo Icardi. (2010) Antibody response against heterogeneous circulating influenza virus strains elicited by MF59- and non-adjuvanted vaccines during seasons with good or partial matching between vaccine strain and clinical isolates. Vaccine 28:25, 4123-4129
CrossRef17
Klaus Stöhr. (2010) Vaccinate before the next pandemic?. Nature 465:7295, 161-161
CrossRef18
Iain Stephenson, Frederick Hayden, Albert Osterhaus, Wendy Howard, Yuri Pervikov, Laszlo Palkonyay, Marie-Paule Kieny. (2010) Report of the fourth meeting on ‘Influenza vaccines that induce broad spectrum and long-lasting immune responses’, World Health Organization and Wellcome Trust, London, United Kingdom, 9–10 November 2009. Vaccine 28:23, 3875-3882
CrossRef19
G. Milne, J. Kelso, H. Kelly. (2010) Strategies for mitigating an influenza pandemic with pre-pandemic H5N1 vaccines. Journal of The Royal Society Interface 7:45, 573-586
CrossRef20
Neetu Singh, Aseem Pandey, Suresh K. Mittal. (2010) Avian influenza pandemic preparedness: developing prepandemic and pandemic vaccines against a moving target. Expert Reviews in Molecular Medicine 12,
CrossRef21
François Roman, Tejaswini Vaman, Beatrice Gerlach, Andre Markendorf, Paul Gillard, Jeanne-Marie Devaster. (2010) Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: Preliminary report of an observer-blind, randomised trial. Vaccine 28:7, 1740-1745
CrossRef22
Suryaprakash Sambhara, Gregory A. Poland. (2010) H5N1 Avian Influenza: Preventive and Therapeutic Strategies Against a Pandemic. Annual Review of Medicine 61:1, 187-198
CrossRef23
S. Khurana, W. Chearwae, F. Castellino, J. Manischewitz, L. R. King, A. Honorkiewicz, M. T. Rock, K. M. Edwards, G. Del Giudice, R. Rappuoli, H. Golding. (2010) Vaccines with MF59 Adjuvant Expand the Antibody Repertoire to Target Protective Sites of Pandemic Avian H5N1 Influenza Virus. Science Translational Medicine 2:15, 15ra5-15ra5
CrossRef24
Nicolas Sabarth, M. Keith Howard, Helga Savidis-Dacho, André van Maurik, P. Noel Barrett, Otfried Kistner. (2010) Comparison of single, homologous prime-boost and heterologous prime-boost immunization strategies against H5N1 influenza virus in a mouse challenge model. Vaccine 28:3, 650-656
CrossRef25
Wendy Keitel, Nicola Groth, Maria Lattanzi, Michaela Praus, Anne Katrin Hilbert, Astrid Borkowski, Ted F. Tsai. (2010) Dose ranging of adjuvant and antigen in a cell culture H5N1 influenza vaccine: Safety and immunogenicity of a phase 1/2 clinical trial. Vaccine 28:3, 840-848
CrossRef26
Rogier Bodewes, Guus F Rimmelzwaan, Albert DME Osterhaus. (2010) Animal models for the preclinical evaluation of candidate influenza vaccines. Expert Review of Vaccines 9:1, 59-72
CrossRef27
Richard Brunner, Erika Jensen-Jarolim, Isabella Pali-Schöll. (2010) The ABC of clinical and experimental adjuvants—A brief overview. Immunology Letters 128:1, 29-35
CrossRef28
Isabel Leroux-Roels, François Roman, Sheron Forgus, Cathy Maes, Fien De Boever, Mamadou Dramé, Paul Gillard, Robbert van der Most, Marcelle Van Mechelen, Emmanuel Hanon, Geert Leroux-Roels. (2010) Priming with AS03A-adjuvanted H5N1 influenza vaccine improves the kinetics, magnitude and durability of the immune response after a heterologous booster vaccination: An open non-randomised extension of a double-blind randomised primary study. Vaccine 28:3, 849-857
CrossRef29
Hancock, Kathy, Veguilla, Vic, Lu, Xiuhua, Zhong, Weimin, Butler, Eboneé N., Sun, Hong, Liu, Feng, Dong, Libo, DeVos, Joshua R., Gargiullo, Paul M., Brammer, T. Lynnette, Cox, Nancy J., Tumpey, Terrence M., Katz, Jacqueline M., . (2009) Cross-Reactive Antibody Responses to the 2009 Pandemic H1N1 Influenza Virus. New England Journal of Medicine 361:20, 1945-1952
Full Text30
Isabella Alberini, Elena Del Tordello, Alba Fasolo, Nigel J. Temperton, Grazia Galli, Chiara Gentile, Emanuele Montomoli, Anne K. Hilbert, Angelika Banzhoff, Giuseppe Del Giudice, John J. Donnelly, Rino Rappuoli, Barbara Capecchi. (2009) Pseudoparticle neutralization is a reliable assay to measure immunity and cross-reactivity to H5N1 influenza viruses. Vaccine 27:43, 5998-6003
CrossRef31
Tino F. Schwarz, Thomas Horacek, Markus Knuf, Hanns-Gerd Damman, François Roman, Mamadou Dramé, Paul Gillard, Wolfgang Jilg. (2009) Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine 27:45, 6284-6290
CrossRef32
Nicole La Gruta, Anne Kelso, Lorena E Brown, Wiesan Chen, David C Jackson, Stephen J Turner. (2009) Role of CD8 + T-cell immunity in influenza infection: potential use in future vaccine development. Expert Review of Respiratory Medicine 3:5, 523-537
CrossRef33
Luc Hessel, . (2009) Pandemic influenza vaccines: meeting the supply, distribution and deployment challenges. Influenza and Other Respiratory Viruses 3:4, 165-170
CrossRef34
Gabriele Neumann, Takeshi Noda, Yoshihiro Kawaoka. (2009) Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459:7249, 931-939
CrossRef35
G. Galli, K. Hancock, K. Hoschler, J. DeVos, M. Praus, M. Bardelli, C. Malzone, F. Castellino, C. Gentile, T. McNally, G. Del Giudice, A. Banzhoff, V. Brauer, E. Montomoli, M. Zambon, J. Katz, K. Nicholson, I. Stephenson. (2009) Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proceedings of the National Academy of Sciences 106:19, 7962-7967
CrossRef36
Isabel Leroux-Roels, Geert Leroux-Roels. (2009) Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Review of Vaccines 8:4, 401-423
CrossRef37
Lance C Jennings, Karl G Nicholson, Arnold S Monto. (2009) Prepandemic influenza vaccines – Authors' reply. The Lancet Infectious Diseases 9:4, 207-209
CrossRef38
Bram Palache, Ryoko Krause. (2009) Progress with human H5N1 vaccines: a perspective from industry. Expert Review of Vaccines 8:4, 391-400
CrossRef39
Manish Pareek, Tristan Clark, Helen Dillon, Rajesh Kumar, Iain Stephenson. (2009) Willingness of healthcare workers to accept voluntary stockpiled H5N1 vaccine in advance of pandemic activity. Vaccine 27:8, 1242-1247
CrossRef40
Jina Lee, Hoan Jong Lee. (2009) Novel swine-origin H1N1 influenza. Korean Journal of Pediatrics 52:8, 862
CrossRef41
Angelika Banzhoff, Michele Pellegrini, Giuseppe Del Giudice, Elena Fragapane, Nicola Groth, Audino Podda. (2008) MF59 ® -adjuvanted vaccines for seasonal and pandemic influenza prophylaxis. Influenza and Other Respiratory Viruses 2:6, 243-249
CrossRef
