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Recombinant Modified Vaccinia Virus Ankara

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Recombinant Modified Vaccinia Virus Ankara MAJOR ARTICLE Recombinant Modified Vaccinia Virus Ankara Expressing the Hemagglutinin Gene Confers Protection against Homologous and Heterologous H5N1 Influenza Virus Infections in Macaques J. H. C. M. Kreijtz,1 Y. Suezer,2 G. de Mutsert,1 J. M. A. van den Brand,1 G. van Amerongen,1 B. S. Schnierle,2 T. Kuiken,1 R. A. M. Fouchier,1 J. Löwer,2 A. D. M. E. Osterhaus,1 G. Sutter,2 and G. F. Rimmelzwaan1 1Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands; 2Paul-Ehrlich-Institut, Langen, Germany Background. Highly pathogenic avian influenza viruses of the H5N1 subtype have been responsible for an in- creasing number of infections in humans since 2003. More than 60% of infected individuals die, and new infections are reported frequently. In light of the pandemic threat caused by these events, the rapid availability of safe and effective vaccines is desirable. Modified vaccinia virus Ankara (MVA) expressing the hemagglutinin (HA) gene of H5N1 viruses is a promising candidate vaccine that induced protective immunity against infection with homologous and heterologous H5N1 influenza virus in mice. Methods. In the present study, we evaluated a recombinant MVA vector expressing the HA gene of H5N1 influenza virus A/Vietnam/1194/04 (MVA-HA-VN/04) in nonhuman primates. Cynomolgus macaques were immu- nized twice and then were challenged with influenza virus A/Vietnam/1194/04 (clade 1) or A/Indonesia/5/05 (clade 2.1) to assess the level of protective immunity. Results. Immunization with MVA-HA-VN/04 induced (cross-reactive) antibodies and prevented virus replica- tion in the upper and lower respiratory tract and the development of severe necrotizing bronchointerstitial pneumonia. Conclusion. Therefore, MVA-HA-VN/04 is a promising vaccine candidate for the induction of protective im- munity against highly pathogenic H5N1 avian influenza viruses in humans. Since 2003, the number of bird-to-human transmissions seasonal influenza A viruses. To limit the influence of a of H5N1 influenza viruses has been increasing, and, as of pandemic outbreak caused by these viruses, expediting 28 February 2008, a total of 369 cases in humans (234 of the availability of safe and effective H5N1 vaccines is which proved to be fatal) had been reported to the highly desirable [2]. World Health Organization [1]. Thus, there is a risk for However, the development of such vaccines and the the emergence of a pandemic H5N1 strain, either production of sufficient vaccine doses for a global vacci- through adaption of the avian viruses to replication in nation campaign pose a challenge; the combined vaccine humans or through the exchange of gene segments with production capacity of all manufacturers of seasonal in- fluenza vaccine is limited and is not sufficient to provide, in a timely fashion, the number of doses sufficient for a Received 6 March 2008; accepted 18 April 2008; electronically published XX November 2008. worldwide vaccination campaign. Therefore, there is Potential conflicts of interest: none reported. considerable interest in dose-sparing vaccination strat- Financial support: The Netherlands Organisation for Health Research and Development (grant 91402008); the European Commission (grants QLK2-CT2002– egies. For example, the use of potent adjuvants may re- 01034 NOVAFLU and SHB-CT-2006-037536 MVACTOR); the Forschungs-Sofort- sult in a reduction in the amount of hemagglutinin (HA) programm Influenza of the Federal Government of Germany. The present study was conducted under the auspices of The Netherlands antigen required for the induction of protective anti- Influenza Vaccine Research Center. body responses. At present, various adjuvants are being Reprints or correspondence: Dr. G. F. Rimmelzwaan, Dept. of Virology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands evaluated in combination with conventional inactivated ([email protected]). vaccine preparations, and these are in various stages of The Journal of Infectious Diseases 2009; 199:xxx development [3–7]. © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2009/19903-00XX$15.00 Alternatively, novel vaccine production technologies DOI: 10.1086/595984 are under development to overcome the shortage of vac- Evaluation of MVA-H5N1 Vaccine in Macaques ● JID 2009:199 (1 February) ● 1 cines in the case of an H5N1 influenza pandemic. Cell lines have observed in humans [36, 37]. To this end, recombinant MVA become available for the production of vaccines that are an al- expressing the HA gene of influenza virus A/Vietnam/1194/04 ternative to vaccines conventionally produced in embryonated was used to immunize cynomolgus macaques twice, which re- chicken eggs [8–13]. The use of reverse genetics for the genera- sulted in strong influenza H5 virus–specific, virus neutralizing tion of vaccine strains will further contribute to faster availability antibody responses. Thus, induced immunity provided protec- of vaccines after the onset of an influenza pandemic [14, 15]. tion against challenge infection with the homologous influenza Other novel production technologies include the use of recom- H5N1 strain from clade 1 and the heterologous strain A/Indo- binant baculoviruses for the production of influenza virus H5 in nesia/5/05 from clade 2.1. It was concluded that recombinant insect cells [16–18]. In general, these protein-based vaccines are MVA is a safe and effective vaccine candidate for the induction poorly immunogenic in immunologically naive individuals, and of protective immunity against H5N1 influenza viruses and war- appreciable antibody responses were induced only when a high rants further clinical development. dose or a combination with an adjuvant was used [19–21]. Since 1997, H5N1 viruses have diverged considerably and are MATERIAL AND METHODS now classified into clades and subclades to reflect their phyloge- netic and antigenic differences [2]. These differences complicate Vaccine preparation. Recombinant MVA expressing the HA vaccine strain selection, and, ideally, vaccines induce cross-clade gene of influenza virus A/Vietnam/1194/04 (MVA-HA-VN/04) protective immunity. was prepared as described elsewhere [25]. MVA clonal isolate F6 New, promising influenza vaccine candidates that may fulfill was used as the parent MVA strain. To generate final vaccine the described requirements include DNA vaccines and viral vec- preparations, the virus was amplified in CEF, purified by ultra- tors that express the HA gene of H5N1 influenza viruses [22–24]. centrifugation through sucrose, reconstituted in 1 mmol/L Tris- It was recently shown that the replication-deficient poxvirus HCL [pH 9.0], and diluted in PBS. modified vaccinia virus Ankara (MVA) expressing the HA gene Influenza viruses. Influenza viruses A/Vietnam/1194/04 of influenza virus A/Vietnam/1194/04 (H5N1) is highly immu- (A/VN/1194/04) and A/Indonesia/5/05 (A/IND/5/05) were cul- nogenic in mice [25]. Two immunizations without an adjuvant tured in Madin-Darby canine kidney (MDCK) cells. Infectious induced strong antibody responses, and immunized mice were virus titers were determined in MDCK cells, as described else- protected from infection with the homologous virus and the where [38]. heterologous H5N1 virus A/Indonesia/5/05 [25]. MVA was Macaques. Colony-bred seronegative cynomolgus macaques originally tested in Ͼ120,000 individuals and was proved to be a (Macaca fascicularis; age, 3 years) were obtained from Grand safe and effective vaccine against smallpox [26]. The use of re- Forest Scientific Primate. combinant MVA expressing foreign genes as vaccine candidates Two weeks before the start of the experiment, animals were induced protective immunity against diseases caused by viruses, anesthetized using a cocktail of ketamin (Nimatek; Eurovet An- bacteria, parasites, or tumors from which the antigens were de- imal Health BV) and domitor (Orion Pharma), and a tempera- rived. Thus, MVA has an excellent safety profile in humans, can ture logger (DST micro-T ultra small temperature logger; Star- be used for the delivery of foreign antigens, and can be produced Oddi) was placed in the peritoneal cavity. This device recorded at large scale under the requirements of good manufacturing the body temperature of the animals every 15 min. Changes in practices [27, 28]. Other properties are extreme host-range re- body temperature were calculated by subtracting the mean day striction; easy production, under biosafety level (BSL) 1 condi- (4-h) and night (4-h) temperatures measured on 4 successive tions, in chicken embryo fibroblasts (CEF) and baby hamster kidney cells; and the possibility of long-term storage (i.e., stock- days during the period before the challenge from the mean day piling) [27, 29–32]. (4-h) and night (4-h) temperatures measured after infection. For the reasons outlined above, MVA expressing the HA gene This was done for each individual animal. of an H5N1 influenza virus is an attractive and promising pan- The macaques were immunized twice, with a 4-week interval 8.5 demic vaccine candidate. However, the immunogenicity and between immunizations, and they received 10 pfu of MVA- ϭ 8.5 protective efficacy of such vaccines have been demonstrated only HA-VN/04 (n 12), 10 pfu of wild-type MVA (wtMVA; in mice and chickens [25, 33, 34]. Because the predictive value of empty vector control) (n ϭ 12), or PBS (n ϭ 10) intramuscu- these models for immunogenicity in humans is limited [34, 35], larly in a volume of 1 mL divided over both legs. Blood samples we wished to evaluate a recombinant MVA-H5 vaccine candi- were collected before immunization and again at 4 weeks after date in a nonhuman primate model, to assess the induction of the first and second immunizations. Four weeks after the second protective immunity against H5N1 viruses from 2 different immunization, each vaccine group was divided into 2 groups of clades. Therefore, we used cynomolgus macaques that, after in- 6 animals (except for the PBS group, which was divided into fection with H5N1 influenza virus, develop severe interstitial groups of 4 and 6 animals) and was placed into BSL-3 isolator necrotizing pneumonia with a pathogenesis comparable to that units.
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