Expert Review of Vaccines
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
H7N9: can H7N3 live-attenuated influenza vaccine be used at the early stage of the pandemic? Larisa Rudenko, Irina Isakova-Sivak & Andrey Rekstin To cite this article: Larisa Rudenko, Irina Isakova-Sivak & Andrey Rekstin (2014) H7N9: can H7N3 live-attenuated influenza vaccine be used at the early stage of the pandemic?, Expert Review of Vaccines, 13:1, 1-4 To link to this article: http://dx.doi.org/10.1586/14760584.2014.864564
Published online: 28 Nov 2013.
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Date: 13 September 2015, At: 06:01
Editorial
H7N9: can H7N3 live-attenuated influenza vaccine be used at the early stage of the pandemic? Expert Rev. Vaccines 13(1), 1–4 (2014)
Downloaded by [206.214.13.114] at 06:01 13 September 2015
Larisa Rudenko Author for correspondence: Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street, St Petersburg, 195220, Russia Tel.: +812 234 9214 Fax: +812 234 9214 [email protected]
Irina Isakova-Sivak Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street, St Petersburg, 195220, Russia
Andrey Rekstin Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street, St Petersburg, 195220, Russia
As of October 2013, H7N9 avian influenza viruses caused 137 human cases with 45 fatalities. Recent studies revealed that only minor adaptive changes are required for H7N9 viruses to become pandemic. Vaccination is a primary measure to protect population from severe disease and reduce the impact of epidemics and pandemics on public health. Several H7N9 candidate vaccine viruses have been generated and are now undergoing preclinical and clinical testings, which will take several months. Meanwhile, there are several vaccine candidates with H7 hemagglutinin, which can be used to prime the immune system for a robust immune response to booster vaccination with H7N9 vaccine, with perspectives of a substantial dose sparing. H7N3 live-attenuated influenza vaccine besides being attractive priming vaccine in prime–boost strategies, has a potential to protect against H7N9 virus, as was demonstrated by immune epitope analysis and by the detection of cross-reactive antibodies in serum samples of volunteers.
Since the emergence of new H7N9 avian influenza viruses in human population in China in early 2013, many studies have been conducted to understand pathogenicity, receptor-binding specificity and transmissibility of new viruses. H7N9 viruses were shown to bind both a2,3 avian type and, to a lesser extent, a2,6 human-type receptors [1,2]. And despite the lack of effective respiratory droplet transmission between ferrets, this dual receptor specificity can be a critical feature for the acquisition of sustained human-to-human transmission [3]. Results of several studies indicate that H7N9 viruses have the capacity for efficient replication in mice (with high mortality rate), ferrets, nonhuman primates and in human airway cells [2,3]. This enhanced virulence and possession of multiple mammalian adaptation markers, as well as the persistence of the virus in avian reservoir, suggest that H7N9 viruses have pandemic potential. To prevent this infection, specific vaccines are needed. But prior to the release of specific H7N9 vaccines, all candidate
vaccine viruses have to pass a number of necessary safety testing that can take for up to several months. And meanwhile, to prepare for the forthcoming H7N9 pandemic, the existing H7 vaccines can be used to prime the population and allow for a rapid and protective antibody response. In compliance with WHO Global Influenza Preparedness Plan [101], a number of H7 candidate vaccine viruses have been developed and tested in clinical trials, but unfortunately none of them contained N9 neuraminidase. It is known that both hemagglutinin (HA) and neuraminidase (NA) are important immunogens in anti-influenza vaccines. Existing H7 vaccines contain N1, N3 or N7 NA genes, and despite the belonging of N3, N7 and N9 proteins to the same phylogenetic group 2 [4], their sequences are very different with amino acid homology not exceeding 50%. N1 neuraminidase belongs to the other phylogenetic group 1 and its sequence is even more distant from N9 [4]. This difference demonstrates low probability of anti-N1, anti-N3 and
KEYWORDS: cross-reactive immune response • H7N9 avian influenza • live-attenuated influenza vaccine • prime–boost strategy
www.expert-reviews.com
10.1586/14760584.2014.864564
2014 Informa UK Ltd
ISSN 1476-0584
1
Downloaded by [206.214.13.114] at 06:01 13 September 2015
Editorial
Rudenko, Isakova-Sivak & Rekstin
anti-N7 antibodies to be cross-reactive against N9 neuraminidase. At the same time, it is known that anti-NA antibodies block the receptor-destroying activity of the neuraminidase and, as a consequence, limit the infection, but nevertheless they cannot prevent infection itself, whereas anti-HA antibodies can neutralize the infection by binding to the receptor-binding site or to the other important positions on the HA molecule. Therefore, if H7N9 pandemic begins before the homologous vaccines are properly tested and become publicly available, the use of heterologous wellstudied H7 vaccines with mismatch neuraminidase will still be a good strategy to control H7N9 at the early stage of pandemic. As was mentioned above, several inactivated (IIV) and liveattenuated influenza vaccine (LAIV) with H7 hemagglutinin and N1, N3 or N7 neuraminidases have been developed. For some of them, Phase I clinical trial has been completed and for others, clinical trials are ongoing. As can be found at the resource Clinical trials [102], H7N7 subvirion, IIV H7N1, H7N7/AA (based on A/Ann Arbor/6/60 backbone) LAIV, H7N3/AA LAIV, H7N3/ Len17 (based on A/Leningrad/134/17/57 backbone) LAIV (ClinicalTrials.gov identifiers: NCT00546585, NCT01934127, NCT00922259, NCT00516035, NCT01511419), as well as split IIV H7N7 and H7N1 [103] have passed or nearly completed Phase I clinical trial and proved to be safe for adults, but varied by their immunogenicity [5–7]. Generally, advantages of LAIV over IIV include painless needle-free delivery (nasal spray) and its significantly higher yield that will allow increasing global vaccine production capabilities and meeting potential demand during a pandemic. IIV is administered parenterally and predominantly induces humoral antibodies, which can neutralize only antigenically similar viruses. In contrast, LAIV administered intranasally mimics natural infection and therefore can induce a much broader immune response, which is supported by animal models and epidemiological studies [8–12]. In addition, LAIV induces mucosal immunity that prevents virus replication in upper respiratory tract and therefore prevents virus spread to contact persons. Furthermore, LAIV can effectively generate virus-specific cytotoxic CD8+ T lymphocytes that may confer heterosubtypic protection, whereas IIVs are not strong inducers of cytotoxic T lymphocytes (CTLs) responses [13,14]. As an example, our study of memory T-cell immune responses in volunteers immunized with prepandemic H5N2 LAIV revealed substantial levels of cross-reactive T cells targeted to evolutionary divergent H1N1 seasonal influenza virus. All these advantages contributed to the inclusion of LAIVs into WHO global influenza preparedness plan [101]. Over the last decade, much attention has been paid to prime–boost strategies for the induction of robust and protective immune responses to potentially pandemic H5N1 viruses [15]. This strategy allows for rapid and protective antibody responses following the booster vaccination even in individuals who had no detectable antibody response following the initial vaccination. Recently, Coelingh et al. demonstrated that H5N1/AA and H7N7/AA LAIVs can prime for long-lasting immune memory and allow a single booster dose of IIV to induce rapid and protective serum antibody immune responses, 2
and what is more important – these antibodies were cross-reactive and could neutralize heterologous H5 or H7 viruses [104]. Analogous prime–boost studies with Russian H5N2 LAIV are currently ongoing in Russia and Thailand, but nevertheless, based on the results by Coelingh and colleagues, we can argue that priming with LAIVs is a promising strategy to protect population at the early stage of pandemics. Among three H7 LAIVs [102], a vaccine strain A/17/mallard/ Netherlands/00/95 (H7N3) developed by Institute of Experimental Medicine (IEM, Russia) in collaboration with PATH (USA) has some advantages over two other vaccines in terms of potential to protect against emerging H7N9 viruses, mostly due to their HA sequence similarities. The H7N3 LAIV was prepared by classical reassortment in chicken embryos from low-pathogenic avian influenza virus A/mallard/Netherlands/ 12/2000 (H7N3) [16]. This virus was selected due to its low pathogenic profile and belonging to the Eurasian lineage of H7 viruses that caused most human cases in the Netherlands in 2003 [17,18]. H7N3 LAIV has undergone full set of preclinical testings including in vitro phenotype studies, safety studies in chickens, mice, guinea pigs and ferrets. We demonstrated that the H7N3 LAIV candidate was indistinguishable from parental master donor virus A/Leningrad/134/17/57 (H2N2) with regards to replication kinetics in the upper and lower respiratory tract of mice. Evaluation of vaccine safety in chickens showed the lack of virus replication in both upper airways and intestine. Despite the fact that H7N3 LAIV could not be isolated from respiratory organs of immunized ferrets, the vaccine was immunogenic after two doses and all animals were fully protected against subsequent challenge with the homologous wild-type H7N3 virus. Additional toxicology studies proved that H7N3 LAIV was safe even when administered at high doses. All these preclinical studies confirmed safety and immunogenicity of H7N3 LAIV candidate that allowed recommending this strain for a Phase I clinical trial. Complete report for the results of H7N3 Phase I clinical trial is under preparation, but nevertheless here we can summarize that this candidate proved to be safe for healthy adult volunteers and induced immune responses in almost 90% volunteers, which was measured by several immunological tests including HAI, microneutralization, serum IgG and IgA and local IgA ELISA, as well as by the assessment of cellular immune responses. It is important to note that according to an agreement between IEM and WHO, all candidate vaccine viruses generated by IEM are transferred and can be produced in other countries that are working with production of LAIV, such as Thailand, India and China, and therefore this vaccine will be available for mostly affected area. In addition, lyophilized form of Russian LAIVs was proved to be stable during at least 5 years, a clear advantage over unstable vaccine formulations in terms of vaccine stockpiling. In our previous study, we analyzed cross-reactive potential of H7N3 LAIV against newly emerged H7N9 viruses [19]. First, we conducted comparative analysis of the HA sequences of the A/17/mallard/Netherlands/00/95 vaccine virus and recent H7N9 human isolates in attempts to identify conserved Expert Rev. Vaccines 13(1), (2014)
Downloaded by [206.214.13.114] at 06:01 13 September 2015
H7N9
immune epitopes for CTLs and B cells (antigenic sites). Using Immune Epitope Database analysis resource, we roughly estimated the identity of B cell and CTL epitopes between H7N3 and H7N9 HA molecules at near 70 and 60%, respectively. Additionally, we tested serum samples of volunteers participated in Phase I clinical trial of H7N3 LAIV for the presence of anti-H7N9 hemagglutination inhibition and neutralizing antibodies and found seroconversions in 44.8% of vaccinated persons, whereas homologous anti-H7N3 antibody responses were detected in 75.9% of vaccinees [19]. These data indicate the substantial level of cross-protection induced by H7N3 LAIV against new avian H7N9 influenza viruses. As was mentioned above, the major advantage of LAIVs over IIVs is stimulation of cellular immunity that provides crossprotective potentials [13,14]. And while the study of the crossreactive memory T cells in volunteers immunized with H7N3 LAIV is ongoing, the presence of conserved CTL
1
2
Shi Y, Zhang W, Wang F et al. Structures and receptor binding of hemagglutinins from human-infecting H7N9 influenza viruses. Science 342(6155), 243–247 (2013). Zhou J, Wang D, Gao R et al. Biological features of novel avian influenza A (H7N9) virus. Nature 499(7459), 500–503 (2013).
3
Belser JA, Gustin KM, Pearce MB et al. Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice. Nature 501(7468), 556–559 (2013).
4
Gamblin SJ, Skehel JJ. Influenza hemagglutinin and neuraminidase membrane glycoproteins. J. Biol. Chem. 285(37), 28403–28409 (2010).
5
Couch RB, Patel SM, Wade-Bowers CL, Nino D. A randomized clinical trial of an inactivated avian influenza A (H7N7) vaccine. PloS ONE 7(12), e49704 (2012).
6
Cox RJ, Madhun AS, Hauge S et al. A phase I clinical trial of a PER.C6 cell grown influenza H7 virus vaccine. Vaccine 27(13), 1889–1897 (2009).
7
Talaat KR, Karron RA, Callahan KA et al. A live attenuated H7N3 influenza virus vaccine is well tolerated and immunogenic in a Phase I trial in healthy adults. Vaccine 27(28), 3744–3753 (2009).
8
Gustin KM, Maines TR, Belser JA et al. Comparative immunogenicity and cross-clade protective efficacy of mammalian cell-grown inactivated and live attenuated H5N1 reassortant vaccines in
www.expert-reviews.com
epitopes between H7N3 and H7N9 viruses support our assumption that T cell-mediated immunity will significantly contribute to the desired cross-protection. Taken together, we suggest that the use of Russian H7N3 LAIV at the early stage of H7N9 pandemic can be a promising strategy for priming naı¨ve population and providing initial protection against H7N9 virus that can be boosted with relevant LAIV or IIV, with a potential for dose sparing. Financial & competing interests disclosure
This work was supported by PATH (USA). L Rudenko is a nonexecutive director of BioDiem ltd. and an employee of IEM. I Isakova-Sivak and A Rekstin are employees of IEM. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
ferrets. J. Infect. Dis. 204(10), 1491–1499 (2011).
References 9
Jang YH, Byun YH, Lee YJ, Lee YH, Lee KH, Seong BL. Cold-adapted pandemic 2009 H1N1 influenza virus live vaccine elicits cross-reactive immune responses against seasonal and H5 influenza A viruses. J. Virol. 86(10), 5953–5958 (2012).
10
Lu X, Edwards LE, Desheva JA et al. Cross-protective immunity in mice induced by live-attenuated or inactivated vaccines against highly pathogenic influenza A (H5N1) viruses. Vaccine 24(44–46), 6588–6593 (2006).
11
12
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Rudenko LG, Slepushkin AN, Monto AS et al. Efficacy of live attenuated and inactivated influenza vaccines in schoolchildren and their unvaccinated contacts in Novgorod, Russia. J. Infect. Dis. 168(4), 881–887 (1993). Rudenko LG, Lonskaya NI, Klimov AI, Vasilieva RI, Ramirez A. Clinical and epidemiological evaluation of a live, cold-adapted influenza vaccine for 3-14year-olds. Bull. World Health Organ. 74(1), 77–84 (1996). Tamura S, Tanimoto T, Kurata T. Mechanisms of broad cross-protection provided by influenza virus infection and their application to vaccines. Jpn J. Infect. Dis. 58(4), 195–207 (2005).
14
Jang YH, Seong BL. Cross-protective immune responses elicited by live attenuated influenza vaccines. Yonsei Med. J. 54(2), 271–282 (2013).
15
Baz M, Luke CJ, Cheng X, Jin H, Subbarao K. H5N1 vaccines in humans.
Virus Res. doi:10.1016/j.virusres.2013.05.006 (2013) (Epub ahead of print). 16
Desheva J, Rudenko L, Rekstin A, Swayne D, Cox N, Klimov A. Development of candidate H7N3 live attenuated cold-adapted influenza vaccine. In: Proceedings of the International Conference on Options for the Control of Influenza VI. Jacqueline M Katz (Ed.). Toronto, ON, Canada, 17–23 June 2007.
17
Belser JA, Davis CT, Balish A et al. Pathogenesis, transmissibility, and ocular tropism of a highly pathogenic avian influenza A (H7N3) virus associated with human conjunctivitis. J. Virol. 87(10), 5746–5754 (2013).
18
Metreveli G, Zohari S, Ejdersund A, Berg M. Phylogenetic analysis of the hemagglutinin gene of low pathogenic avian influenza virus H7N7 strains in mallards in Northern Europe. Avian Dis. 54(1 Suppl.), 453–456 (2010).
19
Rudenko L, Isakova-Sivak I, Donina S. H7N3 live attenuated influenza vaccine has a potential to protect against new H7N9 avian influenza virus. Vaccine 31(42), 4702–4705 (2013).
Websites 101
WHO. WHO global influenza preparedness plan. WHO/CDS/CSR/GIP/2005.5. www.who.int/csr/resources/publications/ influenza/en/ WHO_CDS_CSR_GIP_2005_5.pdf
102
ClinicalTrials.gov. www.clinicaltrials.gov
3
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WHO. Clinical evaluation of influenza vaccines. Last modified: 2 May 2013. www.who.int/vaccine_research/diseases/ influenza/flu_trials_tables/en/
104
Coelingh K, Jin H, Luke C, Talaat K, Karron R, Subbarao K. Safety, infectivity,
and immunogenicity of H2N2, H5N1, H6N1, H7N3, and H9N2 live attenuated influenza vaccines. In: Abstract book of the Options for the Control of Influenza VIII. Cape Town, South Africa, 361–362 (2013). http://optionsviii.controlinfluenza.com/
optionsviii/assets/File/ Options_VIII_Abstracts_2013.pdf
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Expert Rev. Vaccines 13(1), (2014)
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
H7N9: can H7N3 live-attenuated influenza vaccine be used at the early stage of the pandemic? Larisa Rudenko, Irina Isakova-Sivak & Andrey Rekstin To cite this article: Larisa Rudenko, Irina Isakova-Sivak & Andrey Rekstin (2014) H7N9: can H7N3 live-attenuated influenza vaccine be used at the early stage of the pandemic?, Expert Review of Vaccines, 13:1, 1-4 To link to this article: http://dx.doi.org/10.1586/14760584.2014.864564
Published online: 28 Nov 2013.
Submit your article to this journal
Article views: 265
View related articles
View Crossmark data
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierv20 Download by: [206.214.13.114]
Date: 13 September 2015, At: 06:01
Editorial
H7N9: can H7N3 live-attenuated influenza vaccine be used at the early stage of the pandemic? Expert Rev. Vaccines 13(1), 1–4 (2014)
Downloaded by [206.214.13.114] at 06:01 13 September 2015
Larisa Rudenko Author for correspondence: Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street, St Petersburg, 195220, Russia Tel.: +812 234 9214 Fax: +812 234 9214 [email protected]
Irina Isakova-Sivak Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street, St Petersburg, 195220, Russia
Andrey Rekstin Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street, St Petersburg, 195220, Russia
As of October 2013, H7N9 avian influenza viruses caused 137 human cases with 45 fatalities. Recent studies revealed that only minor adaptive changes are required for H7N9 viruses to become pandemic. Vaccination is a primary measure to protect population from severe disease and reduce the impact of epidemics and pandemics on public health. Several H7N9 candidate vaccine viruses have been generated and are now undergoing preclinical and clinical testings, which will take several months. Meanwhile, there are several vaccine candidates with H7 hemagglutinin, which can be used to prime the immune system for a robust immune response to booster vaccination with H7N9 vaccine, with perspectives of a substantial dose sparing. H7N3 live-attenuated influenza vaccine besides being attractive priming vaccine in prime–boost strategies, has a potential to protect against H7N9 virus, as was demonstrated by immune epitope analysis and by the detection of cross-reactive antibodies in serum samples of volunteers.
Since the emergence of new H7N9 avian influenza viruses in human population in China in early 2013, many studies have been conducted to understand pathogenicity, receptor-binding specificity and transmissibility of new viruses. H7N9 viruses were shown to bind both a2,3 avian type and, to a lesser extent, a2,6 human-type receptors [1,2]. And despite the lack of effective respiratory droplet transmission between ferrets, this dual receptor specificity can be a critical feature for the acquisition of sustained human-to-human transmission [3]. Results of several studies indicate that H7N9 viruses have the capacity for efficient replication in mice (with high mortality rate), ferrets, nonhuman primates and in human airway cells [2,3]. This enhanced virulence and possession of multiple mammalian adaptation markers, as well as the persistence of the virus in avian reservoir, suggest that H7N9 viruses have pandemic potential. To prevent this infection, specific vaccines are needed. But prior to the release of specific H7N9 vaccines, all candidate
vaccine viruses have to pass a number of necessary safety testing that can take for up to several months. And meanwhile, to prepare for the forthcoming H7N9 pandemic, the existing H7 vaccines can be used to prime the population and allow for a rapid and protective antibody response. In compliance with WHO Global Influenza Preparedness Plan [101], a number of H7 candidate vaccine viruses have been developed and tested in clinical trials, but unfortunately none of them contained N9 neuraminidase. It is known that both hemagglutinin (HA) and neuraminidase (NA) are important immunogens in anti-influenza vaccines. Existing H7 vaccines contain N1, N3 or N7 NA genes, and despite the belonging of N3, N7 and N9 proteins to the same phylogenetic group 2 [4], their sequences are very different with amino acid homology not exceeding 50%. N1 neuraminidase belongs to the other phylogenetic group 1 and its sequence is even more distant from N9 [4]. This difference demonstrates low probability of anti-N1, anti-N3 and
KEYWORDS: cross-reactive immune response • H7N9 avian influenza • live-attenuated influenza vaccine • prime–boost strategy
www.expert-reviews.com
10.1586/14760584.2014.864564
2014 Informa UK Ltd
ISSN 1476-0584
1
Downloaded by [206.214.13.114] at 06:01 13 September 2015
Editorial
Rudenko, Isakova-Sivak & Rekstin
anti-N7 antibodies to be cross-reactive against N9 neuraminidase. At the same time, it is known that anti-NA antibodies block the receptor-destroying activity of the neuraminidase and, as a consequence, limit the infection, but nevertheless they cannot prevent infection itself, whereas anti-HA antibodies can neutralize the infection by binding to the receptor-binding site or to the other important positions on the HA molecule. Therefore, if H7N9 pandemic begins before the homologous vaccines are properly tested and become publicly available, the use of heterologous wellstudied H7 vaccines with mismatch neuraminidase will still be a good strategy to control H7N9 at the early stage of pandemic. As was mentioned above, several inactivated (IIV) and liveattenuated influenza vaccine (LAIV) with H7 hemagglutinin and N1, N3 or N7 neuraminidases have been developed. For some of them, Phase I clinical trial has been completed and for others, clinical trials are ongoing. As can be found at the resource Clinical trials [102], H7N7 subvirion, IIV H7N1, H7N7/AA (based on A/Ann Arbor/6/60 backbone) LAIV, H7N3/AA LAIV, H7N3/ Len17 (based on A/Leningrad/134/17/57 backbone) LAIV (ClinicalTrials.gov identifiers: NCT00546585, NCT01934127, NCT00922259, NCT00516035, NCT01511419), as well as split IIV H7N7 and H7N1 [103] have passed or nearly completed Phase I clinical trial and proved to be safe for adults, but varied by their immunogenicity [5–7]. Generally, advantages of LAIV over IIV include painless needle-free delivery (nasal spray) and its significantly higher yield that will allow increasing global vaccine production capabilities and meeting potential demand during a pandemic. IIV is administered parenterally and predominantly induces humoral antibodies, which can neutralize only antigenically similar viruses. In contrast, LAIV administered intranasally mimics natural infection and therefore can induce a much broader immune response, which is supported by animal models and epidemiological studies [8–12]. In addition, LAIV induces mucosal immunity that prevents virus replication in upper respiratory tract and therefore prevents virus spread to contact persons. Furthermore, LAIV can effectively generate virus-specific cytotoxic CD8+ T lymphocytes that may confer heterosubtypic protection, whereas IIVs are not strong inducers of cytotoxic T lymphocytes (CTLs) responses [13,14]. As an example, our study of memory T-cell immune responses in volunteers immunized with prepandemic H5N2 LAIV revealed substantial levels of cross-reactive T cells targeted to evolutionary divergent H1N1 seasonal influenza virus. All these advantages contributed to the inclusion of LAIVs into WHO global influenza preparedness plan [101]. Over the last decade, much attention has been paid to prime–boost strategies for the induction of robust and protective immune responses to potentially pandemic H5N1 viruses [15]. This strategy allows for rapid and protective antibody responses following the booster vaccination even in individuals who had no detectable antibody response following the initial vaccination. Recently, Coelingh et al. demonstrated that H5N1/AA and H7N7/AA LAIVs can prime for long-lasting immune memory and allow a single booster dose of IIV to induce rapid and protective serum antibody immune responses, 2
and what is more important – these antibodies were cross-reactive and could neutralize heterologous H5 or H7 viruses [104]. Analogous prime–boost studies with Russian H5N2 LAIV are currently ongoing in Russia and Thailand, but nevertheless, based on the results by Coelingh and colleagues, we can argue that priming with LAIVs is a promising strategy to protect population at the early stage of pandemics. Among three H7 LAIVs [102], a vaccine strain A/17/mallard/ Netherlands/00/95 (H7N3) developed by Institute of Experimental Medicine (IEM, Russia) in collaboration with PATH (USA) has some advantages over two other vaccines in terms of potential to protect against emerging H7N9 viruses, mostly due to their HA sequence similarities. The H7N3 LAIV was prepared by classical reassortment in chicken embryos from low-pathogenic avian influenza virus A/mallard/Netherlands/ 12/2000 (H7N3) [16]. This virus was selected due to its low pathogenic profile and belonging to the Eurasian lineage of H7 viruses that caused most human cases in the Netherlands in 2003 [17,18]. H7N3 LAIV has undergone full set of preclinical testings including in vitro phenotype studies, safety studies in chickens, mice, guinea pigs and ferrets. We demonstrated that the H7N3 LAIV candidate was indistinguishable from parental master donor virus A/Leningrad/134/17/57 (H2N2) with regards to replication kinetics in the upper and lower respiratory tract of mice. Evaluation of vaccine safety in chickens showed the lack of virus replication in both upper airways and intestine. Despite the fact that H7N3 LAIV could not be isolated from respiratory organs of immunized ferrets, the vaccine was immunogenic after two doses and all animals were fully protected against subsequent challenge with the homologous wild-type H7N3 virus. Additional toxicology studies proved that H7N3 LAIV was safe even when administered at high doses. All these preclinical studies confirmed safety and immunogenicity of H7N3 LAIV candidate that allowed recommending this strain for a Phase I clinical trial. Complete report for the results of H7N3 Phase I clinical trial is under preparation, but nevertheless here we can summarize that this candidate proved to be safe for healthy adult volunteers and induced immune responses in almost 90% volunteers, which was measured by several immunological tests including HAI, microneutralization, serum IgG and IgA and local IgA ELISA, as well as by the assessment of cellular immune responses. It is important to note that according to an agreement between IEM and WHO, all candidate vaccine viruses generated by IEM are transferred and can be produced in other countries that are working with production of LAIV, such as Thailand, India and China, and therefore this vaccine will be available for mostly affected area. In addition, lyophilized form of Russian LAIVs was proved to be stable during at least 5 years, a clear advantage over unstable vaccine formulations in terms of vaccine stockpiling. In our previous study, we analyzed cross-reactive potential of H7N3 LAIV against newly emerged H7N9 viruses [19]. First, we conducted comparative analysis of the HA sequences of the A/17/mallard/Netherlands/00/95 vaccine virus and recent H7N9 human isolates in attempts to identify conserved Expert Rev. Vaccines 13(1), (2014)
Downloaded by [206.214.13.114] at 06:01 13 September 2015
H7N9
immune epitopes for CTLs and B cells (antigenic sites). Using Immune Epitope Database analysis resource, we roughly estimated the identity of B cell and CTL epitopes between H7N3 and H7N9 HA molecules at near 70 and 60%, respectively. Additionally, we tested serum samples of volunteers participated in Phase I clinical trial of H7N3 LAIV for the presence of anti-H7N9 hemagglutination inhibition and neutralizing antibodies and found seroconversions in 44.8% of vaccinated persons, whereas homologous anti-H7N3 antibody responses were detected in 75.9% of vaccinees [19]. These data indicate the substantial level of cross-protection induced by H7N3 LAIV against new avian H7N9 influenza viruses. As was mentioned above, the major advantage of LAIVs over IIVs is stimulation of cellular immunity that provides crossprotective potentials [13,14]. And while the study of the crossreactive memory T cells in volunteers immunized with H7N3 LAIV is ongoing, the presence of conserved CTL
1
2
Shi Y, Zhang W, Wang F et al. Structures and receptor binding of hemagglutinins from human-infecting H7N9 influenza viruses. Science 342(6155), 243–247 (2013). Zhou J, Wang D, Gao R et al. Biological features of novel avian influenza A (H7N9) virus. Nature 499(7459), 500–503 (2013).
3
Belser JA, Gustin KM, Pearce MB et al. Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice. Nature 501(7468), 556–559 (2013).
4
Gamblin SJ, Skehel JJ. Influenza hemagglutinin and neuraminidase membrane glycoproteins. J. Biol. Chem. 285(37), 28403–28409 (2010).
5
Couch RB, Patel SM, Wade-Bowers CL, Nino D. A randomized clinical trial of an inactivated avian influenza A (H7N7) vaccine. PloS ONE 7(12), e49704 (2012).
6
Cox RJ, Madhun AS, Hauge S et al. A phase I clinical trial of a PER.C6 cell grown influenza H7 virus vaccine. Vaccine 27(13), 1889–1897 (2009).
7
Talaat KR, Karron RA, Callahan KA et al. A live attenuated H7N3 influenza virus vaccine is well tolerated and immunogenic in a Phase I trial in healthy adults. Vaccine 27(28), 3744–3753 (2009).
8
Gustin KM, Maines TR, Belser JA et al. Comparative immunogenicity and cross-clade protective efficacy of mammalian cell-grown inactivated and live attenuated H5N1 reassortant vaccines in
www.expert-reviews.com
epitopes between H7N3 and H7N9 viruses support our assumption that T cell-mediated immunity will significantly contribute to the desired cross-protection. Taken together, we suggest that the use of Russian H7N3 LAIV at the early stage of H7N9 pandemic can be a promising strategy for priming naı¨ve population and providing initial protection against H7N9 virus that can be boosted with relevant LAIV or IIV, with a potential for dose sparing. Financial & competing interests disclosure
This work was supported by PATH (USA). L Rudenko is a nonexecutive director of BioDiem ltd. and an employee of IEM. I Isakova-Sivak and A Rekstin are employees of IEM. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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