This article was downloaded by: [Georgian Court University] On: 03 April 2015, At: 21:52 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Bringing influenza vaccines into the 21st century ab
ab
Ethan C Settembre , Philip R Dormitzer a
ab
& Rino Rappuoli
Novartis Vaccines and Diagnostics; Cambridge, MA USA
b
Novartis Vaccines and Diagnostics; Siena, Italy Published online: 30 Dec 2013.
Click for updates To cite this article: Ethan C Settembre, Philip R Dormitzer & Rino Rappuoli (2014) Bringing influenza vaccines into the 21st century, Human Vaccines & Immunotherapeutics, 10:3, 600-604, DOI: 10.4161/hv.27600 To link to this article: http://dx.doi.org/10.4161/hv.27600
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Commentary Commentary
Human Vaccines & Immunotherapeutics 10:3, 600–604; March 2014; © 2014 Landes Bioscience
Bringing influenza vaccines into the 21st century Ethan C Settembre1,2, Philip R Dormitzer1,2, and Rino Rappuoli1,2,* Novartis Vaccines and Diagnostics; Cambridge, MA USA; 2Novartis Vaccines and Diagnostics; Siena, Italy
T Downloaded by [Georgian Court University] at 21:52 03 April 2015
he recent H7N9 influenza outbreak in China highlights the need for influenza vaccine production systems that are robust and can quickly generate substantial quantities of vaccines that target new strains for pandemic and seasonal immunization. Although the influenza vaccine system, a public-private partnership, has been effective in providing vaccines, there are areas for improvement. Technological advances such as mammalian cell culture production and synthetic vaccine seeds provide a means to increase the speed and accuracy of targeting new influenza strains with mass-produced vaccines by dispensing with the need for egg isolation, adaptation, and reassortment of vaccine viruses. New influenza potency assays that no longer require the time-consuming step of generating sheep antisera could further speed vaccine release. Adjuvants that increase the breadth of the elicited immune response and allow dose sparing provide an additional means to increase the number of available vaccine doses. Together these technologies can improve the influenza vaccination system in the near term. In the longer term, disruptive technologies, such as RNA-based flu vaccines and ‘universal’ flu vaccines, offer a promise of a dramatically improved influenza vaccine system.
Keywords: influenza, vaccine, cell culture, synthetic seed, potency assay, RNA-based *Correspondence to: Rino Rappuoli; Email: [email protected] Submitted: 11/19/2013 Revised: 12/14/2013 Accepted: 12/20/2013 http://dx.doi.org/10.4161/hv.27600
600
Introduction Influenza virus infections are responsible for significant morbidity and mortality in a broad age range, with particularly severe outcomes in the elderly and young children. Seasonal epidemics are responsible for about 250 000 to 500 000 deaths and between three and five million cases
Human Vaccines & Immunotherapeutics
worldwide. Concern that a new pandemic could arise like the 1918 pandemic that claimed ~50 million lives highlights the need for both constant surveillance and improved preparedness.1 Vaccines against influenza are unique because they require nearly annual reformulation due to continuous viral evolution through antigenic drift (changes in hemagglutinin [HA] surface residues), antigenic shift (new viruses resulting from genome segment swaps), and zoonotic transmission (introduction of non-human animal influenza viruses into the human population).2 The solution to this important problem has been the implementation of a worldwide influenza vaccine production system that includes both public and private components and carries out four major activities: influenza surveillance, vaccine virus generation, vaccine manufacturing, and strain-specific release assay development (Fig. 1). The system must be sufficiently robust to reliably produce seasonal vaccines and bring on line surge capacity for pandemic vaccine production when pandemics arise. Currently, most licensed influenza vaccines (inactivated whole virus, detergent or solvent split vaccines, live attenuated vaccines, and some subunit vaccines) require a viral vaccine seed to produce vaccine, and the virus or viral genes for this seed typically are provided by a WHO Collaborating Center. Generating an influenza vaccine seed begins when an influenza virus is isolated from an infected individual’s respiratory secretions at a WHO-linked National Influenza Center. The virus is then adapted for growth in eggs, generally resulting in egg-specific adaptations that change the virus binding specificity from the receptors dominant in
Volume 10 Issue 3
©2014 Landes Bioscience. Do not distribute.
1
human respiratory epithelium (α2,6linked sialosides) to those dominant in the egg allantoic cavity (α2,3-linked sialosides).3 Egg adaptation can generate mutations in the important neutralizing epitopes that surround the sialoside binding site.4 The HA generated from this process can be a genetic mismatch to the clinical isolate and is sometimes an antigenic mismatch.5 Historically, vaccine antigenic mismatch has been particularly prominent during seasons in which there has been high influenza-like illness leading to particular stresses on the worldwide vaccine production system (Fig. 2). Human immunization with vaccines produced from the egg adapted vaccine seed viruses for both A/H3N2 in the 2010–11 season and influenza B in the 2009–10 and 2010–11 seasons elicited low neutralizing and hemagglutination inhibition (HI) titers to circulating viruses and to the isolates of these viruses on mammalian (Madin-Darby canine kidney [MDCK]) cells, despite high titers to the egg-adapted vaccine strain.6 As recently as the 2012–13 season, egg-adaptations in the A/H3N2 vaccine virus may have contributed to lower vaccine effectiveness.7 A WHO report from after the 2012-13 vaccination campaign began showed that the egg-adapted reference strain appeared to be a mismatch from the circulating
www.landesbioscience.com
strains. An equivalent strain isolated in MDCK cells was a match to circulating strains, but even vaccine manufacturers that can produce vaccine in mammalian cells were required to produce the season’s influenza vaccine using the mismatched egg-adapted vaccine seed virus. Two newer approaches can address the limitations of egg isolation: MDCK cells as an alternate substrate for virus isolation and the use of synthetic seed viruses.9,10 Data on virus isolation rates in 2009 demonstrated that for the H3N2 subtype, a much higher proportion of circulating viruses could be isolated in MDCK cells than in chicken eggs.11 The large difference in isolation rates and declining egg isolation rates over time raised the concern that, if trends continued, a suitable virus match to circulating H3N2 strains would not be available. MDCK cells have both α2,3 and α2,6 sialosides on their surfaces, decreasing the degree of adaptation needed for growth in the laboratory and resulting in higher virus isolation rates.12,13 A collaboration was formed between the World Health Organization (WHO) and International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) to further explore the use of a mammalian cell lines in vaccine virus isolation. For the 2013–14 influenza season, for the first time, the WHO has recommended that the viruses 8
Synthetic Seed and Cell Culture Technology Synthetic vaccine viruses are influenza viruses that have been generated using reverse genetics techniques with synthetic genes for the purpose of preparing vaccine seeds. These viruses are rescued (generated from nucleic acids) in a vaccine-approved MDCK cell line, and the process has robustly rescued viruses (>33) from multiple relevant subtypes while maintaining the original viral HA and neuraminidase (NA) sequences.10 From the time HA and NA sequences are obtained, synthetic vaccine viruses with high growth backbones can be rescued in
Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Bringing influenza vaccines into the 21st century ab
ab
Ethan C Settembre , Philip R Dormitzer a
ab
& Rino Rappuoli
Novartis Vaccines and Diagnostics; Cambridge, MA USA
b
Novartis Vaccines and Diagnostics; Siena, Italy Published online: 30 Dec 2013.
Click for updates To cite this article: Ethan C Settembre, Philip R Dormitzer & Rino Rappuoli (2014) Bringing influenza vaccines into the 21st century, Human Vaccines & Immunotherapeutics, 10:3, 600-604, DOI: 10.4161/hv.27600 To link to this article: http://dx.doi.org/10.4161/hv.27600
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Commentary Commentary
Human Vaccines & Immunotherapeutics 10:3, 600–604; March 2014; © 2014 Landes Bioscience
Bringing influenza vaccines into the 21st century Ethan C Settembre1,2, Philip R Dormitzer1,2, and Rino Rappuoli1,2,* Novartis Vaccines and Diagnostics; Cambridge, MA USA; 2Novartis Vaccines and Diagnostics; Siena, Italy
T Downloaded by [Georgian Court University] at 21:52 03 April 2015
he recent H7N9 influenza outbreak in China highlights the need for influenza vaccine production systems that are robust and can quickly generate substantial quantities of vaccines that target new strains for pandemic and seasonal immunization. Although the influenza vaccine system, a public-private partnership, has been effective in providing vaccines, there are areas for improvement. Technological advances such as mammalian cell culture production and synthetic vaccine seeds provide a means to increase the speed and accuracy of targeting new influenza strains with mass-produced vaccines by dispensing with the need for egg isolation, adaptation, and reassortment of vaccine viruses. New influenza potency assays that no longer require the time-consuming step of generating sheep antisera could further speed vaccine release. Adjuvants that increase the breadth of the elicited immune response and allow dose sparing provide an additional means to increase the number of available vaccine doses. Together these technologies can improve the influenza vaccination system in the near term. In the longer term, disruptive technologies, such as RNA-based flu vaccines and ‘universal’ flu vaccines, offer a promise of a dramatically improved influenza vaccine system.
Keywords: influenza, vaccine, cell culture, synthetic seed, potency assay, RNA-based *Correspondence to: Rino Rappuoli; Email: [email protected] Submitted: 11/19/2013 Revised: 12/14/2013 Accepted: 12/20/2013 http://dx.doi.org/10.4161/hv.27600
600
Introduction Influenza virus infections are responsible for significant morbidity and mortality in a broad age range, with particularly severe outcomes in the elderly and young children. Seasonal epidemics are responsible for about 250 000 to 500 000 deaths and between three and five million cases
Human Vaccines & Immunotherapeutics
worldwide. Concern that a new pandemic could arise like the 1918 pandemic that claimed ~50 million lives highlights the need for both constant surveillance and improved preparedness.1 Vaccines against influenza are unique because they require nearly annual reformulation due to continuous viral evolution through antigenic drift (changes in hemagglutinin [HA] surface residues), antigenic shift (new viruses resulting from genome segment swaps), and zoonotic transmission (introduction of non-human animal influenza viruses into the human population).2 The solution to this important problem has been the implementation of a worldwide influenza vaccine production system that includes both public and private components and carries out four major activities: influenza surveillance, vaccine virus generation, vaccine manufacturing, and strain-specific release assay development (Fig. 1). The system must be sufficiently robust to reliably produce seasonal vaccines and bring on line surge capacity for pandemic vaccine production when pandemics arise. Currently, most licensed influenza vaccines (inactivated whole virus, detergent or solvent split vaccines, live attenuated vaccines, and some subunit vaccines) require a viral vaccine seed to produce vaccine, and the virus or viral genes for this seed typically are provided by a WHO Collaborating Center. Generating an influenza vaccine seed begins when an influenza virus is isolated from an infected individual’s respiratory secretions at a WHO-linked National Influenza Center. The virus is then adapted for growth in eggs, generally resulting in egg-specific adaptations that change the virus binding specificity from the receptors dominant in
Volume 10 Issue 3
©2014 Landes Bioscience. Do not distribute.
1
human respiratory epithelium (α2,6linked sialosides) to those dominant in the egg allantoic cavity (α2,3-linked sialosides).3 Egg adaptation can generate mutations in the important neutralizing epitopes that surround the sialoside binding site.4 The HA generated from this process can be a genetic mismatch to the clinical isolate and is sometimes an antigenic mismatch.5 Historically, vaccine antigenic mismatch has been particularly prominent during seasons in which there has been high influenza-like illness leading to particular stresses on the worldwide vaccine production system (Fig. 2). Human immunization with vaccines produced from the egg adapted vaccine seed viruses for both A/H3N2 in the 2010–11 season and influenza B in the 2009–10 and 2010–11 seasons elicited low neutralizing and hemagglutination inhibition (HI) titers to circulating viruses and to the isolates of these viruses on mammalian (Madin-Darby canine kidney [MDCK]) cells, despite high titers to the egg-adapted vaccine strain.6 As recently as the 2012–13 season, egg-adaptations in the A/H3N2 vaccine virus may have contributed to lower vaccine effectiveness.7 A WHO report from after the 2012-13 vaccination campaign began showed that the egg-adapted reference strain appeared to be a mismatch from the circulating
www.landesbioscience.com
strains. An equivalent strain isolated in MDCK cells was a match to circulating strains, but even vaccine manufacturers that can produce vaccine in mammalian cells were required to produce the season’s influenza vaccine using the mismatched egg-adapted vaccine seed virus. Two newer approaches can address the limitations of egg isolation: MDCK cells as an alternate substrate for virus isolation and the use of synthetic seed viruses.9,10 Data on virus isolation rates in 2009 demonstrated that for the H3N2 subtype, a much higher proportion of circulating viruses could be isolated in MDCK cells than in chicken eggs.11 The large difference in isolation rates and declining egg isolation rates over time raised the concern that, if trends continued, a suitable virus match to circulating H3N2 strains would not be available. MDCK cells have both α2,3 and α2,6 sialosides on their surfaces, decreasing the degree of adaptation needed for growth in the laboratory and resulting in higher virus isolation rates.12,13 A collaboration was formed between the World Health Organization (WHO) and International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) to further explore the use of a mammalian cell lines in vaccine virus isolation. For the 2013–14 influenza season, for the first time, the WHO has recommended that the viruses 8
Synthetic Seed and Cell Culture Technology Synthetic vaccine viruses are influenza viruses that have been generated using reverse genetics techniques with synthetic genes for the purpose of preparing vaccine seeds. These viruses are rescued (generated from nucleic acids) in a vaccine-approved MDCK cell line, and the process has robustly rescued viruses (>33) from multiple relevant subtypes while maintaining the original viral HA and neuraminidase (NA) sequences.10 From the time HA and NA sequences are obtained, synthetic vaccine viruses with high growth backbones can be rescued in
