Comment
simple mathematics: if R0 in this region is around 2·5, as Lewnard and colleagues estimate, incidence in every successive epidemic generation will increase by 150%. If R0 could be pushed to less than one, incident case counts would begin to drop, but because incident cases are a function of prevalent cases, making this decrease happen earlier in the epidemic results in striking reductions in final epidemic size (figure). For example, if R0 is reduced to 0·9 at a time when there are 1000 incident cases per generation, case counts in subsequent generations will be 900, 810, 720, and so on. If intervention is delayed until there are 10 000 cases per generation and R0 is cut to 0·9, subsequent generations will have 9000, 8100, 7200 cases, and so on. Elevated case counts also increase the risk of spread to as yet unaffected areas, sparking new outbreaks. Researchers have asserted that the epidemic is proceeding in virus time, with a response on bureaucrat time.7 From a global perspective, controlling the Ebola epidemic in west Africa is not only a humanitarian duty but also a matter of crude self-interest. The report by Lewnard and colleagues shows that intervention will only be meaningful if it is timely, and so far it has not been.
*David Fisman, Ashleigh R Tuite Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada M5T 3M7 david.fi[email protected] We declare no competing interests. 1 2
3
4
5
6
7
Farrar JJ, Piot P. The Ebola emergency: immediate action, ongoing strategy. N Engl J Med 2014; 371: 1545–46. Doucleff M. No, seriously, how contagious is Ebola? Oct 2, 2014. http:// www.npr.org/blogs/health/2014/10/02/352983774/no-seriously-howcontagious-is-ebola (accessed Oct 19, 2014). Lewnard JA, Ndeffo Mbah ML, Alfaro-Murillo JA, et al. Dynamics and control of Ebola virus transmission in Montserrado, Liberia: a mathematical modelling analysis. Lancet Infect Dis 2014; published online Oct 24. http:// dx.doi.org/10.1016/S1473-3099(14)70995-8. Liberian Ministry of Health and Social Welfare. Situation reports. Oct 11, 2014. http://www.liberianhealthresearch.com/reports.html (accessed Oct 20, 2014). WHO. WHO: Ebola response roadmap situation report. Oct 15, 2014. http:// apps.who.int/iris/bitstream/10665/136508/1/roadmapsitrep15Oct2014. pdf?ua=1 (accessed Oct 20, 2014). Fisman DN, Khoo E, Tuite AR. Early epidemic dynamics of the west African 2014 Ebola outbreak: estimates derived with a simple two-parameter model. PLoS Curr 2014; published online Sept 8. http://dx.doi.org/10.1371/ currents.outbreaks.89c0d3783f36958d96ebbae97348d571. Achenbach J, Sun LH, Dennis B. The ominous math of the Ebola epidemic. Oct 9, 2014. http://www.washingtonpost.com/national/health-science/ the-ominous-math-of-the-ebola-epidemic/2014/10/09/3cad9e76-4fb211e4-8c24-487e92bc997b_story.html (accessed Oct 20, 2014).
The most effective method of protection against disease and death caused by influenza viruses is vaccination. In a recent study, vaccination was calculated to prevent 80 000 influenza-related hospital admissions in the USA (2012–13 season),1 although various international evaluations of vaccine effectiveness showed disappointing values ranging from 45% to 51%,2–4 mainly attributed to a poorly immunogenic H3N2 component due to the production process.5 Reviews have drawn attention to the inability of egg-based technology to deliver products that elicit humoral, cellular, long-lasting, and broadly protective responses;6 and low vaccine uptake is partly due to suboptimum seasonal vaccines,7 emphasising the need for improvement. Vaccine assessment based on traditional, poorly standardised tests8 needs revision with the inclusion of rigorous scientific appraisal of assay choices and cutoffs. In recent years, influenza vaccine development gained momentum from the emergence and spread of highly pathogenic H5N1 avian influenza viruses in poultry. www.thelancet.com/infection Vol 14 December 2014
Although H5N1 is still of great concern, other novel subtypes (H4, H6, H7, H9, and H10) with pandemic potential have emerged. The early-generation pandemic vaccines for H5, H7, and H9 subtypes, based on seasonal vaccine technology, showed disappointing results for immunogenicity, which were only partly remedied by use of high antigen contents, two-dose vaccinations, and adjuvantation. Efforts to develop universal immunisation strategies9 focus on conserved epitopes such as the influenza haemagglutinin stem, extracellular M2 domain, and neuraminidase, and have been tested in DNA-based vaccines and virus-like particles. These particles, which can induce both humoral and cellular immune responses because of their morphology, afforded protection against homologous and heterologous lethal challenge in mice.10 Recombinant vaccines with virus vectors such as modified vaccinia virus Ankara (MVA) and adenovirus are appealing alternatives to traditional vaccines. They permit native antigen expression, leading to improved
Eye Of Science/Science Photo Library
Modern twist on a classic formula for influenza vaccination
Published Online October 30, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70996-X See Articles page 1196
1165
Comment
immunogenicity; can encode more than one foreign antigen and thus function as a multivalent vaccine; and can be delivered to sites of inductive immunity. MVA, a highly attenuated, replication incompetent viral vector, has intrinsic adjuvant capacities and induces humoral and cellular immune responses. In a phase 1 study, an MVA vaccine, expressing the nucleoprotein and matrix protein, coadministered with a commercial trivalent inactivated vaccine was safe, immunogenic, and boosted T-cell responses to conserved influenza antigens.11 In the Lancet Infectious Diseases, Joost Kreijtz and colleagues12 report the safety and immunogenicity data from the first phase 1/2a clinical trial of an MVA vaccine expressing influenza H5N1 haemagglutinin. 79 volunteers received one or two shots of a normal (108 plaque forming units [pfu]) or ten times lower dose of the vaccine. Individuals who were eligible according to the study protocol received a booster 1 year later. The results of this trial and previous trials showed that the MVA vaccine was generally well tolerated, with some mild or moderate local and systemic reactions and no serious adverse events. The immunogenicity was assessed with haemagglutination-inhibition and neutralisation assays by use of homologous and heterologous H5N1 viruses. Two injections of the normal dose vaccine induced the highest seroprotection rate (80% of individuals had haemagglutination inhibition titres ≥40) and geometric mean titre of antibody (108·1), whereas a single shot of the same dose achieved 44% seroprotection (geometric mean titre 30·2), showing substantial benefit with the second shot. Seroprotection (30%) after two injections of the lower dose was significantly less than that with the higher dose, showing a strong dose-dependence effect, whereas improvements in seroprotection and seroconversion were achieved through a booster in all groups. The investigators defined seroconversion arbitrarily as a post-vaccine titre of at least 20, making comparison of their data with those from other trials difficult, and future comparisons with conventional H5 vaccines will be necessary to confirm whether MVA is advantageous in terms of dose sparing and intrinsic adjuvantation. Previous preclinical studies by the same investigators have already shown vaccine efficacy in non-human primates against H5N1 viruses from the same and 1166
different clades.13 The apparent dose-dependence responses together with earlier observations suggest that an upper dose for prophylactic vaccination in the range of 1·0–1·5 × 108 pfu restrict the opportunity to improve immunogenicity by further increases in dose, but as shown in Kreijtz and colleagues’ trial and other MVA vaccine studies, the immunogenicity of this vaccine can be further improved with a robust priming strategy. *Katja Höschler, Catherine I Thompson Virus Reference Department, Public Health England, London, NW9 5HT, UK (KH, CIT) [email protected] We declare no competing interests. We thank M C Zambon for her thoughtful contribution to this Commentary. 1
Bresee J, Reed C, Kim IK, et al. Estimated influenza illnesses and hospitalizations averted by influenza vaccination – United States, 2012–13 influenza season. MMWR Morb Mortal Wkly Rep 2013; 62: 997–1000. 2 Andrews N, McMenamin J, Durnall H, et al. Effectiveness of trivalent seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2012/13 end of season results. Euro Surveill 2014; 19: 5–13. 3 Skowronski DM, Janjua NZ, De Serres G, et al. Interim estimates of influenza vaccine effectiveness in 2012/13 from Canada’s sentinel surveillance network, January 2013. Euro Surveill 2013: 18: 7–17. 4 Valenciano M, Kissling E. Early estimates of seasonal influenza vaccine effectiveness in Europe: results from the I-MOVE multicentre case-control study, 2012/13. Euro Surveill 2013; 18: 12–18. 5 Skowronski DM, Januja NZ, De Serres G, et al. Low 2012–13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS One 2014; 9: e92153. 6 Osterholm MT, Kelley NS, Manke JM, Ballering KS, Leighton TR. The compelling need for game-changing influenza vaccines. An analysis of the influenza vaccine enterprise and recommendations for the future. Center for Infectious Disease and Policy Research, University of Minnesota, 2012. http://www.cidrap.umn.edu/sites/default/files/public/downloads/ccivi_ report.pdf (accessed Oct 23, 2014). 7 Wysocki P, Barragan S, Nurm Ü-K, Würz A. Understanding the behavioural aspects and the role of health communication in mitigating the impact of seasonal influenza. European Centre for Disease Prevention and Control, Stockholm, 2011. http://www.ecdc.europa.eu/en/publications/ Publications/1108_MER_flu_behaviour.pdf (accessed Oct 23, 2014). 8 Committee for Medicinal Products for Human Use. Guideline on influenza vaccines. Non-clinical and clinical module. European Medicines Agency, Committee for Medicinal Products for Human Use, 2014. http://www.ema. europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/07/ WC500170300.pdf (accessed Oct 23, 2014). 9 Pica N, Palese P. Toward a universal influenza virus vaccine: prospects and challenges. Annu Rev Med 2013; 64: 189–202. 10 Kang SM, Kim MC, Compans RW. Virus-like particles as universal influenza vaccines. Expert Rev Vaccines 2012; 11: 995–1007. 11. Antrobus RD, Berthoud TK, Mullarkey CE, et al. Coadministration of seasonal influenza vaccine and MVA-NP+M1 simultaneously achieves potent humoral and cell-mediated responses. Mol Ther 2014; 22: 233–38. 12 Kreijtz JHCM, Goeijenbier M, Moesker FM, et al. Safety and immunogenicity of a Modified-Vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised phase 1/2a clinical trial. Lancet Infect Dis 2014; published online Oct 30. http://dx.doi.org/10.1016/S1473-3099(14)70963-6. 13 Kreijtz JHCM, Suezer Y, de Mutsert G, et al. Recombinant Modified Vaccinia virus Ankara expressing the hemagglutinin gene confers protection against homologous and heterologous H5N1 influenza virus infections in macaques. J Infect Dis 2009; 199: 405–13.
www.thelancet.com/infection Vol 14 December 2014
simple mathematics: if R0 in this region is around 2·5, as Lewnard and colleagues estimate, incidence in every successive epidemic generation will increase by 150%. If R0 could be pushed to less than one, incident case counts would begin to drop, but because incident cases are a function of prevalent cases, making this decrease happen earlier in the epidemic results in striking reductions in final epidemic size (figure). For example, if R0 is reduced to 0·9 at a time when there are 1000 incident cases per generation, case counts in subsequent generations will be 900, 810, 720, and so on. If intervention is delayed until there are 10 000 cases per generation and R0 is cut to 0·9, subsequent generations will have 9000, 8100, 7200 cases, and so on. Elevated case counts also increase the risk of spread to as yet unaffected areas, sparking new outbreaks. Researchers have asserted that the epidemic is proceeding in virus time, with a response on bureaucrat time.7 From a global perspective, controlling the Ebola epidemic in west Africa is not only a humanitarian duty but also a matter of crude self-interest. The report by Lewnard and colleagues shows that intervention will only be meaningful if it is timely, and so far it has not been.
*David Fisman, Ashleigh R Tuite Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada M5T 3M7 david.fi[email protected] We declare no competing interests. 1 2
3
4
5
6
7
Farrar JJ, Piot P. The Ebola emergency: immediate action, ongoing strategy. N Engl J Med 2014; 371: 1545–46. Doucleff M. No, seriously, how contagious is Ebola? Oct 2, 2014. http:// www.npr.org/blogs/health/2014/10/02/352983774/no-seriously-howcontagious-is-ebola (accessed Oct 19, 2014). Lewnard JA, Ndeffo Mbah ML, Alfaro-Murillo JA, et al. Dynamics and control of Ebola virus transmission in Montserrado, Liberia: a mathematical modelling analysis. Lancet Infect Dis 2014; published online Oct 24. http:// dx.doi.org/10.1016/S1473-3099(14)70995-8. Liberian Ministry of Health and Social Welfare. Situation reports. Oct 11, 2014. http://www.liberianhealthresearch.com/reports.html (accessed Oct 20, 2014). WHO. WHO: Ebola response roadmap situation report. Oct 15, 2014. http:// apps.who.int/iris/bitstream/10665/136508/1/roadmapsitrep15Oct2014. pdf?ua=1 (accessed Oct 20, 2014). Fisman DN, Khoo E, Tuite AR. Early epidemic dynamics of the west African 2014 Ebola outbreak: estimates derived with a simple two-parameter model. PLoS Curr 2014; published online Sept 8. http://dx.doi.org/10.1371/ currents.outbreaks.89c0d3783f36958d96ebbae97348d571. Achenbach J, Sun LH, Dennis B. The ominous math of the Ebola epidemic. Oct 9, 2014. http://www.washingtonpost.com/national/health-science/ the-ominous-math-of-the-ebola-epidemic/2014/10/09/3cad9e76-4fb211e4-8c24-487e92bc997b_story.html (accessed Oct 20, 2014).
The most effective method of protection against disease and death caused by influenza viruses is vaccination. In a recent study, vaccination was calculated to prevent 80 000 influenza-related hospital admissions in the USA (2012–13 season),1 although various international evaluations of vaccine effectiveness showed disappointing values ranging from 45% to 51%,2–4 mainly attributed to a poorly immunogenic H3N2 component due to the production process.5 Reviews have drawn attention to the inability of egg-based technology to deliver products that elicit humoral, cellular, long-lasting, and broadly protective responses;6 and low vaccine uptake is partly due to suboptimum seasonal vaccines,7 emphasising the need for improvement. Vaccine assessment based on traditional, poorly standardised tests8 needs revision with the inclusion of rigorous scientific appraisal of assay choices and cutoffs. In recent years, influenza vaccine development gained momentum from the emergence and spread of highly pathogenic H5N1 avian influenza viruses in poultry. www.thelancet.com/infection Vol 14 December 2014
Although H5N1 is still of great concern, other novel subtypes (H4, H6, H7, H9, and H10) with pandemic potential have emerged. The early-generation pandemic vaccines for H5, H7, and H9 subtypes, based on seasonal vaccine technology, showed disappointing results for immunogenicity, which were only partly remedied by use of high antigen contents, two-dose vaccinations, and adjuvantation. Efforts to develop universal immunisation strategies9 focus on conserved epitopes such as the influenza haemagglutinin stem, extracellular M2 domain, and neuraminidase, and have been tested in DNA-based vaccines and virus-like particles. These particles, which can induce both humoral and cellular immune responses because of their morphology, afforded protection against homologous and heterologous lethal challenge in mice.10 Recombinant vaccines with virus vectors such as modified vaccinia virus Ankara (MVA) and adenovirus are appealing alternatives to traditional vaccines. They permit native antigen expression, leading to improved
Eye Of Science/Science Photo Library
Modern twist on a classic formula for influenza vaccination
Published Online October 30, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70996-X See Articles page 1196
1165
Comment
immunogenicity; can encode more than one foreign antigen and thus function as a multivalent vaccine; and can be delivered to sites of inductive immunity. MVA, a highly attenuated, replication incompetent viral vector, has intrinsic adjuvant capacities and induces humoral and cellular immune responses. In a phase 1 study, an MVA vaccine, expressing the nucleoprotein and matrix protein, coadministered with a commercial trivalent inactivated vaccine was safe, immunogenic, and boosted T-cell responses to conserved influenza antigens.11 In the Lancet Infectious Diseases, Joost Kreijtz and colleagues12 report the safety and immunogenicity data from the first phase 1/2a clinical trial of an MVA vaccine expressing influenza H5N1 haemagglutinin. 79 volunteers received one or two shots of a normal (108 plaque forming units [pfu]) or ten times lower dose of the vaccine. Individuals who were eligible according to the study protocol received a booster 1 year later. The results of this trial and previous trials showed that the MVA vaccine was generally well tolerated, with some mild or moderate local and systemic reactions and no serious adverse events. The immunogenicity was assessed with haemagglutination-inhibition and neutralisation assays by use of homologous and heterologous H5N1 viruses. Two injections of the normal dose vaccine induced the highest seroprotection rate (80% of individuals had haemagglutination inhibition titres ≥40) and geometric mean titre of antibody (108·1), whereas a single shot of the same dose achieved 44% seroprotection (geometric mean titre 30·2), showing substantial benefit with the second shot. Seroprotection (30%) after two injections of the lower dose was significantly less than that with the higher dose, showing a strong dose-dependence effect, whereas improvements in seroprotection and seroconversion were achieved through a booster in all groups. The investigators defined seroconversion arbitrarily as a post-vaccine titre of at least 20, making comparison of their data with those from other trials difficult, and future comparisons with conventional H5 vaccines will be necessary to confirm whether MVA is advantageous in terms of dose sparing and intrinsic adjuvantation. Previous preclinical studies by the same investigators have already shown vaccine efficacy in non-human primates against H5N1 viruses from the same and 1166
different clades.13 The apparent dose-dependence responses together with earlier observations suggest that an upper dose for prophylactic vaccination in the range of 1·0–1·5 × 108 pfu restrict the opportunity to improve immunogenicity by further increases in dose, but as shown in Kreijtz and colleagues’ trial and other MVA vaccine studies, the immunogenicity of this vaccine can be further improved with a robust priming strategy. *Katja Höschler, Catherine I Thompson Virus Reference Department, Public Health England, London, NW9 5HT, UK (KH, CIT) [email protected] We declare no competing interests. We thank M C Zambon for her thoughtful contribution to this Commentary. 1
Bresee J, Reed C, Kim IK, et al. Estimated influenza illnesses and hospitalizations averted by influenza vaccination – United States, 2012–13 influenza season. MMWR Morb Mortal Wkly Rep 2013; 62: 997–1000. 2 Andrews N, McMenamin J, Durnall H, et al. Effectiveness of trivalent seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2012/13 end of season results. Euro Surveill 2014; 19: 5–13. 3 Skowronski DM, Janjua NZ, De Serres G, et al. Interim estimates of influenza vaccine effectiveness in 2012/13 from Canada’s sentinel surveillance network, January 2013. Euro Surveill 2013: 18: 7–17. 4 Valenciano M, Kissling E. Early estimates of seasonal influenza vaccine effectiveness in Europe: results from the I-MOVE multicentre case-control study, 2012/13. Euro Surveill 2013; 18: 12–18. 5 Skowronski DM, Januja NZ, De Serres G, et al. Low 2012–13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS One 2014; 9: e92153. 6 Osterholm MT, Kelley NS, Manke JM, Ballering KS, Leighton TR. The compelling need for game-changing influenza vaccines. An analysis of the influenza vaccine enterprise and recommendations for the future. Center for Infectious Disease and Policy Research, University of Minnesota, 2012. http://www.cidrap.umn.edu/sites/default/files/public/downloads/ccivi_ report.pdf (accessed Oct 23, 2014). 7 Wysocki P, Barragan S, Nurm Ü-K, Würz A. Understanding the behavioural aspects and the role of health communication in mitigating the impact of seasonal influenza. European Centre for Disease Prevention and Control, Stockholm, 2011. http://www.ecdc.europa.eu/en/publications/ Publications/1108_MER_flu_behaviour.pdf (accessed Oct 23, 2014). 8 Committee for Medicinal Products for Human Use. Guideline on influenza vaccines. Non-clinical and clinical module. European Medicines Agency, Committee for Medicinal Products for Human Use, 2014. http://www.ema. europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/07/ WC500170300.pdf (accessed Oct 23, 2014). 9 Pica N, Palese P. Toward a universal influenza virus vaccine: prospects and challenges. Annu Rev Med 2013; 64: 189–202. 10 Kang SM, Kim MC, Compans RW. Virus-like particles as universal influenza vaccines. Expert Rev Vaccines 2012; 11: 995–1007. 11. Antrobus RD, Berthoud TK, Mullarkey CE, et al. Coadministration of seasonal influenza vaccine and MVA-NP+M1 simultaneously achieves potent humoral and cell-mediated responses. Mol Ther 2014; 22: 233–38. 12 Kreijtz JHCM, Goeijenbier M, Moesker FM, et al. Safety and immunogenicity of a Modified-Vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised phase 1/2a clinical trial. Lancet Infect Dis 2014; published online Oct 30. http://dx.doi.org/10.1016/S1473-3099(14)70963-6. 13 Kreijtz JHCM, Suezer Y, de Mutsert G, et al. Recombinant Modified Vaccinia virus Ankara expressing the hemagglutinin gene confers protection against homologous and heterologous H5N1 influenza virus infections in macaques. J Infect Dis 2009; 199: 405–13.
www.thelancet.com/infection Vol 14 December 2014
