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H5N1 vaccines: how prepared are we for a pandemic?
Comment
H5N1 vaccines: how prepared are we for a pandemic?
www.thelancet.com Vol 368 September 16, 2006
Worryingly, egg yields of antigen from engineered H5N1 viruses are 30–40% lower than the average of seasonal influenza viruses, reducing further the number of doses that would be available for clinical use. This situation falls far short of global requirements, but in the event of tomorrow’s pandemic, is where we are today. Lin and colleagues’ findings are consistent with experience that whole-virion vaccines have better immunogenicity in immunologically naive individuals than split and subunit vaccines.4,8,9 Human H5N1 cases first occurred in 1997, and whole-virion vaccines were predicted to allow a dose-sparing approach, so why has evaluation taken so long? Manufacturers producing split seasonal vaccines cannot easily switch production to whole-virion approaches without adopting new processing methods that require additional infrastructure and impose regulatory, licensing, and commercial uncertainties. Although well tolerated in Lin and colleagues’ study, earlier wholevirion vaccines were associated with febrile reactions, particularly in children.9,10 Careful investigation is needed before widespread immunisation; although with the potential disruption by pandemic influenza, modest reactogenicity might be acceptable. Because of the antigenic diversity of current circulating H5N1 viruses,1 vaccine prepared from earlier strains and stockpiled by authorities might be poorly matched to an emergent pandemic virus. Effective adjuvants might overcome this problem. A trial of MF59-adjuvanted subunit H5N3 vaccine found a third dose induced cross-reactive antibodies
Published Online September 7, 2006 DOI:10.1016/S01406736(06)69340-9 See Articles page 991
We do not have the rights to reproduce this image on the web.
AP
Highly pathogenic avian influenza (H5N1 strain) continues to cause outbreaks in poultry and migratory birds in Asia, Europe, and Africa. Since 2003, over 240 associated human infections (with 59% mortality) have been reported, with deaths in 2006 so far exceeding those in 2005.1 The A/H1N1 virus responsible for the 1918 pandemic was derived from an avian virus,2 and caused up to 50 million deaths. If pandemic H5 emerges, the consequences could be worse. Vaccination will be central to our response. In today’s Lancet, Jiangtao Lin and colleagues3 assess an alum-adjuvanted whole-virion H5N1 vaccine. Two doses containing 10 μg H5 haemagglutinin induced seroconversions in 78% and 96% of recipients by neutralising and haemagglutinin-inhibition responses, respectively. These findings identify a potential dosesparing approach that could be crucial for a global supply of pandemic vaccine. The development of vaccines against H5 viruses is challenging because these viruses are lethal to embryonated eggs, in which influenza viruses are grown for vaccine production.4 To generate suitable vaccine-reference strains, highly pathogenic viruses are engineered to remove the aminoacid sequence in the haemagglutinin responsible for virulence, and then combined with influenza viruses that grow well in eggs. The bulk material is inactivated and usually processed into split or subunit vaccines containing purified haemagglutinin.5 The calculation of a supply for a pandemic vaccine raises concerns. The global manufacturing capacity of trivalent seasonal influenza vaccine is 300 million doses every 6 months.6 If monovalent vaccine were similarly formulated, 15 μg haemagglutinin per dose, 900 million vaccines would be available. Because the population is non-immune and requires two doses, sufficient vaccine for 450 million people could be produced. Clinical studies of split H5N1 vaccines are disappointing. A US study of non-adjuvanted H5N1 vaccine found that only two doses containing 90 μg haemagglutinin per dose induced acceptable antibody levels.7 In France, two 30 μg doses of alum-adjuvanted H5N1 vaccine were immunogenic, with no effect of alum adjuvant at lower doses.8 So, within current manufacturing constraints of split vaccines, supplies of either of these two vaccines would be limited to 75 or 225 million people only.
965
Comment
to a range of H5N1 variants, suggesting that prepandemic priming of the population might be a useful strategy.11,12 Whether whole-virion vaccines can induce broad cross-reactive responses needs investigation. Because Lin and colleagues did not assess non-adjuvanted whole-virion vaccine, any immunopotentiating effect of alum cannot be determined. Traditional haemagglutinin-inhibition assays for detection of anti-influenza antibody have known correlates of immune-protection and are used for vaccine licensure. However, they are considered generally insensitive for detection of anti-H5 antibody.11–13 Good haemagglutinin-inhibition titres were detected in Lin and colleagues’ study, a finding that merits further investigation. As an alternative, neutralising antibody responses are commonly used to detect antibody to avian influenza.10–12 However, significant interlaboratory variability of assay endpoints, and lack of established correlates of immunity, create challenges for licensing. Development of international standards for assessing serological responses to H5N1 is crucial for comparative analysis of vaccine studies. Until these are available, postvaccination serum samples, or at least a subset, might be best analysed in a single laboratory. Although vaccine manufacturing capacity has had substantial investment from industry, global production capacity remains insufficient to meet pandemic demands. The US administration has invested $1 billion to expand production sites there.14 European Union governments must also respond to the current threat. Although developments including cell-culture systems, liveattenuated vaccines, new adjuvants, and DNA approaches will be important in future planning, studies of dosesparing vaccine formulations in children, adults, and elderly people should be international health priorities to optimise current immunisation strategies.
Iain Stephenson Infectious Diseases Unit, Leicester Royal Infirmary, Leicester LE1 5WW, UK [email protected] I have received grants for scientific research, speakers’ honoraria, and sponsorship for travel to international meetings from drug companies who make influenza vaccines, including Novartis, GlaxoSmithKline, and AventisPasteur. 1
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3
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5
6 7
8
9
10
11
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14
Epidemic and Pandemic Alert and Response. Avian influenza. Aug 29, 2006: http://www.who.int/csr/disease/avian_influenza/en/ (accessed Aug 25, 2006). Tumpey TM, Basler CF, Aguilar PV, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 2005; 310: 77–80. Lin J, Zhang J, Dong X, et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 2006; published online Sept 7. DOI:10.1016/S01406736(06)69294-5. Stephenson I, Nicholson KG, Wood JM, Zambon MC, Katz JM. Confronting the avian influenza threat: vaccine development for a potential pandemic. Lancet Infect Dis 2004; 4: 499–509. Furminger IGS. Vaccine production. In: Nicholson KG, Webster RG, Hay AJ (eds). Textbook of influenza. Oxford: Blackwell Science, 1998: 324–32. Fedson D. Preparing for pandemic vaccination: an international policy agenda for vaccine development. J Pub Health Policy 2005; 26: 4–29. Treanor JJ, Campbell JD, Zangwill KM, Rowe T, Wolff M. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006; 354: 1345–51. Bresson JL, Perronne C, Launay O, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 2006; 367: 1657–64. Nicholson KG, Tyrell DA, Harrison P, et al. Clinical studies of monovalent inactivated whole virus and subunit A/USSR/77 (H1N1) vaccine: serological responses and clinical reactions. J Biol Stand 1979; 7: 123–36. Wright PF, Thompson J, Vaughn WK, Folland DS, Sell SH, Karzon DT. Trials of influenza A/New Jersey/76 virus vaccine in normal children: an overview of age related antigenicity and reactogenicity. J Infect Dis 1977; 136: S731–41. Nicholson KG, Colegate AE, Podda A, et al. Safety and antigenicity of nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 2001; 357: 1937–43. Stephenson I, Bugarini R, Nicholson KG, et al. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses following vaccination with non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 2005; 191: 1210–15. Rowe T, Abernathy RA, Hu-Primmer J, et al. Detection of antibody to avian influenza (H5N1) virus in human sera by using a combination of serological assays. J Clin Microbiol 1999; 37: 937–43. Brown D. $1 billion awarded for flu vaccine. Washington Post May 5, 2006: http://www.washingtonpost.com/wp-dyn/content/article/2006/05/04/ AR2006050401879.html (accessed Aug 25, 2006).
The early invasive strategy revisited: FRISC II at 5 years See Articles page 998
Diseases desperate grown By desperate appliance are reliev’d, Or not at all Hamlet (William Shakespeare)
The merit of routine early invasive management versus non-invasive management for patients with acute coronary syndromes has been debated for over 15 years. 966
This situation is not for want of data. During that time, more than 10 000 such patients worldwide have been in randomised clinical trials. The absence of better outcomes in the TIMI IIIB1 and ICTUS2 trials, and the rather worse outcomes for invasive management in VANQWISH,3 are often cited to advocate a conservative or non-invasive approach to care, whereas the results of FRISC II (Fast www.thelancet.com Vol 368 September 16, 2006
H5N1 vaccines: how prepared are we for a pandemic?
www.thelancet.com Vol 368 September 16, 2006
Worryingly, egg yields of antigen from engineered H5N1 viruses are 30–40% lower than the average of seasonal influenza viruses, reducing further the number of doses that would be available for clinical use. This situation falls far short of global requirements, but in the event of tomorrow’s pandemic, is where we are today. Lin and colleagues’ findings are consistent with experience that whole-virion vaccines have better immunogenicity in immunologically naive individuals than split and subunit vaccines.4,8,9 Human H5N1 cases first occurred in 1997, and whole-virion vaccines were predicted to allow a dose-sparing approach, so why has evaluation taken so long? Manufacturers producing split seasonal vaccines cannot easily switch production to whole-virion approaches without adopting new processing methods that require additional infrastructure and impose regulatory, licensing, and commercial uncertainties. Although well tolerated in Lin and colleagues’ study, earlier wholevirion vaccines were associated with febrile reactions, particularly in children.9,10 Careful investigation is needed before widespread immunisation; although with the potential disruption by pandemic influenza, modest reactogenicity might be acceptable. Because of the antigenic diversity of current circulating H5N1 viruses,1 vaccine prepared from earlier strains and stockpiled by authorities might be poorly matched to an emergent pandemic virus. Effective adjuvants might overcome this problem. A trial of MF59-adjuvanted subunit H5N3 vaccine found a third dose induced cross-reactive antibodies
Published Online September 7, 2006 DOI:10.1016/S01406736(06)69340-9 See Articles page 991
We do not have the rights to reproduce this image on the web.
AP
Highly pathogenic avian influenza (H5N1 strain) continues to cause outbreaks in poultry and migratory birds in Asia, Europe, and Africa. Since 2003, over 240 associated human infections (with 59% mortality) have been reported, with deaths in 2006 so far exceeding those in 2005.1 The A/H1N1 virus responsible for the 1918 pandemic was derived from an avian virus,2 and caused up to 50 million deaths. If pandemic H5 emerges, the consequences could be worse. Vaccination will be central to our response. In today’s Lancet, Jiangtao Lin and colleagues3 assess an alum-adjuvanted whole-virion H5N1 vaccine. Two doses containing 10 μg H5 haemagglutinin induced seroconversions in 78% and 96% of recipients by neutralising and haemagglutinin-inhibition responses, respectively. These findings identify a potential dosesparing approach that could be crucial for a global supply of pandemic vaccine. The development of vaccines against H5 viruses is challenging because these viruses are lethal to embryonated eggs, in which influenza viruses are grown for vaccine production.4 To generate suitable vaccine-reference strains, highly pathogenic viruses are engineered to remove the aminoacid sequence in the haemagglutinin responsible for virulence, and then combined with influenza viruses that grow well in eggs. The bulk material is inactivated and usually processed into split or subunit vaccines containing purified haemagglutinin.5 The calculation of a supply for a pandemic vaccine raises concerns. The global manufacturing capacity of trivalent seasonal influenza vaccine is 300 million doses every 6 months.6 If monovalent vaccine were similarly formulated, 15 μg haemagglutinin per dose, 900 million vaccines would be available. Because the population is non-immune and requires two doses, sufficient vaccine for 450 million people could be produced. Clinical studies of split H5N1 vaccines are disappointing. A US study of non-adjuvanted H5N1 vaccine found that only two doses containing 90 μg haemagglutinin per dose induced acceptable antibody levels.7 In France, two 30 μg doses of alum-adjuvanted H5N1 vaccine were immunogenic, with no effect of alum adjuvant at lower doses.8 So, within current manufacturing constraints of split vaccines, supplies of either of these two vaccines would be limited to 75 or 225 million people only.
965
Comment
to a range of H5N1 variants, suggesting that prepandemic priming of the population might be a useful strategy.11,12 Whether whole-virion vaccines can induce broad cross-reactive responses needs investigation. Because Lin and colleagues did not assess non-adjuvanted whole-virion vaccine, any immunopotentiating effect of alum cannot be determined. Traditional haemagglutinin-inhibition assays for detection of anti-influenza antibody have known correlates of immune-protection and are used for vaccine licensure. However, they are considered generally insensitive for detection of anti-H5 antibody.11–13 Good haemagglutinin-inhibition titres were detected in Lin and colleagues’ study, a finding that merits further investigation. As an alternative, neutralising antibody responses are commonly used to detect antibody to avian influenza.10–12 However, significant interlaboratory variability of assay endpoints, and lack of established correlates of immunity, create challenges for licensing. Development of international standards for assessing serological responses to H5N1 is crucial for comparative analysis of vaccine studies. Until these are available, postvaccination serum samples, or at least a subset, might be best analysed in a single laboratory. Although vaccine manufacturing capacity has had substantial investment from industry, global production capacity remains insufficient to meet pandemic demands. The US administration has invested $1 billion to expand production sites there.14 European Union governments must also respond to the current threat. Although developments including cell-culture systems, liveattenuated vaccines, new adjuvants, and DNA approaches will be important in future planning, studies of dosesparing vaccine formulations in children, adults, and elderly people should be international health priorities to optimise current immunisation strategies.
Iain Stephenson Infectious Diseases Unit, Leicester Royal Infirmary, Leicester LE1 5WW, UK [email protected] I have received grants for scientific research, speakers’ honoraria, and sponsorship for travel to international meetings from drug companies who make influenza vaccines, including Novartis, GlaxoSmithKline, and AventisPasteur. 1
2
3
4
5
6 7
8
9
10
11
12
13
14
Epidemic and Pandemic Alert and Response. Avian influenza. Aug 29, 2006: http://www.who.int/csr/disease/avian_influenza/en/ (accessed Aug 25, 2006). Tumpey TM, Basler CF, Aguilar PV, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 2005; 310: 77–80. Lin J, Zhang J, Dong X, et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 2006; published online Sept 7. DOI:10.1016/S01406736(06)69294-5. Stephenson I, Nicholson KG, Wood JM, Zambon MC, Katz JM. Confronting the avian influenza threat: vaccine development for a potential pandemic. Lancet Infect Dis 2004; 4: 499–509. Furminger IGS. Vaccine production. In: Nicholson KG, Webster RG, Hay AJ (eds). Textbook of influenza. Oxford: Blackwell Science, 1998: 324–32. Fedson D. Preparing for pandemic vaccination: an international policy agenda for vaccine development. J Pub Health Policy 2005; 26: 4–29. Treanor JJ, Campbell JD, Zangwill KM, Rowe T, Wolff M. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006; 354: 1345–51. Bresson JL, Perronne C, Launay O, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 2006; 367: 1657–64. Nicholson KG, Tyrell DA, Harrison P, et al. Clinical studies of monovalent inactivated whole virus and subunit A/USSR/77 (H1N1) vaccine: serological responses and clinical reactions. J Biol Stand 1979; 7: 123–36. Wright PF, Thompson J, Vaughn WK, Folland DS, Sell SH, Karzon DT. Trials of influenza A/New Jersey/76 virus vaccine in normal children: an overview of age related antigenicity and reactogenicity. J Infect Dis 1977; 136: S731–41. Nicholson KG, Colegate AE, Podda A, et al. Safety and antigenicity of nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 2001; 357: 1937–43. Stephenson I, Bugarini R, Nicholson KG, et al. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses following vaccination with non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 2005; 191: 1210–15. Rowe T, Abernathy RA, Hu-Primmer J, et al. Detection of antibody to avian influenza (H5N1) virus in human sera by using a combination of serological assays. J Clin Microbiol 1999; 37: 937–43. Brown D. $1 billion awarded for flu vaccine. Washington Post May 5, 2006: http://www.washingtonpost.com/wp-dyn/content/article/2006/05/04/ AR2006050401879.html (accessed Aug 25, 2006).
The early invasive strategy revisited: FRISC II at 5 years See Articles page 998
Diseases desperate grown By desperate appliance are reliev’d, Or not at all Hamlet (William Shakespeare)
The merit of routine early invasive management versus non-invasive management for patients with acute coronary syndromes has been debated for over 15 years. 966
This situation is not for want of data. During that time, more than 10 000 such patients worldwide have been in randomised clinical trials. The absence of better outcomes in the TIMI IIIB1 and ICTUS2 trials, and the rather worse outcomes for invasive management in VANQWISH,3 are often cited to advocate a conservative or non-invasive approach to care, whereas the results of FRISC II (Fast www.thelancet.com Vol 368 September 16, 2006