- Email: [email protected]
Prepandemic influenza vaccines
Reflection and Reaction
contrasted with the concentrated epidemic in men who have sex with men, offers false reassurance. It is important to remember that the homosexual groups are selling sex, not within each other, but to the general population. To the general public, therefore, homosexual groups serve as pockets of infection that can potentially spread to men from all walks of life. The notion that religion is protective against STDs must be interpreted with caution.
We declare that we have no conflict of interest. 1
2
3
Guriro A. Pakistanis use 130m condoms yearly: firm’s marketing survey, 2008. http://www.dailytimes.com.pk/default.asp?page=2008%5C09% 5C17%5Cstory_17-9-2008_pg12_10 (accessed Feb 18, 2008). Khan S, Bandyopadhyay A, Causey P. Risks and responsibilities: male sexual health and HIV in Asia and the Pacific international consultation. New Delhi, India, Sept 23–26, 2006. Summary report, 2006. http://www. risksandresponsibilities.org/TechnicalReport_Summary.pdf (accessed Feb 18, 2008). Norris AE, Clark LF, Magnus S. Sexual abstinence and the sexual abstinence behavior scale. J Pediatr Health Care 2003; 17: 140–44.
Alefiyah Rajabali, *Syed H Ali Department of Biological and Biomedical Sciences, Aga Khan University Hospital, Karachi, Pakistan [email protected]
Prepandemic influenza vaccines
Philippe Benoist/Eurelios/Science Photo Library
We read the Personal View by Lance Jennings and colleagues1 with great interest. We agree that the benefits obtained from the use of prepandemic vaccines should be balanced against the possible adverse effects. It is thought that prepandemic vaccination could decrease the basic reproductive number of a pandemic outbreak,2–4 and thus retard the spread of infection. There is an ongoing discussion on the different approaches to the distribution of a prepandemic vaccine.5 Given the current limitations of vaccine manufacturing methods, prepandemic vaccination campaigns should probably be applied to a limited proportion of the population. However, as mentioned above, there are potential adverse outcomes to prepandemic vaccines. The
Chickens confined to prevent their exposure to the H5N1 virus in wildfowl
206
antigens contained in the prepandemic vaccine could poorly or partly match the antigens of the pandemic strain, which could induce a state of partial protection against the pandemic virus—avoiding fatal infection and leading to a milder or incomplete form of the disease. In this scenario, it would be more difficult to identify new cases of influenza infection. Transmissibility could even increase, since the milder infection would have a more limited impact on the patient’s activities (eg, work, travel) allowing wider dissemination of the virus. Jennings and colleagues speculate on the introduction of an H5N1 antigen into existing seasonal influenza vaccines. On the basis of the current vaccination guidelines for seasonal influenza, only people included in the risk groups (ie, those older than 65 years, essential workers, and patients with chronic illness) would receive the vaccine. If a pandemic emerges, a high number of mild symptomatic carriers could arise from these groups. Mild cases could transmit the virus to younger or unprotected people—ie, health workers interact with a large number of people at risk (hospitalised, immunocompromised, and children)—who are not included in the seasonal vaccination programmes. Developed countries, with a considerable percentage of elderly people, would be the most affected. A strategy based on a sequential vaccination of successive layers of the population could represent a valid approach. But, who should be the first to receive the vaccine? In the event of a pandemic, elderly people www.thelancet.com/infection Vol 9 April 2009
Reflection and Reaction
might have a degree of immunity based on their memory response acquired during previous exposure to other influenza strains.6,7 The overall proportion of people with a fatal outcome to human H5N1 infection is highest among people aged 10–19 years.8 It is difficult to anticipate if a new pandemic strain would behave in a similar way, but the impact that the death of children and young adults could have on society is thought to be higher than that caused by the death of older people. Children and young adults should be the first to receive the prepandemic vaccine, in our opinion, followed by mature adults and elderly people. If the pandemic starts and the prepandemic vaccine has not reached the entire population, prophylaxis with antivirals could protect those individuals who did not receive the vaccine in time. The concept of antigen sparing—ie, low dose vaccinations—could usefully extend the availability of a prepandemic vaccine.1,5 Alternative routes of vaccine administration (eg, intradermal) could also reduce the necessary dose of antigen.9–10 Finally, vaccines that minimally enhance herd immunity may, by increasing genotype diversity, help facilitate the generation and survival of novel influenza strains.11 Mucosal administration of prepandemic vaccines could more effectively elicit immunity against emerging viruses, since they reproduce the natural route of infection.12 These kind of prepandemic vaccines are not currently available. In conclusion, the administration of a prepandemic vaccine to a limited number of individuals could increase the number of mild symptomatic infected carriers during a pandemic. Prepandemic vaccination could introduce two different models of antigenic drift of an emergent influenza strain, one in primed populations and another in non-primed populations. It could result in the appearance of different viral strains with different infectious capacity, making it difficult to anticipate the morbidity and mortality associated with each one and the consequences on both vaccinated and non-vaccinated populations. Alternative strategies for prepandemic vaccination based on sequential administration of the vaccine by age group, antigen sparing, or mucosal administration should be evaluated to avoid these possible undesirable effects. *Jesus F Bermejo-Martin, Alberto Tenorio-Abreu, Tomas Vega, Jose M Eiros, Javier Castrodeza, Raul Ortiz de Lejarazu www.thelancet.com/infection Vol 9 April 2009
National Centre of Influenza, Universidad de Valladolid, Spain (JFB-M, AT-A, TV, JME, JC, ROdL); Unidad de Infección e Inmunidad, Servicio de Microbiología e Inmunología, Hospital Clínico Universitario de Valladolid-IECSCYL (JFB-M, AT-A, JME, ROdL); and Health Council, Community of Castilla y León, Spain (TV, JC) [email protected] JFB-M and JC declare that they have no conflict of interest. AT-A has received travel grants from GlaxoSmithKline and Wyeth. TV has received an honorarium and a travel grant from Wyeth. JME and ROdL have received honoraria and travel grants from Roche, GlaxoSmithKline, and Steve-Novartis. JFB-M and AT-A are supported by Fondo de Investigaciones Sanitarias, FIS, Ministery of Science and Innovation, Spain, EMER07/050. 1
2
3
4 5 6
7
8
9
10 11
12
Jennings LC, Monto AS, Chan PK, Szucs TD, Nicholson KG. Stockpiling prepandemic influenza vaccines: a new cornerstone of pandemic preparedness plans. Lancet Infect Dis 2008; 8: 650–58. Halloran ME, Ferguson NM, Eubank S, et al. Modeling targeted layered containment of an influenza pandemic in the United States. Proc Natl Acad Sci USA 2008; 105: 4639–44. Germann TC, Kadau K, Longini IM Jr, Macken CA. Mitigation strategies for pandemic influenza in the United States. Proc Natl Acad Sci USA 2006; 103: 5935–40. Longini IM Jr, Nizam A, Xu S, et al. Containing pandemic influenza at the source. Science 2005; 309: 1083–87. Riley S, Wu JT, Leung GM. Optimizing the dose of pre-pandemic influenza vaccines to reduce the infection attack rate. PLoS Med 2007; 4: e218. Sandbulte MR, Jimenez GS, Boon AC, et al. Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans. PLoS Med 2007; 4: e59. Lee LY, Ha DL, Simmons C, et al. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest 2008; 118: 3478–90. Writing committee of the second World Health Organization consultation on clinical aspects of human infection with avian influenza a (H5N1) virus. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med 2008; 358: 261–73. Holland D, Booy R, De Looze F, et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 2008; 198: 650–58. Kenney RT, Frech SA, Muenz LR, et al. Dose sparing with intradermal injection of influenza vaccine. N Engl J Med 2004; 351: 2295–301. Nuño M, Chowell G, Wang X, Castillo-Chavez C. On the role of crossimmunity and vaccines on the survival of less fit flu-strains. Theor Popul Biol 2007; 71: 20–12. Tumpey TM, Renshaw M, Clements JD, et al. Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic crossprotection against lethal influenza A H5N1 virus infection. J Virol 2001; 75: 5141–50.
Authors’ reply Jesus Bermejo-Martin and colleagues’ response to our Personal View1 creates a further opportunity to discuss possible strategies for the use of available H5N1 human vaccines and other prepandemic vaccines under development. Stockpiles of the H5 prepandemic human vaccine are now being considered by a number of countries, and have already been acquired by some. The major benefit from using prepandemic vaccines will be gained by priming populations before the onset of a pandemic, allowing systematic supply, distribution, 207
contrasted with the concentrated epidemic in men who have sex with men, offers false reassurance. It is important to remember that the homosexual groups are selling sex, not within each other, but to the general population. To the general public, therefore, homosexual groups serve as pockets of infection that can potentially spread to men from all walks of life. The notion that religion is protective against STDs must be interpreted with caution.
We declare that we have no conflict of interest. 1
2
3
Guriro A. Pakistanis use 130m condoms yearly: firm’s marketing survey, 2008. http://www.dailytimes.com.pk/default.asp?page=2008%5C09% 5C17%5Cstory_17-9-2008_pg12_10 (accessed Feb 18, 2008). Khan S, Bandyopadhyay A, Causey P. Risks and responsibilities: male sexual health and HIV in Asia and the Pacific international consultation. New Delhi, India, Sept 23–26, 2006. Summary report, 2006. http://www. risksandresponsibilities.org/TechnicalReport_Summary.pdf (accessed Feb 18, 2008). Norris AE, Clark LF, Magnus S. Sexual abstinence and the sexual abstinence behavior scale. J Pediatr Health Care 2003; 17: 140–44.
Alefiyah Rajabali, *Syed H Ali Department of Biological and Biomedical Sciences, Aga Khan University Hospital, Karachi, Pakistan [email protected]
Prepandemic influenza vaccines
Philippe Benoist/Eurelios/Science Photo Library
We read the Personal View by Lance Jennings and colleagues1 with great interest. We agree that the benefits obtained from the use of prepandemic vaccines should be balanced against the possible adverse effects. It is thought that prepandemic vaccination could decrease the basic reproductive number of a pandemic outbreak,2–4 and thus retard the spread of infection. There is an ongoing discussion on the different approaches to the distribution of a prepandemic vaccine.5 Given the current limitations of vaccine manufacturing methods, prepandemic vaccination campaigns should probably be applied to a limited proportion of the population. However, as mentioned above, there are potential adverse outcomes to prepandemic vaccines. The
Chickens confined to prevent their exposure to the H5N1 virus in wildfowl
206
antigens contained in the prepandemic vaccine could poorly or partly match the antigens of the pandemic strain, which could induce a state of partial protection against the pandemic virus—avoiding fatal infection and leading to a milder or incomplete form of the disease. In this scenario, it would be more difficult to identify new cases of influenza infection. Transmissibility could even increase, since the milder infection would have a more limited impact on the patient’s activities (eg, work, travel) allowing wider dissemination of the virus. Jennings and colleagues speculate on the introduction of an H5N1 antigen into existing seasonal influenza vaccines. On the basis of the current vaccination guidelines for seasonal influenza, only people included in the risk groups (ie, those older than 65 years, essential workers, and patients with chronic illness) would receive the vaccine. If a pandemic emerges, a high number of mild symptomatic carriers could arise from these groups. Mild cases could transmit the virus to younger or unprotected people—ie, health workers interact with a large number of people at risk (hospitalised, immunocompromised, and children)—who are not included in the seasonal vaccination programmes. Developed countries, with a considerable percentage of elderly people, would be the most affected. A strategy based on a sequential vaccination of successive layers of the population could represent a valid approach. But, who should be the first to receive the vaccine? In the event of a pandemic, elderly people www.thelancet.com/infection Vol 9 April 2009
Reflection and Reaction
might have a degree of immunity based on their memory response acquired during previous exposure to other influenza strains.6,7 The overall proportion of people with a fatal outcome to human H5N1 infection is highest among people aged 10–19 years.8 It is difficult to anticipate if a new pandemic strain would behave in a similar way, but the impact that the death of children and young adults could have on society is thought to be higher than that caused by the death of older people. Children and young adults should be the first to receive the prepandemic vaccine, in our opinion, followed by mature adults and elderly people. If the pandemic starts and the prepandemic vaccine has not reached the entire population, prophylaxis with antivirals could protect those individuals who did not receive the vaccine in time. The concept of antigen sparing—ie, low dose vaccinations—could usefully extend the availability of a prepandemic vaccine.1,5 Alternative routes of vaccine administration (eg, intradermal) could also reduce the necessary dose of antigen.9–10 Finally, vaccines that minimally enhance herd immunity may, by increasing genotype diversity, help facilitate the generation and survival of novel influenza strains.11 Mucosal administration of prepandemic vaccines could more effectively elicit immunity against emerging viruses, since they reproduce the natural route of infection.12 These kind of prepandemic vaccines are not currently available. In conclusion, the administration of a prepandemic vaccine to a limited number of individuals could increase the number of mild symptomatic infected carriers during a pandemic. Prepandemic vaccination could introduce two different models of antigenic drift of an emergent influenza strain, one in primed populations and another in non-primed populations. It could result in the appearance of different viral strains with different infectious capacity, making it difficult to anticipate the morbidity and mortality associated with each one and the consequences on both vaccinated and non-vaccinated populations. Alternative strategies for prepandemic vaccination based on sequential administration of the vaccine by age group, antigen sparing, or mucosal administration should be evaluated to avoid these possible undesirable effects. *Jesus F Bermejo-Martin, Alberto Tenorio-Abreu, Tomas Vega, Jose M Eiros, Javier Castrodeza, Raul Ortiz de Lejarazu www.thelancet.com/infection Vol 9 April 2009
National Centre of Influenza, Universidad de Valladolid, Spain (JFB-M, AT-A, TV, JME, JC, ROdL); Unidad de Infección e Inmunidad, Servicio de Microbiología e Inmunología, Hospital Clínico Universitario de Valladolid-IECSCYL (JFB-M, AT-A, JME, ROdL); and Health Council, Community of Castilla y León, Spain (TV, JC) [email protected] JFB-M and JC declare that they have no conflict of interest. AT-A has received travel grants from GlaxoSmithKline and Wyeth. TV has received an honorarium and a travel grant from Wyeth. JME and ROdL have received honoraria and travel grants from Roche, GlaxoSmithKline, and Steve-Novartis. JFB-M and AT-A are supported by Fondo de Investigaciones Sanitarias, FIS, Ministery of Science and Innovation, Spain, EMER07/050. 1
2
3
4 5 6
7
8
9
10 11
12
Jennings LC, Monto AS, Chan PK, Szucs TD, Nicholson KG. Stockpiling prepandemic influenza vaccines: a new cornerstone of pandemic preparedness plans. Lancet Infect Dis 2008; 8: 650–58. Halloran ME, Ferguson NM, Eubank S, et al. Modeling targeted layered containment of an influenza pandemic in the United States. Proc Natl Acad Sci USA 2008; 105: 4639–44. Germann TC, Kadau K, Longini IM Jr, Macken CA. Mitigation strategies for pandemic influenza in the United States. Proc Natl Acad Sci USA 2006; 103: 5935–40. Longini IM Jr, Nizam A, Xu S, et al. Containing pandemic influenza at the source. Science 2005; 309: 1083–87. Riley S, Wu JT, Leung GM. Optimizing the dose of pre-pandemic influenza vaccines to reduce the infection attack rate. PLoS Med 2007; 4: e218. Sandbulte MR, Jimenez GS, Boon AC, et al. Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans. PLoS Med 2007; 4: e59. Lee LY, Ha DL, Simmons C, et al. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest 2008; 118: 3478–90. Writing committee of the second World Health Organization consultation on clinical aspects of human infection with avian influenza a (H5N1) virus. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med 2008; 358: 261–73. Holland D, Booy R, De Looze F, et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 2008; 198: 650–58. Kenney RT, Frech SA, Muenz LR, et al. Dose sparing with intradermal injection of influenza vaccine. N Engl J Med 2004; 351: 2295–301. Nuño M, Chowell G, Wang X, Castillo-Chavez C. On the role of crossimmunity and vaccines on the survival of less fit flu-strains. Theor Popul Biol 2007; 71: 20–12. Tumpey TM, Renshaw M, Clements JD, et al. Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic crossprotection against lethal influenza A H5N1 virus infection. J Virol 2001; 75: 5141–50.
Authors’ reply Jesus Bermejo-Martin and colleagues’ response to our Personal View1 creates a further opportunity to discuss possible strategies for the use of available H5N1 human vaccines and other prepandemic vaccines under development. Stockpiles of the H5 prepandemic human vaccine are now being considered by a number of countries, and have already been acquired by some. The major benefit from using prepandemic vaccines will be gained by priming populations before the onset of a pandemic, allowing systematic supply, distribution, 207