FrenchieGirl
Senior Moderator
[Note - article from 2008 - but may have relevance now. Emphasis in the text is mine]
Editorial
Vaccines against seasonal and avian influenza: Recent advances
Albert D.M.E. Osterhaus1, , c, and Gregory A. Polanda, b, 2
aMayo Vaccine Research Group and the Program in Translational Immunovirology and Biodefense, United States
bDepartment of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
cDepartment of Virology, Erasmus MC, Dr Molewaterplein 50, 3015GE Rotterdam, The Netherlands
Received 25 July 2008. Available online 15 September 2008.
Keywords: Influenza; Vaccines
Seasonal influenza kills as many as 250,000?500,000 people around the world every year. Influenza pandemics in the 20th century varied from moderate to severe with the 1918 pandemic killing an estimated 50?100 million people worldwide. Vaccination is by far the most cost-effective medical intervention to combat seasonal influenza. More than half a century ago classical vaccines against seasonal influenza were introduced and ever since vaccination coverage for seasonal influenza has increased in the industrialized world. The first influenza vaccines were produced by inoculating embryonated chicken eggs with the virus strains of choice, harvesting the allantoic fluid from which the virus was partially purified and subsequently inactivated. This basic method of producing inactivated seasonal influenza vaccines remains unchanged. These vaccines are updated annually, based on epidemiological data collected by the WHO led influenza surveillance network. Importantly, these data are increasingly robust as an ever increasing number of national and collaborating reference laboratories contribute their seasonal influenza surveillance data. Currently the total global production capacity for seasonal influenza vaccines has increased to 400 million doses of trivalent vaccine per season. In spite of all the technologic advances that would allow for newer methods of influenza vaccine production, current practice is still entirely dependent on the use of embryonated chicken eggs. The formulations for these vaccines include whole inactivated virus (WIV), split virus, viral subunits or surface antigens and live attenuated virus (LAIV).
In the context of a pandemic, seasonal influenza vaccines would have to be used for the production of a pandemic vaccine, resulting in three major issues that would have to be solved: the long response time, the limited production capacity and the lack of efficacy of vaccines produced with the platform used for seasonal vaccine production. In addition safety issues and regulatory processes would have to be addressed in advance. The current response time between the seasonal influenza virus strain selection and production of the first vaccine doses is more than 6 months. This would be too long in the situation where a pandemic virus starts to spread globally. Given that the overall world influenza vaccine production capacity does not exceed 400 million doses of trivalent vaccine and that with a current production platform using split virus, unadjuvanted vaccine, more than 10 times the amount of viral antigen would need to be administered in a two dose regimen to induce adequate protection. Thus, the implementation of techniques that allow antigen sparing have become a major priority in the field of pandemic vaccine development. These considerations have prompted academic groups and influenza vaccine manufacturers to develop new generation vaccine development and production technologies that would solve these problems. Among the ?smaller? changes that are relatively easy to incorporate are the development of novel production systems, and virus strain selection tools and methods to prepare seed strains. Novel production systems based on the use of continuous cell lines like MDCK-, VERO- and PERC-6 cells, rather than embryonated chicken eggs would make the production systems more flexible, although it should be realized that the continued availability of these production substrates should also be planned well in advance. The use of well-defined cell lines would also offer the opportunity to optimize vaccine production by using genetically modified cell lines that have increased production levels of the desired HA and NA antigens. Another development in this area is the use of baculovirus-expressed influenza virus HA of the desired virus clade. Furthermore, it should be realized that if LAIV pandemic vaccine could be produced, the vaccine production capacity would increase dramatically, since lower viral vaccine doses could be used.
In the field of vaccine virus strain selection considerable progress has been made over the past decade. Novel mathematical techniques of antigenic mapping that were originally developed to determine the best seasonal influenza vaccine strain candidates are now also being employed for the measurement of antigenic distances between recently emerging HPAI H5N1 viruses. This will have important and direct consequences for the identification and preparation of the best matching seed virus, using a repository of recently collected avian influenza viruses and state-of-the-art reverse genetic techniques.
The correlate of protective immunity induced by all the current seasonal influenza vaccines is thought to be virus-neutralizing antibodies directed against the haemagglutinin (HA) of the virus. Consequently, the measurement of haemagglutination inhibiting or virus neutralizing antibodies upon vaccination is used for quality assurance of influenza vaccines. It should be realized that other correlates of protection against influenza do exist. Antibodies against neuraminidase (NA) have been shown to be involved in protection. Since only nine NA subtypes of influenza A viruses have been identified versus 16 HA subtypes, the use of NA as an additional vaccine antigen should seriously be considered. Similarly it has been suggested that the ectodomain of the M2 protein influenza A viruses induces antibodies that that may confer broad protection against ?all? influenza A viruses and may thus be used as a ?universal? influenza vaccine.
In addition to the role of protective antibody responses, the protective role of cell-mediated immune responses upon influenza vaccination has barely been studied. More attention should be paid to the identification of targets and adequate modes of antigen delivery that allow the induction of the appropriate T cell responses. This could also potentially result in a certain level of cross-protective immunity between virus subtypes. Finally it should be realized that in the context of pandemic vaccines the induction of suboptimal levels of clinical protection could be beneficial in terms of limiting virus spread and in reducing overall mortality at the population level.
In the past few years considerable progress has been made in the improvement of the efficacy of influenza vaccine candidates, by using novel adjuvants and delivery systems, without a major negative impact on their safety profile. The first adjuvanted seasonal influenza vaccine has been licensed in Europe, and has demonstrated promise for an avian or pre-pandemic influenza vaccine by allowing antigen sparing and by inducing broad inter-clade protective immunity. Other novel adjuvants demonstrate a similar performance in pre-clinical and clinical evaluations and the first pre-pandemic influenza vaccine was recently registered in Europe. It may be expected that the registration of other pre-pandemic adjuvanted vaccines will follow and that these vaccines will also form the basis for the eventual use of pandemic vaccines that will be prepared with the actual pandemic seed virus strain. Finally, several viral vectored vaccines like adeno- and poxvruses expressing the HA of HPAI H5N1 virus have shown great promise in relevant animal models by inducing broad intra-typic inter-clade protective immunity. It may be expected that influenza vaccines based on these technologies will also enter into clinical trials soon and that this approach may also result in the registration of human seasonal and (pre-)pandemic vaccines.
This Supplement of the journal Vaccine focuses entirely on new developments in the area of human influenza vaccines, by bringing together key experts from many of the relevant disciplines in this field. Special attention is paid to the relationship between seasonal and (pre-)pandemic influenza vaccines, vaccine adjuvants, influenza epidemiology, influenza vaccine immunogenetics, and other important topics. With the current pandemic threat posed by human infections with avian influenza viruses, this subject is of great importance to the global public health and to inform the necessary prepandemic preparedness. We hope readers will find this a useful state-of-the-art review of the major advances occurring in this arena.
Corresponding author. Tel. 31 10 7044066.
1 Dr. Osterhaus is chief scientific officer of Viroclinics B.V., a CRO involved in vaccine and antiviral trials as well as scientific consultancy.
2 Dr. Poland is the chair of a DMSB for an investigational influenza peptide vaccine trial being conducted by Merck Research Laboratories, and has offered consultative advice to CSL Limited, Avianax, Novavax, Merck, GlaxoSMithKline.
Vaccine
Volume 26, Supplement 4, 12 September 2008, Pages D1-D2
Influenza Vaccines: Research, Development and Public Health Challenges
Editorial
Vaccines against seasonal and avian influenza: Recent advances
Albert D.M.E. Osterhaus1, , c, and Gregory A. Polanda, b, 2
aMayo Vaccine Research Group and the Program in Translational Immunovirology and Biodefense, United States
bDepartment of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
cDepartment of Virology, Erasmus MC, Dr Molewaterplein 50, 3015GE Rotterdam, The Netherlands
Received 25 July 2008. Available online 15 September 2008.
Keywords: Influenza; Vaccines
Seasonal influenza kills as many as 250,000?500,000 people around the world every year. Influenza pandemics in the 20th century varied from moderate to severe with the 1918 pandemic killing an estimated 50?100 million people worldwide. Vaccination is by far the most cost-effective medical intervention to combat seasonal influenza. More than half a century ago classical vaccines against seasonal influenza were introduced and ever since vaccination coverage for seasonal influenza has increased in the industrialized world. The first influenza vaccines were produced by inoculating embryonated chicken eggs with the virus strains of choice, harvesting the allantoic fluid from which the virus was partially purified and subsequently inactivated. This basic method of producing inactivated seasonal influenza vaccines remains unchanged. These vaccines are updated annually, based on epidemiological data collected by the WHO led influenza surveillance network. Importantly, these data are increasingly robust as an ever increasing number of national and collaborating reference laboratories contribute their seasonal influenza surveillance data. Currently the total global production capacity for seasonal influenza vaccines has increased to 400 million doses of trivalent vaccine per season. In spite of all the technologic advances that would allow for newer methods of influenza vaccine production, current practice is still entirely dependent on the use of embryonated chicken eggs. The formulations for these vaccines include whole inactivated virus (WIV), split virus, viral subunits or surface antigens and live attenuated virus (LAIV).
In the context of a pandemic, seasonal influenza vaccines would have to be used for the production of a pandemic vaccine, resulting in three major issues that would have to be solved: the long response time, the limited production capacity and the lack of efficacy of vaccines produced with the platform used for seasonal vaccine production. In addition safety issues and regulatory processes would have to be addressed in advance. The current response time between the seasonal influenza virus strain selection and production of the first vaccine doses is more than 6 months. This would be too long in the situation where a pandemic virus starts to spread globally. Given that the overall world influenza vaccine production capacity does not exceed 400 million doses of trivalent vaccine and that with a current production platform using split virus, unadjuvanted vaccine, more than 10 times the amount of viral antigen would need to be administered in a two dose regimen to induce adequate protection. Thus, the implementation of techniques that allow antigen sparing have become a major priority in the field of pandemic vaccine development. These considerations have prompted academic groups and influenza vaccine manufacturers to develop new generation vaccine development and production technologies that would solve these problems. Among the ?smaller? changes that are relatively easy to incorporate are the development of novel production systems, and virus strain selection tools and methods to prepare seed strains. Novel production systems based on the use of continuous cell lines like MDCK-, VERO- and PERC-6 cells, rather than embryonated chicken eggs would make the production systems more flexible, although it should be realized that the continued availability of these production substrates should also be planned well in advance. The use of well-defined cell lines would also offer the opportunity to optimize vaccine production by using genetically modified cell lines that have increased production levels of the desired HA and NA antigens. Another development in this area is the use of baculovirus-expressed influenza virus HA of the desired virus clade. Furthermore, it should be realized that if LAIV pandemic vaccine could be produced, the vaccine production capacity would increase dramatically, since lower viral vaccine doses could be used.
In the field of vaccine virus strain selection considerable progress has been made over the past decade. Novel mathematical techniques of antigenic mapping that were originally developed to determine the best seasonal influenza vaccine strain candidates are now also being employed for the measurement of antigenic distances between recently emerging HPAI H5N1 viruses. This will have important and direct consequences for the identification and preparation of the best matching seed virus, using a repository of recently collected avian influenza viruses and state-of-the-art reverse genetic techniques.
The correlate of protective immunity induced by all the current seasonal influenza vaccines is thought to be virus-neutralizing antibodies directed against the haemagglutinin (HA) of the virus. Consequently, the measurement of haemagglutination inhibiting or virus neutralizing antibodies upon vaccination is used for quality assurance of influenza vaccines. It should be realized that other correlates of protection against influenza do exist. Antibodies against neuraminidase (NA) have been shown to be involved in protection. Since only nine NA subtypes of influenza A viruses have been identified versus 16 HA subtypes, the use of NA as an additional vaccine antigen should seriously be considered. Similarly it has been suggested that the ectodomain of the M2 protein influenza A viruses induces antibodies that that may confer broad protection against ?all? influenza A viruses and may thus be used as a ?universal? influenza vaccine.
In addition to the role of protective antibody responses, the protective role of cell-mediated immune responses upon influenza vaccination has barely been studied. More attention should be paid to the identification of targets and adequate modes of antigen delivery that allow the induction of the appropriate T cell responses. This could also potentially result in a certain level of cross-protective immunity between virus subtypes. Finally it should be realized that in the context of pandemic vaccines the induction of suboptimal levels of clinical protection could be beneficial in terms of limiting virus spread and in reducing overall mortality at the population level.
In the past few years considerable progress has been made in the improvement of the efficacy of influenza vaccine candidates, by using novel adjuvants and delivery systems, without a major negative impact on their safety profile. The first adjuvanted seasonal influenza vaccine has been licensed in Europe, and has demonstrated promise for an avian or pre-pandemic influenza vaccine by allowing antigen sparing and by inducing broad inter-clade protective immunity. Other novel adjuvants demonstrate a similar performance in pre-clinical and clinical evaluations and the first pre-pandemic influenza vaccine was recently registered in Europe. It may be expected that the registration of other pre-pandemic adjuvanted vaccines will follow and that these vaccines will also form the basis for the eventual use of pandemic vaccines that will be prepared with the actual pandemic seed virus strain. Finally, several viral vectored vaccines like adeno- and poxvruses expressing the HA of HPAI H5N1 virus have shown great promise in relevant animal models by inducing broad intra-typic inter-clade protective immunity. It may be expected that influenza vaccines based on these technologies will also enter into clinical trials soon and that this approach may also result in the registration of human seasonal and (pre-)pandemic vaccines.
This Supplement of the journal Vaccine focuses entirely on new developments in the area of human influenza vaccines, by bringing together key experts from many of the relevant disciplines in this field. Special attention is paid to the relationship between seasonal and (pre-)pandemic influenza vaccines, vaccine adjuvants, influenza epidemiology, influenza vaccine immunogenetics, and other important topics. With the current pandemic threat posed by human infections with avian influenza viruses, this subject is of great importance to the global public health and to inform the necessary prepandemic preparedness. We hope readers will find this a useful state-of-the-art review of the major advances occurring in this arena.
Corresponding author. Tel. 31 10 7044066.
1 Dr. Osterhaus is chief scientific officer of Viroclinics B.V., a CRO involved in vaccine and antiviral trials as well as scientific consultancy.
2 Dr. Poland is the chair of a DMSB for an investigational influenza peptide vaccine trial being conducted by Merck Research Laboratories, and has offered consultative advice to CSL Limited, Avianax, Novavax, Merck, GlaxoSMithKline.
Vaccine
Volume 26, Supplement 4, 12 September 2008, Pages D1-D2
Influenza Vaccines: Research, Development and Public Health Challenges