RESUMO
The emergence of a novel swine-origin pandemic influenza virus in 2009, together with the continuing circulation of highly pathogenic avian H5N1 viruses and the urgent global need to produce effective vaccines against such public health threats, has prompted a renewed interest in improving our understanding of the immune correlates of protection against influenza. As new influenza vaccine technologies, including non-HA based approaches and novel production platforms are developed and undergo clinical evaluation, it has become clear that existing immune correlates such as serum hemagglutination-inhibition antibodies may be unsuitable to estimate vaccine immunogenicity and protective efficacy of such vaccines. This International Society for Influenza and other Respiratory Virus Diseases (ISIRV) sponsored international meeting held in Miami, Florida USA on March 1-3, 2010, brought together scientists from industry, academia, and government agencies that develop and evaluate seasonal and pandemic influenza vaccines and scientists from regulatory authorities that approve them, to identify approaches to develop expanded immune correlates of protection to aid in vaccine licensure.
Assuntos
Aprovação de Drogas , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/normas , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Licenciamento/normas , Biomarcadores , Florida , Humanos , Estados UnidosRESUMO
Vaccination is the best available measure of limiting the impact of the next influenza pandemic. Ideally, a candidate pandemic influenza vaccine should be easy to administer and should elicit strong mucosal and systemic immune responses. Production of influenza subunit antigen in transient plant expression systems is an alternative to overcome the bottleneck in vaccine supply during influenza pandemic. Furthermore, a needle-free intranasal influenza vaccine is an attractive approach, which may provide immunity at the portal of virus entry. The present study investigated the detailed humoral and cellular immune responses in mice vaccinated intranasally or intramuscularly with plant-derived influenza H5N1 (A/Anhui/1/05) antigen alone or formulated with bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP) as adjuvant. The use of c-di-GMP as intramuscular adjuvant did not enhance the immune response to plant-derived influenza H5 antigen. However, intranasal c-di-GMP-adjuvanted vaccine induced strong mucosal and systemic humoral immune responses. Additionally, the intranasal vaccine elicited a balanced Th1/Th2 profile and, most importantly, high frequencies of multifunctional Th1 CD4(+) cells. Our results highlight that c-di-GMP is a promising mucosal adjuvant for pandemic influenza vaccine development.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antivirais/sangue , GMP Cíclico/análogos & derivados , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunidade nas Mucosas , Vacinas contra Influenza/imunologia , Células Th1/imunologia , Administração Intranasal , Animais , GMP Cíclico/administração & dosagem , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/genética , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos BALB C , Plantas Geneticamente Modificadas , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
Ideally, a candidate pandemic influenza vaccine should elicit rapid and strong cell-mediated and humoral immune responses, which are long-lasting and exhibit broad cross-reactivity against drifted strains. The present study investigated the detailed humoral and cellular immune responses in mice vaccinated intranasally or intramuscularly with inactivated influenza H5N1 (NIBRG-14) virosomal vaccine alone or formulated with Matrix-M adjuvant. The intramuscular Matrix-M-adjuvanted vaccine induced a strong immediate and long-term humoral immune response with high cross-reactivity against drifted H5N1 viruses and showed a dose-sparing potential. Additionally, the vaccine induced a balanced Th1/Th2 cytokine profile and most importantly high frequencies of multifunctional Th1 CD4(+) cells. Our results highlight that Matrix-M adjuvant is a promising parenteral adjuvant for formulating pandemic candidate vaccines.
Assuntos
Adjuvantes Imunológicos/farmacologia , Formação de Anticorpos , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Células Th1/imunologia , Administração Intranasal , Animais , Anticorpos Antivirais/sangue , Reações Cruzadas , Feminino , Testes de Inibição da Hemaglutinação , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos BALB C , Baço/citologia , Baço/imunologia , Virossomos/imunologiaRESUMO
BACKGROUND: Highly pathogenic avian influenza (HPAI) outbreaks in domestic poultry bring humans into close contact with new influenza subtypes and represent a threat to human health. In 1999, an HPAI outbreak of H7N1 virus occurred in domestic poultry in Italy, and a wild-type virus isolate from this outbreak was chosen as a pandemic vaccine candidate. OBJECTIVES: We conducted a pilot study to investigate the kinetics of the humoral immune response induced after immunisation with an egg grown whole inactivated H7N1 virus vaccine in BALB/c mice. METHODS: Mice were vaccinated with one or two doses of H7N1 vaccine (15 microg total protein) to investigate the influenza specific antibody secreting cell (IS-ASC) and serum antibody responses. RESULTS: After the first dose of vaccine, only IgM IS-ASC were detected in the spleen and bone marrow, whereas IgG, IgA and IgM IS-ASC were found after the second dose. Low antibody titres were detected after the first immunisation, whilst the second dose of vaccine significantly boosted the HI (range 128-512), neutralising and IgG antibody titres. The IgG subclass response was dominated by IgG2a indicating a dominant Th1 response after the first vaccination, whereas a more mixed Th1/Th2 profile was observed after the second dose. CONCLUSIONS: This pilot study shows the value of using a number of immunological methods to evaluate the quality of the immune response to potential pandemic candidate vaccines.
Assuntos
Vírus da Influenza A/imunologia , Vírus da Influenza A/isolamento & purificação , Vacinas contra Influenza/imunologia , Influenza Aviária/virologia , Animais , Anticorpos Antivirais/sangue , Células Produtoras de Anticorpos/imunologia , Medula Óssea/imunologia , Surtos de Doenças , Feminino , Imunização Secundária , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Influenza Aviária/epidemiologia , Itália/epidemiologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/prevenção & controle , Projetos Piloto , Aves Domésticas , Baço/imunologia , Vacinas de Produtos Inativados/imunologiaRESUMO
BACKGROUND: In recent years, several avian influenza subtypes (H5, H7 and H9) have transmitted directly from birds to man, posing a pandemic threat. OBJECTIVES: We have investigated the immunogenicity and protective efficacy of a cell based candidate pandemic influenza H7 vaccine in pre-clinical animal models. METHODS: Mice and ferrets were immunised with two doses of the split virus vaccine (12-24 microg haemagglutinin) with or without aluminium hydroxide adjuvant and challenged 3 weeks after second dose with the highly pathogenic A/chicken/Italy/13474/99 (H7N1) virus. The H7N1-specific serum antibody response was also measured. After challenge, viral shedding, weight loss, disease signs and death (only mice) were recorded. RESULTS: Low-to-modest serum antibody titres were detected after vaccination. Nevertheless, the vaccine induced significant protection from disease after challenge with the wild-type virus. In the murine lethal challenge model, vaccination effectively prevented death and, furthermore, formulation with adjuvant reduced excessive weight loss and viral shedding. In ferrets, vaccination reduced viral shedding and protected against systemic spread of the virus. CONCLUSIONS: We have extended to the H7 subtype the finding that protective efficacy may not be directly correlated with the pre-challenge levels of serum antibodies, a finding which could be of great importance in assessing the potential effectiveness of pandemic influenza vaccines.
Assuntos
Antígenos Virais/imunologia , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/farmacologia , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/isolamento & purificação , Peso Corporal , Embrião de Galinha , Feminino , Furões , Imunização Secundária , Itália , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/prevenção & controle , Índice de Gravidade de Doença , Análise de Sobrevida , Vacinas de Subunidades Antigênicas/imunologia , Vírion/imunologia , Vírion/isolamento & purificação , Eliminação de Partículas ViraisRESUMO
The reappearance of highly pathogenic avian influenza H5N1 in poultry in 2003, and the subsequent high-fatality zoonoses in Asia, Europe and Africa, has heightened the awareness of a potential pandemic and the need for global vaccine supply. Most manufacturers still use embryonated hens' eggs to produce influenza vaccines, a system that has demonstrated its value throughout six decades. There are, however, some challenges with this approach, both for seasonal and particularly for pandemic vaccine production. This review highlights some of these challenges and describes emerging alternative production platforms with the potential to deliver safe and effective vaccines to the global market in a timely fashion. A particular emphasis of this review will be on the production of recombinant influenza vaccines using transient plant expression systems.
Assuntos
Biotecnologia/métodos , Indústria Farmacêutica/métodos , Vacinas contra Influenza/genética , Plantas/genética , Técnicas de Cultura de Células/métodos , Humanos , Vacinas Sintéticas/genéticaRESUMO
Avian influenza H7 viruses have transmitted from poultry to man causing human illness and fatality, highlighting the need for pandemic preparedness against this subtype. We have developed and tested the first cell-based human vaccine against H7 avian influenza virus in a phase I clinical trial. Sixty healthy volunteers were intramuscularly vaccinated with two doses of split H7N1 virus vaccine containing 12 microg or 24 microg haemagglutinin alone or with aluminium hydroxide adjuvant (300 microg or 600 microg, respectively). The vaccine was well tolerated in all subjects and no serious adverse events occurred. The vaccine elicited low haemagglutination inhibition and microneutralisation titres, although the addition of aluminium adjuvant augmented the antibody response. We found a higher number of antibody secreting cells and an association with IL-2 production in subjects with antibody response. In conclusion, our study shows that producing effective H7 pandemic vaccines is as challenging as has been observed for H5 vaccines.
Assuntos
Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adulto , Hidróxido de Alumínio/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Interleucina-2/sangue , Interleucina-2/imunologia , Masculino , Testes de Neutralização , Vacinas Atenuadas/imunologia , Adulto JovemRESUMO
Recent years' enzootic spread of highly pathogenic H5N1 virus among poultry and the many lethal zoonoses in its wake has stimulated basic and applied pandemic vaccine research. The quest for an efficacious, affordable and timely accessible pandemic vaccine has been high on the agenda. When a variant H1N1 strain of swine origin emerged as a pandemic virus, it surprised many, as this subtype is well-known to man as a seasonal virus. This review will cover some difficult vaccine questions, such as the immunological challenges, the new production platforms, and the limited supply and global equity issues.
RESUMO
So far, most published results from clinical trials using various avian influenza virus vaccine formulations have been disappointing. Should the pandemic strike, we still do not have the ability to provide an efficacious pandemic vaccine in time and in sufficient quantities for the world. The H5N1 enzootic could potentially give rise to a pandemic at any time. Transcontinental air traffic could seed the pandemic virus to most corners of the globe within a few weeks/months. We still have a unique window of opportunity to stimulate and support academia and the pharmaceutical industry to accelerate the urgently needed vaccine research. The political inertia is surprising, particularly as politicians, if and when a pandemic eventuates, will be asked why, despite repeated warnings, they did not take appropriate action in time. It is a governmental obligation--and not that of the WHO or the pharmaceutical industry--to protect their nationals. Moreover, when the poorer nations of this world realize that equitable quantities of the scarce supplies of vaccines, drugs and medical essentials will not come their way, the post-pandemic international scene will be one of even more deep distrust for many years. This scenario is not acceptable.