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1.
Expert Rev Vaccines ; 22(1): 579-595, 2023.
Article in English | MEDLINE | ID: mdl-37395004

ABSTRACT

INTRODUCTION: With a limited global supply of vaccines and an increasing vaccine hesitancy, improving vaccination coverage has become a priority. Current vaccination regimes require multiple doses to be administered in a defined schedule where missed doses may lead to incomplete vaccine coverage and failure of immunization programmes. As such, there is an ever-increasing demand to convert multi-dose injectable vaccines into single-dose formats, often called single administration vaccines (SAVs). AREAS COVERED: This review summarizes recent developments in the field of SAVs, with a focus on pulsatile or controlled-release formulations. It will identify the technical challenges, translational as well as commercial barriers to SAVs development. Furthermore, the progress of SAV formulations for hepatitis B and polio vaccines will be reviewed thoroughly as case studies, with a focus on the development challenges and the preclinical immunogenicity/reactogenicity data. EXPERT OPINION: Despite the efforts to develop SAVs, few attempts have advanced to Phase-I trials. Considering the SAV development journey and bottlenecks, including commercial barriers from the early stages, may overcome some of the hurdles around the technology. The renewed global focus on vaccines since the COVID-19 pandemic could facilitate development of a new generation of technologies for pandemic preparedness including strategies for SAVs.


Subject(s)
COVID-19 , Vaccines , Humans , Pandemics , COVID-19/prevention & control , Immunization , Vaccination
2.
Vaccines (Basel) ; 10(11)2022 Oct 30.
Article in English | MEDLINE | ID: mdl-36366345

ABSTRACT

Solid dose vaccine formulation and delivery systems offer potential advantages over traditional liquid vaccine formulations. In addition to enhanced thermostability, needle-free delivery of unit solid dose injectable (USDI) vaccines offers safe, rapid, and error-free administration, with applicability to both human and animal health. Solid dose formulation technologies can be adapted for delivery of different vaccine formats including live attenuated vaccines, which remain the 'gold standard' for many disease targets. Porcine reproductive and respiratory syndrome viruses (PRRSV) cause one of the most economically important diseases affecting the global pig industry. Despite several shortcomings, live attenuated vaccines are widely used to control PRRSV. We optimised a freeze-dried USDI formulation of live attenuated PRRSV-1, which fully retained infectious titre, and evaluated its immunogenicity in comparison to virus delivered in liquid suspension via intramuscular and subcutaneous needle inoculation. Pigs vaccinated with the USDI formulation displayed vaccine viraemia, and PRRSV-specific antibody and T cell responses comparable to animals immunised with the liquid vaccine. The USDI vaccine formulation was stable for at least 6 months when stored refrigerated. These data demonstrate the potential for a solid dose vaccine delivery system as an alternative to conventional needle-syringe delivery of live attenuated PRRSV vaccines.

3.
J Virol ; 90(4): 1964-72, 2016 02 15.
Article in English | MEDLINE | ID: mdl-26656681

ABSTRACT

UNLABELLED: Studies evaluating the immunogenicity of two pediatric tick-borne encephalitis virus (TBEV) vaccines have reported contradictory results. These vaccines are based on two different strains of the European TBEV subtype: FSME-Immun Junior is based on the Neudörfl (Nd) strain, whereas Encepur Children is based on the Karlsruhe (K23) strain. The antibody (Ab) response induced by these two vaccines might be influenced by antigenic differences in the envelope (E) protein, which is the major target of neutralizing antibodies. We used an established hybrid virus assay platform to compare the levels of induction of neutralizing antibodies against the two vaccine virus strains in children aged 1 to 11 years who received two immunizations with FSME-Immun Junior or Encepur Children. The influence of amino acid differences between the E proteins of the Nd and K23 vaccine strains was investigated by mutational analyses and three-dimensional computer modeling. FSME-Immun Junior induced 100% seropositivity and similar neutralizing antibody titers against hybrid viruses containing the TBEV E protein of the two vaccine strains. Encepur Children induced 100% seropositivity only against the hybrid virus containing the E protein of the homologous K23 vaccine strain. Antibody responses induced by Encepur Children to the hybrid virus containing the E protein of the heterologous Nd strain were substantially and significantly (P < 0.001) lower than those to the K23 vaccine strain hybrid virus. Structure-based mutational analyses of the TBEV E protein indicated that this is due to a mutation in the DI-DII hinge region of the K23 vaccine strain E protein which may have occurred during production of the vaccine seed virus and which is not present in any wild-type TBE viruses. IMPORTANCE: Our data suggest that there are major differences in the abilities of two European subtype pediatric TBEV vaccines to induce antibodies capable of neutralizing heterologous TBEV strains. This is a result of a mutation in the DI-DII hinge region of the E protein of the K23 vaccine virus strain used to manufacture Encepur Children which is not present in the Nd strain used to manufacture FSME-Immun Junior or in any other known naturally occurring TBEVs.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Encephalitis Viruses, Tick-Borne/immunology , Viral Vaccines/immunology , Child , Child, Preschool , DNA Mutational Analysis , Drug Stability , Female , Genomic Instability , Humans , Infant , Male , Models, Molecular , Mutation, Missense , Protein Conformation , Technology, Pharmaceutical , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology , Viral Vaccines/administration & dosage
4.
PLoS One ; 10(2): e0113963, 2015.
Article in English | MEDLINE | ID: mdl-25719901

ABSTRACT

BACKGROUND: A novel avian H7N9 virus with a high case fatality rate in humans emerged in China in 2013. We evaluated the immunogenicity and protective efficacy of a candidate Vero cell culture-derived whole-virus H7N9 vaccine in small animal models. METHODS: Antibody responses induced in immunized DBA/2J mice and guinea pigs were evaluated by hemagglutination inhibition (HI), microneutralization (MN), and neuraminidase inhibition (NAi) assays. T-helper cell responses and IgG subclass responses in mice were analyzed by ELISPOT and ELISA, respectively. Vaccine efficacy against lethal challenge with wild-type H7N9 virus was evaluated in immunized mice. H7N9-specific antibody responses induced in mice and guinea pigs were compared to those induced by a licensed whole-virus pandemic H1N1 (H1N1pdm09) vaccine. RESULTS: The whole-virus H7N9 vaccine induced dose-dependent H7N9-specific HI, MN and NAi antibodies in mice and guinea pigs. Evaluation of T-helper cell responses and IgG subclasses indicated the induction of a balanced Th1/Th2 response. Immunized mice were protected against lethal H7N9 challenge in a dose-dependent manner. H7N9 and H1N1pdm09 vaccines were similarly immunogenic. CONCLUSIONS: The induction of H7N9-specific antibody and T cell responses and protection against lethal challenge suggest that the Vero cell culture-derived whole-virus vaccine would provide an effective intervention against the H7N9 virus.


Subject(s)
Influenza A Virus, H7N9 Subtype/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/prevention & control , Animals , Antibodies, Viral/immunology , Antibody Formation , Chlorocebus aethiops , Female , Guinea Pigs , Hemagglutination Inhibition Tests , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Immunoglobulin G/analysis , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H1N1 Subtype/physiology , Influenza A Virus, H7N9 Subtype/physiology , Interferon-gamma/analysis , Interleukin-4/analysis , Mice , Mice, Inbred DBA , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/mortality , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Vero Cells
5.
Virol J ; 11: 70, 2014 Apr 16.
Article in English | MEDLINE | ID: mdl-24739285

ABSTRACT

BACKGROUND: Convalescent plasma and fractionated immunoglobulins have been suggested as prophylactic or therapeutic interventions during an influenza pandemic. FINDINGS: Intravenous immunoglobulin (IVIG) preparations manufactured from human plasma collected before the 2009 H1N1 influenza pandemic, and post-pandemic hyperimmune (H)-IVIG preparations were characterized with respect to hemagglutination inhibition (HI), microneutralization (MN) and neuraminidase-inhibiting (NAi) antibody titers against pandemic H1N1 (pH1N1) and seasonal H1N1 (sH1N1) viruses. The protective efficacy of the IVIG and H-IVIG preparations was evaluated in a SCID mouse challenge model.Substantial levels of HI, MN and NAi antibodies against pH1N1 (GMTs 1:45, 1:204 and 1: 727, respectively) and sH1N1 (GMTs 1:688, 1:4,946 and 1:312, respectively) were present in pre-pandemic IVIG preparations. In post-pandemic H-IVIG preparations, HI, MN and NAi antibody GMTs against pH1N1 were 1:1,280, 1:11,404 and 1:2,488 (28-, 56- and 3.4-fold enriched), respectively, compared to pre-pandemic IVIG preparations (p < 0.001). Post-pandemic H-IVIG (HI titer 1:1,280) provided complete protection from lethality of SCID mice against pH1N1 challenge (100% of mice survived for 29 days post-challenge). Pre-pandemic IVIG (HI titer 1:70) did not provide significant protection against pH1N1 challenge (50% of mice survived 29 days post-challenge compared to 40% survival in the buffer control group). There was a highly significant correlation between circulating in vivo HI and MN antibody titers and survival (p < 0001). CONCLUSION: The substantial enrichment of HA- and NA-specific antibodies in H-IVIG and the efficacious protection of SCID mice against challenge with pH1N1 suggests H-IVIG as a promising intervention against pandemic influenza for immunocompromised patients and other risk groups.


Subject(s)
Antibodies, Viral/administration & dosage , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Immunoglobulins, Intravenous/administration & dosage , Influenza A Virus, H1N1 Subtype/immunology , Neuraminidase/antagonists & inhibitors , Orthomyxoviridae Infections/prevention & control , Viral Proteins/antagonists & inhibitors , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Immunocompromised Host , Mice , Mice, SCID , Neuraminidase/immunology , Survival Analysis , Treatment Outcome , Viral Proteins/immunology
6.
J Infect Dis ; 209(1): 12-23, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24041789

ABSTRACT

BACKGROUND: Children are highly vulnerable to infection with novel influenza viruses. It is essential to develop candidate pandemic influenza vaccines that are safe and effective in the pediatric population. METHODS: Infants and children aged 6-35 months and 3-8 years, respectively, were randomized to receive 2 immunizations with a 7.5-µg or 3.75-µg hemagglutinin (HA) dose of a nonadjuvanted whole-virus A/Vietnam(H5N1) vaccine; adolescents aged 9-17 years received a 7.5-µg dose only. A subset of participants received a booster immunization with an A/Indonesia(H5N1) vaccine approximately 1 year later. HA and neuraminidase antibody responses were assessed. RESULTS: Vaccination was safe and well tolerated; adverse reactions were transient and predominantly mild. Two immunizations with the 7.5-µg dose of A/Vietnam vaccine induced virus microneutralization (MN) titers of ≥1:20 against the A/Vietnam strain in 68.8%-85.4% of participants in the different age groups. After the booster, 93.1%-100% of participants achieved MN titers of ≥1:20 against the A/Vietnam and A/Indonesia strains. Neuraminidase-inhibiting antibodies were induced in ≥90% of participants after 2 immunizations with the 7.5 µg A/Vietnam vaccine and in 100% of participants after the booster. CONCLUSIONS: A whole-virus influenza A(H5N1) vaccine is suitable for prepandemic or pandemic immunization in a pediatric population. CLINICAL TRIALS REGISTRATION: NCT01052402.


Subject(s)
Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/administration & dosage , Adolescent , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Child , Child, Preschool , Chlorocebus aethiops , Female , Humans , Infant , Influenza Vaccines/adverse effects , Influenza Vaccines/immunology , Male , Vero Cells
7.
Open Forum Infect Dis ; 1(2): ofu072, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25734142

ABSTRACT

Neuraminidase-inhibiting (NAi) antibodies have been reported to be an independent correlate of protection from influenza disease, but the NAi antibody response to influenza vaccination has never been assessed in chronically ill or immunocompromised participants. Using an enzyme-linked lectin assay, we demonstrated that 2 immunizations with a Vero cell culture-derived, whole-virus H5N1 A/Vietnam vaccine induces NAi antibodies in 94.3% of chronically ill and 83.8% of immunocompromised participants. A booster with a heterologous A/Indonesia H5N1 vaccine induced comparable NAi antibody titers in both groups and resulted in 100% seropositivity. These data support prepandemic H5N1 vaccination strategies for these highly vulnerable risk groups.

8.
Vaccine ; 30(37): 5533-40, 2012 Aug 10.
Article in English | MEDLINE | ID: mdl-22749797

ABSTRACT

BACKGROUND: Preparation for an H5N1 influenza pandemic in humans could include priming the population in the pre-pandemic period with a vaccine produced from an existing H5N1 vaccine strain, with the possibility of boosting with a pandemic virus vaccine when it becomes available. We investigated the longevity of the immune response after one or two priming immunizations with a whole-virus H5N1 vaccine and the extent to which this can be boosted by later immunization with either a homologous or heterologous vaccine. METHODS: Mice received one or two priming immunizations with a Vero cell culture-derived, whole-virus clade 1 H5N1 vaccine formulated to contain either 750 ng or 30 ng hemagglutinin. Six months after the first priming immunization, mice received either a booster immunization with the same clade 1 vaccine or a heterologous clade 2.1 vaccine, or buffer. Humoral and cellular immune responses were evaluated before and at regular intervals after immunizations. Three weeks after booster immunization, mice were challenged with a lethal dose of wild-type H5N1 virus from clades 1, 2.1 or 2.2 and survival was monitored for 14 days. RESULTS: One or two priming immunizations with the 750 ng or 30 ng HA formulations, respectively, induced H5N1-neutralizing antibody titers which were maintained for ≥ 6 months and provided long-term cross-clade protection against wild-type virus challenge. Both humoral and cellular immune responses were substantially increased by a booster immunization after 6 months. The broadest protective immunity was provided by an immunization regimen consisting of one or two priming immunizations with a clade 1 vaccine and a boosting immunization with a clade 2.1 vaccine. CONCLUSIONS: These data support the concept that pre-pandemic vaccination can provide robust and long-lasting H5N1 immunity which could be effectively boosted by immunization either with another pre-pandemic vaccine or with the pandemic strain vaccine.


Subject(s)
Immunization, Secondary , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/immunology , Animals , Antibodies, Heterophile , Antibodies, Neutralizing , Chlorocebus aethiops , Cross Reactions/immunology , Dose-Response Relationship, Immunologic , Female , Immunity, Cellular/immunology , Immunity, Humoral , Immunization Schedule , Influenza A Virus, H5N1 Subtype/pathogenicity , Mice , Vero Cells/virology
9.
Vaccine ; 30(31): 4625-31, 2012 Jun 29.
Article in English | MEDLINE | ID: mdl-22580355

ABSTRACT

BACKGROUND: Influenza viruses of subtype A/H9N2 are enzootic in poultry across Asia and the Middle East and are considered to have pandemic potential. The development of new vaccine manufacturing technologies is a cornerstone of influenza pandemic preparedness. METHODS: A non-adjuvanted whole-virus H9N2 vaccine was developed using Vero cell culture manufacturing technology. The induction of hemagglutination inhibition (HI) and virus-neutralizing antibodies was assessed in CD1 mice and guinea pigs. A highly sensitive enzyme-linked lectin assay was used to investigate the induction of antibodies capable of inhibiting the enzymatic activity of the H9N2 neuraminidase. Protective efficacy against virus replication in the lung after challenge with the homologous virus was evaluated in BALB/c mice by a TCID(50) assay, and prevention of virus replication in the lung and associated pathology were evaluated by histology and immunohistochemistry. To investigate the ability of the vaccine to prevent severe disease, BALB/c mice were challenged with a highly virulent mouse-adapted H9N2 isolate which was generated by multiple lung-to-lung passage of wild-type virus. RESULTS: The vaccine elicited high titers of functional H9N2-specific HA antibodies in both mice and guinea pigs, as determined by HI and virus neutralization assays. High titer H9N2-specific neuraminidase inhibiting (NAi) antibodies were also induced in both species. Vaccinated mice were protected from lung virus replication in a dose-dependent manner after challenge with the homologous H9N2 virus. Immunohistochemical analyses confirmed the lack of virus replication in the lung and an associated substantial reduction in lung pathology. Dose-dependent protection from severe weight loss was also provided after challenge with the highly virulent mouse-adapted H9N2 virus. CONCLUSIONS: The induction of high titers of H9N2-specific HI, virus-neutralizing and NAi antibodies and dose-dependent protection from virus replication and severe disease in animal models suggest that the Vero cell culture-derived whole-virus vaccine will provide an effective intervention in the event of a H9N2 pandemic situation.


Subject(s)
Hemagglutinin Glycoproteins, Influenza Virus/immunology , Influenza A Virus, H9N2 Subtype/immunology , Influenza Vaccines/immunology , Neuraminidase/immunology , Orthomyxoviridae Infections/prevention & control , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Dose-Response Relationship, Immunologic , Female , Guinea Pigs , Hemagglutination Inhibition Tests , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Neutralization Tests , Orthomyxoviridae Infections/immunology , Weight Loss
10.
Transfusion ; 52(10): 2122-30, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22339168

ABSTRACT

BACKGROUND: Chikungunya virus (CHIKV) outbreaks were previously restricted to parts of Africa, Indian Ocean Islands, South Asia, and Southeast Asia. In 2007, however, the first autochthonous CHIKV transmission was reported in Europe. High-level viremia, a mosquito vector that is also present in large urban areas of Europe and America, and uncertainty around the resistance of this Alphavirus toward physiochemical inactivation processes raised concerns about the safety of plasma derivatives. To verify the safety margins of plasma products with respect to CHIKV, commonly used virus inactivation steps were investigated for their effectiveness to inactivate this newly emerging virus. STUDY DESIGN AND METHODS: Pasteurization for human serum albumin (HSA), vapor heating for Factor VIII inhibitor bypassing activity, solvent/detergent (S/D) treatment for intravenous immunoglobulin (IVIG), and incubation at low pH for IVIG were investigated for their capacity to inactivate CHIKV and the closely related Sindbis virus (SINV). The obtained results were compared to previous studies with West Nile virus and the commonly used model virus bovine viral diarrhea virus. RESULTS: The data generated demonstrate the effective inactivation of CHIKV as well as SINV by the inactivation steps investigated and thereby support results from earlier validation studies in which model viruses were used. CONCLUSION: High inactivation capacities with respect to CHIKV were demonstrated. This provides solid reassurance for the safety of plasma products and the results verify that the use of model viruses is appropriate to predict the inactivation characteristics of newly emerging viruses when their physicochemical properties are well characterized.


Subject(s)
Alphavirus Infections/prevention & control , Blood Coagulation Factors/isolation & purification , Blood Safety , Chikungunya virus/isolation & purification , Immunoglobulins, Intravenous/isolation & purification , Plasma/virology , Serum Albumin/isolation & purification , Virus Inactivation , Acids/pharmacology , Aged , Alphavirus Infections/blood , Alphavirus Infections/epidemiology , Alphavirus Infections/transmission , Animals , Cell Line/virology , Chikungunya virus/drug effects , Chikungunya virus/growth & development , Communicable Diseases, Emerging/prevention & control , Detergents/pharmacology , Disease Outbreaks , Freeze Drying , Global Health , Hot Temperature , Humans , Hydrogen-Ion Concentration , Pasteurization , Sindbis Virus/drug effects , Sindbis Virus/growth & development , Sindbis Virus/isolation & purification , Surface-Active Agents/pharmacology , Viral Load , Viremia/virology , West Nile virus/drug effects , West Nile virus/growth & development , West Nile virus/isolation & purification
11.
J Infect Dis ; 205(1): 28-34, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-22090447

ABSTRACT

A Vero cell-derived whole-virus H5N1 influenza vaccine has been shown to induce neutralizing antibodies directed against the hemagglutinin (HA) protein of diverse H5N1 strains in animal studies and clinical trials. However, neuraminidase-inhibiting (NAi) antibodies can reduce viral spread and may be of particular importance in the event of an H5N1 pandemic, where immunity due to HA antibodies is likely absent in the general population. Here we demonstrate the effective induction of NAi antibody titers after H5N1 vaccination in humans. In contrast to the immune response directed toward HA, a single vaccine dose induced a strong NAi response that was not significantly boosted by a second dose, most probably due to priming by previous vaccination or infection with seasonal influenza viruses. After 2 immunizations, seroconversion rates based on antibody titers against HA and NA were similar, indicating the induction of equally strong immune responses against both proteins by this H5N1 vaccine.


Subject(s)
Antibodies, Viral/blood , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/immunology , Neuraminidase/antagonists & inhibitors , Adolescent , Adult , Animals , Chlorocebus aethiops , Humans , Influenza Vaccines/administration & dosage , Influenza, Human/blood , Middle Aged , Vero Cells , Young Adult
12.
PLoS One ; 6(8): e23791, 2011.
Article in English | MEDLINE | ID: mdl-21876771

ABSTRACT

BACKGROUND: Vero cell culture-derived whole-virus H5N1 vaccines have been extensively tested in clinical trials and consistently demonstrated to be safe and immunogenic; however, clinical efficacy is difficult to evaluate in the absence of wide-spread human disease. A lethal mouse model has been utilized which allows investigation of the protective efficacy of active vaccination or passive transfer of vaccine induced sera following lethal H5N1 challenge. METHODS: We used passive transfer of immune sera to investigate antibody-mediated protection elicited by a Vero cell-derived, non-adjuvanted inactivated whole-virus H5N1 vaccine. Mice were injected intravenously with H5N1 vaccine-induced rodent or human immune sera and subsequently challenged with a lethal dose of wild-type H5N1 virus. RESULTS: Passive transfer of H5N1 vaccine-induced mouse, guinea pig and human immune sera provided dose-dependent protection of recipient mice against lethal challenge with wild-type H5N1 virus. Protective dose fifty values for serum H5N1 neutralizing antibody titers were calculated to be ≤1∶11 for all immune sera, independently of source species. CONCLUSIONS: These data underpin the confidence that the Vero cell culture-derived, whole-virus H5N1 vaccine will be effective in a pandemic situation and support the use of neutralizing serum antibody titers as a correlate of protection for H5N1 vaccines.


Subject(s)
Antibodies, Neutralizing/immunology , Immunization, Passive , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/immunology , Models, Immunological , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Animals , Antibodies, Neutralizing/blood , Dose-Response Relationship, Immunologic , Humans , Immune Sera/immunology , Influenza, Human/immunology , Influenza, Human/virology , Mice , Orthomyxoviridae Infections/virology , Survival Analysis , Titrimetry
13.
Vaccine ; 28(3): 650-6, 2010 Jan 08.
Article in English | MEDLINE | ID: mdl-19896446

ABSTRACT

Preparation for an H5N1 influenza pandemic in humans may involve priming the population with a vaccine produced from an existing, available H5N1 strain. We have used a mouse challenge model to compare the immunogenicity and efficacy of inactivated, Vero cell-derived, whole virus H5N1 vaccines in single immunization and homologous or heterologous prime-boost regimes. A single immunization was sufficient to protect against a lethal challenge with strains from matched and unmatched H5N1 clades. Homologous and heterologous prime-boost regimes induced cross-neutralizing antibodies and cross-protection against representative viruses of H5N1 clade 1, clade 2.1, clade 2.2 and clade 2.3. Moreover, the results indicate that heterologous prime-boost immunization regimes might broaden the specificity of the anti-H5N1 antibody response.


Subject(s)
Immunization, Secondary/methods , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Vaccination/methods , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Cross Protection , Cross Reactions , Disease Models, Animal , Female , Humans , Influenza Vaccines/administration & dosage , Mice , Orthomyxoviridae Infections/prevention & control , Survival Analysis
14.
Expert Rev Vaccines ; 8(5): 607-18, 2009 May.
Article in English | MEDLINE | ID: mdl-19397417

ABSTRACT

The development of cell culture systems for virus propagation has led to major advances in virus vaccine development. Primary and diploid cell culture systems are now being replaced by the use of continuous cell lines (CCLs). These substrates are gaining increasing acceptance from regulatory authorities as improved screening technologies remove fears regarding their potential oncogenic properties. The Vero cell line is the most widely accepted CCL by regulatory authorities and has been used for over 30 years for the production of polio and rabies virus vaccines. The recent licensure of a Vero cell-derived live virus vaccine (ACAM2000, smallpox vaccine) has coincided with an explosion in the development of a range of new viral vaccines, ranging from live-attenuated pediatric vaccines against rotavirus infections to inactivated whole-virus vaccines against H5N1 pandemic influenza. These developments have illustrated the value of this cell culture platform in the rapid development of vaccines against a range of virus diseases.


Subject(s)
Viral Vaccines/biosynthesis , Animals , Cell Culture Techniques , Chlorocebus aethiops , Drug Approval , Humans , Influenza A Virus, H5N1 Subtype/immunology , Rabies virus/immunology , Rotavirus/immunology , Smallpox/immunology , Vaccines, Attenuated/immunology , Vaccines, Inactivated/immunology , Vero Cells , Viral Vaccines/genetics
15.
Biol Chem ; 389(5): 569-77, 2008 May.
Article in English | MEDLINE | ID: mdl-18953724

ABSTRACT

The rapid spread of avian influenza (H5N1) and its transmission to humans has raised the possibility of an imminent pandemic and concerns over the ability of standard influenza vaccine production methods to supply sufficient amounts of an effective vaccine. We report here on a robust and flexible strategy which uses wild-type virus grown in a continuous cell culture (Vero) system to produce an inactivated whole virus vaccine. Candidate vaccines based on clade 1 and clade 2 influenza H5N1 strains, produced at a variety of manufacturing scales, were demonstrated to be highly immunogenic in animal models without the need for adjuvant. The vaccines induce cross-neutralising antibodies and are protective in a mouse challenge model not only against the homologous virus but against other H5N1 strains, including those from other clades. These data indicate that cell culture-grown, whole virus vaccines, based on the wild-type virus, allow the rapid high-yield production of a candidate pandemic vaccine.


Subject(s)
Disease Outbreaks , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/immunology , Influenza, Human/immunology , Animals , Antibodies, Viral/analysis , Antibodies, Viral/biosynthesis , Antibody Specificity , Cell Line , Chlorocebus aethiops , Enzyme-Linked Immunosorbent Assay , Fermentation , Guinea Pigs , Hemagglutination Tests , Humans , Immunodiffusion , Influenza Vaccines/therapeutic use , Influenza, Human/prevention & control , Mice , Neutralization Tests , Vero Cells
16.
Vaccine ; 25(32): 6028-36, 2007 Aug 10.
Article in English | MEDLINE | ID: mdl-17614165

ABSTRACT

The rapid spread and the transmission to humans of avian influenza virus (H5N1) have induced world-wide fears of a new pandemic and raised concerns over the ability of standard influenza vaccine production methods to rapidly supply sufficient amounts of an effective vaccine. We report here on a robust and flexible strategy which uses wild-type virus grown in a continuous cell culture (Vero) system to produce an inactivated whole virus vaccine. Candidate vaccines based on clade 1 and clade 2 influenza H5N1 strains were developed and demonstrated to be highly immunogenic in animal models. The vaccines induce cross-neutralising antibodies, highly cross-reactive T-cell responses and are protective in a mouse challenge model not only against the homologous virus but also against other H5N1 strains, including those from another clade. These data indicate that cell culture-grown whole virus vaccines, based on the wild-type virus, allow the rapid high yield production of a candidate pandemic vaccine.


Subject(s)
Cross Reactions/immunology , Influenza A Virus, H5N1 Subtype/classification , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Vaccines, Inactivated/immunology , Animals , Chlorocebus aethiops , Guinea Pigs , Mice , Orthomyxoviridae Infections/virology , T-Lymphocytes, Helper-Inducer/immunology , Vero Cells
17.
Clin Vaccine Immunol ; 13(7): 747-57, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16829611

ABSTRACT

The FP9 strain of F has been described as a more immunogenic recombinant vaccine vector than the Webster FPV-M (FPW) strain (R. J. Anderson et al., J. Immunol. 172:3094-3100, 2004). This study expands the comparison to include two separate recombinant antigens and multiple, rather than single, independent viral clones derived from the two strains. Dual-poxvirus heterologous prime-boost vaccination regimens using individual clones of recombinant FP9 or FPW in combination with recombinant modified V Ankara expressing the same antigen were evaluated for their ability to elicit T-cell responses against recombinant antigens from Plasmodium berghei (circumsporozoite protein) or human immunodeficiency virus type 1 (a Gag-Pol-Nef fusion protein). Gamma interferon enzyme-linked immunospot assay and fluorescence-activated cell sorting assays of the responses to specific epitopes confirmed the approximately twofold-greater cellular immunogenicity of FP9 compared to FPW, when given as the priming or boosting immunization. Equality of transgene expression in mouse cells infected with the two strains in vitro was verified by Western blotting. Directed partial sequence analysis and PCR analysis of FPW and comparison to available whole-genome sequences revealed that many loci that are mutated in the highly attenuated and culture-adapted FP9 strain are wild type in FPW, including the seven multikilobase deletions. These "passage-specific" alterations are hypothesized to be involved in determining the immunogenicity of fowlpox virus as a recombinant vaccine vector.


Subject(s)
Fowlpox virus/classification , Fowlpox virus/immunology , Genetic Vectors/immunology , HIV-1/genetics , Plasmodium berghei/immunology , T-Lymphocytes/immunology , Vaccines, DNA/immunology , AIDS Vaccines/genetics , AIDS Vaccines/immunology , Animals , Female , Fowlpox virus/genetics , Fusion Proteins, gag-pol/genetics , Fusion Proteins, gag-pol/immunology , Gene Products, nef/genetics , Gene Products, nef/immunology , Gene Products, nef/metabolism , HIV-1/immunology , Humans , Immunization, Secondary , Interferon-gamma/metabolism , Malaria Vaccines/genetics , Malaria Vaccines/immunology , Mice , Mice, Inbred BALB C , Plasmodium berghei/genetics , Polyproteins/genetics , Polyproteins/immunology , Protozoan Proteins/genetics , Protozoan Proteins/immunology , Vaccination , nef Gene Products, Human Immunodeficiency Virus
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