Novel influenza vaccine M2SR protects against drifted H1N1 and H3N2 influenza virus challenge in ferrets with pre-existing immunity (original) (raw)
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Pandemic H1N1 vaccine requires the use of an adjuvant to protect against challenge in naïve ferrets
Vaccine, 2011
In the context of an A/H1N1 influenza pandemic situation, this study demonstrates that heterologous vaccination with an AS03-adjuvanted 2008/2009 seasonal trivalent and pandemic H5N1 monovalent split vaccine conferred partial protection in influenza-naïve ferrets after challenge with the influenza pandemic H1N1 A/The Netherlands/602/09 virus. Further, unlike saline control and non-adjuvanted vaccine, it was shown that immunization of naïve ferrets with an AS03-adjuvanted pandemic H1N1 A/California/7/09 influenza split vaccine induced increased antibody response and enhanced protection against the challenge strain, including significant reduction in viral shedding in the upper respiratory tract and reduced lung pathology post-challenge. These results show the need for vaccination with the adjuvanted vaccine to fully protect against viral replication and influenza disease in unprimed ferrets.
Pandemic H1N1 vaccine requires the use of an adjuvant to protect against challenge in na�ve ferrets
Vaccine, 2011
In the context of an A/H1N1 influenza pandemic situation, this study demonstrates that heterologous vaccination with an AS03-adjuvanted 2008/2009 seasonal trivalent and pandemic H5N1 monovalent split vaccine conferred partial protection in influenza-naïve ferrets after challenge with the influenza pandemic H1N1 A/The Netherlands/602/09 virus. Further, unlike saline control and non-adjuvanted vaccine, it was shown that immunization of naïve ferrets with an AS03-adjuvanted pandemic H1N1 A/California/7/09 influenza split vaccine induced increased antibody response and enhanced protection against the challenge strain, including significant reduction in viral shedding in the upper respiratory tract and reduced lung pathology post-challenge. These results show the need for vaccination with the adjuvanted vaccine to fully protect against viral replication and influenza disease in unprimed ferrets.
npj Vaccines, 2017
Influenza viruses evade human adaptive immune responses due to continuing antigenic changes. This makes it necessary to re-formulate and re-administer current seasonal influenza vaccines on an annual basis. Our pan-influenza vaccination approach attempts to redirect antibody responses from the variable, immuno-dominant hemagglutinin head towards the conserved—but immuno-subdominant—hemagglutinin stalk. The strategy utilizes sequential immunization with chimeric hemagglutinin-based vaccines expressing exotic head domains, and a conserved hemagglutinin stalk. We compared a live-attenuated influenza virus prime followed by an inactivated split-virus boost to two doses of split-virus vaccines and assessed the impact of adjuvant on protection against challenge with pandemic H1N1 virus in ferrets. All tested immunization regimens successfully induced broadly cross-reactive antibody responses. The combined live-attenuated/split virus vaccination conferred superior protection against pandem...
Journal of Virology, 2011
Serum antibodies induced by seasonal influenza or seasonal influenza vaccination exhibit limited or no cross-reactivity against the 2009 pandemic swine-origin influenza virus of the H1N1 subtype (pH1N1). Ferrets immunized once or twice with MF59-adjuvanted seasonal influenza vaccine exhibited significantly reduced lung virus titers but no substantial clinical protection against pH1N1-associated disease. However, priming with MF59-adjuvanted seasonal influenza vaccine significantly increased the efficacy of a pandemic MF59adjuvanted influenza vaccine against pH1N1 challenge. Elucidating the mechanism involved in this priming principle will contribute to our understanding of vaccine-and infection-induced correlates of protection. Furthermore, a practical consequence of these findings is that during an emerging pandemic, the implementation of a priming strategy with an available adjuvanted seasonal vaccine to precede the eventual pandemic vaccination campaign may be useful and life-saving.
Journal of virology, 2017
Most pre-clinical animal studies test influenza vaccines in immunologically naïve animal models, even though the results of vaccination may not accurately reflect the effectiveness of vaccine candidates in humans that have pre-existing immunity to influenza. In this study, novel, broadly-reactive influenza vaccine candidates were assessed in pre-immune ferrets. These animals were infected with different H1N1 isolates before being vaccinated or infected with another influenza virus. Previously, our group has described the design and characterization of computationally optimized broadly reactive HA antigens (COBRA) for H1N1 isolates. Vaccinating ferrets with virus-like particle (VLP) vaccines expressing COBRA HA proteins elicited antibodies with HAI activity against more H1N1 viruses in the panel than VLP vaccines expressing wild-type HA proteins. Specifically, ferrets infected with the 1986 virus and vaccinated with a single dose of the COBRA HA VLP vaccines elicited antibodies with ...
Vaccine, 2011
The identification of immune correlates of protection against highly pathogenic human-adapted influenza is instrumental in the development of the next generation of vaccines. Towards this, ferrets received either one dose of a conventionally produced vaccine, two inoculations of a hemagglutinin (HA)-expressing DNA vaccine, or a prime-boost regimen of the DNA vaccine followed by injection of a HA-expressing adenoviral vector. In addition to the antibody response, ferret-specific interferon-gamma (IFN-␥) ELISpot and flow cytometry assays were developed to follow the cellular immune response. Animals that received the conventional vaccine mounted a humoral response, while the DNA vaccinated groups also developed IFN-␥ producing T cells. Upon challenge with the matched highly pathogenic A/South Carolina/1/18 H1N1 influenza A virus, the conventionally vaccinated group developed moderate to severe signs of disease, whereas the DNA vaccinated animals experienced mild disease. In the presence of an antibody response within the protective range, the extent of the T cell response correlated more accurately with reduced morbidity in vaccinated ferrets.
BioMed Research International
Background. Currently, two genetic lineages of influenza B virus, B/Victoria and B/Yamagata, are cocirculating in humans in various countries. This situation has raised a question regarding the possibility of cross-protection between B components of live attenuated influenza vaccine (LAIV) belonging to different lineages. This study aimed to assess in naïve ferrets the potential protective activity of monovalent B-LAIVs against challenge with homologous and heterologous wild-type (WT) influenza B viruses. Methods. Groups of seronegative female ferrets 5-6 months of age were given one dose of monovalent LAIV based on B/Victoria or B/Yamagata lineage virus. Ferrets were challenged 21 days later with B/Victoria or B/Yamagata WT virus. Ferrets were monitored closely for clinical signs and morbidity outcomes including febrile response, body weight loss, nasal symptoms, and level of activity one week prior to vaccination and for three days following vaccination/challenge. Nasal washes wer...
Pathogenicity testing of influenza candidate vaccine viruses in the ferret model
Virology, 2017
The development of influenza candidate vaccine viruses (CVVs) for pre-pandemic vaccine production represents a critical step in pandemic preparedness. The multiple subtypes and clades of avian or swine origin influenza viruses circulating world-wide at any one time necessitates the continuous generation of CVVs to provide an advanced starting point should a novel zoonotic virus cross the species barrier and cause a pandemic. Furthermore, the evolution and diversity of novel influenza viruses that cause zoonotic infections requires ongoing monitoring and surveillance, and, when a lack of antigenic match between circulating viruses and available CVVs is identified, the production of new CVVs. Pandemic guidelines developed by the WHO Global Influenza Program govern the design and preparation of reverse genetics-derived CVVs, which must undergo numerous safety and quality tests prior to human use. Confirmation of reassortant CVV attenuation of virulence in ferrets relative to wild-type ...
Vaccine, 2017
The emergence of highly pathogenic avian influenza H5N1 viruses has heightened global concern about the threat posed by pandemic influenza. To address the need for a highly effective universal influenza vaccine, we developed a novel M2-deficient single replication (M2SR) influenza vaccine virus and previously reported that it provided strong heterosubtypic protection against seasonal influenza viruses in mice. In the current study, we assessed M2SR induced protection against H5N1 influenza in mice and ferrets. Mice were intranasally inoculated with M2SR viruses containing the HA and NA from A/Vietnam/1203/2004 (M2SR H5N1) or A/California/07/2009 (M2SR H1N1). All M2SR vaccinated mice survived lethal challenge with influenza A/Vietnam/1203/2004 (H5N1), whereas 40% of mice vaccinated with recombinant H5 HA and none of the naïve controls survived. M2SR H5N1 provided sterile immunity, whereas low levels of virus were detected in the lungs of some M2SR H1N1 vaccinated mice. In contrast, recombinant H5 HA vaccinated mice and naïve controls showed systemic infection. M2SR H5N1 induced strong serum and mucosal antibody responses (IgG and IgA classes) against H5 HA, with high hemagglutination inhibition (HAI) titers. In contrast, while M2SR H1N1 elicited crossreactive antibodies recognizing the H5 HA2 stalk region or the neuraminidase, no HAI activity against H5N1 virus was detected after M2SR H1N1 immunization. Both M2SR H5N1 and H1N1 also protected ferrets against lethal challenge with A/Vietnam/1203/2004. A prime-boost regimen provided optimal protection with no virus detected in the respiratory tract or brain after challenge. As in the mouse model, only the M2SR H5N1 vaccine induced HAI antibodies against the challenge virus in ferrets, while the M2SR H1N1 was able to provide protection without the induction of HAI antibodies. In summary, effective protection against highly pathogenic H5N1 influenza virus was provided by both homologous H5N1 M2SR and heterologous H1N1 M2SR demonstrating the cross-protective attributes of the M2SR platform.
Journal of General Virology, 1989
Neonatal ferrets are protected against infection with influenza virus by milk-derived anti-influenza virus IgG after suckling on an immune mother. Live vaccines protect better than killed vaccines despite their stimulation of lower maternal haemagglutination-inhibiting antibody levels. This suggests that antibody to virus proteins other than the haemagglutinin may also be involved. To investigate this, adult ferrets were immunized intradermally with live vaccinia-influenza virus recombinants each expressing one of the 10 influenza virus polypeptides. Adult ferrets immunized with a recombinant expressing the H3 haemagglutinin were completely protected, and also passively protected their offspring, against a live challenge with clone 7a of the reassortant influenza virus A/Puerto Rico/8/34-A/England/939/69 (H3N2), immunity being mediated by IgG antibody. However, ferrets immunized similarly with recombinants expressing the H1 haemagglutinin, neuraminidase (N1 or N2), polymerases (PB1, PB2 or PAC), matrix protein (M1 or M2), nucleoprotein (NP) or non-structural proteins (NS1 or NS2) were completely susceptible to the influenza virus.
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2021
BACKGROUND Current influenza vaccines are strain-specific and demonstrate low vaccine efficacy against H3N2 influenza disease, especially when vaccine is mis-matched to circulating virus. The novel influenza vaccine candidate, M2SR (M2-deficient Single Replication), induces a broad, multi-effector immune response. METHODS A phase 2 challenge study was conducted to assess efficacy of M2SR vaccine expressing HA and NA from A/Brisbane/10/2007 (H3N2, clade 1). Four weeks after vaccination subjects were challenged with antigenically distinct H3N2 virus (A/Belgium/4217/2015, clade 3C.3b), and assessed for infection and clinical symptoms. RESULTS Adverse events following vaccination were mild and similar in frequency between placebo and M2SR recipients. A single dose of Bris2007 M2SR induced neutralizing antibody to the vaccine (48% of recipients) and challenge strain (27% of recipients). Overall, 54% of M2SR subjects were infected after challenge, compared to 71% of placebo subjects. The ...
Vaccines, 2021
M2SR (M2-deficient single replication) is an investigational live intranasal vaccine that protects against multiple influenza A subtypes in influenza-naïve and previously infected ferrets. We conducted a phase 1, first-in-human, randomized, dose-escalation, placebo-controlled study of M2SR safety and immunogenicity. Adult subjects received a single intranasal administration with either placebo or one of three M2SR dose levels (106, 107 or 108 tissue culture infectious dose (TCID50)) expressing hemagglutinin and neuraminidase from A/Brisbane/10/2007 (H3N2) (24 subjects per group). Subjects were evaluated for virus replication, local and systemic reactions, adverse events (AE), and immune responses post-vaccination. Infectious virus was not detected in nasal swabs from vaccinated subjects. At least one AE (most commonly mild nasal rhinorrhea/congestion) was reported among 29%, 58%, and 83% of M2SR subjects administered a low, medium or high dose, respectively, and among 46% of placebo...
Journal of Biological Chemistry, 2020
One strategy for the development of a next generation influenza vaccine centers upon using conserved domains of the virus to induce broader and long-lasting immune responses. The production of artificial proteins by mimicking native-like structure has shown to be a promising approach for vaccine design against diverse enveloped viruses. The amino terminus of Influenza A virus Matrix 2 ectodomain (M2e) is highly conserved among influenza subtypes, and previous studies have shown M2e-based vaccines are strongly immunogenic, making it an attractive target for further exploration. We hypothesized that stabilizing M2e protein in the mammalian system might influence the immunogenicity of M2e with the added advantage to robustly produce the large scale of proteins with nativelike fold and hence can act as an efficient vaccine candidate. In this study, we created an engineered construct in which the amino terminus of M2e is linked to the tetramerizing domain tGCN4, expressed the construct in a mammalian system and tested for immunogenicity in BALB/c mice. We have also constructed a stand-alone M2e construct (without tGCN4) and compared the protein expressed in mammalian cells and in E. coli using in vitro and in vivo methods. The mammalian-expressed protein was found to be more stable, antigenic than the E. coli protein, and form higher-order oligomers. In an intramuscular protein priming and boosting regimen in mice, these proteins induced high titers of antibodies and elicited a mixed Th1/Th2 response. These results highlight the mammalian expressed M2e soluble proteins as a promising vaccine development platform.
Immune Imprinting in the Influenza Ferret Model
Vaccines, 2020
The initial exposure to influenza virus usually occurs during childhood. This imprinting has long-lasting effects on the immune responses to subsequent infections and vaccinations. Animal models that are used to investigate influenza pathogenesis and vaccination do recapitulate the pre-immune history in the human population. The establishment of influenza pre-immune ferret models is necessary for understanding infection and transmission and for designing efficacious vaccines.
Frontiers in Immunology, 2020
There is an urgent need for effective countermeasures against the current emergence and accelerating expansion of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Induction of herd immunity by mass vaccination has been a very successful strategy for preventing the spread of many infectious diseases, hence protecting the most vulnerable population groups unable to develop immunity, for example individuals with immunodeficiencies or a weakened immune system due to underlying medical or debilitating conditions. Therefore, vaccination represents one of the most promising counter-pandemic measures to COVID-19. However, to date, no licensed vaccine exists, neither for SARS-CoV-2 nor for the closely related SARS-CoV or Middle East respiratory syndrome-CoV. In addition, a few vaccine candidates have only recently entered human clinical trials, which hampers the progress in tackling COVID-19 infection. Here, we discuss potential prophylactic interventions for SARS-CoV-2 with a focus on the challenges existing for vaccine development, and we review pre-clinical progress and ongoing human clinical trials of COVID-19 vaccine candidates. Although COVID-19 vaccine development is currently accelerated via so-called fast-track programs, vaccines may not be timely available to have an impact on the first wave of the ongoing COVID-19 pandemic. Nevertheless, COVID-19 vaccines will be essential in the future for reducing morbidity and mortality and inducing herd immunity, if SARS-CoV-2 becomes established in the population like for example influenza virus.
Viruses, 2020
On average, there are 3–5 million severe cases of influenza virus infections globally each year. Seasonal influenza vaccines provide limited protection against divergent influenza strains. Therefore, the development of a universal influenza vaccine is a top priority for the NIH. Here, we report a comprehensive summary of all universal influenza vaccines that were tested in clinical trials during the 2010–2019 decade. Of the 1597 studies found, 69 eligible clinical trials, which investigated 27 vaccines, were included in this review. Information from each trial was compiled for vaccine target, vaccine platform, adjuvant inclusion, clinical trial phase, and results. As we look forward, there are currently three vaccines in phase III clinical trials which could provide significant improvement over seasonal influenza vaccines. This systematic review of universal influenza vaccine clinical trials during the 2010–2019 decade provides an update on the progress towards an improved influenza...
Better influenza vaccines: an industry perspective
Journal of Biomedical Science, 2020
Vaccination is the most effective measure at preventing influenza virus infections. However, current seasonal influenza vaccines are only protective against closely matched circulating strains. Even with extensive monitoring and annual reformulation our efforts remain one step behind the rapidly evolving virus, often resulting in mismatches and low vaccine effectiveness. Fortunately, many next-generation influenza vaccines are currently in development, utilizing an array of innovative techniques to shorten production time and increase the breadth of protection. This review summarizes the production methods of current vaccines, recent advances that have been made in influenza vaccine research, and highlights potential challenges that are yet to be overcome. Special emphasis is put on the potential role of glycoengineering in influenza vaccine development, and the advantages of removing the glycan shield on influenza surface antigens to increase vaccine immunogenicity. The potential f...
Vaccines
Seasonal influenza and the threat of global pandemics present a continuing threat to public health. However, conventional inactivated influenza vaccines (IAVs) provide little cross-protective immunity and suboptimal efficacy, even against well-matched strains. Furthermore, the protection against matched strains has been shown to be of a short duration in both mouse models and humans. M2SR (M2-deficient single-replication influenza virus) is a single-replication vaccine that has been shown to provide effective cross-protection against heterosubtypic influenza viruses in both mouse and ferret models. In the present study, we investigated the duration and mechanism of heterosubtypic protection induced by M2SR in a mouse model. We previously showed that M2SR generated from influenza A/Puerto Rico/8/34 (H1N1) significantly protected C57BL/6 mice against lethal challenge with both influenza A/Puerto Rico/8/34 (H1N1, homosubtypic) and influenza A/Aichi/2/1968 (H3N2, heterosubtypic), wherea...
Vaccines
Current influenza vaccines demonstrate low vaccine efficacy, especially when the predominantly circulating strain and vaccine are mismatched. The novel influenza vaccine platform M2- or BM2-deficient single replication (M2SR and BM2SR) has been shown to safely induce strong systemic and mucosal antibody responses and provide protection against significantly drifted influenza strains. In this study, we demonstrate that both monovalent and quadrivalent (Quad) formulations of M2SR are non-pathogenic in mouse and ferret models, eliciting robust neutralizing and non-neutralizing serum antibody responses to all strains within the formulation. Following challenge with wildtype influenza strains, vaccinated mice and ferrets demonstrated reduced weight loss, decreased viral replication in the upper and lower airways, and enhanced survival as compared to mock control groups. Mice vaccinated with H1N1 M2SR were completely protected from heterosubtypic H3N2 challenge, and BM2SR vaccines provide...
Vaccines
Current SARS-CoV-2 vaccines provide protection for COVID-19-associated hospitalization and death, but remain inefficient at inhibiting initial infection and transmission. Despite updated booster formulations, breakthrough infections and reinfections from emerging SARS-CoV-2 variants are common. Intranasal vaccination to elicit mucosal immunity at the site of infection can improve the performance of respiratory virus vaccines. We developed SARS-CoV-2 M2SR, a dual SARS-CoV-2 and influenza vaccine candidate, employing our live intranasal M2-deficient single replication (M2SR) influenza vector expressing the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein of the prototype strain, first reported in January 2020. The intranasal vaccination of mice with this dual vaccine elicits both high serum IgG and mucosal IgA titers to RBD. Sera from inoculated mice show that vaccinated mice develop neutralizing SARS-CoV-2 antibody titers against the prototype and Delta virus strains, wh...
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Journal of Virology, 2009
As part of influenza pandemic preparedness, policy decisions need to be made about how best to utilize vaccines once they are manufactured. Since H5N1 avian influenza virus has the potential to initiate the next human pandemic, isolates of this subtype have been used for the production and testing of prepandemic vaccines. Clinical trials of such vaccines indicate that two injections of preparations containing adjuvant will be required to induce protective immunity. However, this is a working assumption based on classical serological measures only. Examined here are the dose of viral hemagglutinin (HA) and the number of inoculations required for two different H5N1 vaccines to achieve protection in ferrets after lethal H5N1 challenge. Ferrets inoculated twice with 30 g of A/Vietnam/1194/2004 HA vaccine with AlPO 4 , or with doses as low as 3.8 g of HA with Iscomatrix (ISCOMATRIX, referred to as Iscomatrix herein, is a registered trademark of CSL Limited) adjuvant, were completely protected against death and disease after H5N1 challenge, and the protection lasted at least 15 months. Cross-clade protection was also observed with both vaccines. Significantly, complete protection against death could be achieved with only a single inoculation of H5N1 vaccine containing as little as 15 g of HA with AlPO 4 or 3.8 g of HA with Iscomatrix adjuvant. Ferrets vaccinated with the single-injection Iscomatrix vaccines showed fewer clinical manifestations of infection than those given AlPO 4 vaccines and remained highly active. Our data provide the first indication that in the event of a future influenza pandemic, effective mass vaccination may be achievable with a low-dose "single-shot" vaccine and provide not only increased survival but also significant reduction in disease severity.
Clinical and Vaccine Immunology, 2010
Human influenza pandemics occur when influenza viruses to which the population has little or no immunity emerge and acquire the ability to achieve human-to-human transmission. In April 2009, cases of a novel H1N1 influenza virus in children in the southwestern United States were reported. It was retrospectively shown that these cases represented the spread of this virus from an ongoing outbreak in Mexico. The emergence of the pandemic led to a number of national vaccination programs. Surprisingly, early human clinical trial data have shown that a single dose of nonadjuvanted pandemic influenza A (H1N1) 2009 monovalent inactivated vaccine (pMIV) has led to a seroprotective response in a majority of individuals, despite earlier studies showing a lack of cross-reactivity between seasonal and pandemic H1N1 viruses. Here we show that previous exposure to a contemporary seasonal H1N1 influenza virus and to a lesser degree a seasonal influenza virus trivalent inactivated vaccine is able to prime for a higher antibody response after a subsequent dose of pMIV in ferrets. The more protective response was partially dependent on the presence of CD8 ؉ cells. Two doses of pMIV were also able to induce a detectable antibody response that provided protection from subsequent challenge. These data show that previous infection with seasonal H1N1 influenza viruses likely explains the requirement for only a single dose of pMIV in adults and that vaccination campaigns with the current pandemic influenza vaccines should reduce viral burden and disease severity in humans.
Journal of immunology (Baltimore, Md. : 1950), 2018
Influenza is a major health threat, and a broadly protective influenza vaccine would be a significant advance. Signal Minus FLU (S-FLU) is a candidate broadly protective influenza vaccine that is limited to a single cycle of replication, which induces a strong cross-reactive T cell response but a minimal Ab response to hemagglutinin after intranasal or aerosol administration. We tested whether an H3N2 S-FLU can protect pigs and ferrets from heterosubtypic H1N1 influenza challenge. Aerosol administration of S-FLU to pigs induced lung tissue-resident memory T cells and reduced lung pathology but not the viral load. In contrast, in ferrets, S-FLU reduced viral replication and aerosol transmission. Our data show that S-FLU has different protective efficacy in pigs and ferrets, and that in the absence of Ab, lung T cell immunity can reduce disease severity without reducing challenge viral replication.
PLoS ONE, 2008
Background. Unprecedented spread between birds and mammals of highly pathogenic avian influenza viruses (HPAI) of the H5N1 subtype has resulted in hundreds of human infections with a high fatality rate. This has highlighted the urgent need for the development of H5N1 vaccines that can be produced rapidly and in sufficient quantities. Potential pandemic inactivated vaccines will ideally induce substantial intra-subtypic cross-protection in humans to warrant the option of use, either prior to or just after the start of a pandemic outbreak. In the present study, we evaluated a split H5N1 A/H5N1/Vietnam/1194/04, clade 1 candidate vaccine, adjuvanted with a proprietary oil-in-water emulsion based Adjuvant System proven to be well-tolerated and highly immunogenic in the human (Leroux-Roels et al. (2007) The Lancet 370:580-589), for its ability to induce intrasubtypic cross-protection against clade 2 H5N1/A/Indonesia/5/05 challenge in ferrets. Methodology and Principal Findings. All ferrets in control groups receiving non-adjuvanted vaccine or adjuvant alone failed to develop specific or cross-reactive neutralizing antibodies and all died or had to be euthanized within four days of virus challenge. Two doses of adjuvanted split H5N1 vaccine containing $1.7 mg HA induced neutralizing antibodies in the majority of ferrets to both clade 1 (17/23 (74%) responders) and clade 2 viruses (14/23 (61%) responders), and 96% (22/23) of vaccinees survived the lethal challenge. Furthermore lung virus loads and viral shedding in the upper respiratory tract were reduced in vaccinated animals relative to controls suggesting that vaccination might also confer a reduced risk of viral transmission. Conclusion. These protection data in a stringent challenge model in association with an excellent clinical profile highlight the potential of this adjuvanted H5N1 candidate vaccine as an effective tool in pandemic preparedness.
Vaccine, 2012
The pandemic H1N1 2009 influenza virus caused relatively mild disease in most infected people but some suffered extensively from primary lung infection, many more than would have occurred with seasonal influenza infection. Early commercially available pandemic H1N1 vaccines did not contain adjuvant, as did many of the subsequent vaccines, and could not stop infection with the pandemic virus in vaccinated ferrets. Nevertheless, we showed that virus loads in the lungs were greatly diminished in ferrets vaccinated once with an unadjuvanted pandemic vaccine and challenged with 10 6 EID 50 wildtype A/California/07/2009 (H1N1). In addition, a single inoculation with seasonal vaccine showed beneficial reduction in pandemic pulmonary virus loads in the absence of any detectable cross-reactive serological responses. Ferrets primed with either seasonal or pandemic vaccine and then boosted with pandemic vaccine also showed less extensive lung infection when challenged with a tenfold higher dose of pandemic virus. These results implicate non-classical protective mechanisms that prevent severe pulmonary disease but not viral shedding and imply that particular non-adjuvanted vaccines may have retained the ability to induce these responses.
Journal of Virology, 2013
The clinical symptoms caused by infection with influenza A virus vary widely and depend on the strain causing the infection, the dose and route of inoculation, and the presence of preexisting immunity. In most cases, seasonal influenza A viruses cause relatively mild upper respiratory tract disease, while sometimes patients develop an acute severe pneumonia. Heterosubtypic immunity induced by previous infections with influenza A viruses may dampen the development of clinical symptoms caused by infection with influenza A viruses of another subtype, as is the case during influenza pandemics. Here we show that ferrets acquire protective immunity after infection of the upper respiratory tract with a seasonal influenza A(H3N2) virus against subsequent infection with influenza A(H1N1)pdm09 virus inoculated by the intranasal route. However, protective heterosubtypic immunity was afforded locally, since the prior infection with the A(H3N2) virus did not provide protection against the development of pneumonia induced after intratracheal inoculation with the A(H1N1)pdm09 virus. Interestingly, some of these animals developed more severe disease than that observed in naïve control animals. These findings are of interest in light of the development of so-called universal influenza vaccines that aim at the induction of cross-reactive T cell responses.
Influenza and Other Respiratory Viruses, 2020
BackgroundThe 2009 pandemic H1N1 (A(H1N1)pdm09) influenza A virus (IAV) has replaced the previous seasonal H1N1 strain in humans and continues to circulate worldwide. The comparative performance of inactivated A(H1N1)pdm09 influenza vaccines remains of considerable interest. The objective of this study was to evaluate the efficacy of two licensed A(H1N1)pdm09 inactivated vaccines (AS03B adjuvanted split virion Pandemrix from GlaxoSmithKline and referred here as (V1) and non‐adjuvanted whole virion Celvapan from Baxter and referred here as (V2)) in ferrets as a pre‐clinical model for human disease intervention.MethodsNaïve ferrets were divided into two groups (V1 and V2) and immunised intramuscularly with two different A/California/07/2009‐derived inactivated vaccines, V1 administered in a single dose and V2 administered in 2 doses separated by 21 days. Six weeks after the first immunisation, vaccinated animals and a non‐vaccinated control (NVC) group were intra‐nasally challenged wi...
Efficacy of A/H1N1/2009 split inactivated influenza A vaccine (GC1115) in mice and ferrets
Journal of Microbiology
To evaluate the efficacy of a non-adjuvant A/H1N1/2009 influenza A vaccine (GC1115), we demonstrated the immunogenicity and protective efficacy of GC1115 in mouse and ferret models. The immunogenicity of GC1115 was confirmed after intramuscular administration of 1.875, 3.75, 7.5, and 15 μg hemagglutinin antigen (HA) in mice and 7.5, 15, and 30 μg HA in ferrets at 3-week intervals. A single immunization with GC1115 at HA doses > 7.5 μg induced detectable seroconversion in most mice, and all mice given a second dose exhibited high antibody responses in a dose-dependent manner. The mice in the mock (PBS) and 1.875 μg HA immunized groups succumbed by 13 days following A/California/04/09 infection, while all mice in groups given more than 3.75 μg HA were protected from lethal challenge with the A/California/04/09 virus. In ferrets, although immunization with even a single dose of 15 or 30 μg of HA induced detectable HI antibodies, all ferrets given two doses of vaccine seroconverted and exhibited HI titers greater than 80 units. Following challenge with A/California/04/09, the mock (PBS) immunized ferrets showed influenza-like clinical symptoms, such as increased numbers of coughs, elevated body temperature, and body weight loss, for 7 days, while GC1115immunized ferrets showed attenuated clinical symptoms only for short time period (3-4 days). Further, GC1115-immunized ferrets displayed significantly lower viral titers in the upper respiratory tract (nasal cavity) than the mock vaccinated group in a dose-dependent manner. Taken together, this study demonstrates the immunogenicity and protective efficacy of GC1115 as a non-adjuvanted vaccine.
PLOS ONE
Background and aim The majority of seasonal influenza vaccines are trivalent, containing two A virus strains (H1N1 and H3N2) and one B virus strain. The co-circulation of two distinct lineages of B viruses can lead to mismatch between the influenza B virus strain recommended for the trivalent seasonal vaccine and the circulating B virus. This has led some manufacturers to produce quadrivalent influenza vaccines containing one strain from each B lineage in addition to H1N1 and H3N2 strains. However, it is also important to know whether vaccines containing a single influenza B strain can provide cross-protectivity against viruses of the antigenically distinct lineage. The aim of this study was to assess in naïve ferrets the potential crossprotective activity of trivalent live attenuated influenza vaccine (T-LAIV) against challenge with a heterologous wild-type influenza B virus belonging to the genetically different lineage and to compare this activity with effectiveness of quadrivalent LAIV (Q-LAIV) in the ferret model. Methods and results Ferrets were vaccinated with either one dose of trivalent LAIV containing B/Victoria or B/ Yamagata lineage virus, or quadrivalent LAIV (containing both B lineages), or placebo. They were then challenged with B/Victoria or B/Yamagata lineage wild-type virus 28 days after vaccination. The ferrets were monitored for clinical signs and morbidity. Nasal swabs and lung tissue samples were analyzed for the presence of challenge virus. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay. All LAIVs tested were found to be safe and effective against wild-type influenza B viruses
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