scholarly journals 159. efficacy of CD377, a Novel Antiviral Fc-conjugate, Against Seasonal Influenza in Lethal Mouse Infection Models

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S209-S209
Author(s):  
James Levin ◽  
Karin Amundson ◽  
Kim Shathia ◽  
Allen Borchardt ◽  
Thanh Lam ◽  
...  

Abstract Background Cidara’s AVCs (antiviral Fc-conjugates) are novel conjugates of potent, antiviral agents with the Fc domain of human IgG1. CD377 is an AVC development candidate for prevention and treatment of influenza that has broad anti-neuraminidase activity in both enzymatic and cell-based assays and the potential to engage the immune system, as well as a long half-life. Methods Efficacy studies were conducted in BALB/c mice lethally challenged intranasally at 3x the LD95 with influenza A (H1N1, H3N2) and influenza B (both lineages). CD377 was administered as a single dose subcutaneously (SC) 2 hours after viral challenge. Body weights (BW) and health scores were monitored daily, with 20% BW loss recorded as a mortality. Results In mice challenged with a lethal dose of an H1N1 strain (A/California/12/2012), a single 0.3 mg/kg dose of CD377 administered 2 hours post-challenge was fully protective (P=0.0015 relative to vehicle) (Fig 1A). In a similar study against a mouse-adapted H3N2 subtype (A/Hong Kong/1/1968), a single dose of CD377 at 0.1 mg/kg was fully protective (P=0.0025) (Fig 1B). In both studies, only a transient loss of BW was observed before mice began recovering weight. The activity of CD377 was also evaluated against both lineages of influenza B (Fig 1C, 1D). Against influenza B/Colorado/06/2017 (Victoria), a single CD377 dose of 0.3 mg/kg was fully protective (P=0.0035) while the Fc-only control dosed at 1 mg/kg was not, as expected. Against the Yamagata lineage (B/Florida/4/2006), CD377 demonstrated full protection at a dose of only 0.03 mg/kg (P=0.0023). Conclusion A single dose of CD377 (0.3 mg/kg or less) was protective against lethal challenge with several seasonal influenza A/B subtypes. The exceptional PK profile of CD377 combined with potent broad-spectrum activity highlight its potential for use as a long-term preventative against seasonal influenza. Seasonal influenza efficacy Disclosures James Levin, PhD, Cidara Therapeutics (Shareholder) Karin Amundson, BSc, Cidara Therapeutics (Shareholder) Allen Borchardt, PhD, Cidara Therapeutics (Employee) Thanh Lam, PhD, Cidara Therapeutics (Shareholder) Tom Brady, PhD, Cidara Therapeutics (Shareholder) Alain Noncovich, PhD, Cidara Therapeutics (Shareholder) Les Tari, PhD, Cidara Therapeutics (Shareholder)

2009 ◽  
Vol 14 (32) ◽  
Author(s):  
H Uphoff ◽  
S Geis ◽  
A Grüber ◽  
A M Hauri

For the next influenza season (winter 2009-10) the relative contributions to virus circulation and influenza-associated morbidity of the seasonal influenza viruses A(H3N2), A(H1N1) and B, and the new influenza A(H1N1)v are still unknown. We estimated the chances of seasonal influenza to circulate during the upcoming season using data of the German influenza sentinel scheme from 1992 to 2009. We calculated type and subtype-specific indices for past exposure and the corresponding morbidity indices for each season. For the upcoming season 2009-10 our model suggests that it is unlikely that influenza A(H3N2) will circulate with more than a low intensity, seasonal A(H1N1) with more than a low to moderate intensity, and influenza B with more than a low to median intensity. The probability of a competitive circulation of seasonal influenza A with the new A(H1N1)v is low, increasing the chance for the latter to dominate the next influenza season in Germany.


2015 ◽  
Vol 20 (6) ◽  
pp. 39-43
Author(s):  
A. F Popov ◽  
A. I Simakova ◽  
K. A Dmitrenko ◽  
I. V Zenin

There was analyzed the medical history of 561 patients with influenza during the period of 2009-2014, Influenza A (H1N1) pdm09 was diagnosed in 261 cases, accounting for 46.5% of the total number of patients; Influenza A (H1N1) - in 148 cases (26.4%); Influenza A (H3N2) - in 102 cases (18.2%); Influenza B - in 50 cases (8.9%). The clinical picture of influenza A (H1N1) pdm09 differed from seasonal influenza A (H1N1), A (H3N2), and B by more severe course, the high rate of complications and mortality.


2018 ◽  
Vol 92 (21) ◽  
Author(s):  
Zhimin Wan ◽  
Stivalis Cardenas Garcia ◽  
Jing Liu ◽  
Jefferson Santos ◽  
Silvia Carnaccini ◽  
...  

ABSTRACT Influenza virus infections continue to pose a major public health threat worldwide associated with seasonal epidemics and sporadic pandemics. Vaccination is considered the first line of defense against influenza. Live attenuated influenza virus vaccines (LAIVs) may provide superior responses compared to inactivated vaccines because the former can better elicit a combination of humoral and cellular responses by mimicking a natural infection. Unfortunately, during the 2013–2014, 2014–2015, and 2015–2016 seasons, concerns emerged about the effectiveness of the only LAIV approved in the United States that prevented the Advisory Committee on Immunization Practices (ACIP) from recommending its use. Such drawbacks open up the opportunity for alternative LAIV strategies that could overcome such concerns. Previously, we developed a combined strategy of temperature-sensitive mutations in the PB2 and PB1 segments and an epitope tag in the C terminus of PB1 that effectively attenuates influenza A viruses of avian and mammalian origin. More recently, we adopted a similar strategy for influenza B viruses. The resulting attenuated (att) influenza A and B viruses were safe, immunogenic, and protective against lethal influenza virus challenge in a variety of animal models. In this report, we provide evidence of the potential use of our att strategy in a quadrivalent LAIV (QIV) formulation carrying H3N2 and H1N1 influenza A virus subtype viruses and two antigenic lineages of influenza B viruses. In naive DBA/2J mice, two doses of the QIV elicited hemagglutination inhibition (HI) responses with HI titers of ≥40 and effectively protected against lethal challenge with prototypical pandemic H1N1 influenza A and influenza B virus strains. IMPORTANCE Seasonal influenza viruses infect 1 billion people worldwide and are associated with ∼500,000 deaths annually. In addition, the never-ending emergence of zoonotic influenza viruses associated with lethal human infections and of pandemic concern calls for the development of better vaccines and/or vaccination strategies against influenza virus. Regardless of the strategy, novel influenza virus vaccines must aim at providing protection against both seasonal influenza A and B viruses. In this study, we tested an alternative quadrivalent live attenuated influenza virus vaccine (QIV) formulation whose individual components have been previously shown to provide protection. We demonstrate in proof-of principle studies in mice that the QIV provides effective protection against lethal challenge with either influenza A or B virus.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1054-1054
Author(s):  
Honar Cherif ◽  
Martin Hoglund ◽  
Karlis Pauksens

Abstract Abstract 1054 Background: Patients with hematological malignancies are more susceptible for viral infections including influenza, which may be associated with prolonged illness, increased morbidity and mortality. In 2009, the World Health Organization classified the novel influenza A(H1N1) virus as pandemic. The impact of this viral infection in patients (pts) with hematological disorders was unknown, and there were concerns about the risk of serious complications. In Sweden, institutional guidelines recommended two doses of the AS03-adjuvanted inactivated H1N1 split vaccine Pandemrix™ from GlaxoSmithKline in these pts. Aims: Prospectively determine the safety, immunogenicity, and clinical efficacy of influenza A (H1N1) 2009 vaccination in patients with hematological diseases. Compare the immunological response to that obtained by the trivalent seasonal influenza vaccine (TIV). Patients and methods: 31 pts were included (myeloma 9, CLL 5, AML 6, ALL 2, CML 2, others 5), out of which 13 had undergone hematopoietic stem cell transplantation (HSCT). All received influenza A(H1N1) 2009 vaccine at day 0, and 28, and the majority (n=25) seasonal influenza vaccine at day 56. Serum for antibody analyses by validated HI-assays was taken at day 0, 28, 56 and 86 and at 1 year. The response to vaccination (seroconversion) was defined as at least a four-fold increase in antibody titer after vaccination or, in case prevaccination HI-titer was < 10, a post-vaccination titer of HI > 40 or greater. Considering that the HI-assay for influenza B differed from the A strains only the seroconversion rate was considered for the influenza B. Results: The A (H1N1) vaccine was well tolerated and no severe adverse events were reported. At day 28, a total of 16(52%) patients had protective levels of antibodies to A (H1N1) 2009 and 15(48%) had a seroconversion response. After the second dose of the vaccine, 25(81%) reached both protective levels of antibodies and seroconversion. At 1 year, protective levels of antibodies against A (H1N1) 2009 remained in 56% of responding patients. Seroconversion response was observed in 9/13 patients who had undergone HSCT, including 5/9 pts who had been transplanted within1–5 months, as well as in all (n=9) pts with myeloma having advanced disease and/or ongoing intense treatment. Following vaccination with TIV and evaluated at day 86, protective antibody levels and seroconversion response against A/Brisbane/59/2007 H1N1-like virus were detected in 10(40%) respective 7(28%), and against A/Uruguay/10/2007/H3N2-like virus in 14(56%) respective 10(40%). As for B/Brisbane/60/2008-like virus, seroconversion response was found in 5(20%) of all pts. Response to the pandemic influenza A (H1N1) 2009 vaccine was better than that to the three TIV strains (p<0.001, p<0.009 and p<0.001 respectively). Conclusion: A substantial proportion of patients with hematological malignancies including even heavily treated Myeloma and HSCT patients mounted a good response to the adjuvanted influenza A (H1N1) 2009 vaccine. This vaccine was well tolerated and had a significantly better immunogenicity than that of the non-adjuvanted seasonal influenza vaccine. Disclosures: Cherif: GSK: Research Funding. Pauksens:GSK: Research Funding.


2015 ◽  
Vol 23 (1) ◽  
Author(s):  
Daniela Pitigoi ◽  
George Necula ◽  
Viorel Alexandrescu ◽  
Maria Elena Mihai ◽  
Carmen Maria Cherciu ◽  
...  

AbstractBackgound. Using influenza epidemiological and virological surveillance data, we aimed at investigating the profile of influenza viruses circulating in Romania during the season 2012-2013 and estimating the effectiveness (VE) of the seasonal vaccine. Methods. We tested all specimens collected from patients with influenza like illness (ILI) in the national surveillance system between week 40/2012 to week 20/2013. Influenza A/B positive specimens identified by molecular detection (RT-PCR) were further characterized. We used hemagglutination inhibition assay for antigenic characterization and chemiluminiscence assay for the antiviral susceptibility testing. Subsequently we conducted nucleotide sequencing of hemagglutinin and neuraminidase genes and phylogenetic tree analyses. We estimated influenza VE using the test negative case-control study design, as 1-odds ratio of vaccination among ILI cases positive for influenza and ILI negative controls. Results and Discussions. We tested 1087 specimens, and 537 cases were positive (56.2% influenza B, 40.6% A(H1N1)pdm09, 3.2% A(H3N2). Sixty-four influenza viruses were antigenically and/or genetically characterized. A(H1N1)pdm09 viruses were related to the vaccine strain A/ California/07/2009 and clustered with genetic group 6 similar to A/St. Petersburg/27/2011. Influenza B viruses belonged to clade 2 of type B/Yamagata lineage, related to B/Estonia/55669/2011 except one, B/Victoria lineage, representative strain B/Brisbane/60/2008. A(H3) viruses clustered with group 3C of the A/Victoria/208/2009 clade, similar to the vaccine strain A/Victoria/361/2011. All tested strains (57) demonstrated susceptibility to oseltamivir and zanamivir. The adjusted seasonal influenza vaccine effectiveness against influenza A(H1N1)pdm09 (N=119) was 76.9% (95% CI: -113.4, 98.5), suggesting a good protection, consistent with the good match between the vaccine and circulating strains.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nungruthai Suntronwong ◽  
Sirapa Klinfueng ◽  
Sumeth Korkong ◽  
Preeyaporn Vichaiwattana ◽  
Thanunrat Thongmee ◽  
...  

AbstractWe monitored the circulating strains and genetic variation among seasonal influenza A and B viruses in Thailand between July 2017 and March 2020. The hemagglutinin gene was amplified and sequenced. We identified amino acid (AA) changes and computed antigenic relatedness using the Pepitope model. Phylogenetic analyses revealed multiple clades/subclades of influenza A(H1N1)pdm09 and A(H3N2) were circulating simultaneously and evolved away from their vaccine strain, but not the influenza B virus. The predominant circulating strains of A(H1N1)pdm09 belonged to 6B.1A1 (2017–2018) and 6B.1A5 (2019–2020) with additional AA substitutions. Clade 3C.2a1b and 3C.2a2 viruses co-circulated in A(H3N2) and clade 3C.3a virus was found in 2020. The B/Victoria-like lineage predominated since 2019 with an additional three AA deletions. Antigenic drift was dominantly facilitated at epitopes Sa and Sb of A(H1N1)pdm09, epitopes A, B, D and E of A(H3N2), and the 120 loop and 190 helix of influenza B virus. Moderate computed antigenic relatedness was observed in A(H1N1)pdm09. The computed antigenic relatedness of A(H3N2) indicated a significant decline in 2019 (9.17%) and 2020 (− 18.94%) whereas the circulating influenza B virus was antigenically similar (94.81%) with its vaccine strain. Our findings offer insights into the genetic divergence from vaccine strains, which could aid vaccine updating.


2012 ◽  
Vol 19 (3) ◽  
pp. 313-318 ◽  
Author(s):  
Zoltan Vajo ◽  
Ferenc Tamas ◽  
Istvan Jankovics

ABSTRACTWith the recent pandemic of influenza A (H1N1) and vaccine shortages, there has been considerable interest in developing influenza vaccines with reduced doses, allowing for increased production capacity. Here we report a prospective, randomized, double-blind, single-center clinical trial of a reduced-dose whole-virion inactivated, adjuvanted influenza vaccine in adult and elderly volunteers. A total of 234 subjects, including 120 adults (18 to 60 years of age) and 114 elderly subjects (>60 years of age) were enrolled to receive either 6 μg or the conventional 15-μg dose of seasonal trivalent influenza vaccines. The subjects were followed for safety analysis, and serum samples were obtained to assess immunogenicity by hemagglutination inhibition testing. The subjects developed antibody responses against the seasonal influenza A virus H1N1 and H3N2 strains, as well as the seasonal influenza B virus included in the vaccines. Single doses of 6 μg fulfilled licensing criteria for seasonal influenza vaccines. No significant differences in rates of seroconversion or seroprotection or in geometric mean titers were found between the two dosage levels. All adverse events were rare, mild, and transient. We found that the present reduced-dose vaccine is safe and immunogenic in healthy adult and elderly subjects and triggers immune responses that comply with licensing criteria.


Author(s):  
Guozhong He ◽  
Pengfei Yang ◽  
Qingli Yan ◽  
Chenglong Xiong

Abstract Background Annual influenza vaccination is the most effective way to prevent influenza. Influenza vaccines have traditionally included the hemagglutinins (HA) and neuraminidases (NA) from the two A viruses (H1N1 and H3N2) and either B Yamagata or B Victoria. Mismatches between circulating isolates of influenza B and the vaccines are very common. Taking 2017/2018 winter in northern hemisphere as an example, this study was designed to find out the reasons for mismatch between the trivalent influenza vaccine (TIV) and most of the epidemic isolates at that time, and to discuss if there are some optimized programs for seasonal influenza vaccines. Methods HA and NA sequences of the seasonal isolates circulating from December 1, 2017 to February 28, 2018, and in the previously other 7 winters in northern hemisphere from Global Initiative on Sharing All Influenza Data (GISAID) and the influenza database of National Center for Biotechnology Information (NCBI). Phylogenetic trees and genetic distances were constructed or calculated by using MAFFT and MEGA 6.0 software. Results Influenza B composition in the TIV recommendation mismatched most of circulating viruses in 2017/2018 winter; the vaccine strain was from the B/Victoria lineage, while most of epidemic isolates were from the B/Yamagata lineage. The epidemic lineage of influenza B reached its peak a little late in the previous winter might be responsible for this mismatch. During 2010–2018, the mean genetic distances between epidemic isolates of influenza A (H1N1 and H3N2) and the vaccines were no higher than 0.02375 ± 0.00341 in both HA and NA. However, concerning influenza B virus, when forecasting done well, the mean genetic distances between epidemic isolates and the vaccines were no higher than 0.02368 ± 0.00272; otherwise, the distances could reach 0.13695 ± 0.00238. Conclusion When applying quadrivalent influenza vaccines (QIVs) for vaccination, the recommendations of compositions for influenza B could be altered and assessed once in 3 or 4 years; when economic burden was considered intensively and TIVs were utilized, the recommended compositions for influenza B could be announced in April or May, rather than in February or March as now.


2018 ◽  
Vol 10 (1) ◽  
Author(s):  
Vusie Lokotfwako ◽  
Nhlanhla Nhlabatsi ◽  
Phinda Khumalo ◽  
Siphiwe Shongwe ◽  
Bongani Tsabedze ◽  
...  

ObjectiveTo establish morbidity patterns of influenza A/H1N1 in Swaziland from 10th July to 15th August 2017.IntroductionInfluenza infection is caused by the influenza virus, a single-stranded RNA virus belonging to the Orthomyxoviridae family. Influenza viruses are classified as types A, B and C. Influenza A and B viruses can cause epidemic disease in humans and type C viruses usually cause a mild, cold-like illness. The influenza virus spreads rapidly around the world in seasonal epidemics, resulting in significant morbidity and mortality. On the 10th of July 2017, a case of confirmed Influenza A/H1N1 was reported through the immediate disease notification system from a private hospital in the Hhohho region. A 49 year old female was diagnosed of Influenza A/H1N1 after presenting with flu-like symptoms. Contacts of the index case were followed and further positive cases were identified.MethodsUpon identification of the index case, the rapid response teams conducted further investigations. Two nasal swaps from each sample were taken and sent to a private laboratory in South Africa for the detection of the virus RNA using RT-PCR to assess for the presence Influenza A, B and Influenza A/H1N1. Further laboratory results were sourced from a private laboratory to monitor trends of influenza. Data was captured and analyzed in STATA version 12 from STATA cooperation. Descriptive statistics were carried out using means and standard deviations. The Pearson Chi square test and student t test were used to test for any possible association between influenza A/H1N1 and the explanatory variables (age and sex).ResultsSurveillance data captured between 10th July 2017 and 15th August 2017 indicated that a total of 87 patients had their samples taken for laboratory confirmation. There were 45 females and 42 males and the mean age was 27 years (SD= 17). At least 25 of the 87 patients tested positive for influenza A while only 1 tested positive for influenza B. The prevalence of influenza A/H1N1 was 16%. The prevalence of influenza A/H1N1 among males was 19% compared to 13% in females; however the difference was not statistically significant (p=0.469). There was no association noted between age and influenza A/H1N1 (p=427). Upon further sub-typing results indicated that the circulating strain was influenza A/H1N1 pdm 09 strain which is a seasonal influenza. The epidemic task forces held weekly and ad-hoc meetings to provide feedback to principals and health messaging to the general population to allay anxiety.ConclusionsThough WHO has classified the influenza A/H1N1 strain pdm 0029 as a seasonal influenza, surveillance remains important for early detection and management. There is therefore an urgent need to set up sentinel sites to monitor and understand the circulating influenza strains. Health promotion remains crucial to dispel anxiety as the general public still link any influenza to the 2009 pandemic influenza. Finally the Ministry of Health should consider introducing influenza vaccines into the routine immunization schedule especially for children.References1. Global Epidemiological Surveillance Standards for Influenza. 2014 [cited 2015 15 April]; Available from: http://www.who.int/influenza/resources/documents/influenza_surveillance_manual/en/.2. Human cases of influenza at the human-animal interface, 2013. Wkly Epidemiol Rec, 2014.89(28): p. 309-20.3. WHO Global Influenza Surveillance Network. Manual for the laboratory diagnosis and virological surveillance of influenza. 2011 [cited 2015 April27]; Available from: http://www.who.int/influenza/gisrs_laboratory/manual_diagnosis_surveillance_influenza/en/.


2021 ◽  
Vol 45 ◽  
Author(s):  
Heidi Peck ◽  
Jean Moselen ◽  
Sook Kwan Brown ◽  
Megan Triantafilou ◽  
Hilda Lau ◽  
...  

As part of its role in the World Health Organization’s (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a record total of 9,266 human influenza positive samples during 2019. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties. Selected viruses were propagated in qualified cells or embryonated hen’s eggs for potential use in seasonal influenza virus vaccines. In 2019, influenza A(H3N2) viruses predominated over influenza A(H1N1)pdm09 and B viruses, accounting for a total of 51% of all viruses analysed. The majority of A(H1N1)pdm09, A(H3N2) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2019. However, phylogenetic analysis indicated that a significant proportion of circulating A(H3N2) viruses had undergone genetic drift relative to the WHO recommended vaccine strain for 2019. Of 5,301 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir, four A(H1N1)pdm09 viruses showed highly reduced inhibition with oseltamivir, one A(H1N1)pdm09 virus showed highly reduced inhibition with zanamivir and three B/Victoria viruses showed highly reduced inhibition with zanamivir.


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