Evaluation in children of cold-adapted influenza B live attenuated intranasal vaccine prepared by reassortment between wild-type B/Ann Arbor/1/86 and cold-adapted B/Leningrad/14/55 viruses

Obrosova-Serova, N. P.; Slepushkin, A. N.; Kendal, Alan P.; Harmon, Maurice W.; Burtseva, Elena; Bebesheva, N.I.; Beljaev, A. L.; Lonskaja, N.I.; Medvedeva, T. E.; Egorov, Andrej; Peklisova, L.V.; Alexandrova, Galina I.

doi:10.1016/0264-410x(90)90178-o

Cited by 18 publications

(3 citation statements)

References 11 publications

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“…Current human vaccines are inactivated vaccines that reduce Clinical trials of cold-adapted live attenuated vaccines have generated promising results with respect to both efficacy and safety (1,2,3,4,8,19,25,32,38,44). However, a molecular basis for the attenuation of the master vaccine strain of influenza B viruses remains unknown.…”

Section: Discussionmentioning

confidence: 99%

The NB Protein of Influenza B Virus Is Not Necessary for Virus Replication In Vitro

Hatta

Kawaoka

2003

J Virol

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The NB protein of influenza B virus is thought to function as an ion channel and therefore would be expected to have an essential function in viral replication. Because direct evidence for its absolute requirement in the viral life cycle is lacking, we generated NB knockout viruses by reverse genetics and tested their growth properties both in vitro and in vivo. Mutants not expressing NB replicated as efficiently as the wild-type virus in cell culture, whereas in mice they showed restricted growth compared with findings for the wild-type virus. Thus, the NB protein is not essential for influenza B virus replication in cell culture but promotes efficient growth in mice.The genome of Influenza B virus, a member of the family Orthomyxoviridae, consists of eight negative-strand RNA segments, which encode 11 proteins. Of these, nine are also found in influenza A virus: three RNA-dependent RNA polymerase subunits (PB1, PB2, and PA), hemagglutinin (HA), nucleoprotein (NP), neuraminidase (NA), matrix protein (M1), and two nonstructural proteins (NS1 and NS2). Two proteins, NB and BM2, are unique to influenza B virus. NB is encoded by RNA segment 6, which also encodes NA, while BM2 is encoded by segment 7.The NB protein of influenza B virus is a type III integral membrane protein, expressed abundantly on the surface of virus-infected cells (5,30,31), and is incorporated into virions (5, 7). This small protein (100 amino acids) possesses an 18-residue N-terminal ectodomain, a 22-residue transmembrane domain, and a 60-residue cytoplasmic tail (5, 42). From previous studies measuring membrane currents and by analogy with the M2 protein of influenza A virus (12,13,35), NB is thought to function as an ion channel protein. However, the electrophysiological measurements of the NB protein based on the lipid bilayer system are difficult to interrupt. That is, proteins and peptides containing hydrophobic domains, which are believed to lack ion channel activity in cells, can yield channel recordings in lipid bilayers (22,39,40). Moreover, in the studies of Fischer et al. (13) and Sunstrom et al. (35), amantadine was used to demonstrate the loss of channel activity by the NB protein, despite the inability of this drug to inhibit influenza B virus replication. Thus, the available evidence challenges the notion that the NB protein has ion channel activity.Recently, members of our group and others (14, 16, 23) established a reverse genetics system for generating influenza A virus entirely from cloned cDNAs, based on the in vivo synthesis of viral RNA. This innovation led us to devise a similar system to determine the importance of the NB protein in the life cycle of influenza B virus (Hoffmann et al. [17] and Jackson et al. [20] reported a reverse-genetics strategy for influenza B virus while this report was being prepared). Here, we generated influenza B virus NB knockout viruses by reverse genetics and tested their growth characteristics and other properties both in cell culture and in mice. MATERIALS AND METHODSCells, viruses, and...

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Section: Discussionmentioning

confidence: 99%

The NB Protein of Influenza B Virus Is Not Necessary for Virus Replication In Vitro

Hatta

Kawaoka

2003

J Virol

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“…No wheeze signal was identified for the Leningrad- backbone LAIV, but the clinical development of this product preceded the Ann-Arbor backbone LAIV and wheezing was not directly solicited as an adverse event in these trials [5]. Because the burden of influenza is greatest in children <2 years of age [6], determining the safety of LAIV vaccines in this age group is a priority [7].…”

Section: Introductionmentioning

confidence: 99%

Wheeze as an adverse event in pediatric vaccine and drug randomized controlled trials: A systematic review

Marangu

Kovacs

Walson

et al. 2015

Vaccine

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Introduction Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs). Objective To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement. Methods We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥ 1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement. Results Of 1,205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity. Conclusion Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as new vaccines and drugs are evaluated.

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“…Mucosal vaccination offers unique advantages over parenteral vaccination in the prevention of infectious diseases such as the induction of both mucosal and systemic immunity compared to solely systemic immunity for subcutaneous and intramuscular vaccines. − Administration of a vaccine to a mucosal surface can induce immunity at multiple mucosal sites in addition to the application site. ,, Nasal immunization, for example, can induce antigen-specific antibody production and a cellular memory response in the respiratory tract as well as in the genital tract mucosa. − The nasal cavity is a prime site for vaccination as it is easily accessible, has a moderately permeable epithelium with a high availability of immune-reactive sites, and provides minimal exposure to degradative environments. , Intranasal (IN) vaccines are currently in development for the prophylaxis of pathogens such as Neisseria meningitidis , respiratory syncytial, and herpes simplex type 2 viruses and are licensed for influenza virus. ,− As infectious diseases transmitted through mucosal surfaces may be most effectively prevented through mucosal immunity, development of compounds that are both effective adjuvants and delivery agents for IN antigen administration is highly desirable.…”

Section: Introductionmentioning

confidence: 99%

Formulation and Characterization of Nanoemulsion Intranasal Adjuvants: Effects of Surfactant Composition on Mucoadhesion and Immunogenicity

et al. 2013

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Development of effective intranasal vaccines is of great interest due to their potential to induce both mucosal and systemic immunity. Here we produced oil-in-water nanoemulsion (NE) formulations containing various cationic and nonionic surfactants for use as adjuvants for the intranasal delivery of vaccine antigens. NE induced immunogenicity and antigen delivery are believed to be facilitated through initial contact interactions between the NE droplet and mucosal surfaces which promote prolonged residence of the vaccine at the site of application, and thus cellular uptake. However, the details of this mechanism have yet to be fully characterized experimentally. We have studied the physicochemical properties of the NE droplet surfactant components and demonstrate that properties such as charge and polar head group geometry influence the association of the adjuvant with the mucus protein, mucin. Association of NE droplets with mucin in vitro was characterized by various biophysical and imaging methods including dynamic light scattering (DLS), zeta potential (ZP), and surface plasmon resonance (SPR) measurements as well as transmission electron microscopy (TEM). Emulsion surfactant compositions were varied in a systematic manner to evaluate the effects of hydrophobicity and polar group charge/size on the NE-mucin interaction. Several cationic NE formulations were found to facilitate cellular uptake of the model antigen, ovalbumin (OVA), in a nasal epithelial cell line. Furthermore, fluorescent images of tissue sections from mice intranasally immunized with the same NEs containing green fluorescent protein (GFP) antigen demonstrated that these NEs also enhanced mucosal layer penetration and cellular uptake of antigen in vivo. NE-mucin interactions observed through biophysical measurements corresponded with the ability of the NE to enhance cellular uptake. Formulations that enhanced antigen uptake in vitro and in vivo also led to the induction of a more consistent antigen specific immune response in mice immunized with NEs containing OVA, linking NE-facilitated mucosal layer penetration and cellular uptake to enhancement of the immune response. These findings suggest that biophysical measurement of the mucoadhesive properties of emulsion based vaccines constitutes an effective in vitro strategy for selecting NE candidates for further evaluation in vivo as mucosal adjuvants.

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Evaluation in children of cold-adapted influenza B live attenuated intranasal vaccine prepared by reassortment between wild-type B/Ann Arbor/1/86 and cold-adapted B/Leningrad/14/55 viruses

Cited by 18 publications

References 11 publications

The NB Protein of Influenza B Virus Is Not Necessary for Virus Replication In Vitro

The NB Protein of Influenza B Virus Is Not Necessary for Virus Replication In Vitro

Wheeze as an adverse event in pediatric vaccine and drug randomized controlled trials: A systematic review

Formulation and Characterization of Nanoemulsion Intranasal Adjuvants: Effects of Surfactant Composition on Mucoadhesion and Immunogenicity

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