39 results found
Narean JS, Glanville N, Nunn CM, et al., 2019, Epitope mapping of antibodies induced with a conserved rhinovirus protein generating protective anti-rhinovirus immunity, Vaccine, Vol: 37, Pages: 2805-2813, ISSN: 0264-410X
Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations. Currently there is no vaccine for RV which is largely due to the existence of ∼160 serotypes/strains. We demonstrated previously that immunising mice with highly conserved VP4 and VP2 regions of the RV polyprotein (RV-A16 VP0) generated cross-reactive immunity to RV in vivo. The current study investigated and mapped the epitopes of RV-A16 VP0 that are targets for antibodies in serum samples from VP0 immunisation and RV challenge studies in mice. Recombinant capsid proteins, peptide pools and individual peptides spanning the immunogen sequence (RV-A16 VP0) were assessed for IgG binding sites to identify epitopes. We found that peptide pools covering the C-terminus of VP4, the N-terminus of VP2 and the neutralising NIm-II site within VP2 were bound by serum IgG from immunised mice. The NIm-II site peptide pool blocked IgG binding to the immunogen RV-A16 VP0 and individual peptides within the pool binding IgG were further mapped. Thus, we have identified immunodominant epitopes of RV vaccine candidate RV-A16 VP0, noting that strong IgG binding antibodies were observed that target a key neutralising epitope that is highly variable amongst RV serotypes.
Baraniak I, Kropff B, Ambrose L, et al., 2018, Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies., Proc Natl Acad Sci U S A, Vol: 115, Pages: 6273-6278
Human cytomegalovirus (HCMV) is an important pathogen in transplant patients and in congenital infection. Previously, we demonstrated that vaccination with a recombinant viral glycoprotein B (gB)/MF59 adjuvant formulation before solid organ transplant reduced viral load parameters post transplant. Reduced posttransplant viremia was directly correlated with antibody titers against gB consistent with a humoral response against gB being important. Here we show that sera from the vaccinated seronegative patients displayed little evidence of a neutralizing antibody response against cell-free HCMV in vitro. Additionally, sera from seronegative vaccine recipients had minimal effect on the replication of a strain of HCMV engineered to be cell-associated in a viral spread assay. Furthermore, although natural infection can induce antibody-dependent cellular cytotoxicity (ADCC) responses, serological analysis of seronegative vaccinees again presented no evidence of a substantial ADCC-promoting antibody response being generated de novo. Finally, analyses for responses against major antigenic domains of gB following vaccination were variable, and their pattern was distinct compared with natural infection. Taken together, these data argue that the protective effect elicited by the gB vaccine is via a mechanism of action in seronegative vaccinees that cannot be explained by neutralization or the induction of ADCC. More generally, these data, which are derived from a human challenge model that demonstrated that the gB vaccine is protective, highlight the need for more sophisticated analyses of new HCMV vaccines over and above the quantification of an ability to induce potent neutralizing antibody responses in vitro.
Baraniak I, Kropff B, McLean GR, et al., 2018, Epitope-Specific Humoral Responses to Human Cytomegalovirus Glycoprotein-B Vaccine With MF59: Anti-AD2 Levels Correlate With Protection From Viremia., J Infect Dis, Vol: 217, Pages: 1907-1917
The human cytomegalovirus (HCMV) virion envelope protein glycoprotein B (gB) is essential for viral entry and represents a major target for humoral responses following infection. Previously, a phase 2 placebo-controlled clinical trial conducted in solid organ transplant candidates demonstrated that vaccination with gB plus MF59 adjuvant significantly increased gB enzyme-linked immunosorbent assay (ELISA) antibody levels whose titer correlated directly with protection against posttransplant viremia. The aim of the current study was to investigate in more detail this protective humoral response in vaccinated seropositive transplant recipients. We focused on 4 key antigenic domains (AD) of gB (AD1, AD2, AD4, and AD5), measuring antibody levels in patient sera and correlating these with posttransplant HCMV viremia. Vaccination of seropositive patients significantly boosted preexisting antibody levels against the immunodominant region AD1 as well as against AD2, AD4, and AD5. A decreased incidence of viremia correlated with higher antibody levels against AD2 but not with antibody levels against the other 3 ADs. Overall, these data support the hypothesis that antibodies against AD2 are a major component of the immune protection of seropositives seen following vaccination with gB/MF59 vaccine and identify a correlate of protective immunity in allograft patients.
Schrader JW, McLean GR, 2018, Multispecificity of a recombinant anti-ras monoclonal antibody, JOURNAL OF MOLECULAR RECOGNITION, Vol: 31, ISSN: 0952-3499
Manghera A, McLean GR, 2016, Human cytomegalovirus vaccination: progress and perspectives of recombinant gB, FUTURE VIROLOGY, Vol: 11, Pages: 439-449, ISSN: 1746-0794
Williams GR, Kubajewska I, Glanville NS, et al., 2016, The potential for a protective vaccine for rhinovirus infections., Expert Review of Vaccines, Vol: 15, Pages: 569-571, ISSN: 1744-8395
Rhinovirus (RV) infections impose a major disease burden as they cause around three out offour common colds and are responsible for the majority of acute exacerbations of chronicobstructive pulmonary disease (COPD) and asthma [1, 2]. RVs therefore are associated withan enormous economic cost in missed work or school and medical attention. Prophylacticvaccination against infection is arguably the most effective medical intervention everdeveloped, and has proven enormously effective in protecting against a large number ofdiseases. However, at the present time no effective vaccine exists for RVs. This is largelydue to the existence of 100 serotyped antigenically distinct RV strains - such variabilitymeans that a vaccine designed to elicit immune responses against a particular RV is unlikelyto be able to provide protection against the full range of virus subtypes successfully . Infact, this phenomenon was observed as early as 1965 when immunising with formalininactivated whole RV and is confirmed by the knowledge that the immunity induced followingRV infection does not significantly protect from future infection by different RV serotypes .More sophisticated attempts at immunisation with multiple inactivated RV serotypes alsofailed to induce significant cross-serotype protection . Thus, an effective cross-serotyperesponsive RV vaccine has remained elusive. The relatively recent description of a newclade of RV types (RV-C) has increased the number of identified strains/serotypes to ~160. Perhaps the quest for a RV vaccine has been dismissed as too difficult or evenimpossible, but new developments suggest that it may be feasible to generate a significantbreadth of immune protection.
McLean GR, 2014, Developing a vaccine for human rhinoviruses., Journal of Vaccines and Immunization, Vol: 2, Pages: 16-20, ISSN: 2053-1273
Rhinoviruses (RV's) are common human pathogens of the respiratory tract being the most frequent cause of mild diseases of the upper respiratory tract (common cold) but more importantly they are a major initiator of acute exacerbations of chronic airway diseases. Infections can be life threatening in the latter context however RV -induced common colds have an associated economic cost from loss of productivity due to absence from work or school. There are no appropriate antiviral therapies available and vaccine strategies have failed because of the large number of viral serotypes and the lack of cross-serotype protection generated. Here, approaches past and present for development of a vaccine to these widespread human pathogens are highlighted.
Privolizzi R, Solari R, Johnston SL, et al., 2014, The application of prophylactic antibodies for rhinovirus infections., Antivir Chem Chemother, Vol: 23, Pages: 173-177
Rhinoviruses are extremely common pathogens of the upper respiratory tract with adults experiencing on average 2-5 infections per year and children up to 12 infections. Although infections are not life threatening, except in cases of chronic lung disease where rhinoviruses are the major precipitant of acute exacerbations of disease, there is a high associated economic cost resulting from lost productivity due to absence from work or school. Treatment of infections focuses on symptom relief with anti-pyretics/analgesics as there are no antiviral therapies available and vaccine strategies face difficulties because of the large number of viral serotypes. Here, we assess the potential for prophylactic antibody intervention for these ubiquitous human pathogens.
McLean G, Glanville N, Guy B, et al., 2013, Immunization with a conserved rhinovirus capsid protein generates cross-serotype protective immune responses, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 39-39, ISSN: 0019-2805
Mader JR, Resch ZT, McLean GR, et al., 2013, Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy., J Endocrinol, Vol: 219, Pages: 51-58
We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice. Renal histopathology was evaluated after 4 months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman's capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration to those of diabetic WT mice, indicating that these changes were predominantly age-related. However, thickened Bowman's capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic Papp-A KO mice had significantly reduced or no evidence of changes in Bowman's capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT mice compared with Papp-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.
Glanville N, Mclean GR, Guy B, et al., 2013, Cross-Serotype Immunity Induced by Immunization with a Conserved Rhinovirus Capsid Protein, PLOS PATHOGENS, Vol: 9, ISSN: 1553-7374
Traub S, Nikonova A, Carruthers A, et al., 2013, An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation, PLOS PATHOGENS, Vol: 9, ISSN: 1553-7366
McLean GR, Walton RP, Shetty S, et al., 2013, Rhinovirus infections and immunisation induce cross-serotype reactive antibodies to VP1 (vol 95, pg 193, 2012), ANTIVIRAL RESEARCH, Vol: 97, Pages: 381-381, ISSN: 0166-3542
Some antibodies contain variable (V) domain catalytic sites. We report the superior amide and peptide bond-hydrolyzing activity of the same heavy and light chain V domains expressed in the IgM constant domain scaffold compared with the IgG scaffold. The superior catalytic activity of recombinant IgM was evident using two substrates, a small model peptide that is hydrolyzed without involvement of high affinity epitope binding, and HIV gp120, which is recognized specifically by noncovalent means prior to the hydrolytic reaction. The catalytic activity was inhibited by an electrophilic phosphonate diester, consistent with a nucleophilic catalytic mechanism. All 13 monoclonal IgMs tested displayed robust hydrolytic activities varying over a 91-fold range, consistent with expression of the catalytic functions at distinct levels by different V domains. The catalytic activity of polyclonal IgM was superior to polyclonal IgG from the same sera, indicating that on average IgMs express the catalytic function at levels greater than IgGs. The findings indicate a favorable effect of the remote IgM constant domain scaffold on the integrity of the V-domain catalytic site and provide a structural basis for conceiving antibody catalysis as a first line immune function expressed at high levels prior to development of mature IgG class antibodies.
McLean GR, Walton RP, Shetty S, et al., 2012, Rhinovirus infections and immunisation induce cross-serotype reactive antibodies to VP1, ANTIVIRAL RESEARCH, Vol: 95, Pages: 193-201, ISSN: 0166-3542
McLean G, Walton R, Shetty S, et al., 2012, Rhinovirus infections and immunisation induce cross-serotype reactive antibodies to VP1, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 644-644, ISSN: 0019-2805
Thompson RS, Khaskhely NM, Malhotra KR, et al., 2012, Isolation and characterization of human polyreactive pneumococcal polysaccharide antibodies, Open Journal of Immunology, Vol: 02, Pages: 98-110, ISSN: 2162-450X
Peel T, McLean G, Noble A, et al., 2010, Th17 responses in rhinovirus-induced asthma exacerbations, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 130-130, ISSN: 0019-2805
McLean GR, Bartlett NW, Walton RP, et al., 2009, Allergic responses to human rhinoviruses in a mouse model, JOURNAL OF IMMUNOLOGY, Vol: 182, ISSN: 0022-1767
Bartlett N, Walton R, Mclean G, et al., 2009, Rhinovirus infection enhances allergen specific Th2 responses, allergic airway inflammation and IgE production, 28th Congress of the European-Academy-of-Allergy-and-Clinical-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 88-89, ISSN: 0105-4538
Thomson CA, Bryson S, McLean GR, et al., 2008, Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus, EMBO JOURNAL, Vol: 27, Pages: 2592-2602, ISSN: 0261-4189
Noseda M, McLean GR, 2008, Where did the scientific method go?, NATURE BIOTECHNOLOGY, Vol: 26, Pages: 28-29, ISSN: 1087-0156
Schrader JW, McLean GR, 2007, Location, location, timing: Analysis of cytornegalovirus epitopes for neutralizing antibodies, IMMUNOLOGY LETTERS, Vol: 112, Pages: 58-60, ISSN: 0165-2478
McLean GR, Cho C-W, Trotter B, et al., 2006, RIVETS: The recombinant immunoglobulin and viral epitope tag system, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 315, Pages: 208-213, ISSN: 0022-1759
McLean GR, Cho C-W, Schrader JW, 2006, Autoreactivity of primary human immunoglobulins ancestral to hypermutated human antibodies that neutralize HCMV, MOLECULAR IMMUNOLOGY, Vol: 43, Pages: 2012-2022, ISSN: 0161-5890
McLean GR, Torres M, Trotter B, et al., 2005, A point mutation in the CH3 domain of human IgG3 inhibits antibody secretion without affecting antigen specificity, MOLECULAR IMMUNOLOGY, Vol: 42, Pages: 1111-1119, ISSN: 0161-5890
McLean GR, Olsen OA, Watt IN, et al., 2005, Recognition of human cytomegalovirus by human primary immunoglobulins identifies an innate foundation to an adaptive immune response, JOURNAL OF IMMUNOLOGY, Vol: 174, Pages: 4768-4778, ISSN: 0022-1767
McLean GR, Miller KK, Schrader JW, et al., 2004, Biased immunoglobulin G (IgG) subclass production in a case of hyper-IgM syndrome, CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY, Vol: 11, Pages: 1192-1193, ISSN: 1071-412X
Lucas AH, McLean GR, Reason DC, et al., 2003, Molecular ontogeny of the human antibody repertoire to the Haemophilus influenzae type b polysaccharide: expression of canonical variable regions and their variants in vaccinated infants, CLINICAL IMMUNOLOGY, Vol: 108, Pages: 119-127, ISSN: 1521-6616
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