HPV vaccine-induced cross-neutralising antibodies target complex epitopes on the major capsid protein

The current human papillomavirus (HPV) vaccines consist of major capsid protein (L1) virus-like particles (VLP) and target the two most prevalent oncogenic genotypes, HPV16 and HPV18. Prophylactic HPV vaccination is highly effective at preventing HPV16 and HPV18 infection and associated cervical disease, with type-specific neutralising antibodies thought to be the immune mediators of vaccine type protection. A degree of vaccine-induced cross-protection has also been demonstrated against genetically-related genotypes in the Alpha-7 (HPV18-like) and Alpha-9 (HPV16-like) species groups and although the underlying immune mechanism is uncertain, cross-protection is coincident with the detection of cross-neutralising antibodies. The aim of this thesis was to delineate the HPV L1 domains that are recognised by inter-genotype cross-neutralising antibodies. The formal analysis of the vaccine-induced A9 L1 antibody response demonstrated that cross-neutralising antibodies were a minor component of the total HPV16 antibody response and comprised antibody specificities which recognised single and multiple non-vaccine genotypes. The bioinformatic examination of A9 capsid amino acid sequences demonstrated that the L1L2 pseudovirions (PsV) used to measure cross-neutralising responses were generally representative of available contemporary sequences. The potential impact of amino acid variation within the L1 capsid protein was investigated for HPV31 and found differences in cross-neutralising antibody recognition of the L1 variants; however, this was of a low magnitude. L1 crystallographic homology models predicted structural changes in the loops between HPV16 and the non-vaccine A9 genotypes, informing the design and generation of chimeric PsV with inter-genotype loop swaps. These chimeric PsV demonstrated that cross-neutralising antibodies recognise DE and FG loop amino acid residues within close proximity to each other on the capsid surface. These data contribute to our understanding of the antigenicity of the L1 major capsid protein of HPV by identifying the L1 regions recognised by vaccine-induced cross-neutralising antibodies. Such specificities may play a critical role in vaccine-induced cross-protection.Open Acces

A Study Of The Interaction Of Simian Virus 40 With Human Cells In Vitro.

PhDMicrobiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/179689/2/6606573.pd

Another failed refutation of scepticism

Jessica Wilson has recently offered a more sophisticated version of the self-defeat objection to Cartesian scepticism. She argues that the assertion of Cartesian scepticism results in an unstable vicious regress. The way out of the regress is to not engage with the Cartesian sceptic at all, to stop the regress before it starts, at the warranted assertion that the external world exists. We offer three reasons why this objection fails: first, the sceptic need not accept Wilson’s characterization of the sceptical thesis and thus need not start her regress; second, even if she did commit to the regress, it would not undermine scepticism in the way Wilson envisages; and third, the appeal to mental state scepticism which is necessary to generate the second and subsequent steps in the regress is not justified

The Clinical Significance of Anomalous Experiences in the Explanation of Monothematic Delusion

Monothematic delusions involve a single theme, and often occur in the absence of a more general delusional belief system. They are cognitively atypical insofar as they are said to be held in the absence of evidence, are resistant to correction, and have bizarre contents. Empiricism about delusions has it that anomalous experience is causally implicated in their formation, whilst rationalism has it that delusions result from top down malfunctions from which anomalous experiences can follow. Within empiricism, two approaches to the nature of the abnormality/abnormalities involved have been touted by philosophers and psychologists. One-factor approaches have it that monothematic delusions are a normal response to anomalous experiences whilst two-factor approaches seek to identify a clinically abnormal pattern of reasoning in addition to anomalous experience to explain the resultant delusion. In this paper we defend a one-factor approach. We begin by making clear what we mean by atypical, abnormal, and factor. We then identify the phenomenon of interest (monothematic delusion) and overview one and two-factor empiricism about its formation. We critically evaluate the cases for various second factors, and find them all wanting. In light of this we turn to our one-factor account, identifying two ways in which ‘normal response’ may be understood, and how this bears on the discussion of one-factor theories up until this point. We then conjecture that what is at stake is a certain view about the epistemic responsibility of subjects with delusions, and the role of experience, in the context of familiar psychodynamic features. After responding to two objections, we conclude that the onus is on two-factor theorists to show that the one-factor account is inadequate. Until then, the one-factor account ought to be understood as the default position for explaining monothematic delusion formation and retention. We don’t rule out the possibility that, for particular subjects with delusions there may be a second factor at work causally implicated in their delusory beliefs but, until the case for the inadequacy of the single factor is made, the second factor is redundant and fails to pick out the minimum necessary for a monothematic delusion to be present

Another Defence of Owens’s Exclusivity Objection to Beliefs Having Aims

David Owens objected to the truth-aim account of belief on the grounds that the putative aim of belief does not meet a necessary condition on aims, namely, that aims can be weighed against other aims. If the putative aim of belief cannot be weighed, then belief does not have an aim after all. Asbjørn Steglich-Petersen responded to this objection by appeal to other deliberative contexts in which the aim could be weighed, and we argued that this response to Owens failed for two reasons. Steglich-Petersen has since responded to our defence of Owens’s objection. Here we reply to Steglich- Petersen and conclude, once again, that Owens’s challenge to the truth-aim approach remains to be answered

Characterisation of above-ground endophytic and soil fungal communities associated with dieback-affected and healthy plants in five exotic invasive species

In Australia, several well-established invasive plant species have experienced unexplained dieback. To investigate this issue, we used internal transcribed spacer (ITS) amplicon pyrosequencing to characterise fungal communities within stems (endophytes) and soils associated with dieback-affected and healthy plants from populations of five exotic invasive species (Jatropha gossypiifolia, Mimosa pigra, Parkinsonia aculeata, Tamarix aphylla and Vachellia nilotica) across northern Australia. M. pigra and P.\ua0aculeata were sampled from multiple geographic regions. A total of 353 and 4926 fungal operational taxonomic units (OTUs) were identified in stem and soil samples, respectively. Members of Ascomycota were common, representing 75% of stem and 49% of soil OTUs. Four common endophytes, including Cladosporium perangustum, were at least 50% more prevalent in healthy than dieback-affected samples for the five invasive species combined. Fungal community structure within stem and soil samples varied among invasive species. For the two species sampled across multiple regions, M. pigra had similar fungal communities within stems among regions, but a significant difference in associated soil fungi, suggesting that host plant rather than environment determined endophytic communities in this species. Irrespective of the invasive species and sample type (stem vs. soil), no significant differences were observed in fungal richness, diversity or community structure between dieback-affected and healthy plants, either locally or regionally. Our work failed to identify fungi that were either unique or relatively more abundant in dieback than healthy plants in these invasive species. Future investigations of biotic factors other than fungi, such as bacteria, archaea and oomycetes, may provide more insights into the mechanism of the dieback phenomenon affecting these species

Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)

COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44–45 weeks) between the first and second dose, and response to a third dose as a booster given 28–38 weeks after the second dose.In this substudy, volunteers aged 18–55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44–45 weeks after first dose) or a third dose of the vaccine (28–38 weeks after second dose). Data from volunteers aged 18–55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting.Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83–91·08] vs 1·75 EUs [1·60–1·93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525–1764] with an 8–12 week interval; 1860 EUs [917–4934] with a 15–25 week interval; and 3738 EUs [1824–6625] with a 44–45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR 899–4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127–389] immediately before the third dose to 399 SFUs per milion PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose.An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses.UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome