The role of p53 in virus-induced and multi-step lymphomagenesis

It has previously been demonstrated that p53 loss and Moloney murine leukaemia virus (MMLV) infection are weakly collaborative in T cell lymphomagenesis. The work described in this thesis aimed to investigate the role of p53 in MMLV-induced lymphoma and explore the basis of their relatively weak collaboration. The effects of p53 loss in combination with MMLV were explored first in primary fibroblasts. While no viral cytopathology was observed in these cells, it was found that the virus conferred a growth advantage on infected cells that was additive with the effects of p53 loss. MMLV has been reported to induce a preleukaemic phase of apoptosis in the thymus of infected mice and the role of p53 in this phenomenon was investigated next. The response was found to be short-lived, with peak onset varying according to host mouse strain. No evidence of direct induction of p53 was observed in thymus tissue in vivo, but evidence on the p53 dependence of the MMLV-induced apoptosis was equivocal, yielding only provisional conclusions. The role of p53 was then examined at the later stages of MMLV disease and tumours were analysed for loss of heterozygosity of the wild type p53 allele and expression of functional p53 protein with prolonged in vitro and in vivo passage. Two mouse models were used; a cohort of MMLV-infected mice and also a Runx2/Myc surrogate model which develop tumours after a significantly reduced latent period. The data suggested that whilst p53 loss is obligatory for in vitro culture of tumour cells, it is not required for the growth of tumours passaged in vivo. The sparing effect was not absolute, however, and there was some evidence of p53 pathway inactivation and allele loss in progressing tumours. In summary, I conclude that the weak synergy observed between MMLV and p53 loss is principally due to functional overlap, largely driven by activation of MMLV target genes such as Myc and Runx2 that collaborate to suppress p53-dependent pathways in vivo

Subclinical infection without encephalitis in mice following intranasal exposure to Nipah virus-Malaysia and Nipah virus-Bangladesh

BACKGROUND: Nipah virus and Hendra virus are closely related and following natural or experimental exposure induce similar clinical disease. In humans, encephalitis is the most serious outcome of infection and, hitherto, research into the pathogenesis of henipavirus encephalitis has been limited by the lack of a suitable model. Recently we reported a wild-type mouse model of Hendra virus (HeV) encephalitis that should facilitate detailed investigations of its neuropathogenesis, including mechanisms of disease recrudescence. In this study we investigated the possibility of developing a similar model of Nipah virus encephalitis. FINDINGS: Aged and young adult wild type mice did not develop clinical disease including encephalitis following intranasal exposure to either the Malaysia (NiV-MY) or Bangladesh (NiV-BD) strains of Nipah virus. However viral RNA was detected in lung tissue of mice at euthanasia (21 days following exposure) accompanied by a non-neutralizing antibody response. In a subsequent time course trial this viral RNA was shown to be reflective of an earlier self-limiting and subclinical lower respiratory tract infection through successful virus re-isolation and antigen detection in lung. There was no evidence for viremia or infection of other organs, including brain. CONCLUSIONS: Mice develop a subclinical self-limiting lower respiratory tract infection but not encephalitis following intranasal exposure to NiV-BD or NiV-MY. These results contrast with those reported for HeV under similar exposure conditions in mice, demonstrating a significant biological difference in host clinical response to exposure with these viruses. This finding provides a new platform from which to explore the viral and/or host factors that determine the neuroinvasive ability of henipaviruses

Good and ‘bad’ deaths during the COVID-19 pandemic: insights from a rapid qualitative study

Dealing with excess death in the context of the COVID-19 pandemic has thrown the question of a good or bad death' into sharp relief as countries across the globe have grappled with multiple peaks of cases and mortality; and communities mourn those lost. In the UK, these challenges have included the fact that mortality has adversely affected minority communities. Corpse disposal and social distancing guidelines do not allow a process of mourning in which families and communities can be involved in the dying process. This study aimed to examine the main concerns of faith and non-faith communities across the UK in relation to death in the context of the COVID-19 pandemic. The research team used rapid ethnographic methods to examine the adaptations to the dying process prior to hospital admission, during admission, during the disposal and release of the body, during funerals and mourning. The study revealed that communities were experiencing collective loss, were making necessary adaptations to rituals that surrounded death, dying and mourning and would benefit from clear and compassionate communication and consultation with authorities

'A good death' during the Covid-19 pandemic in the UK: a report on key findings and recommendations

Dealing with death and bereavement in the context of the Covid-19 Pandemic will present significant challenges for at least the next three months. The current situation does not allow for families andbcommunities to be involved in the process of death in ways in which they would normally hope or expect to be. In addition, mortality rates will disproportionately affect vulnerable households. The government has identified the following communities as being at increased risk: single parent households; multi-generational Black and Minority Ethnic groups; men without degrees in lone households and/or in precarious work; small family business owners in their 50s; and elderlyhouseholds. Our study focused on these groups. This report presents a summary of findings and key recommendations by a team of anthropologists from the London School of Economics who conducted a public survey and 58 cross-community interviews between 3 and 9 April 2020. It explores ways to prepare these communities and households for impending deaths with communications and policy support. More information on the research methodology, data protection and ethical procedures is available in Appendix 1. A summary of relevant existing research can be found in Appendix 2. A list of key contacts across communities for consultation is available on request. Research was focused on “what a good death looks like” for people across all faiths and for vulnerable groups. It examined how communities were already adapting how they dealt with processes of dying, burials, funerals and bereavement during the pandemic, and responding to new government regulations. It specifically focused on five transitions in the process of death, and what consultation processes, policies and communications strategies could be mobilised to support communities through these phases

A right to care: the social foundations of recovery from Covid-19

This report presents key findings from a 6-month ethnographic study on the impact of the Covid-19 pandemic on disadvantaged households and communities across the UK conducted by anthropologists from the London School of Economics, and associates. This research involved in-depth interviews and multiple surveys with people across communities in the UK, with particular focus on a number of case studies of intersecting disadvantage. Crucially, our research has found that Government policy can improve adherence to restrictions and reduce the negative impacts of the pandemic on disadvantaged communities by placing central importance on communities, social networks and households to the economy and social life. This would be the most effective way to increase public trust and adherence to Covid-19 measures, because it would recognise the suffering that communities have experienced and would build policy on the basis of what is most important to people - the thriving of their families and communities

Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite--MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors--ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses

Impact on Malaria Parasite Multiplication Rates in Infected Volunteers of the Protein-in-Adjuvant Vaccine AMA1-C1/Alhydrogel+CPG 7909

BACKGROUND: Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA) is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria. METHODS: In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes. RESULTS: A significant correlation was observed between parasite multiplication rate in 48 hours (PMR) and both vaccine-induced growth-inhibitory activity (Pearson r = -0.93 [95% CI: -1.0, -0.27] P = 0.02) and AMA1 antibody titres in the vaccine group (Pearson r = -0.93 [95% CI: -0.99, -0.25] P = 0.02). However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70). Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5-9], control group median 9 days [range 7-9]). CONCLUSIONS: Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers. TRIAL REGISTRATION: ClinicalTrials.gov [NCT00984763]

Phase Ia Clinical Evaluation of the Safety and Immunogenicity of the Plasmodium falciparum Blood-Stage Antigen AMA1 in ChAd63 and MVA Vaccine Vectors

Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question

Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01

We study whether the relationship between the state unemployment rate at the time of conception and infant health, infant mortality and maternal characteristics in the United States has changed over the years 1980-2004. We use microdata on births and deaths for years 1980-2004 and find that the relationship between the state unemployment rate at the time of conception and infant mortality and birthweight changes over time and is stronger for blacks than whites. For years 1980-1989 increases in the state unemployment rate are associated with a decline in infant mortality among blacks, an effect driven by mortality from gestational development and birth weight, and complications of placenta while in utero. In contrast, state economic conditions are unrelated to black infant mortality in years 1990-2004 and white infant mortality in any period, although effects vary by cause of death. We explore potential mechanisms for our findings and, including mothers younger than 18 in the analysis, uncover evidence of age-related maternal selection in response to the business cycle. In particular, in years 1980-1989 an increase in the unemployment rate at the time of conception is associated with fewer babies born to young mothers. The magnitude and direction of the relationship between business cycles and infant mortality differs by race and period. Age-related selection into motherhood in response to the business cycle is a possible explanation for this changing relationship