Vaccine efficacy trials for Crimean-Congo haemorrhagic fever: Insights from modelling different epidemiological settings.

BACKGROUND: Crimean-Congo haemorrhagic fever (CCHF) is a priority emerging pathogen for which a licensed vaccine is not yet available. We aim to assess the feasibility of conducting phase III vaccine efficacy trials and the role of varying transmission dynamics. METHODS: We calibrate models of CCHF virus (CCHFV) transmission among livestock and spillover to humans in endemic areas in Afghanistan, Turkey and South Africa. We propose an individual randomised controlled trial targeted to high-risk population, and use the calibrated models to simulate trial cohorts to estimate the minimum necessary number of cases (trial endpoints) to analyse a vaccine with a minimum efficacy of 60%, under different conditions of sample size and follow-up time in the three selected settings. RESULTS: A mean follow-up of 160,000 person-month (75,000-550,000) would be necessary to accrue the required 150 trial endpoints for a target vaccine efficacy of 60 % and clinically defined endpoint, in a setting like Herat, Afghanistan. For Turkey, the same would be achieved with a mean follow-up of 175,000 person-month (50,000-350,000). The results suggest that for South Africa the low endemic transmission levels will not permit achieving the necessary conditions for conducting this trial within a realistic follow-up time. In the scenario of CCHFV vaccine trial designed to capture infection as opposed to clinical case as a trial endpoint, the required person-months is reduced by 70 % to 80 % in Afghanistan and Turkey, and in South Africa, a trial becomes feasible for a large number of person-months of follow-up (>600,000). Increased expected vaccine efficacy > 60 % will reduce the required number of trial endpoints and thus the sample size and follow-time in phase III trials. CONCLUSIONS: Underlying endemic transmission levels will play a central role in defining the feasibility of phase III vaccine efficacy trials. Endemic settings in Afghanistan and Turkey offer conditions under which such studies could feasibly be conducted.

Transmission dynamics and vaccination strategies for Crimean-Congo haemorrhagic fever virus in Afghanistan: A modelling study.

BACKGROUND: Crimean-Congo haemorrhagic fever virus (CCHFV) is a highly pathogenic virus for which a safe and effective vaccine is not yet available, despite being considered a priority emerging pathogen. Understanding transmission patterns and the use of potential effective vaccines are central elements of the future plan against this infection. METHODS: We developed a series of models of transmission amongst livestock, and spillover infection into humans. We use real-world human and animal data from a CCHFV endemic area in Afghanistan (Herat) to calibrate our models. We assess the value of environmental drivers as proxy indicators of vector activity, and select the best model using deviance information criteria. Finally we assess the impact of vaccination by simulating campaigns targeted to humans or livestock, and to high-risk subpopulations (i.e, farmers). FINDINGS: Saturation deficit is the indicator that better explains tick activity trends in Herat. Recent increments in reported CCHFV cases in this area are more likely explained by increased surveillance capacity instead of changes in the background transmission dynamics. Modelling suggests that clinical cases only represent 31% (95% CrI 28%-33%) of total infections in this area. Vaccination campaigns targeting humans would result in a much larger impact than livestock vaccination (266 vs 31 clinical cases averted respectively) and a more efficient option when assessed in courses per case averted (35 vs 431 respectively). Targeted vaccination of farmers is impactful and more efficient, resulting in 19 courses per case averted (95% CrI 7-62) compared to targeting the general population (35 courses 95% CrI 16-107). CONCLUSIONS: CCHFV is endemic in Herat, and transmission cycles are well predicted by environmental drivers like saturation deficit. Vaccinating humans is likely to be more efficient and impactful than animals, and importantly targeted interventions to high risk groups like farmers can offer a more efficient approach to vaccine roll-out.

Naturally Acquired Rift Valley Fever Virus Neutralizing Antibodies Predominantly Target the Gn Glycoprotein.

Rift Valley fever (RVF) is a viral hemorrhagic disease first discovered in Kenya in 1930. Numerous animal studies have demonstrated that protective immunity is acquired following RVF virus (RVFV) infection and that this correlates with acquisition of virus-neutralizing antibodies (nAbs) that target the viral envelope glycoproteins. However, naturally acquired immunity to RVF in humans is poorly described. Here, we characterized the immune response to the viral envelope glycoproteins, Gn and Gc, in RVFV-exposed Kenyan adults. Long-lived IgG (dominated by IgG1 subclass) and T cell responses were detected against both Gn and Gc. However, antigen-specific antibody depletion experiments showed that Gn-specific antibodies dominate the RVFV nAb response. IgG avidity against Gn, but not Gc, correlated with nAb titers. These data are consistent with the greater level of immune accessibility of Gn on the viral envelope surface and confirm the importance of Gn as an integral component for RVF vaccine development.

A single dose of ChAdOx1 MERS provides protective immunity in rhesus macaques.

Developing a vaccine to protect against the lethal effects of the many strains of coronavirus is critical given the current global pandemic. For Middle East respiratory syndrome coronavirus (MERS-CoV), we show that rhesus macaques seroconverted rapidly after a single intramuscular vaccination with ChAdOx1 MERS. The vaccine protected against respiratory injury and pneumonia and reduced viral load in lung tissue by several orders of magnitude. MERS-CoV replication in type I and II pneumocytes of ChAdOx1 MERS-vaccinated animals was absent. A prime-boost regimen of ChAdOx1 MERS boosted antibody titers, and viral replication was completely absent from the respiratory tract tissue of these rhesus macaques. We also found that antibodies elicited by ChAdOx1 MERS in rhesus macaques neutralized six different MERS-CoV strains. Transgenic human dipeptidyl peptidase 4 mice vaccinated with ChAdOx1 MERS were completely protected against disease and lethality for all different MERS-CoV strains. The data support further clinical development of ChAdOx1 MERS.

Safety and efficacy of ChAdOx1 RVF vaccine against Rift Valley fever in pregnant sheep and goats.

Rift Valley fever virus (RVFV) is a zoonotic mosquito-borne virus that was first discovered in Kenya in 1930 and has since spread to become endemic in much of Africa and the Arabian Peninsula. Rift Valley fever (RVF) causes recurrent outbreaks of febrile illness associated with high levels of mortality and poor outcomes during pregnancy-including foetal malformations, spontaneous abortion and stillbirths-in livestock, and associated with miscarriage in humans. No vaccines are available for human use and those licensed for veterinary use have potential drawbacks, including residual virulence that may contraindicate their use in pregnancy. To address this gap, we previously developed a simian adenovirus vectored vaccine, ChAdOx1 RVF, that encodes RVFV envelope glycoproteins. ChAdOx1 RVF is fully protective against RVF in non-pregnant livestock and is also under development for human use. Here, we now demonstrate that when administered to pregnant sheep and goats, ChAdOx1 RVF is safe, elicits high titre RVFV neutralizing antibody, and provides protection against viraemia and foetal loss, although this protection is not as robust for the goats. In addition, we provide a description of RVFV challenge in pregnant goats and contrast this to the pathology observed in pregnant sheep. Together, our data further support the ongoing development of ChAdOx1 RVF vaccine for use in livestock and humans.

Systematic literature review of Rift Valley fever virus seroprevalence in livestock, wildlife and humans in Africa from 1968 to 2016.

BACKGROUND: Rift Valley fever virus (RVFV) is a zoonotic arbovirus that causes severe disease in livestock and humans. The virus has caused recurrent outbreaks in Africa and the Arabian Peninsula since its discovery in 1931. This review sought to evaluate RVFV seroprevalence across the African continent in livestock, wildlife and humans in order to understand the spatio-temporal distribution of RVFV seroprevalence and to identify knowledge gaps and areas requiring further research. Risk factors associated with seropositivity were identified and study designs evaluated to understand the validity of their results. METHODOLOGY: The Preferred Reporting of Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to produce a protocol to systematically search for RVFV seroprevalence studies in PubMed and Web of Science databases. The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement guided the evaluation of study design and analyses. PRINCIPAL FINDINGS: A total of 174 RVFV seroprevalence studies in 126 articles fulfilled the inclusion criteria. RVFV seroprevalence was recorded in 31 African countries from 1968 to 2016 and varied by time, species and country. RVFV seroprevalence articles including either livestock and humans or livestock and wildlife seroprevalence records were limited in number (8/126). No articles considered wildlife, livestock and human seroprevalence concurrently, nor wildlife and humans alone. Many studies did not account for study design bias or the sensitivity and specificity of diagnostic tests. CONCLUSIONS: Future research should focus on conducting seroprevalence studies at the wildlife, livestock and human interface to better understand the nature of cross-species transmission of RVFV. Reporting should be more transparent and biases accounted for in future seroprevalence research to understand the true burden of disease on the African continent.

Seroprevalence and awareness of porcine cysticercosis across different pig production systems in south-central Cambodia.

BACKGROUND: Taeniasis/cysticercosis, caused by the pork tapeworm Taenia solium, represents an important public health and economic burden in endemic countries. However, there is a paucity of data on infection among pigs in many parts of Southeast Asia, particularly Cambodia. We aimed to estimate seroprevalence of porcine cysticercosis, and investigate husbandary practices and knowledge of the disease among livestock workers, across different pig sector units in south-central Cambodia. METHODS: A cross sectional survey was conducted among pig smallholders, commercial farms, slaughterhouses and traders/middlemen from south-central Cambodia, selected through multistage sampling in proportion to local pig populations sizes. Questionnaires were administered to 163 pig workers to obtain data pig production, trading and slaughtering practices. Sera from 620 pigs were tested for Taenia antigens using a commercial ELISA-based test. Associations between seroprevalence and pig husbandry practices were assessed using generalised linear mixed models, adjusting for random-effects at herd-level. RESULTS: Of 620 pigs sampled, 29 (4.7%) tested positive for Taenia antigens. Seropositivity was associated with type of pig sector unit (P = 0.008), with the highest seroprevalence among pigs sampled from traders/middlemen (16.7%; 95% CI: 4.4%-37.8%), smallholders (7.6%; 95% CI: 3.8%-14.1%) and slaughterhouses (4.1%; 95% CI: 2.0%-7.5%), while none of the pigs sampled from small/medium or large commercial farms tested positive. Although the vast majority of pigs were penned, practices that might facilitate human-to-pig transmission, such as use of household waste and surface water sources to feed pigs, were prevalent among smallholders. However these were not found to be significantly associated with infection. Of 163 interviewed pig workers, 115 (70.5%) were aware of porcine cysticercosis, and 78 (47.8%) also knew it could affect humans. Twenty-six (16.0%) reported having noticed lesions typical of cysticercosis in their pigs. CONCLUSIONS: Despite most pigs being kept confined in pens rather than raised in free-roaming systems, porcine cysticercosis appears to be endemic in south-central Cambodia and is associated with smallholder production. Further investigation is needed to identify which Taenia species are causing infections among pigs, and how seroprevalence and zoonotic risk may vary across the country, to understand the risks to public health and assess where interventions might be needed.

Working with GM vaccines: engaging the public.

The UK Veterinary Vaccinology Network was among the sponsors of this year's Cheltenham Science Festival, which took place from June 7 to 12. During the festival, Adrian Hill and Andrew Pollard, of the Jenner Institute, and Bryan Charleston, of the Pirbright Institute, represented the network and discussed the development of genetically modified vaccines and the issues surrounding them in animal and human health. Madeleine Clark sums up their presentation.

Ceritinib: first global approval.

Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Novartis for the treatment of tumours characterised by genetic abnormalities in ALK. ALK is a member of the insulin receptor family of tyrosine kinases that can become oncogenic when fused to other proteins. Ceritinib has been approved in the US under 'Breakthrough Therapy' designation for the second-line treatment of ALK-positive non-small cell lung cancer (NSCLC). Regulatory submissions have also been made in the EU and other countries. Phase III development is ongoing worldwide to evaluate ceritinib both as a first- and second-line therapy for ALK-positive NSCLC. This article summarizes the milestones in the development of ceritinib leading to this first approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.