Patenting government funded innovations as a strategy to increase budget for academic vaccine R&D

Vaccine development is a lengthy, expensive and risky venture, with the research and development (R&D) process costing billions of dollars. The pre-clinical stage of vaccine R&D is largely performed by academic research institutions, then continued by the pharmaceutical industry though licensing agreements, taking the most promising candidates to the clinical testing stage. Governments play a major role in de-risking the early stages of vaccine R&D for the pharmaceutical industry through the funding of research in public institutes and academic research laboratories, and providing loans and tax credit to pharmaceutical companies involved in vaccine R&D. Through these initiatives, governments fuel the industry, shape markets and aid the development of novel products and technologies. Many of the blockbuster vaccines currently on the market benefited greatly from government funding, however, pharmaceutical companies are reaping most of the rewards of the billions of dollars these vaccines generate every year. The present review will discuss the role that government funding and academic research has played in vaccines R&D. Furthermore, it will discuss some of the elaborate schemes pharmaceutical companies use to reduce their tax payments, and how strategies such as patenting government-funded innovations can help ensure that governments receive a share of the generated revenues

The patent buyout price for Human Papilloma Virus (HPV) vaccine and the ratio of R&D costs to the patent value

Human papillomavirus (HPV) is responsible for almost all of the 530,000 new cases of cervical cancer and approximately 266,000 deaths per year. HPV vaccination is an integral component of the World Health Organization’s global strategy to fight the disease. However, high vaccine prices enforced through patent protection are limiting vaccine expansion, particularly in low- and middle-income countries. This raises the question of the patent buyout price for Merck’s HPV vaccines (Gardasil-4 and 9), which hold 87% of the global HPV vaccine market. It also raises the question about the market power from patent protection, that we assess by estimating the ratio of R&D costs for Gardasil and its patent value. We estimate the patent buyout price for various groups of countries and in total. The estimated global Gardasil patent buyout price in 2020 is between US$15.33 - 18.32 billion (in 2018 US$), the estimated present discounted value of the profit stream for 2007-2028 amounts to US 22.29 - 33.08 billion, and the estimated total R&D cost is between US 1.10 – 1.21 billion. Thus, we arrive at a ratio of R&D costs to the patent value of the order of 3-5%, suggesting that patent protection provides Merck with extraordinarily strong market power

Estrogen-related receptor alpha (ERR?) is a key regulator of intestinal homeostasis and protects against colitis

The estrogen-related receptor alpha (ERR?) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERR? is abundantly expressed in the intestine and in cells of the immune system. However, its role in inflammatory bowel disease (IBD) remains unknown. Here, we report a protective role of ERR? in the intestine. We found that mice deficient in ERR? were susceptible to experimental colitis, exhibiting increased colon inflammation and tissue damage. This phenotype was mediated by impaired compensatory proliferation of intestinal epithelial cells (IEC) following injury, enhanced IEC apoptosis and necrosis and reduced mucus-producing goblet cell counts. Longitudinal analysis of the microbiota demonstrated that loss of ERR? lead to a reduction in microbiome ?-diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERR? mediated its protective effects by acting within the radio-resistant compartment of the intestine. It promoted disease tolerance through transcriptional control of key genes involved in intestinal tissue homeostasis and repair. These findings provide new insights on the role of ERR? in the gut and extends our current knowledge of nuclear receptors implicated in IBD

The patent buyout price for human papilloma virus (HPV) vaccine and the ratio of R&D costs to the patent value

Human papillomavirus (HPV) is responsible for almost all of the 570,000 new cases of cervical cancer and approximately 311,000 deaths per year. HPV vaccination is an integral component of the World Health Organization’s (WHO) global strategy to fight the disease. However, high vaccine prices enforced through patent protection are limiting vaccine expansion, particularly in low- and middle-income countries. By limiting market power, patent buyouts could reduce vaccine prices and raise HPV vaccination rates while keeping innovation incentives. We estimate the global patent buyout price as the present discounted value (PDV) of the future profit stream over the remaining patent length for Merck’s HPV vaccines (Gardasil-4 and 9), which hold 87% of the global HPV vaccine market, in the range of US$15.6–27.7 billion (in 2018 US$). The estimated PDV of the profit stream since market introduction amounts to US 17.8–42.8 billion and the estimated R&D cost to US 1.05–1.21 billion. Thus, we arrive at a ratio of R&D costs to the patent value of the order of 2.5–6.8%. We relate this figure to typical estimates of the probability of success (POS) for clinical trials of vaccines to discuss if patent protection provides Merck with extraordinarily strong price setting power

Host immunity to Clostridium difficile PCR ribotype 017 strains.

Clostridium difficile is an important nosocomial pathogen and the leading cause of antibiotic-associated diarrhea. Multilocus sequence typing indicates that C. difficile strains belong to five distinct genetic clades encompassing several PCR ribotypes (RT). Since their emergence in 2003, hypervirulent RT027 strains have been a major focus of research; in contrast, our current understanding of RT017-mediated disease pathogenesis lags far behind. In this study, we aimed to characterize host immunity to CF5 and M68, two genetically well-defined RT017 strains. Both strains engaged with host Toll-like receptor 2/6 (TLR2/6), TLR2-CD14, and TLR5 to similar extents in a model cell line. Despite this, CF5 mediated significantly greater dendritic cell (DC) interleukin-12 (IL-12), IL-27, and IL-10 immunity than M68. Both strains elicited similar IL-1β mRNA levels, and yet only M68 caused a marked increase in secretory IL-1β. A CF5 cocultured-DC cytokine milieu drove an equipotent Th1 and Th17 response, while M68 promoted greater Th17 immunity. Human gastrointestinal ex vivo cytokine responses to both strains were characterized. Taken together, our data suggest that C. difficile strains mediate overlapping and yet distinct mucosal and DC/T cell immunity. Finally, toxin-driven IL-1β release supports the hypothesis that this cytokine axis is a likely target for therapeutic intervention for C. difficile infection

Polymorphisms in autophagy genes and susceptibility to tuberculosis

Contains fulltext : 109084.pdf (publisher's version ) (Open Access)Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB) among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana. We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls, and between patients infected with different M. tuberculosis genotypes, as determined by spoligotyping. The same autophagy polymorphisms were studied in correlation with ex-vivo production of TNF, IL-1beta, IL-6, IL-8, IFN-gamma and IL-17 in healthy volunteers. No association was found between TB and polymorphisms in the genes ATG10, ATG16L2, ATG2B, ATG5, ATG9B, IRGM, LAMP1, LAMP3, P2RX7, WIPI1, MTOR and ATG4C. Associations were found between polymorphisms in LAMP1 (p = 0.02) and MTOR (p = 0.02) and infection with the successful M. tuberculosis Beijing genotype. The polymorphisms examined were not associated with M. tuberculosis induced cytokines, except for a polymorphism in ATG10, which was linked with IL-8 production (p = 0.04). All associations found lost statistical significance after correction for multiple testing. This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB, with M. tuberculosis Beijing genotype infection or with ex-vivo pro-inflammatory cytokine production

Cost-effectiveness analysis of interventions to improve diagnosis and preventive therapy for paediatric tuberculosis in 9 sub-Saharan African countries: A modelling study.

BackgroundOver 1 million children aged 0 to 14 years were estimated to develop tuberculosis in 2021, resulting in over 200,000 deaths. Practical interventions are urgently needed to improve diagnosis and antituberculosis treatment (ATT) initiation in children aged 0 to 14 years and to increase coverage of tuberculosis preventive therapy (TPT) in children at high risk of developing tuberculosis disease. The multicountry CaP-TB intervention scaled up facility-based intensified case finding and strengthened household contact management and TPT provision at HIV clinics. To add to the limited health-economic evidence on interventions to improve ATT and TPT in children, we evaluated the cost-effectiveness of the CaP-TB intervention.Methods and findingsWe analysed clinic-level pre/post data to quantify the impact of the CaP-TB intervention on ATT and TPT initiation across 9 sub-Saharan African countries. Data on tuberculosis diagnosis and ATT/TPT initiation counts with corresponding follow-up time were available for 146 sites across the 9 countries prior to and post project implementation, stratified by 0 to 4 and 5 to 14 year age-groups. Preintervention data were retrospectively collected from facility registers for a 12-month period, and intervention data were prospectively collected from December 2018 to June 2021 using project-specific forms. Bayesian generalised linear mixed-effects models were used to estimate country-level rate ratios for tuberculosis diagnosis and ATT/TPT initiation. We analysed project expenditure and cascade data to determine unit costs of intervention components and used mathematical modelling to project health impact, health system costs, and cost-effectiveness. Overall, ATT and TPT initiation increased, with country-level incidence rate ratios varying between 0.8 (95% uncertainty interval [UI], 0.7 to 1.0) and 2.9 (95% UI, 2.3 to 3.6) for ATT and between 1.6 (95% UI, 1.5 to 1.8) and 9.8 (95% UI, 8.1 to 11.8) for TPT. We projected that for every 100 children starting either ATT or TPT at baseline, the intervention package translated to between 1 (95% UI, -1 to 3) and 38 (95% UI, 24 to 58) deaths averted, with a median incremental cost-effectiveness ratio (ICER) of US$634 per disability-adjusted life year (DALY) averted. ICERs ranged between US$135/DALY averted in Democratic of the Congo and US$6,804/DALY averted in Cameroon. The main limitation of our study is that the impact is based on pre/post comparisons, which could be confounded.ConclusionsIn most countries, the CaP-TB intervention package improved tuberculosis treatment and prevention services for children aged under 15 years, but large variation in estimated impact and ICERs highlights the importance of local context.Trial registrationThis evaluation is part of the TIPPI study, registered with ClinicalTrials.gov (NCT03948698)

Variation in cytokine level associated with polymorphisms in autophagy genes.

a<p>Values are expressed as the ratio of cytokine production associated with different genotypes (median for all individuals bearing the same genotype), using the genotype groups with the highest and lowest cytokine production.</p>b<p>Significantly differences (P<0.05) in genotype groups with highest and lowest cytokine production calculated by Wilcoxon signed rank test.</p><p>n.a. not analysed; SNP not polymorphous in this population.</p

The overlap of study subjects between the current study (n = 1974) and the previous genome-wide association study (GWAS, n = 1139) [<b>29</b>].

<p>The overlap of study subjects between the current study (n = 1974) and the previous genome-wide association study (GWAS, n = 1139) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041618#pone.0041618-Png1" target="_blank">[<b>29</b>]</a>.</p

Demographic information of the study population.

<p>Demographic information of the study population.</p