Public sector replacement of privately funded pharmaceutical R&D: cost and efficiency considerations.

AIMS: Economic studies have found that public support of basic medical research provides important long-term benefits. In response to suggestions that private pharmaceutical research and development (R&D) funding could be totally replaced by public funding, we investigate the economic implications of such a substitution in funding roles that maintain the recent pace of pharmaceutical innovation. MATERIALS AND METHODS: Total lifecycle R&D costs were estimated using the latest available R&D expenditures per novel molecule entering clinical trials, likelihood of approval, pre-clinical and post-approval expenditures, using a published survey and a review of publicly available financial accounts from US-listed multinational developers. This estimate was then stratified by the average number of annual FDA approvals to estimate total costs of R&D funding born by the private sector. RESULTS: We find total lifecycle R&D costs were US$2.83 billion per approved medicine. Estimated uncapitalized costs to replace private R&D funding for one year of FDA approvals were $139.6 billion. These additional costs are equivalent to 302% of the entire National Institute for Health 2022 budget of $46.2 billion, and around 25 times NIH's estimated annual $5.6 billion currently dedicated to clinical research trials for pharmaceuticals. Further assessing the policy proposition through a literature review, we found little evidence for improvements in economic efficiency via public funding substitution, while there may be additional challenges including asymmetric information, adverse selection, yardstick competition, hold-up, under-rewarding of incremental innovation and political rent-seeking. LIMITATIONS: Our calculations may undervalue full replacement costs, by excluding non-R&D expenses for manufacturing, distribution, or financing. CONCLUSIONS: The bulk of investment in R&D is underwritten by the private sector. Political discourse portraying the NIH as the central force in bringing a new drug to market may underappreciate the pivotal role of private at-risk capital. Replacing such investment while maintaining the current innovation output in terms of approved therapies would necessitate substantial increases in taxpayer financing.

Understanding the emergence of highly pathogenic avian Influenza A virus H5N1 in pinnipeds: an evolutionary approach.

Highly pathogenic influenza A virus (HPIAV) H5N1 within the genetic clade 2.3.4.4b has emerged in wild birds in different regions of the world, leading to the death of more than 70 million birds. When these strains spread to pinniped species a remarkable mortality has also been observed. A detailed genetic characterization of HPIAV isolated from pinnipeds is essential to understand the potential spread of these viruses to other mammalian species, including humans. To gain insight into these matters a detailed phylogenetic analysis of HPIAV H5N1 2.3.4.4b strains isolated from pinniped species was performed. The results of these studies revealed multiple transmission events from birds to pinnipeds in all world regions. Different evolutionary histories of different genes of HPIAV H5N1 2.3.4.4b strains gave rise to the viruses infecting pinnipeds in different regions of the world. European strains isolated from pinnipeds represent a completely different genetic lineage from strains isolated from South American ones. All strains isolated from pinnipeds bear characteristics of a highly pathogenic form for of avian influenza in poultry. Amino acid substitutions, previously shown to confer an adaptive advantage for infecting mammals, were observed in different genes in all pinniped species studied.

Vaccine optimization for highly pathogenic avian influenza: Assessment of antibody responses and protection for virus-like particle vaccines in chickens.

Background: Recent outbreaks of clade 2.3.4.4b highly pathogenic avian influenza (HPAI) H5N1 viruses in regions previously less affected since 2020 have raised global concerns. Implementing mass immunization or ring vaccination in poultry should be a countermeasure ready to contain disease outbreaks. This study focuses on developing a recombinant H5N2 vaccine based on virus-like particles (VLPs) against clade 2.3.4.4c, the predominant HPAI subclade in Taiwan since its emergence, leading to a large outbreak in 2015. Methods: The study aimed to confirm the effectiveness of clade 2.3.4.4c H5N2 VLPs in protecting chickens and identify the best adjuvants for the VLP vaccine. We used Montanide 71VG-adjuvanted inactivated RG6 to establish the immunization protocol, followed by prime-boost H5N2-VLP immunizations. We compared adjuvants: 71VG, 71VG with VP3, and Alum with VP3. Serum samples were tested for antibodies against homologous vaccine antigens and cross-clade antigens by hemagglutination inhibition (HI) assays. Finally, we evaluated the protective efficacy by lethally challenging immunized chickens with H5 viruses from clade 1 or 2.3.4.4c. Results: Poultry adjuvant 71VG significantly enhanced antibody responses in chickens with inactivated RG6 compared to unadjuvanted inactivated virus. While increasing antigen dosage enhanced 71VG adjuvanted RG6-induced antibody titers, the vaccine displayed minimal cross-reactivity against locally circulating HPAI H5N2. In contrast, H5N2-VLP containing the HA protein of clade 2.3.4.4c, adjuvanted with (FMDV) VP3 in 71VG, significantly promoted HI antibody responses. All H5N2-VLP immunized chickens survived lethal challenges with the local clade 2.3.4.4c H5 strain. Conclusion: The study demonstrated the immunogenic potential of the VLP vaccine in chickens. Our findings offer insights for optimizing VLP vaccines, allowing the incorporation of the HA of currently circulating H5 viruses to effectively mitigate the impact of the rapidly evolving clade 2.3.4.4 H5 outbreaks.

Multiplexed Spatial Imaging at the Single-Cell Level Reveals Mutually Exclusive Expression of B7 Family Proteins.

Targeting novel inhibitory ligands beyond anti-PD-1 and PD-L1 and CTLA-4 therapies is essential for the next decade of the immunotherapy era. Agents for the B7 family molecules B7-H3, B7-H4, and B7-H5 are emerging in clinical trial phases; therefore, further accumulation of evidence from both clinical and basic aspects is vital. Here, we applied a 7-color multiplexed imaging technique to analyze the profile of B7 family B7-H3/B7-H4/B7-H5 expression, in addition to PD-L1, and the spatial characteristics of immune cell infiltrates in urothelial carcinoma (UC). The results revealed that B7-H3 and B7-H4 were mainly expressed on tumor cells and B7-H5 on immune cells in UC, and most of the B7-H3/B7-H4/B7-H5-positive cells were mutually exclusive with PD-L1-positive cells. Also, the expression of B7-H4 was elevated in patients with advanced pathologic stages, and high B7-H4 expression was a significant factor affecting overall mortality following surgery in UC. Furthermore, spatial analysis revealed that the distance from the B7-H4+ cells to the nearest CD8+ cells was markedly far compared with other B7 family-positive tumor cells. Interestingly, the distance from B7-H4+ cells to the nearest CD8+ cells was significantly farther in patients dying from cancer after surgery or immune checkpoint inhibitors compared with cancer survivors; thus, high B7-H4 expression in tumor cells may inhibit CD8 infiltration into the tumor space and that B7-H4-positive cells form a specific spatial niche. In summary, we performed a comprehensive evaluation of B7 family member expression and found that the spatial distribution of B7-H4 suggests the potentially useful role of combination blockade with both B7-H4 and the current anti-PD-1/PD-L1 axis in the treatment of UC.

Experimental infection of Clades 2.2.1.2 (H5N1) and 2.3.4.4b (H5N8) of highly pathogenic avian influenza virus infection in commercial broilers.

In this study the pathogenicity, infectivity, and transmissibility of H5N1 highly pathogenic avian influenza (HPAI) clade 2.2.1.2 and H5N8 HPAI clade 2.3.4.4b viruses were evaluated in commercial broilers on days 24 and 31. The mortality rate was 100 % in both challenge viruses and in contact birds either on day 24 or day 31 which confirmed the highly pathogenicity of both clades (2.2.1.2/ 2.3.4.4b) in commercial broilers. Both clades (H5N8 clade 2.3.4.4b/ H5N1 clade 2.2.1.2 viruses) were efficiently replicate within and transmitted between commercial broilers. The H5N8-infected birds shed high titer of viruses from oropharynx and cloaca, which associated with the field spread of AIV-H5N8 in commercial broilers. Mean lesion score in both challenged clades showed similar scores, which confirmed the pathogenicity of both clades in commercial broilers' organs (mainly spleen, cerebellum, thymus, Bursa, Lung) which confirm the neurogenic affinity of the virus. In the central nervous system, non-suppurative encephalitis consisting in multifocal areas of necrosis in cerebral hemispheres, intense spongiosis, neuronal chromatolysis and gliosis were commonly observed. In cerebrum, chromatolysis of Purkinje neurons was a common finding. In the lung, interstitial pneumonia consisting of moderate to severe increase of the cellularity (macrophages and lymphoid cells) in air capillaries and focal areas of necrosis associated with intense viral replication was commonly observed. In lymphoid tissues, including spleen, thymus, and bursa of Fabricius, multifocal areas of necrosis/apoptosis of variable intensity in mononuclear cells were present. Particularly, diffuse necrotic areas were present in the spleen. In the liver, we detected focal areas of necrosis with mild distention of hepatic sinusoids. To conclude the AIV either H5N1 or H5N8 have neurological affinity with immune suppression effect based on necrosis and apoptosis of lymphoid tissues.

An Update on Highly Pathogenic Avian Influenza A(H5N1) Virus, Clade 2.3.4.4b.

Since the resurgence of highly pathogenic avian influenza (HPAI) A(H5N1) virus, clade 2.3.4.4b, during 2021, these viruses have spread widely among birds worldwide, causing poultry outbreaks and infections of a wide range of terrestrial and marine mammal species. During 2024, HPAI A(H5N1) virus, clade 2.3.4.4b, was detected in dairy cattle for the first time and caused an ongoing multistate outbreak, with high levels of virus documented in raw cow milk. Human infections with clade 2.3.4.4b viruses from exposures to infected poultry or dairy cattle have resulted in a wide spectrum of illness severity, from conjunctivitis or mild respiratory illness to severe and fatal pneumonia in different countries. Vigilance, and stronger global virologic surveillance among birds, poultry, terrestrial and marine mammals, and humans, with virus characterization and rapid data sharing, is needed to inform the threat of clade 2.3.4.4b viruses, as they continue to evolve, to public health.

Recent Occurrence, Diversity, and Candidate Vaccine Virus Selection for Pandemic H5N1: Alert Is in the Air.

The prevalence of the highly pathogenic avian influenza virus H5N1 in wild birds that migrate all over the world has resulted in the dissemination of this virus across Asia, Europe, Africa, North and South America, the Arctic continent, and Antarctica. So far, H5N1 clade 2.3.4.4.b has reached an almost global distribution, with the exception of Australia and New Zealand for autochthonous cases. H5N1 clade 2.3.4.4.b, derived from the broad-host-range A/Goose/Guangdong/1/96 (H5N1) lineage, has evolved, adapted, and spread to species other than birds, with potential mammal-to-mammal transmission. Many public health agencies consider H5N1 influenza a real pandemic threat. In this sense, we analyzed H5N1 hemagglutinin sequences from recent outbreaks in animals, clinical samples, antigenic prototypes of candidate vaccine viruses, and licensed human vaccines for H5N1 with the aim of shedding light on the development of an H5N1 vaccine suitable for a pandemic response, should one occur in the near future.

Avian influenza A H5N1 hemagglutinin protein models have distinct structural patterns re-occurring across the 1959-2023 strains.

Influenza A H5N1 hemagglutinin (HA) plays a crucial role in viral pathogenesis and changes in the HA receptor binding domain (RBD) have been attributed to alterations in viral pathogenesis. Mutations often occur within the HA which in-turn results in HA structural changes that consequently contribute to protein evolution. However, the possible occurrence of mutations that results to reversion of the HA protein (going back to an ancestral protein conformation) which in-turn creates distinct HA structural patterns across the 1959-2023 H5N1 viral evolution has never been investigated. Here, we generated and verified the quality of the HA models, identified similar HA structural patterns, and elucidated the possible variations in HA RBD structural dynamics. Our results show that there are 7 distinct structural patterns occurring among the 1959-2023 H5N1 HA models which suggests that reversion of the HA protein putatively occurs during viral evolution. Similarly, we found that the HA RBD structural dynamics vary among the 7 distinct structural patterns possibly affecting viral pathogenesis.

Susceptibilities and viral shedding of peridomestic wildlife infected with clade 2.3.4.4b highly pathogenic avian influenza virus (H5N1).

We tested the ability of six peridomestic wildlife species to replicate a highly pathogenic (HP) clade 2.3.4.4b AIV (H5N1) isolated in the U.S. during 2022. All tested species replicated and shed virus, at least to some degree. Of the six species evaluated (house sparrows (Passer domesticus), European starlings (Sturnus vulgaris), feral pigeons (Columba livia), striped skunks (Mephitis mephitis), Virginia opossums (Didelphis virginiana), and cottontails (Sylvilagus sp.)), striped skunks and Virginia opossums shed the highest viral titers of 106.3 PFU/mL and 105.0 PFU/mL, respectively. Overall, the results of this study indicate that certain peridomestic species could pose a biosecurity threat to poultry operations in some situations. In addition, this study and field reports indicate that the HP AIVs circulating in the U.S. during 2022-2024 may have an extremely broad range of species that can be impacted by and/or replicate and shed these viruses.

Short- and long-term cost-effectiveness of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis in China.

BACKGROUNDS: Biologics and JAK inhibitors were the most effective innovative systemic treatments for moderate-to-severe atopic dermatitis (AD). However, their cost-effectiveness in China remains unclear. This study aims to compare both the short- and long-term cost-effectiveness of abrocitinib and dupilumab in adults with moderate-to-severe AD from the perspective of the Chinese healthcare system. METHODS: A hybrid decision tree and Markov model were developed to simulate the costs and health outcomes of interventions on both short-term and long-term horizons. Short- and long-term horizons were employed to reflect the 26-week induction treatment and model the extended 10-year maintenance treatment period, respectively. The cost-effectiveness of strategies was measured by incremental cost-effectiveness ratios (ICERs), which were then compared with the willingness-to-pay threshold (WTP) that was equivalent to the gross domestic product (GDP) per capita of China in 2023 ($12,681 [€11679.26]). One-way and probabilistic sensitivity analyses were conducted to validate the robustness of the model. RESULTS: Over the short-term horizon, the QALYs (quality-adjusted life years) gained were 0.43 for the abrocitinib group and 0.42 for the dupilumab group, with the costs being $2,716.01 (€2501.46) and $3,940.33 (€3629.06), respectively. Over the long-time horizon, abrocitinib therapy yields higher QALYs (6.60 versus 6.53) and incurs a lower cost ($22,765.15 [€20966.81] versus $30,683.38 [€28259.54]) compared to dupilumab. The probability of abrocitinib being cost-effective was nearly 100% under the current WTP. Both short- and long-term results showed that abrocitinib was more effective and less costly than dupilumab, making abrocitinib the dominant option. CONCLUSIONS: Abrocitinib was dominant compared to dupilumab both over the short- and long-term horizon for moderate-to-severe AD in China. Future research incorporating real-world evidence and long-term efficacy outcomes could further refine these economic evaluations.

Highly Pathogenic Avian Influenza A(H5N1) Virus Clade 2.3.4.4b Infections in Seals, Russia, 2023.

Highly pathogenic avian influenza A(H5N1) virus was detected in dead seals on Tyuleniy Island in eastern Russia, in the Sea of Okhotsk. Viruses isolated from dead northern fur seals belong to clade 2.3.4.4b and are closely related to viruses detected predominantly in the Russian Far East and Japan in 2022-2023.

Pathogenicity of Highly Pathogenic Avian Influenza A(H5N1) Viruses Isolated from Cats in Mice and Ferrets, South Korea, 2023.

The prevalence of highly pathogenic avian influenza (HPAI) A(H5N1) viruses has increased in wild birds and poultry worldwide, and concomitant outbreaks in mammals have occurred. During 2023, outbreaks of HPAI H5N1 virus infections were reported in cats in South Korea. The H5N1 clade 2.3.4.4b viruses isolated from 2 cats harbored mutations in the polymerase basic protein 2 gene encoding single amino acid substitutions E627K or D701N, which are associated with virus adaptation in mammals. Hence, we analyzed the pathogenicity and transmission of the cat-derived H5N1 viruses in other mammals. Both isolates caused fatal infections in mice and ferrets. We observed contact infections between ferrets, confirming the viruses had high pathogenicity and transmission in mammals. Most HPAI H5N1 virus infections in humans have occurred through direct contact with poultry or a contaminated environment. Therefore, One Health surveillance of mammals, wild birds, and poultry is needed to prevent potential zoonotic threats.

Susceptibility of Synanthropic Rodents (Mus musculus, Rattus norvegicus and Rattus rattus) to H5N1 Subtype High Pathogenicity Avian Influenza Viruses.

Synanthropic wild rodents associated with agricultural operations may represent a risk path for transmission of high pathogenicity avian influenza viruses (HPAIVs) from wild birds to poultry birds. However, their susceptibility to HPAIVs remains unclear. In the present study, house mice (Mus musculus), brown rats (Rattus norvegicus), and black rats (Rattus rattus) were experimentally exposed to H5N1 subtype HPAIVs to evaluate their vulnerability to infection. After intranasal inoculation with HA clade 2.2 and 2.3.2.1 H5N1 subtype HPAIVs, wild rodents did not show any clinical signs and survived for 10- and 12-day observation periods. Viruses were isolated from oral swabs for several days after inoculation, while little or no virus was detected in their feces or rectal swabs. In euthanized animals at 3 days post-inoculation, HPAIVs were primarily detected in respiratory tract tissues such as the nasal turbinates, trachea, and lungs. Serum HI antibodies were detected in HA clade 2.2 HPAIV-inoculated rodents. These results strongly suggest that synanthropic wild rodents are susceptible to infection of avian-origin H5N1 subtype HPAIVs and contribute to the virus ecosystem as replication-competent hosts. Detection of infectious viruses in oral swabs indicates that wild rodents exposed to HPAIVs could contaminate food, water, and the environment in poultry houses and play roles in the introduction and spread of HPAIVs in farms.

Review of the Highly Pathogenic Avian Influenza in Argentina in 2023: Chronicle of Its Emergence and Control in Poultry.

Highly pathogenic avian influenza (HPAI) is a highly contagious viral disease that represents a significant threat to poultry production worldwide. Variants of the HPAI virus (HPAIV) H5A/Goose/GuangDong/1/96 (H5 Gs/GD/96) lineage have caused five intercontinental epizootic waves, with the most recent, clade 2.3.4.4b, reaching Argentina in February 2023. Initially detected in wild birds, the virus quickly spread to backyard and commercial poultry farms, leading to economic losses, including the loss of influenza-free status (IFS). By March/April 2023 the epidemic had peaked and vaccination was seriously considered. However, the success of strict stamping-out measures dissuaded the National Animal Health Authority (SENASA) from authorizing any vaccine. Suspected cases sharply declined by May, and the last detection in commercial poultry was reported in June. The effective control and potential eradication of HPAIV in Argentina were due to SENASA's early detection and rapid response, supported by private companies, veterinarians, and other stakeholders. Stamping-out measures have been effective for virus elimination and reduced farm-to-farm transmission; however, as the virus of this clade may remain present in wild birds, the risk of reintroduction into poultry production is high. Therefore, maintaining continuous active surveillance will be crucial for promptly detecting any new HPAIV incursion and taking appropriate action to contain virus dissemination.

Detection and Monitoring of Highly Pathogenic Influenza A Virus 2.3.4.4b Outbreak in Dairy Cattle in the United States.

The emergence and spread of highly pathogenic avian influenza virus A subtype H5N1 (HP H5N1-IAV), particularly clade H5N1 2.3.4.4b, pose a severe global health threat, affecting various species, including mammals. Historically, cattle have been considered less susceptible to IAV, but recent outbreaks of H5N1-IAV 2.3.4.4b in dairy farms suggest a shift in host tropism, underscoring the urgency of expanded surveillance and the need for adaptable diagnostic tools in outbreak management. This study investigated the presence of anti-nucleoprotein (NP) antibodies in serum and milk and viral RNA in milk on dairy farms affected by outbreaks in Texas, Kansas, and Michigan using a multi-species IAV ELISA and RT-qPCR. The analysis of ELISA results from a Michigan dairy farm outbreak demonstrated a positive correlation between paired serum and milk sample results, confirming the reliability of both specimen types. Our findings also revealed high diagnostic performance during the convalescent phase (up to 96%), further improving sensitivity through serial sampling. Additionally, the evaluation of diagnostic specificity using serum and milk samples from IAV-free farms showed an excellent performance (99.6%). This study underscores the efficacy of the IAV NP-blocking ELISA for detecting and monitoring H5N1-IAV 2.3.4.4b circulation in dairy farms, whose recent emergence raises significant animal welfare and zoonotic concerns, necessitating expanded surveillance efforts.

Complex Evolutionary Dynamics of H5N8 Influenza A Viruses Revealed by Comprehensive Reassortment Analysis.

Influenza A viruses (IAVs) circulate among different species and have the potential to cause significant pandemics in humans. This study focuses on reassortment events in the H5N8 subtype of IAV, which poses a serious threat to public health due to its high pathogenicity in birds and potential for cross-species transmission. We retrieved 2359 H5N8 IAV sequences from GISAID, and filtered and analyzed 442 complete genomic sequences for reassortment events using pairwise distance deviation matrices (PDDMs) and pairwise distance correspondence plots (PDCPs). This detailed case study of specific H5N8 viruses revealed previously undescribed reassortment events, highlighting the complex evolutionary history and potential pandemic threat of H5N8 IAVs.

Comparison of Extraction Methods for the Detection of Avian Influenza Virus RNA in Cattle Milk.

Since early 2024, a multistate outbreak of highly pathogenic avian influenza H5N1 has been affecting dairy cattle in the USA. The influenza viral RNA concentrations in milk make it an ideal matrix for surveillance purposes. However, viral RNA detection in multi-component fluids such as milk can be complex, and optimization of influenza detection methods is thus required. Raw bulk tank milk and mastitis milk samples were artificially contaminated with an avian influenza strain and subjected to five extraction methods. HCoV-229E and synthetic RNA were included as exogenous internal process controls. Given the high viral load usually observed in individual raw milk samples, four out of five tested methods would enable influenza detection in milk with normal texture, over a time window of at least 2 weeks post-onset of clinical signs. Nevertheless, sample dilution 1:3 in molecular transport medium prior to RNA extraction provided the best results for dilution of inhibitory substances and a good recovery rate of influenza RNA, that reached 12.5 ± 1.2% and 10.4 ± 3.8% in two independent experiments in bulk milk and 11.2 ± 3.6% and 10.0 ± 2.9% on two cohorts of mastitis milk samples. We have also shown compatibility of an influenza RT-qPCR system with synthetic RNA detection for simultaneous validation of the RNA extraction and RT-qPCR processes.