ImmunoFrontiers

[immunofrontiers-blog]

Inovio Receives $5 Million Grant from Bill and Melinda Gates Foundation for COVID-19 Vaccine Program

In a recent press release, Pennsylvania-based American biotechnology company Inovio Pharmaceuticals (Nasdaq: INO) reported that the Bill and Melinda Gates Foundation has provided a $5 million grant to support the accelerated evaluation and production of their "CELLECTRA 3PSP" medical device, which is integral to the intradermal delivery of their DNA-based COVID-19 vaccine INO-4800. INO-4800 is currently being tested in preclinical studies and is anticipated to progress to Phase 1 clinical trials in the United States during April 2020. President and CEO of Inovio Dr. J. Joseph Kim stated, "INOVIO is grateful to the Bill & Melinda Gates Foundation for their continued investment in INOVIO's DNA medicines platform and for their support for DNA vaccines to potentially protect those at risk globally given the current COVID-19 outbreak. Our team of vaccine experts are working around the clock to advance INO-4800 and we look forward to attracting additional partnerships to expedite its development to meet this urgent global health need." According to the press release, "The next generation CELLECTRA 3PSP device is designed specifically for a COVID-19 type pandemic scenario. It is a small, portable, hand-held, user-friendly device that runs on readily available "AA" batteries. This allows for stockpiling of the device in quantity without maintenance. It is easy to use and is based on our current device with extensive history (over 6,000 administrations) which has received the CE mark and has an acceptable safety profile. The streamlined design also allows it to be readily produced at reduced costs and large scale." "The device has been designed with reliability, challenging environments, user needs and ease of large scale manufacturing in mind. INOVIO's San Diego Device Manufacturing facility will build initial quantities and demonstrate the design and scale up of manufacturing processes which can then be transferred to additional contract manufacturers for increased capacity. Initial development of CELLECTRA 3PSP was started in 2019 with $8.1 million funding from the medical arm of the U.S. Defense Threat Reduction Agency (DTRA)'s Medical CBRN Defense Consortium. The new funding will help to accelerate the testing and completion of the device development and scale up to combat the COVID-19 disease," the press release stated. Inovio intends to deliver one million doses of the INO-4800 vaccine by the end of 2020, and "is working to scale up both INO-4800 and CELLECTRA 3PSP devices to potentially make available millions of doses to combat this outbreak." The company has announced plans to start US-based human clinical trials of INO-4800 in April. During a meeting with the US Coronavirus Task Force on March 2nd at the White House, Inovio President and CEO Dr. J. Joseph Kim stated, "Inovio is the leader in coronavirus vaccine development and the only company with a Phase 2 vaccine for a related coronavirus that causes Middle East Respiratory Syndrome (MERS). Using our modern DNA medicines platform, we designed our DNA vaccine INO-4800 in three hours after the publication of the genetic sequence of the novel coronavirus that causes COVID-19." Stay aware of breaking immuno-biotech news and the latest advancements in the field of immunology. "We immediately began preclinical testing and small-scale manufacture and have already shared robust preclinical data with our public and private partners. We plan to begin human clinical trials in the U.S. in April and soon thereafter in China and South Korea, where the outbreak is impacting the most people. We plan on delivering one million doses by year end with existing resources and capacity. However, we will need additional resources to scale up to make enough doses to help protect Americans from COVID-19 as well as to lead global efforts to curtail this virus," continued Dr. Kim. On January 23rd, 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) issued Inovio a grant of up to $9 million to fund preclinical and clinical development of INO-4800. CEPI CEO Richard Hatchett stated, "Given the rapid global spread of the 2019-nCoV virus the world needs to act quickly and in unity to tackle this disease. Our intention with this work is to leverage our work with Inovio on the MERS coronavirus and rapid response platform to speed up vaccine development." Dr. Kim responded, "We're extremely honored to expand our partnership with CEPI to tackle this new threat to global public health. Our DNA medicine platform represents the best modern day approach to combatting emerging pandemics. We have already demonstrated positive clinical outcomes with our vaccine against MERS-CoV, another coronavirus. Importantly, following the Zika viral infection outbreak, Inovio and our partners developed a vaccine that went from bench to human testing in just seven months – the fastest vaccine development on record in recent decades. We believe we can further improve upon this accelerated timeline to meet the current challenge of the emerging Chinese coronavirus 2019-nCoV." On January 30th, 2020, Inovio announced that it would develop INO-4800 in collaboration with China-based Beijing Advaccine Biotechnology Co., with the goal of expediting the testing of INO-4800. Dr. Kim stated, "Our collaboration with Beijing Advaccine and its Founder, Emeritus Professor Bin Wang from the prestigious Fudan University and China's premier DNA vaccine expert, will tremendously accelerate our coronavirus vaccine INO-4800 development in China because of its expertise and experience with regulatory authorities and clinical trial management. This collaboration allows us to enter China and deliver our vaccine into the areas where they need it most as soon as possible. Our shared goal is to utilize both company's expertise in developing vaccines for emerging infectious diseases and hopefully achieve an accelerated regulatory approval for INO-4800." Since January, Inovio Pharmaceuticals has demonstrated immune responses to their vaccine in animal models and initiated plans for a human clinical trial. The company intends to finalize their clinical trial design in March and prepare 3,000 doses of their vaccine for trials in the United States, South Korea, and China. The first clinical trial will include 30 healthy volunteers in the United States, with the Asia-based trials occurring afterwards. Inovio's DNA-based vaccine platform is centered around speed of manufacturing, stability during transport and storage, and efficacy for inducing a robust immune response. INO-4800 consists of small circles of engineered DNA that can be directly injected into cells through the controlled use of electricity, which creates temporary pores in the membranes of target cells and allows the double-stranded DNA circles contained within the vaccine to enter cells, alter their activity, and eventually lead to an immune response. Since Inovio's formulation is composed only of highly purified DNA, water, and salt, it avoids potential toxicity and can be manufactured relatively quickly and stored and transported without freezing. During the epidemic of the Middle East Respiratory Syndrome (MERS), a coronavirus related to the virus that causes COVID-19, Inovio was the first biotechnology company to test a vaccine against the MERS virus (INO-4700) in humans. The company plans to further evaluate INO-4700 in a Phase 2 clinical trial in the Middle East, where the majority of MERS cases have occurred. Stay aware of breaking immuno-biotech news and the latest advancements in the field of immunology. The results of a Phase 1 clinical trial evaluating the immunogenicity, safety, and tolerability of the MERS coronavirus vaccine GLS-5300 (INO-4700), published in the journal Lancet Infectious Diseases, demonstrated that their DNA-based vaccine technology is well-tolerated and capable of inducing an antiviral immune response. After two vaccinations, 47 of 66 (71%) study participants showed evidence of a T-cell response. 44 of 58 (76%) participants demonstrated a T-cell response after three vaccinations. Seroconversion was detected by S1-ELISA in 59 of 69 (86%) and 61 of 65 (94%) participants after two and three vaccinations, respectively, and 34 of 68 (50%) individuals were found to bear neutralizing antibodies. No serious adverse events were associated with the use of the MERS coronavirus vaccine. The authors stated that the antibody and cellular immune responses associated with the vaccine were durable and similar to those of patients that recovered naturally from infection by the MERS coronavirus. The Bill and Melinda Gates Foundation, founded in 2000, has financially supported a variety of developments related to human health, social sciences, and education. Disclosure: We do not have positions or business relationships with the stocks or companies mentioned in this article. This article does not in any way constitute a recommendation. Please refer to the statement on Forward Looking Statements in the press release. Modjarrad K, Roberts CC, Mills KT, et al. (2019) Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial. Lancet Infectious Diseases, 19(9), P1013-1022. DOI: https://doi.org/10.1016/S1473-3099(19)30266-X Read the full article

[immunofrontiers-blog]

Clinical Trial Demonstrates Enhancement of Immune Response to HIV by Gilead's TLR7 Agonist Vesatolimod

California-based biopharmaceutical company Gilead Sciences, Inc. (Nasdaq: GILD) has announced results from a Phase 1b clinical trial evaluating the safety and efficacy of toll-like receptor 7 (TLR7) agonist Vesatolimod for the treatment of human immunodeficiency virus (HIV) infection. The results of the clinical trial and those of additional preclinical studies evaluating the drug will be presented at the 2020 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, Massachusetts. According to the US Centers for Disease Control and Prevention (CDC), as of 2016, approximately 1.1 million people were HIV-positive, with a 9% decrease in the number of yearly diagnoses between 2010 and 2016. In 2018, an estimated 37.9 million people were diagnosed with the virus worldwide and 1.7 million new cases were reported. Principal Investigator and Professor of Medicine at the University of California, San Francisco (UCSF) Steven Deeks stated, “This is the first study done in people that has shown with an immunotherapy that you can enhance immune function resulting in both a smaller viral reservoir and an increased time to viral rebound after treatment is interrupted. The effects are modest, and no one came close to any definition of a cure, but the data suggests real progress might be made when the drug is used in combination with other approaches." Senior Vice President, HIV and Emerging Viruses at Gilead Sciences Diana Brainard, MD, stated, “While HIV treatment has advanced dramatically over the past three decades, people living with HIV still face a lifetime of therapy and potential complications. Curing HIV remains the ultimate long-term goal for Gilead’s HIV research and development efforts. The breadth of our research presented at CROI 2020 furthers the collective scientific knowledge on potential pathways to achieve a ‘functional cure’, or long-term viral suppression in the absence of ART, for people living with HIV.” The randomized, double-blind, placebo-controlled clinical trial, titled "Safety and Analytic Treatment Interruption Outcomes of Vesatolimod in HIV Controllers", involved the treatment of 25 HIV-positive individuals with either Vesatolimod or a placebo twice weekly for 10 weeks, followed by a period of suspended treatment during which the participants were monitored for changes in virus levels and adverse events. Individuals selected to participate in the study were capable of partially controlling the virus without anti-retroviral therapy (known as "HIV controllers"), and had low titers of the virus in their bloodstream, with HIV RNA levels of 50 to 5,000 copies per milliliter. According to a publication in The Lancet, only a small proportion of HIV-infected individuals are capable of controlling the virus in this manner. The clinical trial found that, after the cessation of therapy, individuals treated with Vesatolimod suppressed the virus for a longer period of time than those that received a placebo. Viral rebound (the return of HIV RNA levels to greater than 50 copies per milliliter) occurred after a median of 4.1 weeks for the group of patients treated with Vesatolimod and 3.9 weeks for those that received a placebo (p=0.036). Rebound of viral titers to greater than HIV RNA copies per milliliter occurred after a median of 5 weeks for the Vesatolimod group and 4 weeks for the placebo group (p=0.024). Among individuals treated with Vesatolimod, four did not experience a viral rebound of 50 HIV RNA copies per milliliter for at least six weeks. However, the press release noted that "Vesatolimod is an investigational agent and has not been approved anywhere globally; its safety and efficacy has not been established." Stay aware of the latest advancements in the field of immunology and breaking immuno-biotech news. One of the preclinical studies, "Combined Active and Passive Immunization in SHIV-Infected Rhesus Monkeys", assessed the efficacy of Vesatolimod, vaccination (Ad26/MVA vaccine), and anti-HIV broadly-neutralizing antibodies (bNAbs; PGT121) for treating infected rhesus monkeys. bNAbs are antibodies derived from HIV-infected individuals with a robust antibody-based immune response against the virus. The study involved the administration of Ad26/MVA, PGT121, and Vesatolimod to 49 rhesus monkeys infected with the Simian-Human Immunodeficiency Virus (SHIV). After 24 weeks of treatment with a cocktail of anti-retroviral drugs including tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC/DTG), the monkeys received one of four treatments (Ad26/MVA and Vesatolimod: n=12; PGT121 and Vesatolimod: n=12; Ad26/MVA, PGT121, and Vesatolimod: n=10; control: n=15) until week 86, when therapy was stopped. The monkeys were then assessed for viral rebound over the following 140 days. While 6 out of 10 monkeys in the Ad26/MVA, PGT121, and Vesatolimod treatment group experienced delayed viral rebound and controlled the virus after rebound, these were achieved by 0 out of 15 monkeys in the control group. According to the press release, "These results support further study of this multi-pronged approach." Another study, "PGT121 and Vesatolimod in Chronically Treated SHIV-Infected Rhesus Monkeys", involved the treatment of 24 SHIV-infected rhesus monkeys with PGT121 and Vesatolimod (n=8), a modified version of PGT121 (known as GS-9721) and Vesatolimod (n=9), or a control (n=7) for 24 weeks and the TDF/FTC/DTG anti-retroviral drug cocktail for 42 weeks (for an additional 24 weeks after the cessation of treatment with Vesatolimod and PGT121 or GS-9721). Therapy was then discontinued and the monkeys were evaluated for recurrence of the virus over the following 140 days. While 7 out of 7 monkeys treated with a control experienced "rapid viral rebound" (median 21 days), according to the press release, "the combination of vesatolimod and either PGT121 or GS-9721 prevented viral rebound in 41 percent of subjects. These results suggest the potential therapeutic efficacy of combining bNAbs with TLR7 stimulation in targeting the viral reservoir in rhesus monkeys that initiated ART during the chronic infection phase." Dan H. Barouch, MD, PhD, co-author of the study and Professor of Medicine at Harvard Medical School and Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, stated, “These data help inform strategies aimed at a functional cure for HIV. These findings help focus research efforts in support of the goal to help transform care for people living with HIV.” The press release noted, "Vesatolimod, the bNAbs PGT121 and GS-9721, and the other experimental compounds noted are investigational and are not approved by the U.S. Food and Drug Administration or any other regulatory authority. Their safety and efficacy have not been established. There is no cure for HIV infection or AIDS." The toll-like receptor (TLR) family of proteins, which recognize molecular patterns associated with pathogens, are important for the early stages of immune responses. TLR7 recognizes single-stranded ribonucleic acid (RNA), such as that of HIV or the hepatitis C virus (HCV), and induces the expression of inflammatory cytokines important for the anti-viral immune response. Given the immune-activating properties of TLR7 agonists, these drugs have been investigated for the treatment of cancer delivered as a liposomal formulation or via nanoparticles. Stay aware of the latest advancements in the field of immunology and breaking immuno-biotech news. When left unchecked, infection by the human immunodeficiency virus leads to a progressive breakdown in the functionality of the immune system and can eventually result in the Acquired Immune Deficiency Syndrome (AIDS), a state of severe immune compromise that involves the occurrence of opportunistic infections or cancers. HIV targets an important subpopulation of white blood cells known as CD4+ T cells, which are important for orchestrating the anti-viral immune response, directly eliminating virally-infected cells, and protecting the body from re-infection. It is thought that HIV was introduced into the human population from a species of chimpanzee in Central Africa. Following the exposure of hunters to chimpanzee blood containing a chimpanzee version of the virus known as the simian immunodeficiency virus (SIV), the virus likely mutated into a human version (HIV) and has since spread throughout the globe. According to the US Centers for Disease Control and Prevention (CDC), while HIV-infected individuals could perish from the virus within a few years prior to the availability of anti-retroviral therapy, they can now live "nearly as long" as individuals not infected by the virus. Read the full article

[immunofrontiers-blog]

Clinical Trial Demonstrates Enhancement of Immune Response to HIV by Gilead's TLR7 Agonist Vesatolimod

California-based biopharmaceutical company Gilead Sciences, Inc. (Nasdaq: GILD) has announced results from a Phase 1b clinical trial evaluating the safety and efficacy of toll-like receptor 7 (TLR7) agonist Vesatolimod for the treatment of human immunodeficiency virus (HIV) infection. The results of the clinical trial and those of additional preclinical studies evaluating the drug will be presented at the 2020 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, Massachusetts. According to the US Centers for Disease Control and Prevention (CDC), as of 2016, approximately 1.1 million people were HIV-positive, with a 9% decrease in the number of yearly diagnoses between 2010 and 2016. In 2018, an estimated 37.9 million people were diagnosed with the virus worldwide and 1.7 million new cases were reported. Principal Investigator and Professor of Medicine at the University of California, San Francisco (UCSF) Steven Deeks stated, “This is the first study done in people that has shown with an immunotherapy that you can enhance immune function resulting in both a smaller viral reservoir and an increased time to viral rebound after treatment is interrupted. The effects are modest, and no one came close to any definition of a cure, but the data suggests real progress might be made when the drug is used in combination with other approaches." Senior Vice President, HIV and Emerging Viruses at Gilead Sciences Diana Brainard, MD, stated, “While HIV treatment has advanced dramatically over the past three decades, people living with HIV still face a lifetime of therapy and potential complications. Curing HIV remains the ultimate long-term goal for Gilead’s HIV research and development efforts. The breadth of our research presented at CROI 2020 furthers the collective scientific knowledge on potential pathways to achieve a ‘functional cure’, or long-term viral suppression in the absence of ART, for people living with HIV.” The randomized, double-blind, placebo-controlled clinical trial, titled "Safety and Analytic Treatment Interruption Outcomes of Vesatolimod in HIV Controllers", involved the treatment of 25 HIV-positive individuals with either Vesatolimod or a placebo twice weekly for 10 weeks, followed by a period of suspended treatment during which the participants were monitored for changes in virus levels and adverse events. Individuals selected to participate in the study were capable of partially controlling the virus without anti-retroviral therapy (known as "HIV controllers"), and had low titers of the virus in their bloodstream, with HIV RNA levels of 50 to 5,000 copies per milliliter. According to a publication in The Lancet, only a small proportion of HIV-infected individuals are capable of controlling the virus in this manner. Stay aware of the latest advancements in the field of immunology and breaking immuno-biotech news. The clinical trial found that, after the cessation of therapy, individuals treated with Vesatolimod suppressed the virus for a longer period of time than those that received a placebo. Viral rebound (the return of HIV RNA levels to greater than 50 copies per milliliter) occurred after a median of 4.1 weeks for the group of patients treated with Vesatolimod and 3.9 weeks for those that received a placebo (p=0.036). Rebound of viral titers to greater than HIV RNA copies per milliliter occurred after a median of 5 weeks for the Vesatolimod group and 4 weeks for the placebo group (p=0.024). Among individuals treated with Vesatolimod, four did not experience a viral rebound of 50 HIV RNA copies per milliliter for at least six weeks. However, the press release noted that "Vesatolimod is an investigational agent and has not been approved anywhere globally; its safety and efficacy has not been established." One of the preclinical studies, "Combined Active and Passive Immunization in SHIV-Infected Rhesus Monkeys", assessed the efficacy of Vesatolimod, vaccination (Ad26/MVA vaccine), and anti-HIV broadly-neutralizing antibodies (bNAbs; PGT121) for treating infected rhesus monkeys. bNAbs are antibodies derived from HIV-infected individuals with a robust antibody-based immune response against the virus. The study involved the administration of Ad26/MVA, PGT121, and Vesatolimod to 49 rhesus monkeys infected with the Simian-Human Immunodeficiency Virus (SHIV). After 24 weeks of treatment with a cocktail of anti-retroviral drugs including tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC/DTG), the monkeys received one of four treatments (Ad26/MVA and Vesatolimod: n=12; PGT121 and Vesatolimod: n=12; Ad26/MVA, PGT121, and Vesatolimod: n=10; control: n=15) until week 86, when therapy was stopped. The monkeys were then assessed for viral rebound over the following 140 days. While 6 out of 10 monkeys in the Ad26/MVA, PGT121, and Vesatolimod treatment group experienced delayed viral rebound and controlled the virus after rebound, these were achieved by 0 out of 15 monkeys in the control group. According to the press release, "These results support further study of this multi-pronged approach." Another study, "PGT121 and Vesatolimod in Chronically Treated SHIV-Infected Rhesus Monkeys", involved the treatment of 24 SHIV-infected rhesus monkeys with PGT121 and Vesatolimod (n=8), a modified version of PGT121 (known as GS-9721) and Vesatolimod (n=9), or a control (n=7) for 24 weeks and the TDF/FTC/DTG anti-retroviral drug cocktail for 42 weeks (for an additional 24 weeks after the cessation of treatment with Vesatolimod and PGT121 or GS-9721). Therapy was then discontinued and the monkeys were evaluated for recurrence of the virus over the following 140 days. While 7 out of 7 monkeys treated with a control experienced "rapid viral rebound" (median 21 days), according to the press release, "the combination of vesatolimod and either PGT121 or GS-9721 prevented viral rebound in 41 percent of subjects. These results suggest the potential therapeutic efficacy of combining bNAbs with TLR7 stimulation in targeting the viral reservoir in rhesus monkeys that initiated ART during the chronic infection phase." Dan H. Barouch, MD, PhD, co-author of the study and Professor of Medicine at Harvard Medical School and Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, stated, “These data help inform strategies aimed at a functional cure for HIV. These findings help focus research efforts in support of the goal to help transform care for people living with HIV.” The press release noted, "Vesatolimod, the bNAbs PGT121 and GS-9721, and the other experimental compounds noted are investigational and are not approved by the U.S. Food and Drug Administration or any other regulatory authority. Their safety and efficacy have not been established. There is no cure for HIV infection or AIDS." The toll-like receptor (TLR) family of proteins, which recognize molecular patterns associated with pathogens, are important for the early stages of immune responses. TLR7 recognizes single-stranded ribonucleic acid (RNA), such as that of HIV or the hepatitis C virus (HCV), and induces the expression of inflammatory cytokines important for the anti-viral immune response. Given the immune-activating properties of TLR7 agonists, these drugs have been investigated for the treatment of cancer delivered as a liposomal formulation or via nanoparticles. Stay aware of the latest advancements in the field of immunology and breaking immuno-biotech news. When left unchecked, infection by the human immunodeficiency virus leads to a progressive breakdown in the functionality of the immune system and can eventually result in the Acquired Immune Deficiency Syndrome (AIDS), a state of severe immune compromise that involves the occurrence of opportunistic infections or cancers. HIV targets an important subpopulation of white blood cells known as CD4+ T cells, which are important for orchestrating the anti-viral immune response, directly eliminating virally-infected cells, and protecting the body from re-infection. It is thought that HIV was introduced into the human population from a species of chimpanzee in Central Africa. Following the exposure of hunters to chimpanzee blood containing a chimpanzee version of the virus known as the simian immunodeficiency virus (SIV), the virus likely mutated into a human version (HIV) and has since spread throughout the globe. According to the US Centers for Disease Control and Prevention (CDC), while HIV-infected individuals could perish from the virus within a few years prior to the availability of anti-retroviral therapy, they can now live "nearly as long" as individuals not infected by the virus. Read the full article

[immunofrontiers-blog]

Clinical Trial Demonstrates Enhancement of Immune Response to HIV by Gilead's TLR7 Agonist Vesatolimod

California-based biopharmaceutical company Gilead Sciences, Inc. (Nasdaq: GILD) has announced results from a Phase 1b clinical trial evaluating the safety and efficacy of toll-like receptor 7 (TLR7) agonist Vesatolimod for the treatment of human immunodeficiency virus (HIV) infection. The results of the clinical trial and those of additional preclinical studies evaluating the drug will be presented at the 2020 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, Massachusetts. According to the US Centers for Disease Control and Prevention (CDC), as of 2016, approximately 1.1 million people were HIV-positive, with a 9% decrease in the number of yearly diagnoses between 2010 and 2016. In 2018, an estimated 37.9 million people were diagnosed with the virus worldwide and 1.7 million new cases were reported. Principal Investigator and Professor of Medicine at the University of California, San Francisco (UCSF) Steven Deeks stated, “This is the first study done in people that has shown with an immunotherapy that you can enhance immune function resulting in both a smaller viral reservoir and an increased time to viral rebound after treatment is interrupted. The effects are modest, and no one came close to any definition of a cure, but the data suggests real progress might be made when the drug is used in combination with other approaches." Senior Vice President, HIV and Emerging Viruses at Gilead Sciences Diana Brainard, MD, stated, “While HIV treatment has advanced dramatically over the past three decades, people living with HIV still face a lifetime of therapy and potential complications. Curing HIV remains the ultimate long-term goal for Gilead’s HIV research and development efforts. The breadth of our research presented at CROI 2020 furthers the collective scientific knowledge on potential pathways to achieve a ‘functional cure’, or long-term viral suppression in the absence of ART, for people living with HIV.” The randomized, double-blind, placebo-controlled clinical trial, titled "Safety and Analytic Treatment Interruption Outcomes of Vesatolimod in HIV Controllers", involved the treatment of 25 HIV-positive individuals with either Vesatolimod or a placebo twice weekly for 10 weeks, followed by a period of suspended treatment during which the participants were monitored for changes in virus levels and adverse events. Individuals selected to participate in the study were capable of partially controlling the virus without anti-retroviral therapy (known as "HIV controllers"), and had low titers of the virus in their bloodstream, with HIV RNA levels of 50 to 5,000 copies per milliliter. According to a publication in The Lancet, only a small proportion of HIV-infected individuals are capable of controlling the virus in this manner. Stay aware of the latest advancements in the field of immunology and breaking immuno-biotech news. The clinical trial found that, after the cessation of therapy, individuals treated with Vesatolimod suppressed the virus for a longer period of time than those that received a placebo. Viral rebound (the return of HIV RNA levels to greater than 50 copies per milliliter) occurred after a median of 4.1 weeks for the group of patients treated with Vesatolimod and 3.9 weeks for those that received a placebo (p=0.036). Rebound of viral titers to greater than HIV RNA copies per milliliter occurred after a median of 5 weeks for the Vesatolimod group and 4 weeks for the placebo group (p=0.024). Among individuals treated with Vesatolimod, four did not experience a viral rebound of 50 HIV RNA copies per milliliter for at least six weeks. However, the press release noted that "Vesatolimod is an investigational agent and has not been approved anywhere globally; its safety and efficacy has not been established." One of the preclinical studies, "Combined Active and Passive Immunization in SHIV-Infected Rhesus Monkeys", assessed the efficacy of Vesatolimod, vaccination (Ad26/MVA vaccine), and anti-HIV broadly-neutralizing antibodies (bNAbs; PGT121) for treating infected rhesus monkeys. bNAbs are antibodies derived from HIV-infected individuals with a robust antibody-based immune response against the virus. The study involved the administration of Ad26/MVA, PGT121, and Vesatolimod to 49 rhesus monkeys infected with the Simian-Human Immunodeficiency Virus (SHIV). After 24 weeks of treatment with a cocktail of anti-retroviral drugs including tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC/DTG), the monkeys received one of four treatments (Ad26/MVA and Vesatolimod: n=12; PGT121 and Vesatolimod: n=12; Ad26/MVA, PGT121, and Vesatolimod: n=10; control: n=15) until week 86, when therapy was stopped. The monkeys were then assessed for viral rebound over the following 140 days. While 6 out of 10 monkeys in the Ad26/MVA, PGT121, and Vesatolimod treatment group experienced delayed viral rebound and controlled the virus after rebound, these were achieved by 0 out of 15 monkeys in the control group. According to the press release, "These results support further study of this multi-pronged approach." Another study, "PGT121 and Vesatolimod in Chronically Treated SHIV-Infected Rhesus Monkeys", involved the treatment of 24 SHIV-infected rhesus monkeys with PGT121 and Vesatolimod (n=8), a modified version of PGT121 (known as GS-9721) and Vesatolimod (n=9), or a control (n=7) for 24 weeks and the TDF/FTC/DTG anti-retroviral drug cocktail for 42 weeks (for an additional 24 weeks after the cessation of treatment with Vesatolimod and PGT121 or GS-9721). Therapy was then discontinued and the monkeys were evaluated for recurrence of the virus over the following 140 days. While 7 out of 7 monkeys treated with a control experienced "rapid viral rebound" (median 21 days), according to the press release, "the combination of vesatolimod and either PGT121 or GS-9721 prevented viral rebound in 41 percent of subjects. These results suggest the potential therapeutic efficacy of combining bNAbs with TLR7 stimulation in targeting the viral reservoir in rhesus monkeys that initiated ART during the chronic infection phase." Dan H. Barouch, MD, PhD, co-author of the study and Professor of Medicine at Harvard Medical School and Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, stated, “These data help inform strategies aimed at a functional cure for HIV. These findings help focus research efforts in support of the goal to help transform care for people living with HIV.” The press release noted, "Vesatolimod, the bNAbs PGT121 and GS-9721, and the other experimental compounds noted are investigational and are not approved by the U.S. Food and Drug Administration or any other regulatory authority. Their safety and efficacy have not been established. There is no cure for HIV infection or AIDS." The toll-like receptor (TLR) family of proteins, which recognize molecular patterns associated with pathogens, are important for the early stages of immune responses. TLR7 recognizes single-stranded ribonucleic acid (RNA), such as that of HIV or the hepatitis C virus (HCV), and induces the expression of inflammatory cytokines important for the anti-viral immune response. Given the immune-activating properties of TLR7 agonists, these drugs have been investigated for the treatment of cancer delivered as a liposomal formulation or via nanoparticles. Stay aware of the latest advancements in the field of immunology and breaking immuno-biotech news. When left unchecked, infection by the human immunodeficiency virus leads to a progressive breakdown in the functionality of the immune system and can eventually result in the Acquired Immune Deficiency Syndrome (AIDS), a state of severe immune compromise that involves the occurrence of opportunistic infections or cancers. HIV targets an important subpopulation of white blood cells known as CD4+ T cells, which are important for orchestrating the anti-viral immune response, directly eliminating virally-infected cells, and protecting the body from re-infection. It is thought that HIV was introduced into the human population from a species of chimpanzee in Central Africa. Following the exposure of hunters to chimpanzee blood containing a chimpanzee version of the virus known as the simian immunodeficiency virus (SIV), the virus likely mutated into a human version (HIV) and has since spread throughout the globe. According to the US Centers for Disease Control and Prevention (CDC), while HIV-infected individuals could perish from the virus within a few years prior to the availability of anti-retroviral therapy, they can now live "nearly as long" as individuals not infected by the virus. Read the full article

[immunofrontiers-blog]

NuVasive Announces Publication Demonstrating Efficacy of Synthetic Putty in Lumbar Fusion

Medical device company NuVasive, Inc. (Nasdaq: NUVA), based in San Diego, California, has announced a recent publication in the journal Spine demonstrating the efficacy of their synthetic bioactive putty as a bone graft substitute in posterolateral lumbar fusion, a widely-performed lower-spine surgery intended to stabilize the vertebral column. The surgery involves the restoration of normal spacing between two or more vertebrae via the insertion of a metal cage into the space between the vertebrae, and is intended to reduce pressure on highly painful pinched nerves. The efficacy of a spinal fusion surgery depends not only on the removal of pain-causing structures by the surgeon, including herniated discs, tumors, or bone spurs, but also the stimulation of bone growth and healing between the linked vertebrae by the insertion of bone graft or another substance into the metal cage. Historically, bone graft needed to be harvested from the pelvis of the patient, extending the duration of the surgical procedure and leading to higher levels of pain during the recovery period after surgery. Today, in addition to bone derived from the pelvis, surgeons may use bone recycled from the site of the spinal fusion (autograft), bone harvested from a cadaver (allograft), or synthetic bone grafts including demineralized bone matrices (DBMs), bone morphogenetic proteins (BMPs), and synthetic bone ("ceramics"), which are often composed of calcium or phosphate and share many qualities with autograft bone. The NuVasive putty falls into the synthetic bone category. President of NuVasive Matt Link stated, "A study of this quality immediately differentiates Attrax Putty from other biologics on the market. Attrax has proven the critical role surface optimization plays in the effectiveness of bone grafting technology, and underscores the NuVasive approach to developing innovative solutions which deliver positive clinical outcomes for surgeons and their patients." Stay aware of breaking immuno-biotech news and the latest advancements in the field of immunology by subscribing to our weekly newsletter. The randomized trial (NCT01982045), which involved 100 patients treated at four Dutch hospitals, evaluated the efficacy and safety of NuVasive's putty versus that of autograft bone for supporting the fusion of linked vertebrae in the first year following surgery. During the treatment of each patient, NuVasive's putty was applied to one side of the spine, chosen at random, and autograft bone material to the other, such that each patient received both putty and autograft bone and served as their own control. The degree of spinal fusion was determined by CT scan at one year post-procedure and demonstrated a 55% fusion rate for the putty-treated side and a 52% fusion rate for the autograft-treated side. The overall rate of spinal fusion was 71%. The safety of the putty was assessed based upon the incidence of adverse events. While adverse events such as wound complications and serious adverse events including surgical site infection, screw malpositioning, cage dislocation, and persistent leakage of cereberospinal fluid occurred among patients in the cohort during the first year following surgery, the authors stated that the adverse events could not be directly related to the synthetic putty. According to the press release, "Attrax Putty alone successfully demonstrated non-inferior fusion performance compared to autograft in instrumented PLF." Associate Professor of Neurological Surgery and Orthopedic Surgery at Northwestern Memorial Hospital Dr. Tyler Koski stated, "With increased focus on value-based medicine, surgeons and hospitals seek improved evidence when choosing a biologic for spinal fusion. Most data for bone graft materials is of lower quality and supports their use as bone graft extenders combined with autograft. The fact that Attrax Putty by itself demonstrates non-inferiority to autograft, the gold standard for bone grafts, speaks to the power of its unique surface technology, and with this study, I'm better informed in my clinical decision-making." Approximately 500,000 spinal fusions are performed in the United States every year. According to NuVasive's press release, "Attrax™ Putty is a synthetic, bioactive and osteoconductive bone void filler for the repair of bone defects. This proprietary, advanced biomaterial features a surface microarchitecture which provides an instructive environment for bone formation without added cells or growth factors. The moldable graft material is resorbed and replaced by bone during the healing process." NuVasive has received 510(k) clearance by the United States Food and Drug Administration (FDA) for the "expanded use of Attrax Putty without autograft." Stay aware of breaking immuno-biotech news and the latest advancements in the field of immunology by subscribing to our weekly newsletter. Read the full article

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Biocept Reports Publication Further Validating Cancer-Detecting Liquid Biopsy Platform

California-based biotechnology company Biocept, Inc. (Nasdaq: BIOC), which has developed an assay-based technology designed to identify cancer-associated genetic mutations from liquid biopsy tests, has announced the publication of clinical data demonstrating high sensitivity and specificity of their assay as compared to that of traditional tissue biopsies. Biocept's liquid biopsy-based assay is intended to provide physicians with a method for detecting cancer metastases to the brain or central nervous system using cerebrospinal fluid samples drawn from their patients. The assay is already clinically available for breast or lung cancer patients with suspected brain metastases. "Up to 30% and 36% of patients diagnosed with breast and lung cancer, respectively, will develop brain metastases," a recent press release stated. Senior Vice President and Senior Medical Director Veena Singh, MD, stated, "Results from this study showed a very high concordance rate between our liquid biopsy testing and tissue biopsy, providing further clinical validation of our Target Selector™ technology. Our clinical testing demonstrates best-in-class detection of alterations down to a single mutant copy, not only in an analytical setting but in a clinical setting as well. Further the ability to inform clinical decision making in a significantly more cost-effective manner potentially affords the healthcare system a highly sensitive and cost-effective option." The study, published in the Journal of Clinical Pathology, compared the efficacy of the liquid biopsy technology versus that of traditional tissue biopsies for detecting three genes commonly mutated in various types of cancer: the gene encoding the epidermal growth factor receptor (EGFR), which is frequently altered in lung cancer patients, particularly those with non-small cell lung cancer; the gene encoding B-Raf, whose mutations have been associated with many types of cancer from melanoma to colorectal and lung cancer; and the KRAS gene, whose mutations can lead to lung, pancreatic, colorectal, and other cancers. Stay aware of breaking immuno-biotech news and the latest advancements in the field of immunology by subscribing to our weekly newsletter. According to Biocept,"The study examined 127 clinical assays for mutations commonly associated with cancer found in the EGFR, BRAF and KRAS genes. Each Target Selector™ assay in the study demonstrated extremely high accuracy, sensitivity and specificity when compared to results obtained from tissue samples, showing a 93%-96% concordance to blinded tissue samples across all assays." President and Chief Executive Officer of Biocept Michael Nall stated, "The continued validation of our technology demonstrates its ability to non-invasively identify biomarkers specific to cancer, and to aid physicians in selecting optimal therapeutic treatments for their patients. We are pleased to report that our biomarker testing has been performed in more than 25,000 patients to date, and results from this study further illustrate the enhanced performance of our Target Selector™ technology." Biocept's liquid biopsy-based approach involves the amplification and sequencing of cancer-associated DNA isolated from the cerebrospinal fluid or peripheral blood of cancer patients and is intended to overcome common limitations of traditional tissue-based biopsies including procedural risks and difficulty, potentially biased sampling, and challenges associated with capturing multiple biopsies to track cancer progression. The authors of the publication concluded that Biocept's liquid biopsy technology offers a "highly effective" and non-invasive method of characterizing cancer patients' "molecular signatures." Liquid biopsies are useful for detecting circulating tumor cells (CTC), which are derived from the original tumor site and circulate throughout the body in the bloodstream, and for the detection of circulating tumor DNA (ctDNA), which can be released by the original tumor or by CTCs. Since the mutations in ctDNA reflect those of the original tumor, ctDNA can be used as a diagnostic and prognostic marker and enable physicians to track the disease progression and the effectiveness of cancer treatments. According to the American Cancer Society, an increase in ctDNA levels can be observed months before the "visible" recurrence of cancer, providing physicians with the opportunity to respond more quickly. In addition to cancer, liquid biopsies can be used to support the diagnosis of a heart attack through sampling circulating endothelial cells and for diagnosing unborn children via samples collected from the amniotic fluid or from the blood of the pregnant mother. In January 2020, Biocept announced the availability of its liquid biopsy assays in the clinic for lung and breast cancer patients with possible brain or central nervous system metastases. Cerebrospinal fluid collected by lumbar puncture could, with the discretion of the treating physician, be evaluated using the technology for the presence of cancer-associated DNA. Santosh Kesari, MD, PhD, Chair and Professor, Department of Translational Neurosciences and Neurotherapeutics, Director of Neuro-oncology at the Pacific Neuroscience Institute and John Wayne Cancer Institute, stated, "Testing the CSF for cancer biomarkers in patients suspected to have brain metastases can be important, as the rapid confirmation and characterization of CNS involvement enables appropriate treatment selection in a timely manner. Liquid biopsy tests offer the ability to analyze an additional specimen type, beyond blood, to help physicians identify biomarkers and hence inform clinical decision making." Stay aware of breaking immuno-biotech news and the latest advancements in the field of immunology by subscribing to our weekly newsletter. Biocept President and CEO Michael Nall stated, "We are very pleased to make our Target Selector™ platform available for testing CSF, as a more rapid identification of molecular alterations in brain metastases can aid physicians in choosing the best treatment options for their patients with breast or lung cancer. Among the significant capabilities of our technology is its versatility, which enables applications in a variety of clinical situations and for use with multiple types of biofluids." Arnold L, Alexiadis V, Watanaskul T, et al. (2020) Clinical validation of qPCR Target Selector™ assays using highly specific switch-blockers for rare mutation detection. The Journal of Clinical Pathology. Published Online First: 04 March 2020. DOI: http://dx.doi.org/10.1136/jclinpath-2019-206381 Read the full article

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Moderna Completes Enrollment of Phase 2 Study Evaluating Cytomegalovirus Vaccine

Massachusetts-based biotechnology company Moderna, Inc. (Nasdaq: MRNA) has announced the completion of enrollment for its Phase 2 clinical trial evaluating the immunogenicity and safety of cytomegalovirus (CMV) vaccine mRNA-1647. This follows the announcement of positive Phase 1 clinical trial results in January, which provided data for three participant dose cohorts after a third and final vaccination. According to the press release, an interim analysis for the Phase 2 trial is expected to be available in the third quarter of 2020. Chief Executive Officer Stéphane Bancel stated, “I would like to thank the dedicated Moderna CMV team and our partners at clinical trial sites for their support in completing enrollment of the Phase 2 study ahead of plan. We recognize the urgent need for a preventative vaccine against CMV in women of childbearing age, which we believe positions our wholly owned mRNA-1647 program as a potential blockbuster commercial and clinical opportunity. We believe our CMV vaccine will build Moderna’s future and embodies our mission of creating a new generation of transformative medicines for patients. The Moderna team is working diligently to start the Phase 3 study in 2021.” Stay aware of breaking news in the immuno-biotech sphere and the latest advancements in the field of immunology. The mRNA-1647 vaccine, which is designed to promote an immune response against components of the virus essential for infecting human cells, consists of six mRNAs that encode two virus-associated antigens. One of the mRNAs encodes the envelope protein glycoprotein B (gB), which is expressed on the surface of the virus. gB is involved in mediating the entry of the virus into cells and in the spread of the virus from cell-to-cell. Five of the six mRNAs encode CMV pentamer complex subunits, which are also important for the entry of the virus into cells and targeted by the majority of neutralizing antibody during the anti-viral immune response. Both glycoprotein B and the pentamer complex subunits are highly immunogenic, meaning that the immune system can generate a powerful response against these components and therefore protect against CMV infection. Currently, there is no approved CMV vaccine. The Phase 2 clinical trial will involve the administration of vaccine to 252 healthy adults in the United States, including both CMV-seronegative and CMV-seropositive individuals, at three dose levels (50, 100, and 150 micrograms) at three time points over the course of six months (0, 2, and 6 months). At three months (one month after the administration of the second dose), the company will provide an interim analysis of the trial which will support preparation for a Phase 3 trial that is expected to be initiated in 2021. According to the press release, the Phase 3 clinical trial "will evaluate prevention of primary CMV infection in a population that includes women of childbearing age." Moderna provided insight into plans for its Phase 3 study in the recent press release. "The Company is actively preparing for a global randomized, observer-blind, placebo-controlled Phase 3 pivotal study to evaluate the efficacy of mRNA-1647 against primary CMV infection. Moderna has solicited and received Type C meeting feedback from the FDA on the preliminary design of the pivotal trial, which will evaluate prevention of primary CMV infection in a population that includes women of childbearing age. The Company believes this can be achieved with a trial with no more than 8,000 participants and feasibility assessments of study sites has already begun across North America and Europe. After the Phase 2 three-month data are analyzed, which is expected in the third quarter of 2020, these data will inform the dose selection for the Phase 3 pivotal study. The pivotal trial design will be finalized after discussion with the FDA and other global health authorities. Manufacturing and planning are already underway for this pivotal study, which is expected to start in 2021." In addition to the CMV vaccine, Moderna is developing vaccine candidates against other prevalent infectious agents including the Epstein-Barr virus (EBV), Zika virus, respiratory syncytial virus (RSV), influenza H7N9, and the novel coronavirus (SARS-CoV-2). The US Food and Drug Administration (FDA) granted Fast Track designation to the Zika vaccine, which is currently being evaluated in a Phase 1 clinical trial. According to Moderna, "The potential advantages of an mRNA approach to prophylactic vaccines include the ability to mimic natural infection to stimulate a more potent immune response, combining multiple mRNAs into a single vaccine, rapid discovery to respond to emerging pandemic threats and manufacturing agility derived from the platform nature of mRNA vaccine design and production." The herpesvirus CMV naturally infects humans and moneys and has the characteristic ability to persist latently within the body for extended periods of time. The virus, which is normally transmitted through contact, saliva, and urine, and can be transmitted from infected mothers to their unborn children, impacts 25,000 newborns in the United States each year and is the leading infectious cause of birth defects in the country, resulting in a variety of neurodevelopmental abnormalities from vision problems to hearing loss. Stay aware of breaking news in the immuno-biotech sphere and the latest advancements in the field of immunology. In March 2013, Moderna signed a contract with AstraZeneca for the discovery, development, and commercialization of mRNA therapeutics for the treatment of diseases associated with metabolism, kidneys, the cardiovascular system, and cancer. In January 2020, the National Institute of Allergy and Infectious Disease (NIAID) partnered with Moderna to develop a vaccine against the virus that causes COVID-19. Read the full article

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Gilead Initiates Two Phase 3 Trials of Remdesivir for Treatment of COVID-19

Two phase 3 clinical trials evaluating the use of the pharmacologic antiviral agent Remdesivir for the treatment of the Coronavirus Disease (COVID-19) have been initiated, according to a recent press release by the American biopharmaceutical company Gilead Sciences, Inc. (Nasdaq: GILD). The randomized, multicenter, open-label trials will assess whether intravenously administered Remdesivir can safely and effectively treat COVID-19, the disease caused by the severe acute respiratory syndrome 2 coronavirus (SARS-2-CoV), a virus thought to have originated in Wuhan, China, possibly following transmission from illegally trafficked pangolins. Starting in March, the Gilead-sponsored clinical trials will primarily enroll patients in Asian countries but are expected to incorporate medical centers worldwide. Data from the trials will accompany that of current trials already evaluating Remdesivir for the treatment of COVID-19, two of which are being conducted by the China-Japan Friendship Hospital in China's Hubei Province, and another in the United States under the guidance of the National Institute of Allergy and Infectious Diseases (NIAID). According to their press release, Gilead has "donated drug and provided scientific input" for these clinical trials. The Chinese trials are expected to be completed in April 2020. The Gilead trials were initiated after the company filed an investigational new drug (IND) application for the use of remdesivir in the treatment of COVID-19. After rapid review, the IND application was accepted by the US Food and Drug Administration (FDA) and Gilead has since moved forwards with the clinical trials. Stay aware of breaking news from the immuno-biotech sphere by subscribing to our weekly newsletter. Chief Medical Officer of Gilead Sciences Merdad Parsey, MD, PhD, stated, “Gilead’s primary focus is on rapidly determining the safety and efficacy of remdesivir as a potential treatment for COVID-19, and this complementary array of studies helps to give us a more expansive breadth of data globally on the drug’s profile in a short amount of time. The speed with which remdesivir has moved into clinical development for this coronavirus reflects the pressing need for treatment options and the shared commitment of industry, governments, global health organizations and healthcare providers to respond to this public health threat with the highest urgency." In total, the Gilead trials are expected to enroll 1,000 patients. 400 patients severely affected by COVID-19 will receive 5 or 10 days of intravenous remdesivir at a starting dose of 200 mg followed by 100 mg daily until day 5 or 10, based on random assortment into treatment groups at a 1:1 ratio. These patients will receive remdesivir in addition to standard-of-care therapies. 600 patients found to have moderate clinical manifestations of the disease will be treated with five or ten days of intravenous remdesivir in the same arrangement as the 400-patient trial or by standard-of-care therapies alone, with patients randomly assorted into these three treatment groups according to a 1:1:1 ratio. The primary endpoint of the trials is clinical improvement as measured by a sustained return of fever and oxygen saturation to normal levels for at least 24 hours through Day 14 after the initiation of treatment. In addition, the trials will measure the proportion of patients from each group discharged by Day 14. Gilead may have decided to include evaluate these symptoms given the high incidence of fever and respiratory problems among patients infected by the virus. While remdesivir has not yet been licensed or approved anywhere globally for the treatment of COVID-19 or other uses, Gilead is providing the drug on a compassionate use basis for the emergency treatment of "qualified patients" not included in their clinical trials. Currently, according to Gilead, remdesivir has "not been demonstrated to be safe or effective for any use." However, previous animals models and in vitro studies of remdesivir have shown the drug to have antiviral activity against multiple viral pathogens including the Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) coronaviruses, human coronaviruses in the same family as the SARS-2-CoV. Although remdesivir has been studied in people infected by the Ebola virus and in healthy volunteers, Gilead stated, "Individual compassionate use cases are not sufficient to determine the safety and efficacy of remdesivir in treating COVID-19, which can only be determined through prospective clinical trials." According to Belgian virologist and physician Dr. Erik de Clerq, who co-discovered the important anti-viral agent Tenofovir, and Dr. Guangdi Li, coronavirus treatment strategies may include existing antiviral agents such as remdesivir instead of novel vaccines or compounds. “No drug or vaccine has yet been approved to treat human coronavirus” and “new interventions are likely to require months to years to develop,” stated Clercq and Li. Stay aware of breaking news from the immuno-biotech sphere by subscribing to our weekly newsletter. Remdesivir, which has a structure similar to the HIV inhibitor Tenofovir, has shown efficacy against the 2019 coronavirus in vitro. The recovery of an infected US patient, who received intravenous infusions of Remdesivir, may be attributable to the drug. In addition to the Gilead studies, two phase III trials evaluating the efficacy of intravenous Remdesivir for the treatment of the coronavirus were initiated in February and are anticipated to be completed by April 2020. SARS-2-CoV, which has spread from China to the United States and other nations around the world, has an incubation period of up to two weeks and may survive for up to 9 days on surfaces at room temperature. Clercq ED, Li G. (2020) Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery. doi: 10.1038/d41573-020-00016-0 Read the full article

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OPKO Health Subsidiary to Offer Coronavirus Test

BioReference Laboratories, Inc., a subsidiary of OPKO Health (NASDAQ: OPK) with numerous patient service centers across the United States, has announced that it will offer a test for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes the Coronavirus Disease (COVID-19). The company has previously developed diagnostic tests for infectious diseases in collaboration with the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC). Executive Chairman of BioReference Dr. Jon R. Cohen M.D., who attended the Coronavirus Task Force meeting at the White House last week, stated, "COVID-19 testing is imperative in aiding front-line healthcare professionals and public health authorities to identify infected patients more quickly, limit the spread of infection and promote earlier diagnosis and treatment. We want to specifically recognize how engaged and responsive HHS, the CDC and the FDA have been in helping us navigate quickly through the scientific and regulatory issues necessary to make testing available as soon as possible to the U.S. population." Stay aware of breaking coronavirus research and the latest advancements in the field of immunology. How soon will a coronavirus test be available? Following a meeting with the Coronavirus Task Force at the White House, President of the American Clinical Laboratory Association (ACLA) Julie Khani stated, "We appreciated the opportunity to meet with Vice President Pence and members of the White House’s Coronavirus Task Force this afternoon on the critical issues related to testing capacity. As an industry, clinical labs have taken steps to meet the growing demand for national testing and are working together with the Administration, the CDC and FDA as well as state and local public health labs, hospitals and academic medical centers. Currently, clinical labs are working around the clock to bring new tests online with the goal of processing several thousand tests in the coming days." According to the ACLA, "In any outbreak, Centers for Disease Control and Prevention (CDC) laboratories, supported by state public health laboratories, have primary responsibility for diagnosing patients. In recent public health emergencies, including the SARS and Zika outbreaks, commercial laboratories have supported public response and expanded test capacity." Ms. Khani continued, "On Saturday, February 29, the FDA issued new guidance for high complexity laboratories, including commercial laboratories, to perform coronavirus testing as soon as validation is complete. Prior to Saturday’s announcement, ACLA members were already working to develop novel tests for COVID-19 and remain in close communication with our public health partners at the CDC. As of Wednesday, March 4, 2020 ACLA members are not yet collecting, processing or transporting specimens for COVID-19 testing from patients suspected of having, or confirmed to have, COVID-19." "ACLA is committed to supporting our public health partners and rapid response efforts. We’re working closely with our members—and in close coordination with state and local public health labs, hospitals, the CDC and the FDA—to increase overall national capacity. Over the next several weeks, commercial labs are working to bring online additional testing capacity at which point we will have a more informed assessment on the number of tests that can be processed." According to a recent press release, BioReference Laboratories is "expecting to receive specimens for testing, and begin to provide testing next week." Stay aware of breaking coronavirus research and the latest advancements in the field of immunology. In addition to diagnostic services provided through BioReference Laboratories, OPKO Health offers therapies for a variety of illnesses. Somatrogon, a human growth hormone (hGH) therapy, has been evaluated in phase 3 clinical trials for the treatment of pediatric and adult growth hormone deficiency. OPK88003, an analog of the peptide Oxyntomodulin which binds to the glucagon and GLP-1 receptors to regulate metabolism, is intended to treat diabetes and obesity. Rayaldee (calciferol) is a therapy for secondary hyperparathyroidism (SHPT) in patients with vitamin D insufficiency and stage 3-4 chronic kidney disease (CKD) approved by the US Food and Drug Administration (FDA). This article references a post found on ACLA website: https://www.acla.com/acla-statement-on-developing-coronavirus-updates/ Read the full article

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Inovio Pharmaceuticals Announces Human Trials of Coronavirus Vaccine

Inovio Pharmaceuticals (NASDAQ: INO), an American biotechnology company from Plymouth Meeting, Pennsylvania, has announced plans to start US-based human clinical trials of its DNA-based coronavirus vaccine INO-4800 in April. During a meeting with the US Coronavirus Task Force on Tuesday March 2nd at the White House, Inovio President and CEO Dr. J. Joseph Kim stated, "Inovio is the leader in coronavirus vaccine development and the only company with a Phase 2 vaccine for a related coronavirus that causes Middle East Respiratory Syndrome (MERS). Using our modern DNA medicines platform, we designed our DNA vaccine INO-4800 in three hours after the publication of the genetic sequence of the novel coronavirus that causes COVID-19." "We immediately began preclinical testing and small-scale manufacture and have already shared robust preclinical data with our public and private partners. We plan to begin human clinical trials in the U.S. in April and soon thereafter in China and South Korea, where the outbreak is impacting the most people. We plan on delivering one million doses by year end with existing resources and capacity. However, we will need additional resources to scale up to make enough doses to help protect Americans from COVID-19 as well as to lead global efforts to curtail this virus," continued Dr. Kim. Stay aware of breaking coronavirus research and the latest advances in the field of immunology. What progress has been made in the development of their coronavirus vaccine? On January 23rd, 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) issued Inovio a grant of up to $9 million to fund preclinical and clinical development of INO-4800. CEPI CEO Richard Hatchett stated, "Given the rapid global spread of the 2019-nCoV virus the world needs to act quickly and in unity to tackle this disease. Our intention with this work is to leverage our work with Inovio on the MERS coronavirus and rapid response platform to speed up vaccine development." Dr. Kim responded, "We're extremely honored to expand our partnership with CEPI to tackle this new threat to global public health. Our DNA medicine platform represents the best modern day approach to combatting emerging pandemics. We have already demonstrated positive clinical outcomes with our vaccine against MERS-CoV, another coronavirus. Importantly, following the Zika viral infection outbreak, Inovio and our partners developed a vaccine that went from bench to human testing in just seven months – the fastest vaccine development on record in recent decades. We believe we can further improve upon this accelerated timeline to meet the current challenge of the emerging Chinese coronavirus 2019-nCoV." On January 30th, 2020, Inovio announced that it would develop INO-4800 in collaboration with China-based Beijing Advaccine Biotechnology Co., with the goal of expediting the testing of INO-4800. Dr. Kim stated, "Our collaboration with Beijing Advaccine and its Founder, Emeritus Professor Bin Wang from the prestigious Fudan University and China's premier DNA vaccine expert, will tremendously accelerate our coronavirus vaccine INO-4800 development in China because of its expertise and experience with regulatory authorities and clinical trial management. This collaboration allows us to enter China and deliver our vaccine into the areas where they need it most as soon as possible. Our shared goal is to utilize both company's expertise in developing vaccines for emerging infectious diseases and hopefully achieve an accelerated regulatory approval for INO-4800." Since January, Inovio Pharmaceuticals has demonstrated immune responses to their vaccine in animal models and initiated plans for a human clinical trial. The company intends to finalize their clinical trial design in March and prepare 3,000 doses of their vaccine for trials in the United States, South Korea, and China. The first clinical trial will include 30 healthy volunteers in the United States, with the Asia-based trials occurring afterwards. Inovio's DNA-based vaccine platform is centered around speed of manufacturing, stability during transport and storage, and efficacy for inducing a robust immune response. INO-4800 consists of small circles of engineered DNA that can be directly injected into cells through the controlled use of electricity, which creates temporary pores in the membranes of target cells and allows the double-stranded DNA circles contained within the vaccine to enter cells, alter their activity, and eventually lead to an immune response. Since Inovio's formulation is composed only of highly purified DNA, water, and salt, it avoids potential toxicity and can be manufactured relatively quickly and stored and transported without freezing. During the epidemic of the Middle East Respiratory Syndrome (MERS), a coronavirus related to the virus that causes COVID-19, Inovio was the first biotechnology company to test a vaccine against the MERS virus (INO-4700) in humans. The company plans to further evaluate INO-4700 in a Phase 2 clinical trial in the Middle East, where the majority of MERS cases have occurred. Stay aware of breaking coronavirus research and the latest advances in the field of immunology. The results of a Phase 1 clinical trial evaluating the immunogenicity, safety, and tolerability of the MERS coronavirus vaccine GLS-5300 (INO-4700), published in the journal Lancet Infectious Diseases, demonstrated that their DNA-based vaccine technology is well-tolerated and capable of inducing an antiviral immune response. After two vaccinations, 47 of 66 (71%) study participants showed evidence of a T-cell response. 44 of 58 (76%) participants demonstrated a T-cell response after three vaccinations. Seroconversion was detected by S1-ELISA in 59 of 69 (86%) and 61 of 65 (94%) participants after two and three vaccinations, respectively, and 34 of 68 (50%) individuals were found to bear neutralizing antibodies. No serious adverse events were associated with the use of the MERS coronavirus vaccine. The authors stated that the antibody and cellular immune responses associated with the vaccine were durable and similar to those of patients that recovered naturally from infection by the MERS coronavirus. Modjarrad K, Roberts CC, Mills KT, et al. (2019) Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial. Lancet Infectious Diseases, 19(9), P1013-1022. DOI: https://doi.org/10.1016/S1473-3099(19)30266-X Read the full article

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Coronavirus Source Potentially Traced to Malayan Pangolins

by ImmunoFrontiers Team Since the first cases of infection by the 2019 novel coronavirus (2019-nCoV) were reported in Wuhan, China, in December 2019, the virus has caused over 90,000 cases of the disease COVID-19 around the world with an estimated mortality rate of 3.4%. Currently, the virus has spread across the globe to the United States and, according to the CDC, presumptively infected individuals in Florida, Georgia, New Hampshire, New York, Rhode Island, and Washington among other states. Since understanding the origins of the 2019-nCoV in greater detail could support the development of better therapies for COVID-19 and more effective measures for preventing the transmission of deadly viruses to humans from other species in the future, research in this sphere is critically important, and over the past month considerable progress has been made. The 2019-nCoV source may be traced to Malayan Pangolins, which could have served as intermediate hosts for a bat-derived virus. Where did the coronavirus originate? Following epidemiological investigation, researchers identified that human cases of the virus originated at a seafood market in Wuhan, Hubei Province, China, known to sell live poultry and exotic animals. Genetic analysis demonstrated that the genome of the 2019-nCoV is more similar to that of a bat coronavirus (bat-SL-CoVZC45) than that of the human SARS-CoV, suggesting that the novel coronavirus infecting humans may have originated in bats. Since bats are known to be a natural reservoir for numerous SARS-related coronaviruses (SARSr-CoVs), some of which have the potential to infect humans, this bat-origin hypothesis of the 2019-nCoV has gained traction and is supported by considerable evidence. Stay aware of breaking coronavirus research and important advances in the field of immunology. To shed light on this hypothesis, chinese scientists sequenced the genomes of coronaviruses isolated from humans and bats and discovered that the coronavirus RaTG13, endemic to the horseshoe bat (Rhinolophus), has an overall genome sequence similarity of 96.2% to that of the novel human coronavirus. Since the human SARS-CoV, responsible for an epidemic 18 years ago, was also traced to SARS-like coronaviruses found naturally in horseshoe bats, it seems likely that the 2019-nCoV may have followed in similar footsteps. While evidence most strongly supports the hypothesis that the 2019-nCoV originated in bats, the transmission events that led to cases of infection among humans remain less clear. The virus is unlikely to have been directly transmitted from bats to humans during December, a period of natural bat hibernation. How could the coronavirus have been transmitted from bats to humans? Researchers have proposed that the virus did not transmit directly from bats to humans but rather through an intermediate host such as the Malayan Pangolin. Pangolins, or scaly anteaters, are nocturnal mammals native to Asia and Sub-Saharan Africa that are largely solitary, dine on termites and ants, and are covered by large defensive scales made of keratin. Unfortunately, pangolins are highly trafficked by poachers. As of January 2020, three of the eight pangolin species were regarded as critically endangered by the International Union for Conservation of Nature Red List of Threatened Species. Pangolins are hunted in southern China for their scales, which are thought to have medicinal properties in Chinese traditional medicine, and for their meat, which is regarded as a delicacy. Using published data regarding SARS-like coronaviruses isolated from lung samples of deceased Malayan Pangolins, Dr. Tao Zhang and other researchers from Yunnan University identified the occurrence of a virus in pangolins highly similar to the 2019-nCoV (known as Pangolin-CoV), which shares a whole genome similarity of 91.02% and 90.55% to the human 2019-nCoV and bat RaTG13, respectively. The researchers demonstrated that the Pangolin-CoV is the lowest common ancestor 2019-nCOV and RaTG13, and that the Pangolin-CoV shares key amino acid residues with the human 2019-nCoV at a structural location important for enabling transmission into human cells. While these residues were consistent between Pangolin-CoV and human 2019-nCoV, they were not shared with the bat coronavirus RaTG13, indicating that the pangolin virus, but not the bat coronavirus, could potentially infect human cells with similar pathogenicity to 2019-nCoV. This phenotype fits logically within the proposed bat-to-pangolin-to-human progression of the virus and, according a recent publication in bioRxiv, suggests that the 2019-nCoV could have resulted from the recombination of a pangolin and a bat coronavirus. Did the coronavirus come from Pangolins? Since a whole genome match rate of at least 99.8% is required to definitively ascertain whether the human coronavirus was directly transmitted from pangolins, researchers are still uncertain whether this mode of transmission actually occurred. However, it remains possible, and even reasonable given the widespread nature of illegal pangolin trafficking in China. Indeed, 2019-nCoV was found to have emerged from the Huanan Seafood Wholesale Market in the central Chinese city of Wuhan. Until its closure in January 2020, the market was regarded as the largest wholesale seafood market in central China, and offered exotic and wild animals in addition to seafood. Indeed, pangolins were offered at the market, in addition to hedgehog, crocodiles, koalas, peacocks, wolf puppies, and other animals. While the market passed inspection by city officials in late 2019, it was reported to have "unsanitary" conditions by Time magazine and "dismal with poor ventilation and garbage piled on wet floors" by the New York Times. Stay aware of breaking coronavirus research and important advances in the field of immunology. Coronaviruses are known to circulate naturally within pangulins, and viruses similar to the 2019-nCoV have been identified from samples of pangolin tissue. A recent study evaluating frozen tissue samples collected from smuggled Malayan pangolins by the Guangxi Customs between August 2017 and January 2018 identified the presence of 2019-nCoV-related viruses in blood, lung, and intestinal tissue. There are clinical similarities between coronavirus infection in pangolins and in humans. Histopathological examination of coronavirus-infected pangolins has demonstrated hemorrhaging in the alveolar ducts of the lungs and interstitial pneumonia, traits shared with the disease course of 2019-nCoV. Other researchers have indicated that, while genetic studies support an association between nCoV-2019 and pangolin coronaviruses, phylogenetic analyses do not provide evidence for the hypothesis that 2019-nCoV arose directly from a pangolin coronavirus. While the researchers regarded pangolin coronaviruses as genetically similar to the 2019-nCoV and bat coronaviruses, including a high sequence match rate between pangolin coronaviruses and 2019-nCoV, phylogenetic trees assembled using the genomic sequence of the virus indicated the likely involvement of another intermediate host. The researchers concluded by stating that, while their study did not support the hypothesis that pangolins served as intermediate hosts for the 2019-nCoV, the occurrence of this mode of transmission remains possible given the presence of other pangolin coronaviruses not evaluated within the scope of their study, which could have been the predecessors of 2019-nCoV. Beyond enhancing our understanding of the origins of the 2019-nCoV, this research has highlighted the critical importance of implementing more effective countermeasures against the illegal trafficking of exotic animals, which is not only morally deplorable but also a potential source of zoonotic transmission of lethal pathogens. Zhang T, Wu Q, Zhang Z. (2020) Probable Pangolin Origin of 2019-nCoV Associated with Outbreak of COVID-19. CURRENT-BIOLOGY-D-20-00299. http://dx.doi.org/10.2139/ssrn.3542586 Read the full article

[immunofrontiers-blog]

Research Suggests Coronavirus Infectious for Up to 9 Days on Surfaces

by ImmunoFrontiers Team Since the outbreak of the 2019 novel coronavirus (2019-nCoV) in Wuhan, China, the virus has spread to over 40 countries globally, with 90,893 reported cases, 3110 deaths, and a mortality rate of approximately 3.4%. Given the relatively efficient transmission dynamics of the virus, which is already thought to have been transmitted in the United States by community spread, understanding how the virus survives outside of the human body may provide important insights for halting the spread of this disease. This approach to preventing infection, focused on disinfecting potentially contaminated surfaces to reduce transmission of the virus, is particularly relevant due to the lack of proven therapies. In a recent publication in the Journal of Hospital Infection, researchers suggest that the coronavirus may remain infectious for up to 9 days outside of the human body on inanimate surfaces, and that particular biocidal agents may be effective for deactivating the virus before transmission occurs, offering opportunities for potential interventions in healthcare and other settings. Researchers from Bochum and Greifswald, Germany, recently published a review of available data on the longevity of coronaviruses on inanimate surfaces outside of the human body, and also the potential effectiveness of frequently used disinfectants for clearing potential contamination. The scientists analyzed data from 22 studies in the scientific literature related to the human coronaviruses Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) and the veterinary coronaviruses mouse hepatitis virus (MHV), transmissible gastroenteritis virus (TGEV), and canine coronavirus (CCV). After reviewing the longevity of coronavirus strains on metal, wood, glass, plastic, surgical gloves, disposable gowns, and other materials, the Kampf et al found that, in general, the duration of coronavirus persistence is reduced at higher temperatures but extended at lower temperatures and that the quantity of virus particles on the surface is directly associated with the length of persistence in a strain-dependent manner. While SARS-CoV (strain GVU6109) at a particular concentration was found to persist on a disposable gown at room temperature for only 1 hour, a higher concentration of the virus could last for 2 days. Although TGEV was shown to persist on steel for 4-96 hours at 40 degrees celsius, the virus could last for longer than 28 days at 4 degrees celsius. In other words, coronaviruses tend to live longer when present on surfaces at higher concentrations and in environments with lower temperatures. Stay aware of breaking coronavirus research and news. Common disinfectants including ethanol-based cleansers were shown to be effective for inactivating coronaviruses. After being exposed to solutions containing 78% to 95% ethanol for 30 seconds, a greater than 10,000-times reduction in the infectivity of the SARS coronavirus was observed. The publication also provided information on the efficacy of cleansers containing hydrogen peroxide, 2-propanol, benzalkonium chloride, and chlorhexidine digluconate, among other agents. While the effectiveness of the biocidal agents appeared to depend upon the coronavirus strain, length of exposure, and other factors, in general, the ethanol-based solutions showed greater efficacy for inactivating coronaviruses than chlorhexidine-based solutions. Of note, the researchers highlighted the relevance of human behavior to self-inoculation with the virus from contaminated surfaces. Referencing an observational study which showed that students, on average, touch their face with their own hands 23 times per hour, the scientists emphasized that the coronavirus can be transmitted in this manner from contaminated dry surfaces to mucous membranes of the nose, eyes, or mouth, and lead to infection. Accordingly, the researchers noted the WHO recommendation that individuals “ ensure that environmental cleaning and disinfection procedures are followed consistently and correctly. Thoroughly cleaning environmental surfaces with water and detergent and applying commonly used hospital-level disinfectants (such as sodium hypochlorite) are effective and sufficient procedures.” This is particularly relevant to healthcare settings where frequently-touched objects and surfaces in highly trafficked areas could contribute to the spread of the virus. Research evaluating the incidence of the SARS virus on hospital surfaces found that, even after the implementation of preventative measures, multiple locations including the computer mouses at nursing stations and the public elevator handrail tested positive for the virus by RT-PCR. Given that 21% of SARS cases worldwide were among healthcare workers during the 2003 epidemic, introducing better methods for regulating the spread of coronaviruses in healthcare settings is important for ensuring that patients can be effectively treated and that the spread of disease can be well-controlled. The researchers also emphasized the importance of handwashing after contact with potentially contaminated surfaces or infected patients. “The WHO recommends to preferably apply alcohol-based hand rubs for the decontamination of hands, e.g. after removing gloves. Two WHO recommended formulations (based on 80% ethanol or 75% 2-propanol) have been evaluated in suspension tests against SARS-CoV and MERS-CoV, and both were described to be very effective,” Kampf et al stated. While high levels of adherence to best-practice hand-washing may be difficult to achieve, these measures are nevertheless important for countering the spread of disease, particularly in healthcare settings. “In Taiwan, however, it was described that installing hand wash stations in the emergency department was the only infection control measure which was significantly associated with the protection from healthcare workers from acquiring the SARS-CoV, indicating that hand hygiene can have a protective effect.” The authors concluded by stating that “human coronaviruses can remain infectious on inanimate surfaces for up to 9 days” and that, since disinfection of contaminated surfaces with 62–71% ethanol or 0.1% sodium hypochlorite for 1 minute was shown to significantly reduce the infectivity of other coronaviruses, these agents may also work against the 2019-nCoV. Other research groups describing the persistence and infectivity of coronaviruses outside of the human body have emphasized the potential variability between strains. A review article published in 2015 noted that the SARS and MERS coronaviruses seem to survive on dry surfaces better than other human coronaviruses (229E, NL63, and OC43), with MERS coronaviruses demonstrating longer survival than other human coronaviruses. The researchers also described the direct association between virus dose and survival time, noting that both the SARS-CoV and H3N2 influenza viruses persist longer on surfaces when the concentration of virus particles is increased. Some coronaviruses may live longer than others on surfaces outside of the human body, and are favored to live longer when a higher dose of virus is applied to a surface. The medium transmitting the virus onto a dry surface could also influence the duration of infectivity. The researchers noted that, in a study evaluating the survival of influenza on bank notes, the addition of mucus could extend the survival time from hours to up to 17 days. Thus, the data from prior research studies investigating the survival of the coronavirus should be re-considered in the context of real-world materials, such as mucus, that could extend the survival time of the virus to a duration longer than that observed under the controlled conditions of the research laboratory. Stay aware of breaking coronavirus research and news. Overall, the researchers noted, “in all studies that tested varying temperature and relative humidity, lower temperature and relative humidity favoured the survival of both coronaviruses and influenza.” Interestingly, this could predict the limited spread of the novel coronavirus to tropical areas. Indeed, tropical Asian countries with a high temperature and relative humidity, including Malaysia, Indonesia, and Thailand, did not experience major outbreaks of the SARS coronavirus. Additional methods of decontamination, including heating and ultraviolet (UV) irradiation, may also be helpful for containing the spread of the 2019-nCoV. Researchers from the Chinese Center for Disease Control and Prevention in Beijing found that the SARS coronavirus strain CoV-P9 could be rendered non-infectious after exposure to 56 degrees celsius for 90 minutes, 67 degrees celsius for 60 minutes, 75 degrees celsius for 30 minutes, or UV irradiation for 60 minutes. While heating and irradiation was found to effectively decontaminate surfaces of the virus, the researchers nevertheless emphasized that the “survival ability of SARS coronavirus in human specimens and in environments seems to be relatively strong." Addressing the question, “how long do coronaviruses live on a surface” is not straightforward due to the variability between coronaviruses. Indeed, the survival characteristics of the 2019 novel coronavirus and its susceptibility to common disinfectants remain to be determined. Kampf G, Todt D, Pfaender S, Steinmann E. (2020) Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. The Journal of Hospital Infection, 104(3), 246-251. DOI: https://doi.org/10.1016/j.jhin.2020.01.022 Dowell SF, Simmerman JM, Erdman DD, et al. (2004) Severe Acute Respiratory Syndrome Coronavirus on Hospital Surfaces. Clinical Infectious Diseases, 39(5), 652–657. DOI: https://doi.org/10.1086/422652 Otter JA, Donskey C, Yezli S, et al. (2016) Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination. Journal of Hospital Infection, 92(3), 235-250. DOI: https://doi.org/10.1016/j.jhin.2015.08.027 Duan SM, Zhao XS, Wen RF, et al. (2003) Stability of SARS coronavirus in human specimens and environment and its sensitivity to heating and UV irradiation. Biomed Environ Sci, 16(3), 246-55. Read the full article

[immunofrontiers-blog]

Complete Response of Metastatic Pancreatic Cancer to Novel Immunotherapy

by ImmunoFrontiers Team In a recent press release, publicly-traded immuno-oncology company NantKwest (NASDAQ: NK) and privately-held immunotherapy company ImmunityBio announced the complete response of metastatic pancreatic cancer to a novel immunotherapy approach combining targeted natural killer (NK) cells and a fusion protein of the immune-stimulating cytokine interleukin-15 (IL-15). In their approach, natural killer cells, a white blood cell subpopulation typically associated with the innate immune system, were targeted against programmed death-ligand 1, a protein expressed on the surface of pancreatic cancer cells that negatively regulates the anti-cancer response of the immune system. The natural killer cells were combined with an IL-15 superagonist manufactured by ImmunityBio, known as N-803, which promotes the expansion and activation of NK cells and CD8+ T cells without influencing immunosuppressive regulatory T cells. N-803 is engineered to have 30-times greater activity than natural IL-15 and can persist within the bloodstream for a longer period of time, offering a lengthier period of immune-boosting activity. Stay aware of the latest advances in metastatic cancer research and treatment. In a phase 1 clinical trial (NCT04050709), researchers tested the safety and efficacy of this treatment strategy in a patient with second-line metastatic pancreatic cancer, meaning that the combination therapy of PD-L1-targeted NK cells and N-803 was used as a secondary treatment after relapse following a previous standard-of-care therapy. Over 130 doses of the NK cells were successfully delivered to the patient without severe adverse side effects. Chairman and CEO of NantKWest Patrick Soon-Shiong, M.D., announced the findings of the phase 1 trial at the J.P. Morgan Healthcare Conference in San Francisco. “We hypothesize that a common treatment protocol that harnesses both the natural-killer cell and the T cells could be effective in treating cancer across multiple tumor types. This has been supported by the early signals of safety and efficacy in Phase 1 and 2 studies of NantKwest’s natural killer cells in advanced cancers,” said Dr. Soon-Shiong. After five infusions of the NantKWest’s NK cell therapy and N-803, the tumor metastases of a pancreatic cancer patient that had failed standard-of-care treatment completely resolved per initial and follow-up CT and PET scans. In response to the success of his company’s treatment approach, Dr. Soon-Shiong stated, “We are extremely pleased that the FDA granted us this expanded IND authorization to initiate this novel immunotherapy treatment enabling the cross-talk of the innate natural killer system with the adaptive T cell. Achieving complete response in metastatic pancreatic cancer and durable, complete responses in metastatic TNBC patients that have failed all current standards of care is a promising finding which may further validate our approach to orchestrate both the innate and adaptive immune system. Pancreatic cancer and TNBC are highly aggressive cancers with limited treatment options. These results are important, proof-of-concept supporting our hypothesis that comprehensively activating the immune responses of the NK, T and Dendritic cells, the “triangle offense”,  would induce immunogenic cell death leading to durable responses, even among this challenging patient population. Based on these encouraging findings, we plan to initiate clinical trials to confirm efficacy in second-line metastatic pancreatic cancer and third-line Triple Negative Breast cancer.” Metastatic pancreatic cancer is an unresectable form of pancreatic cancer that involves the spread of cancerous tissue from the initial site of tumorigenesis within the pancreas to distant organs, blood vessels, bones, or lymph nodes. Since there are few symptoms of the disease in its early stage and no general screening tools for the early detection of pancreatic cancer, most pancreatic cancers are diagnosed at an advanced stage. Imaging of tumors within the pancreas is challenging due to the location of the pancreas deep within the abdomen behind the stomach and underneath the liver. Symptoms are often vague, including weight loss, jaundice, loss of appetite, nausea, stool changes, and the onset of diabetes. While surgery is the preferred treatment for early-stage pancreatic cancers, metastatic pancreatic cancers are primarily treated by chemotherapy intended to shrink the size of the tumors and slow cancer growth. Common chemotherapies include the nucleoside analog Gemcitabine, albumin-bound paclitaxel (Abraxane), and inhibitor of the epidermal growth factor receptor erlotinib (Tarceva). NantKWest (NASDAQ: NK) is a clinical-stage immuno-oncology company that develops natural killer cell-based cancer immunotherapies. NK cells, a subpopulation of white blood cells historically associated with the innate immune system, are capable of detecting and destroying abnormally altered cells, such as those suffering from viral infection or the genetic changes associated with cancer. NantKWest is developing three types of NK-cell based therapies: (1) antibody-mediated, (2) chimeric antigen receptor-directed, and (3) a combination of these approaches. Their NK cells are modified to lack the expression of immunosuppressive receptors known as Killer Inhibitory Receptors (KIR) and to bear higher levels of the molecules perforin and granzyme which are used to destroy target cells including cancer cells. Stay aware of the latest advances in metastatic cancer research and treatment. The antibody-mediated NK cells express cell surface receptors known as CD16 that bind monoclonal antibodies. When antibodies targeting proteins on the surface of cancer cells are used in combination, these NK cells can migrate to and destroy cancerous tissue. The chimeric antigen receptor-directed cells bear highly specific receptor proteins, known as chimeric antigen receptors, that target unique molecules on the surface of cancer cells. The interaction between these NK cells and cancer cells leads to the destruction of cancerous tissue. The patient with a complete resolution of metastatic pancreatic cancer was treated with NK cells combining both of these approaches and targeted against the cancer-associated protein PD-L1. Pre-clinical models have previously used IL-15 to augment the anti-cancer response of CD8+ T cells, and a phase I clinical trial initiated in 2009 by the National Institutes of Health evaluated the efficacy of IL-15 for the treatment of metastatic renal cell carcinoma and melanoma. IL-15 signalling is known to have an important role in the development of NK cells and in the activation and proliferation of T cells and NK cells. Disclosure: We do not have positions or business relationships with the stocks or companies mentioned in this article. This article does not in any way constitute a recommendation. Read the full article

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Clinical Trials of Possible Coronavirus Treatments Underway

by ImmunoFrontiers Team Effective therapies for the coronavirus are urgently needed. Since the identification of the 2019 coronavirus (2019-nCoV) in Wuhan, China, the virus has spread to dozens of countries and led to over 90,000 infections and 3,000 deaths worldwide. The virus-associated disease course, known as COVID-19, includes symptoms with varying severity from mild coughing to life-threatening organ dysfunction and acute respiratory distress syndrome. Currently, the virus has gained a foothold in the United States, with two virus-associated deaths confirmed in Washington state and presumptive-positive cases in Washington, California, and Oregon. These cases are thought to have resulted from person-to-person community spread of the virus. Since current therapy is limited to supportive care, effective antiviral treatment strategies are critically important for saving the lives of individuals most susceptible to a severe disease course. Clinical trials of possible coronavirus treatments are currently underway. While a vaccine against the virus is currently in development by multiple groups, non-vaccine treatment strategies are also being evaluated, including traditional medicines, small-molecule pharmacologic antiviral agents, and immune-boosting compounds, including monoclonal antibodies and intravenous hyperimmune globulin isolated from individuals that have been exposed to the virus. In a recent publication, the Director of the CDC and other leading federal scientists stated that they “anticipate that the first candidates will enter phase 1 trials by early spring” and that the virus would likely continue to spread. “Given the efficiency of transmission as indicated in the current report, we should be prepared for Covid-19 to gain a foothold throughout the world, including in the United States,” the authors stated. Stay informed of breaking coronavirus research and news. According to a recent article by Dr. Erik de Clercq, a Belgian physician and virologist that co-discovered the important anti-viral agent Tenofovir, and Dr. Guangdi Li, improved treatment strategies for coronavirus infection may include existing antiviral agents instead of novel vaccines or compounds. “No drug or vaccine has yet been approved to treat human coronavirus” and “new interventions are likely to require months to years to develop,” stated Clercq and Li. Since proteins produced by 2019-nCoV and essential to the life cycle of the virus share important structural and sequence similarities to those of other viruses within the coronavirus family, including the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) viruses, existing MERS and SARS anti-viral agents could be repurposed to battle 2019-nCoV. Pharmacologic agents Favipiravir and Ribavirin, which block synthesis of viral RNA and therefore reproduction of the virus, may show efficacy for the treating the disease. Clinical trials evaluating Favipiravir in combination with the immune-boosting compound interferon-alpha or the influenza inhibitor baloxavir marboxil are currently underway. Another drug, Remdesivir, which has a structure smilier to the HIV inhibitor Tenofovir, has shown efficacy against the 2019 coronavirus in vitro. The recovery of an infected US patient, who received intravenous infusions of Remdesivir, may be attributable to the drug. Two phase III trials evaluating the efficacy of intravenous Remdesivir for the treatment of the coronavirus were initiated in February and are anticipated to be completed by April 2020. A recent publication describing the treatment of 138 coronavirus patients in Wuhan, China, has provided preliminary information on the outcomes of patients treated with existing clinical interventions. Among the 138 patients, at the time of the publication, 85 were hospitalized, 6 had died, and 36 were admitted to the intensive care unit (ICU). Most patients received glucocorticoid therapy, antiviral therapy with the anti-influenza drug oseltamivir, and anti-bacterial therapy with multiple agents. Among the 11 patients remaining the ICU, all received ventilation. There was a relatively high incidence of life-threatening complications among the 138 patient cohort. 12 experienced shock (8.7%), 27 acute respiratory distress syndrome (19.6%), 10 acute cardiac injury (7.2%), and 23 arrhythmia (16.7%). The virus is thought to spread via respiratory droplets when patients open their mouth to sneeze, talk, or cough, or via close contact with the mouth, eyes, nose, or hands of infected individuals. This is supported by recent research which suggests that, early in the disease course and prior to the onset of significant symptoms, the virus is present at high levels within and near the tongue and tonsils. Currently, infected individuals are likely to spread the virus on average to 2.2 other people with the elderly and immunosuppressed more susceptible to severe cases of infection. Stay informed of breaking coronavirus research and news. Preventative action by the general public may contribute to halting the spread of the disease. Of note, the CDC has provided recommendations for preventing the spread of the coronavirus. Sick individuals should remain at home instead of traveling to work or school. The nose and mouth should be covered with a tissue when coughing or sneezing, and the tissue should be thrown away afterwards. Hands should be washed frequently with soap and water or an alcohol-based hand rub with at least 60% alcohol, and potentially contaminated surfaces and objects disinfected and cleaned with regular household wipes or cleaning spray. Although the CDC is deciding on a case-by-case basis when to release infected individuals from isolation, the following criteria are currently being used: (1) the absence of fever without fever-reducing medications; (2) the absence of symptoms including coughing; (3) at least two respiratory specimens testing negative for the virus with at least 24 hours between the collection of each sample. In addition, although the physical and chemical properties of the coronavirus are not yet clear, researchers believe that coronaviruses are sensitive to ultraviolet light and heat. Previous studies have shown that these viruses can be inactivated by heating at 56 degrees celsius (133 degrees fahrenheit) for 30 minutes and by the use of lipid solvents such as 75% ethanol and disinfectants that contain chlorine. However, the CDC states that "it is not yet known whether weather and temperature impact the spread of COVID-19. Some other viruses, like the common cold and flu, spread more during cold weather months but that does not mean it is impossible to become sick with these viruses during other months.  At this time, it is not known whether the spread of COVID-19 will decrease when weather becomes warmer.  There is much more to learn about the transmissibility, severity, and other features associated with COVID-19 and investigations are ongoing." Clercq ED, Li G. (2020) Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery. doi: 10.1038/d41573-020-00016-0 Huang C, Wang Y, Li X, et al. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395, 497-506. https://www.sciencedirect.com/science/article/pii/S0140673620301835 Read the full article

[immunofrontiers-blog]

Three Individuals in Washington State Test Presumptive-Positive for the Coronavirus

Three individuals in the state of Washington have tested presumptive-positive for the coronavirus according to a recent announcement by the Centers for Disease Control and Prevention (CDC). While the source of the infections is currently under investigation, public health authorities believe that the patients may have developed COVID-19 following person-to-person spread within the community. Two of the patients are associated with a long-term care facility. Additional staff members and residents of the facility are experiencing respiratory problems or hospitalized due to pneumonia or unknown etiology. The third presumptive-positive case of COVID-19, a male in his 50s, has died from the disease, representing the first death associated with COVID-19 in the United States. In addition to Washington state, community spread of the virus may have occurred in Oregon and two locations in California. The total number of cases of COVID-19 in the US public health system has now risen to 22. The three presumptive-positive cases in Washington state were tested using an rRT-PCR kit provided by the CDC. "Most people in the United States will have little immediate risk of exposure to this virus, but some people will be at increased risk depending on their exposures. The greatest risk is to those who have been in close contact with people with COVID-19. People with suspected or confirmed exposure should reach out to their state or local public health department," stated the CDC. The possibility of a coronavirus outbreak in the United States was recently discussed by federal scientists Dr. Anthony Fauci, Dr. Clifford Lane, and Dr. Robert Redfield, in a publication in the New England Journal of Medicine. Dr. Fauci is the current director of the National Institute of Allergy and Infectious Diseases (NIAID) and Dr. Redfield is the director of the CDC. The authors indicated that the virus would likely "continue to spread" and warned that, "given the efficiency of transmission as indicated in the current report, we should be prepared for Covid-19 to gain a foothold throughout the world, including the United States." The scientists recommended mitigation strategies including telecommuting to work as alternative approaches to containment. According the CDC, N95 filtering facepiece respirators (FFR) may provide protection against inhalation of the virus. "An N95 FFR is a type of respirator which removes particles from the air that are breathed through it. These respirators filter out at least 95% of very small (0.3 micron) particles. N95 FFRs are capable of filtering out all types of particles, including bacteria and viruses," states the CDC website. The most common symptoms of the coronavirus include fever, muscle weakness or fatigue, and coughing, but can also include headache, diarrhea, sputum production, coughing up blood, and labored breathing. Life-threatening complications include acute injury to the heart and acute respiratory distress syndrome. Although current approaches to treating the coronavirus focus on supportive care for infected individuals, a vaccine against the coronavirus is in development, including by Maryland-based biotechnology company Novavax (NASDAQ: NVAX). Alternative non-vaccine treatment strategies including pharmacologic antiviral agents, traditional medicines, and immune-boosting compounds are also under evaluation. Monoclonal antibodies and intravenous hyperimmune globulin isolated from individuals that have been exposed to the virus may also be viable treatment options. Dr. Fauci et al “anticipate that the first candidates will enter phase 1 trials by early spring.” Dr. Nancy Messonnier, spokesperson for the CDC, stated, "We recognize that this is a difficult time; we are facing a historic public health challenge. We will continue to respond to COVID-19 in an aggressive way to contain and blunt the threat of this virus. While we still hope for the best, we continue to prepare for this virus to become widespread in the United States." As coronavirus cases continue to rise in the United States, improving the speed and efficiency of treatment will be critically important for providing live-saving care to as many infected individuals as possible. Patients may be triaged according to a recently-developed mortality index based on age and the marker of inflammation C-reactive protein (CRP). According to recent findings by Chinese researchers, individuals older than 60 and with elevated levels of C-reactive protein (greater than 34 mg/L) experience a higher rate of disease-associated mortality. Among 577 patients included in the study, 33.2% of those older than 60 and with elevated C-reactive protein levels perished in constrat to 0.0% of patients younger than 60 and with CRP of less than 34 mg/L. "Our hearts go out to the family of the patient who died as well as the families of the people who are caught up in this outbreak. The health of the residents, staff and community of this skilled nursing facility are a top priority. We will work with Public Health – Seattle and King County to support the care of the patients, the safety of the health care workers, and the well-being of the people in the surrounding community," said Dr. Messonnier. Read the full article

[immunofrontiers-blog]

CDC Announces Four New Presumptive Cases of COVID-19

by ImmunoFrontiers Team The Centers for Disease Control and Prevention (CDC) announced four new presumptive cases of COVID-19, three of which may be due to community spread, in a press release Friday. Possible instances of community spread, in which the virus is transmitted without a known basis for spreading, were reported by public health authorities in California, Oregon, and Washington, with a total of four new patients testing positive for the virus using a CDC-developed and issued test kit. Subscribe to our newsletter! At the time of the press release, 19 cases of COVID-19 were confirmed in the United States. "The federal government has been working closely with state, local, tribal, and territorial partners, as well as public health partners, to respond to this public health threat. Unprecedented, aggressive efforts have been taken to contain the spread and mitigate the impact of this virus. CDC and federal partners have been preparing for the detection of additional instances of person-to-person spread of COVID-19 for weeks. The federal government will continue to respond aggressively to this rapidly evolving situation," stated the CDC. Read the full article

[immunofrontiers-blog]

Federal Scientists Warn of Coronavirus Outbreak in the United States

by ImmunoFrontiers Team In a recent publication in the New England Journal of Medicine, federal scientists Dr. Anthony Fauci, Dr. Clifford Lane, and Dr. Robert Redfield shared their perspectives on the coronavirus pandemic and the possibility of a coronavirus outbreak in the United States. Their ideas were framed in the context of recent epidemiological and clinical research findings based on the first 425 cases of the Coronavirus Disease 2019 (COVID-19) in Wuhan China. Dr. Fauci is the current director of the National Institute of Allergy and Infectious Diseases (NIAID), Dr. Lane is the NIAID Deputy Director for Clinical Research and Special Projects, and Dr. Redfield is the Director of the Centers for Disease Control and Prevention (CDC). Stay informed of breaking coronavirus research and news. Citing recent research that indicates a case fatality rate of between one and two percent, the authors suggested that “the overall clinical consequences of Covid-19 may ultimately be more akin to those of a severe seasonal influenza (which has a case fatality rate of approximately 0.1%) or a pandemic influenza (similar to those in 1957 and 1968) rather than a disease similar to SARS or MERS, which have had case fatality rates of 9 to 10% and 36%, respectively.” Since infected individuals are currently likely to spread the virus, on average, to an additional 2.2 people, the authors stated that the outbreak would likely “continue to spread.” This is supported by recent research suggesting that the virus is abundantly present within and near the tongue and tonsils early during the disease course prior to the onset of significant symptoms. While the temporary travel restrictions instituted by the United States, China, and other countries may have contributed to slowing the spread of the virus, the authors warned that the pandemic may continue to spread. “Given the efficiency of transmission as indicated in the current report, we should be prepared for Covid-19 to gain a foothold throughout the world, including in the United States,” stated Dr. Fauci et al. The authors proposed that, if community spread of the virus occurs in the United States, “mitigation strategies” such as voluntary stay-cations at home and telecommuting to work or school could be used instead of containment. According the CDC, N95 filtering facepiece respirators (FFR) may provide protection against inhalation of the virus. "An N95 FFR is a type of respirator which removes particles from the air that are breathed through it. These respirators filter out at least 95% of very small (0.3 micron) particles. N95 FFRs are capable of filtering out all types of particles, including bacteria and viruses," states the CDC website. While current treatment focuses on supportive care for infected individuals, research to develop a vaccine against the coronavirus is underway and alternative non-vaccine treatment strategies are also being evaluated, including pharmacologic antiviral agents, traditional medicines, and immune-boosting compounds. The authors indicated that monoclonal antibodies and intravenous hyperimmune globulin isolated from individuals that have been exposed to the virus may also be viable treatment options, and “anticipate that the first candidates will enter phase 1 trials by early spring.” “The Covid-19 outbreak is a stark reminder of the ongoing challenge of emerging and reemerging infectious pathogens and the need for constant surveillance, prompt diagnosis, and robust research to understand the basic biology of new organisms and our susceptibilities to them, as well as to develop effective countermeasures,” the authors stated. Fauci A, Lane C, Redfield RR. (2020) Covid-19 — Navigating the Uncharted. The New England Journal of Medicine. DOI: 10.1056/NEJMe2002387 Read the full article