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    Another trial shows no benefit from Remdesivir, yet it's still being administered thousands of times a day in US hospitals. Why should anyone trust the experts running the show in the US?

    DisCoVeRy Trial Results Mean More Bad News for Remdesivir—No Clinical Benefit

    DisCoVeRy Trial Results Mean More Bad News for Remdesivir—No Clinical Benefit
    INSERM, a successor to the French National Institute of Health, recently had results from the Phase 3 DisCoVeRy clinical trial published in The Lancet,

    INSERM, a successor to the French National Institute of Health, recently had results from the Phase 3 DisCoVeRy clinical trial published in The Lancet, Infectious Diseases. The major French investigation explored the antiviral efficacy of remdesivir, the only therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of COVID-19. A controversial move by the FDA as the pivotal American clinical trial included controversial moves by the sponsor—the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH)—to change the primary endpoint toward the end of the study. It turns out that the drug didn’t meet this endpoint, so as directed by NIAID Director Anthony Fauci, the apex government research institute worked with the industry sponsor, Gilead, to merely modify the endpoint to reduce the duration of hospitalization. The final results in that American trial weren’t impressive—a mere few days reduction in hospitalization. Meanwhile, the World Health Organization (WHO) Solidarity trial concluded remdesivir brought no benefit. The FDA proceeded first to issue an emergency use authorization (EUA). A few months later, they issued a formal approval paving the way for Gilead to generate approximately $3 billion in revenue during the first twelve months of the pandemic. Now more evidence backs the position that the drug does little to help hospitalized COVID-19 patients. After evaluating the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in hospitalized COVID-19 patients, the study team found no clinical benefit in symptomatic patients hospitalized for over seven (7) days also in need of oxygen support.


    TrialSite has reported on the unorthodox way in which Gilead was able to secure the EUA—when Dr. Fauci declared for the world to hear that the drug was a “new standard” for treating COVID-19. Fauci quickly followed up, however, that remdesivir was “no knock out drug.”

    Gilead had what it needed to generate blockbuster returns in the middle of a pandemic, charging thousands of dollars per treatment with the true benefit of the drug up in the air. The move greatly benefited the company management, who could drive unprecedented revenue in the middle of the pandemic.

    By January 2021, TrialSite reported that the WHO Solidarity trial indicated that the drug neither helped reduce mortality nor hospitalization. Yet demand for the drug in key markets soared regardless. By October 2020, the FDA formally approved the drug, the first such approval for COVID-19 in America.

    INSERM DisCoVeRy Study

    Enter the INSERM-sponsored, randomized controlled DisCoVeRy study (NCT04315948) testing multiple drugs, including remdesivir, on those 18 and up hospitalized for COVID-19.

    This is an adaptive, multi-center, and country trial comparing the standard of care with various study drugs, including remdesivir.

    INSERM led this Phase 3, open-label, adaptive, multi-center randomized controlled trial conducted at 48 trial sites across Europe, from France and Belgium to Austria, Portugal, and Luxembourg.


    With findings generated during much of the initial year of the pandemic, the arm of the study investigated 857 participants, with 429 assigned to remdesivir plus the standard of care and 428 assigned to only standard of care. Using the WHO ordinal scale as an endpoint measure, the study authors communicated the following:

    WHO Ordinal Scale Stud Drug vs. Standard of Care

    Not hospitalized/No limitations on activities 61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group

    not hospitalized, limitation on activities 129 [31%] vs 132 [32%]

    hospitalized, not requiring supplemental oxygen 50 [12%] vs 29 [7%]

    hospitalized, requiring supplemental oxygen 76 [18%] vs 67 [16%]

    hospitalized, on non-invasive ventilation or high flow oxygen devices 15 [4%] vs 14 [3%]

    hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 62 [15%] vs 79 [19%]

    death 21 [5%] vs 24 [6%]

    The authors disclosed that the delta associated with treatment groups was not “significant.” (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). They couldn’t find any significant differences in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs. control, 130 [31%] of 418; p=0·48).

    Moreover, the investigator associated remdesivir to three deaths involving acute respiratory syndrome, bacterial infection, and hepatorenal syndrome. The sponsor’s safety team acknowledged only one of the deaths associated with hepatorenal syndrome.


    With approximately 13,000 scientists, including 5,100 permanent research staff, INSERM is the only public research institution solely focused on human health and medical research in France. The public institution operates with a scientific vocation under the dual auspices of the Ministry of Health and the Ministry of Research. Similar to the American NIH, INSERM sponsored research from translational to late state clinical trials via 339 research units.

    Study Funding

    This study was funded by a group of prominent governments and organizations, including:

    · European Union Commission

    · French Ministry of Health

    · Domaine d’intérêt majeur One Health Île-de-France

    · REACTing

    · Fonds Erasme-COVID-Université Libre de Bruxelle

    · Belgian Health Care Knowledge Centre

    · Austrian Group Medical Tumor

    · European Regional Development Fund

    · Portugal Ministry of Health

    · Portugal Agency for Clinical Research and Biomedical Innovation

    Lead Research/Investigator

    Prof. Florence Ader, MD, Corresponding Author, département des Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France

    Legiopath, Université Claude Bernard Lyon 1, CIRI, INSERM U1111, CNRS UMR5308, ENS Lyon, Lyon, France

    Call to Action: Follow the link to read the study at The Lancet Infectious Diseases.

    Spectrum Health’s Vaccine Mandate now Excludes Those who can Prove Natural Immunity

    Spectrum Health’s Vaccine Mandate now Excludes Those who can Prove Natural Immunity
    In a similar move seen by many hospital systems and administrations, Spectrum Health announced a COVID-19 vaccine mandate for all employees in July.

    In a similar move seen by many hospital systems and administrations, Spectrum Health announced a COVID-19 vaccine mandate for all employees in July. However, unlike many other officials, the health system will now allow exemptions for those with natural immunity to the virus. A few studies indicate the possibility that natural immunity may actually be stronger than vaccine-based immunity, although more study is undoubtedly needed. TrialSite reported that a large HMO in Israel sponsored a study indicating that natural immunity was, in fact, superior to vaccine immunity. A notable Cleveland Clinic observational study involving health care workers also indicated a strong natural immunity associated with COVID-19. However, that prestigious institution recently pointed out that the study focused on subjects before the emergence of the Delta variant. Regardless, numerous factors are relevant for this complex topic. More study is required for a broader systematic understanding of COVID-19 natural immunity versus vaccine-based immunity. The topic becomes more top-of-mind now as some hospitals are introducing the natural immunity exemption. This suggests natural immunity may emerge as a prominent discussion in the broader vaccination policy context.

    TrialSite provides a brief overview of this topic reported by several local media in the Midwest, including WWZM13, Grand Rapids, Michigan.

    What are the details of exemption?

    Employees with a positive PCR or antigen test from a CLIA-certified lab, plus a positive qualitative antibody test within the past three months, are allowed an exemption.

    How did they justify this decision?

    The medical exemptions for the mandate are determined by a committee of clinical vaccine and infectious disease experts.

    Does this exemption follow FDA guidelines?

    Spectrum says their decisions are consistent with the FDA and available research.

    What do Spectrum Health officials say about a vaccine?

    Hospital officials stated they still recommend a vaccine for everyone, even those with prior COVID-19 infection. Although, they say new research shows that a natural infection affords protection from reinfection and severe symptoms for a period of time. It is not known how long natural immunity remains effective.

    “Vaccine trials and real-world data have shown that it is safe for previously infected individuals to receive the COVID-19 vaccine; side effects following vaccination were no greater in this group,” said the hospital system in a statement.

    Could this mandate and exemption change in the future?

    Officials say if further research shows a significant waning of protection, longer-lasting protection, or proof of full immunity, their requirements will be updated as they see fit.

    Philippines President: Doctors & Patients Have A Right to Use Ivermectin Off-Label to Target COVID-19

    Philippines President: Doctors & Patients Have A Right to Use Ivermectin Off-Label to Target COVID-19
    Recently the Philippines News Agency reported on President Roberto Duterte’s move, possibly to the chagrin of the World Health Organization (WHO), to

    Philippines President: Doctors & Patients Have A Right to Use Ivermectin Off-Label to Target COVID-19

    Recently the Philippines News Agency reported on President Roberto Duterte’s move, possibly to the chagrin of the World Health Organization (WHO), to leave the determination of what approved, off-label drugs to use with physicians and their consenting patients—the way it used to work in the United States. In this case, a presidential edict declared that this right is applicable to ivermectin as an off-label treatment for COVID-19. President Duterte’s remarks were pre-recorded in a major speech delivered to the Philippines population.

    Duterte has a reputation as a strong-armed nationalist, hostility to the West aside; the Philippines president declared the use of ivermectin was a “good gamble” for those physicians and their consenting patients seeking a treatment targeting COVID-19.

    Reporting for the government’s official news agency, Ruth Abbey Gita-Carlos wrote on the mounting tension in the country between most medical authorities that demand the drug only be used in a clinical trial and large numbers in civil society that have followed the dozens of clinical trials, primarily in low- and middle-income countries (LMICs). The reporter included a quote from Duterte, declaring, “I leave it really to the doctor-patient relationship. If the doctor believes in good faith that it can help, and the patient also believes in his heart that he will get well, we leave it up to you to decide.”

    Duterte said he could not ignore the claims that ivermectin is effective in treating Covid-19 patients.

    “Kasi mahirap naman masisi na kung totoo talagang effective tapos pipigilan mo with the testimony bound, plus ‘yung maraming taong nagsabi na gumaling sila (So, it’s hard to be blamed if it’s really effective and you will stop them despite testimonies and claims of some that they recovered [because of Ivermectin]. So for some people, it would be quite a good gamble to embark on,” he said.

    Different Reality

    Now travel over to Australia and discover that the nation’s drug regulator, the Therapeutic Goods Administration (TGA), has all but banned any off-label prescribing for general practitioners (GPs). This undoubtedly makes it extremely difficult for specialists to get a hold of the drug for any reason remotely close to COVID-19.

    Meanwhile, a similar theme emerges in the United States. Recently, the powerful licensing boards have warned physicians their licenses will be yanked (and thus their livelihood) if they put forth any “misinformation.” Who determines the definition of misinformation increasingly points to a tripartite of a politicized executive branch, elites in academia, and the licensing boards themselves, perhaps with a whisper from the industry lobby.

    Back in the Philippines, while their Food and Drug Administration allows for compassionate use, the Department of Science and Technology (DOST) has been planning for months to launch a clinical trial testing ivermectin. According to the official government media, the plan is to launch the eight-month study this month.

    Major ICMR Study of Indian Healthcare Workers Reveals COVID-19 Vaccine Antibodies Wane within 2 Months for Covaxin & 3 Months for Covishield (AstraZeneca)

    Major ICMR Study of Indian Healthcare Workers Reveals COVID-19 Vaccine Antibodies Wane within 2 Months for Covaxin & 3 Months for Covishield (AstraZeneca)
    In what could be considered problematic implications for COVID-19 vaccination in India, a recent study involving 614 Indian health workers found a

    In what could be considered problematic implications for COVID-19 vaccination in India, a recent study involving 614 Indian health workers found a “significant” drop in the study participant’s COVID-19-fighting antibodies within a couple of months of the second dose in the case of the COVID-19 vaccine product Covaxin. Of course, more data is needed for a better understanding of these results, but such an outcome may indicate a need for a booster program in the world’s second-most populous nation. Led by the prestigious Indian Council of Medical Research (ICMR)—Regional Medical Research Centre, Bhubaneswar, a state-run research institute and apex trial site organization, the findings don’t necessarily indicate that all vaccinated subjects lose their immune resistance, as memory cells may still be at work suggested Sanghamitra Pati in discussion with Reuters. However, the study findings suggest that those participants that received India’s first “indigenous” vaccine called Covaxin produced significantly less antibodies by the second month after the second jab, while with the Covishield vaccine (Oxford/AstraZeneca), antibodies materially dissipate by month number four. Emerging evidence suggests antibodies are important for not only blocking infection but also preventing transmission, while T cells may be highly relevant for preventing advanced disease and death.

    While research in the West, such as the United States and Britain, also indicates waning protection associated with advanced mRNA vaccines such as Pfizer-BioNTech (Comirnaty) and Moderna (mRNA-1273), the new Indian-based research results raise serious questions. The ICMR-RMRC-Bhubaneswar study results are uploaded on the preprint server Research Square.

    The Vaccines

    Generally, vaccines are considered effective with a rate of ≥50% with a >30% lower limit of the 95% confidence interval, according to a study authored by the Organization Solidarity Trial Expert Group. Of course, vaccine efficacy, closely related to effectiveness, does wane over time in all cases, as declared recently by Australian researchers.

    The latest ICMR-sponsored study investigated “India’s first indigenous COVID-19 vaccine” known as “Covaxin,” developed by Bharat Biotech, as well as Covishield, the vaccine originally developed at the University of Oxford (ChAdOx1 nCoV-19). The latter vaccine was licensed from the university to AstraZeneca—thereafter, the British pharmaceutical company inked a co-development, production, and distribution deal with the Serum Institute of India (SII), the largest vaccine producer in the world as measured by volume of output.

    What follows is a brief introduction to the COVID-19 vaccine.

    Covaxin—India’s first ‘Indigenous’ COVID-19 Vaccine

    Produced in Bharat Biotech’s BSL-3 high containment facility, Covaxin was developed using whole-virion inactivated Vero Cell-derived platform technology reports the maker. This class of vaccine doesn’t replicate and hence according to Bharat Biotech, is “unlikely to revert and cause pathological effects.” This particular class of COVID-19 vaccine contains a dead virus incapable of infecting people; however, the product can trigger the immune system to mount some defense against SARS-CoV-2.

    TrialSite has reported on some controversy associated with this vaccine candidate, including what some critics have called a rushed approval to purported ethical breaches identified at a trial site in Bhopal associated with the clinical trials program.

    Bharat Biotech disclosed their vaccine was 64% (95% CI, 29-82%) effective against asymptomatic cases, 78% (65-86%) effective against symptomatic cases, 93% (57-100%) effective against severe COVID-19 infection, and 65% (33-83%) effective against the Delta variant as reported by the COVAXIN Study Group.

    Covishield—the Oxford/AstraZeneca Vaccine

    SII inked a deal with AstraZeneca to co-develop, produce, and distribute the “Oxford” vaccine known originally as ChAdOx1 nCoV-19 (AZD1222), developed from a virus (ChAdOx1), a weakened version of what is the common cold virus known as the adenovirus. The Oxford team added genetic material to produce the Spike glycoprotein (S).

    With mixed results, many nations have adopted this vaccine due to its overall economy and practicality—studies disclosed the candidate was 76% effective at preventing symptomatic COVID-19 starting at 22 days following the first dose and 81% after the second jab. A study in Scotland demonstrated an 81% effective rate against the Alpha variant (B.1.1.7) and 61% against the Delta variant (B.1.617.2).

    This vaccine, while representing enormous promise, triggered enough adverse effects that numerous counties have suspended its use. Although statistically considered rare, nonetheless, from South Africa to numerous nations in Europe stopped the use of this vaccine. The United States never completed Phase 3 clinical trials.

    ICMR Study

    The recent study was led by the government-financed Indian Council of Medical Research (ICMR), the apex body in India for the formulation, coordination, and promotion of biomedical research and one of the oldest and largest medical research institutes in the world. ICMR, Bhubaneswar led the investigation into two vaccines in India, including Covaxin and Covishield.

    Published in Research Square, the study results are still not reviewed and, consequently, cannot be declared as any evidence.

    The study team sought to investigate the “dynamicity of vaccine-induced IgG antibodies against SARS-CoV-2. A 614-patient cross-sectional cohort study, the team investigated IgG antibodies among healthcare workers with a completed dose of either Covaxin or Covishield by monitoring the subjects for 24 weeks after the first dose of either vaccine to document periodic changes in titer, concentration, clinical growth, and persistence of vaccine-induced SARS-CoV-2 antibodies.

    Among the 614 study subjects, 308 (50.2%) received Covishield, while 306 (49.8%) took Covaxin.


    The study team collected serum samples from the 614 participants during established monitoring schedules while testing them in two CLIA-based platforms for testing SARS-CoV-2 antibodies both qualitatively and quantitatively.

    The ICMR-led investigators discovered 81 breakthrough cases (13%) among cohort participants for whom infection served as a form of booster. Of the total study subject count, 257 of the participants had actually been infected with SARS-CoV-2 prior to the study.

    The study team found that in the remaining 533 health care workers without any history of post-vaccination infection, a significant waning of antibody in both vaccines–by month two in Covaxin and month three in Covishield.

    For example, the authors reported “a significant decline of antibody post 2 months and 4 months among Covaxin and Covishield recipients after two doses of BBV-152 and AZD1222 vaccines.”

    The production of vaccine-induced IgG antibodies was found to be notability higher in Covishield as compared to Covaxin. In seronegative individuals, upon 28 days of the first jab, the rate of seroconversion was 81.9% for Covishield and 16.1% for Covaxin.


    Overall, the vaccines appear to be helpful in reducing more severe infection and hospitalization, although some of the breakthrough infections led to hospitalization for lower respiratory infection, reported Sumita Behera, Assistant Professor of Transfusion Medicine at MKCG. However, none of these subjects required a ventilator.

    However, rapid decline of the subject’s antibody production—in just two months for Covaxin and three for Covishield—could be deemed problematic. On the other hand, ICM-RMRC investigator Dr. Debdutta Bhattacharya suggested that just because antibody production wanes within a couple of months doesn’t mean that the subject is vulnerable to infection, declaring, “Memory cells develop due to natural immunity after the infection and vaccine-based immunity and these protect the body against the virus.”

    Dr. Behera advocates for a booster dose based on the study data declaring to Indian media Odishabytes, “It’s difficult to say how long the memory cells will provide the needed protection.”

    Meanwhile, ICMR-Regional Medical Research Centre, Bhubaneswar’s Sanghamitra Patti, revealed to all Indian media that the study will include a follow-up after six months, with plans to continue the study. Dr. Patti informed Reuters that “After six months, we should be able to tell you more clearly whether and when a booster would be needed.”

    The Trial Site Hub

    ICMR’s Regional Medical Research Centre, Bhubaneswar, was established in 1981 to focus on investigation into locally prevailing communicable and non-communicable diseases, tribal health, and malnutrition in Odisha and neighboring states. Dr. Pati serves as the present-day director.

    Lead Research/Investigator

    Debdutta Bhattacharya, ICMR Regional Medical Centre, Bhubaneswar

    Sanghamitra Pati, ICMR Regional Medical Centre, Bhubaneswar

    In Dr. Pati’s own words, he is a “physician turned laboratory epidemiologist and public health researcher.

    Call to Action: The study team suggests these findings indicate the need for a larger cohort study which would help to define correlates of protection to determine whether there is a need to produce modified vaccines or booster doses. Note that the authors shared that this study includes a follow-up plan for two years which will further help in understanding the kinetics model and also to provide a better estimate of the antibody response in both seropositive and seronegative individuals over a significant period.

    Persistence of antibodies against Spike glycoprotein of SARS-CoV-2 in health care workers post double dose of BBV-152 and AZD1222 vaccines
    Research Square is a preprint platform that makes research communication faster, fairer, and more useful.

    US approaching Delta wave peak but Covid-19 virus expected to become endemic

    US approaching Delta wave peak but Covid-19 virus expected to become endemic
    Experts warn against complacency and expect the virus will be part of everyday life for years to come.. Read more at

    WASHINGTON (AFP) - The latest coronavirus wave in the United States driven by the Delta variant could soon peak, but experts warn against complacency and expect the virus will be part of everyday life for years to come.

    The seven-day-average of daily cases as of Monday (Sept 13) was 172,000, its highest level of this surge even as the growth rate is slowing and cases are headed down in most states, according to data compiled by the Covid Act Now tracker.

    But more than 1,800 people are still dying a day, and over 100,000 remain hospitalised with severe Covid-19 - a grim reminder of the challenges authorities have faced in getting enough Americans vaccinated in the face of misinformation and a polarised political climate.

    Bhakti Hansoti, an associate professor in emergency medicine at John Hopkins University and expert in Covid-19 critical care told AFP she saw the US following a similar trajectory to India.

    Countries in western Europe have also seen similar downturns in their Delta surges.

    But while Hansoti breathed a sigh of relief when the spring wave ended, "I'm a little hesitant this time around," she admitted.

    The possible emergence of newer variants of concern and the advent of colder weather leading to more socialization indoors could lead to a rebound, "unless we learn from the lessons of the fourth wave."

    Angela Rasmussen, a virologist at University of Saskatchewan in Canada, added she was not certain the fourth wave was over.

    "If you look at the fall-winter wave, there were periods in which there was a steep exponential increase, and then it looked like it was falling - and then there would be another increase." To ensure gains are sustained, rapidly increasing the number of people vaccinated is vital. Currently 63.1 percent of the eligible population over-12 are fully vaccinated, or 54 per cent of the total population.

    This places the United States well behind global leaders like Portugal and the UAE (81 and 79 percent fully vaccinated), despite its abundance of shots.

    The administration of President Joe Biden last week announced a number of new measures to ramp up the immunization campaign, including new vaccine requirements on companies of over 100 employees, but the impact is yet to be clearly seen.

    Two Americas

    Beyond vaccinations, experts want to see other interventions continue.

    Thomas Tsai, a surgeon and health policy researcher at Harvard, said hotspots need to follow through on masking, adding that the US should also look to other countries that have adopted widespread rapid testing for schools and businesses.

    Such tests are available either for free or at a very nominal cost in Germany, Britain and Canada but remain around US$25 (S$33.60) for a two-pack in the US, despite the Biden administration's efforts to drive costs down through a deal with retailers.

    Of course, the impact of all measures depends on their uptake, and in this regard, a clear and consistent pattern has emerged of two Americas: liberal-leaning regions are far more compliant than conservative.

    Prior to the Delta wave, some experts declared that, between the percent of people vaccinated and those who had gained immunity through natural infection, the country was approaching the point of herd immunity.

    Rasmussen said those predictions had proven incorrect and it remained too early to say when this threshold would be reached.

    "There are still parts of the country where the adult vaccination rate is less than 50 percent," she noted.

    Going endemic

    Though Delta has out-competed all previous variants and is currently dominant, SARS-CoV-2 continues to evolve rapidly and virologists fear that more dangerous variants might emerge.

    "I don't want to be a doomsayer, but I also want to have some humility, because I don't think we know a lot about the basic function of many of these mutations," said Rasmussen.

    Still, experts are hopeful that vaccines will continue to blunt the worst outcomes for most people and look forward to their authorisation in children under-12 in the months to come.

    It's expected that certain populations like the elderly and those with weakened immune systems may need boosters as well as high community vaccination rates to protect them.

    Rather than eradication, the goal has shifted toward taming the virus for vaccinated people such that in rare cases of breakthrough infections, the disease is more flu-like.

    However, uncertainties remain: for instance, people with breakthrough Covid infections might still get long Covid.

    Greg Poland, an infectious diseases expert at Mayo Clinic, predicted humanity would be dealing with Covid "well past the lifespan of the next many generations." "We are still immunising against aspects of the 1918 influenza virus," he said.

    Just how bad is this delta Variant?

    The COVID-19 Hospitalization Metric in the Pre- and Post-vaccination Eras as a Measure of Pandemic Severity: A Retrospective, Nationwide Cohort Study

    The COVID-19 Hospitalization Metric in the Pre- and Post-vaccination Eras as a Measure of Pandemic Severity: A Retrospective, Nationwide Cohort Study
    Research Square is a preprint platform that makes research communication faster, fairer, and more useful.


    Importance: Since the early days of the pandemic, COVID-19 hospitalizations have been used as a measure of pandemic severity. However, case definitions do not include assessments of disease severity, which may be impacted by prior vaccination.

    Objective: To measure how the severity of respiratory disease changed among inpatients with documented SARS-CoV-2 infection and to measure the impact of vaccination status on these trends, in order to evaluate the accuracy of the metric of “hospitalization plus a positive SARS-CoV-2 test” for tracking pandemic severity.

    Design: Retrospective cohort of inpatients with laboratory-confirmed SARS-CoV-2. All data were obtained from electronic health records.

    Setting: Multi-center, nationwide study conducted in the healthcare system of the US Department of Veterans Affairs (VA) from March 1, 2020, through June 30, 2021.

    Participants: All VA patients admitted to a VA hospital with a laboratory-confirmed SARS-CoV-2 infection within the 14-days prior to admission or during the hospital admission.

    Main Outcome: Moderate-to-severe COVID-19 disease, defined by use of any supplemental oxygen or documented SpO2 <94%, during an inpatient hospitalization between one day before and two weeks after a positive SARS-CoV-2 test.

    Exposure: SARS-CoV-2 vaccination status at the time of hospitalization. Patients were regarded as fully vaccinated starting 14 days after receiving the second of a 2-dose regimen or 14 days after receipt of a single-dose vaccine.

    Results: Among 47,742 admissions in 38,508 unique patients with laboratory-confirmed SARS-CoV-2, N=28,731 met the criteria for moderate-to-severe COVID-19. The proportion with moderate-to-severe disease prior to widespread vaccine availability was 64.0% (95% CI, 63.1-64.9%) versus 52.0% in the later period (95% CI, 50.9-53.2%), p-value for non-constant effect, <0.001. Disease severity in the vaccine era among hospitalized patients was lower among both unvaccinated (55.0%, 95% CI, 53.7-56.4%) and vaccinated patients (42.6%, 95% CI, 40.6-44.8%).

    Conclusions and Relevance: The proportion of hospitalizations that are due to severe COVID-19 has changed with vaccine availability, thus, increasing proportions of mild and asymptomatic cases are included in hospitalization reporting metrics. The addition of simple measures of disease severity to the case definition of a SARS-CoV-2 hospitalization is a straightforward and objective change that should improve the value of the metric for tracking SARS-CoV-2 disease burden.

    A thermostable oral SARS-CoV-2 vaccine induces mucosal and protective immunity

    A thermostable oral SARS-CoV-2 vaccine induces mucosal and protective immunity
    An ideal protective vaccine against SARS-CoV-2 should not only be effective in preventing disease, but also in preventing virus transmission. It should also be…


    An ideal protective vaccine against SARS-CoV-2 should not only be effective in preventing disease, but also in preventing virus transmission. It should also be well accepted by the population and have a simple logistic chain. To fulfill these criteria, we developed a thermostable, orally administered vaccine that can induce a robust mucosal neutralizing immune response. We used our platform based on retrovirus-derived enveloped virus-like particles (e-VLPs) harnessed with variable surface proteins (VSPs) from the intestinal parasite Giardia lamblia, affording them resistance to degradation and the triggering of robust mucosal cellular and antibody immune responses after oral administration. We made e-VLPs expressing various forms of the SARS-CoV-2 Spike protein (S), with or without membrane protein (M) expression. We found that prime-boost administration of VSP-decorated e-VLPs expressing a pre-fusion stabilized form of S and M triggers robust mucosal responses against SARS-CoV-2 in mice and hamsters, which translate into complete protection from a viral challenge. Moreover, they dramatically boosted the IgA mucosal response of intramuscularly injected vaccines. We conclude that our thermostable orally administered e-VLP vaccine could be a valuable addition to the current arsenal against SARS-CoV-2, in a stand-alone prime-boost vaccination strategy or as a boost for existing vaccines.


    The differences observed between the same formulations administered either orally or intramuscularly in these animals suggest that although the oral route is expected to show a higher degree of variation among animals, this was not the case. This could be explained by the type of generated Igs. Notably, considering the i.m. administration was done in the absence of any added adjuvant, the high immunogenicity of VSP-e-VLPs can be explained by the adjuvant properties of the VSPs, which have been demonstrated to activate TLR-419. The immunogenicity of the e-VLPs lacking VSPs may mainly rely on the particulate nature of VLPs and the repetitive exposure of the antigen on their surface, even TLR-signaling as been described43.

    Our results first show that it is possible to co-express SARS-CoV-2 envelope proteins together with Giardia VSPs on e-VLPs to generate mucosal Igs and NAbs against SARS-CoV-2 after oral administration. While plain e-VLPs did not generate any Ab responses, VSP-decorated e-VLPs (VSP-e-VLPs) generated Ab responses in the range of, if not higher than, the response to i.m. administration. This is remarkable as it indicates that the SARS-CoV-2 Env proteins are well protected from degradation by VSPs as they preserve their proper conformation, which is needed for NAb production. Thus, this extends our previous results with e-VLP expressing HA of influenza19, demonstrating the versatility of the VSP-e-VLP platform. Actually, the dual properties of VSPs were confirmed: they not only afford protection from degradation, but also have a potent adjuvant effect. Indeed, when vaccines are administered i.m., VSP-e-VLP always led to higher titers of antibodies than their plain e-VLPs. Of note, a SARS-CoV-2 VLP based on our platform technology15 was independently reported to generate a good NAb response after i.m. administration, but with no reports of IgA at mucosal sites.

    Besides its ease, oral administration is known for also having the advantage of triggering better mucosal immunity. This is indeed the case here, with high levels of plasma but also bronchoalveolar lavage IgA detectable only after oral administration. This is an obvious advantage for a vaccine against SARS-CoV-2, as it should reduce viral transmission. In this line, SARS-CoV-2 was still detected in BAL of i.m. vaccinated macaques that otherwise appeared protected from infection. Whether a better mucosal response, as afforded by VSP-e-VLPs, will completely sterilize challenged macaques requires further investigation.

    We have not tested the specific T cell response in this study. However, it is known that e-VLPs do induce robust cellular responses; indeed, using VSP-HA-VLPs, a strong cytotoxic T lymphocyte response was generated that was able to kill HA-expressing tumor cells25. Moreover, the IgG and IgA responses here are notoriously T cell-dependent and the good antibody response thus attests to a good T cell response44. In this line, we previously showed that the fusion of a viral peptide to Gag, the retroviral protein precursor that drives the formation and release of the viral particle/VLPs, produces additional strong T cell responses against this peptide12. The fusion to Gag of large fragments or the SARS-CoV-2 N structural protein, or a stretch of immunodominant and/or conserved peptides, would be a mean to further enhance the immunogenicity of VSP-e-VLPs and enhance protection against variants.

    SARS-CoV-2 e-VLPs and VSP-e-VLPs could be used as a stand-alone vaccine, likely with a prime-boost scheme of administration. VSP-e-VLPs are thermostable 19, retaining their properties at room temperature and tolerating several freeze-thaw cycles, and could thus be particularly advantageous for vaccination in countries where refrigeration of vaccine supplies is problematic. VSP-e-VLPs could also be used as a boost for other vaccine designs. In this regard, it is still unknown how long the protection afforded by the currently used vaccines will last. The follow-up of infected patients indicates that, at least for some patients, the persistence of NAbs and the duration of protection might last a few months45. These findings, plus the advent of viral variants, make it likely that the global population will need to boost the immune response of vaccinees regularly. For some vaccine designs, and particularly those based on adenoviral vectors, the re-administration of the same vector might not be very efficient due to the immune response generated against the vector. For these, a boost with VSP-e-VLPs might be particularly interesting. For other vaccine designs, and especially if repeated administrations are needed over the years, an orally administered vaccine might be more acceptable.

    The SARS-CoV-2 pandemic calls for vaccination of very large groups of people. This requires a suitable production of vaccine with an excellent safety profile. Noteworthy, we contributed to the design of an anti-CMV e-VLP vaccine based on our e-VLP platform that has already been used in patients, demonstrating scalable GMP production and an excellent safety profile15,17,46.

    Altogether, given the specific issues of each vaccine design (thermostability, side effects, lack of mucosal immunity induction, immunogenicity against the vector, among other benefits), the availability of multiple vaccines against SARS-CoV-2 improves our chances of controlling the pandemic. In this regard, a thermostable orally administered e-VLP vaccine will be a valuable addition to the current arsenal against this virus.

    Israeli scientists say their antiviral drug could stop COVID-19

    Israeli scientists say their antiviral drug could stop COVID-19
    An Israeli antiviral drug previously used to treat HIV may be able to stop coronavirus in a matter of days.

    A team of Israeli scientists say that a drug previously used in an uncontrolled fashion to treat HIV has a direct antiviral effect against coronavirus, sending patients home virus-free within only a few days.

    Code Pharma, which is headquartered in the Netherlands but has its research and development office in Israel and an Israeli CEO, recently completed a Phase I trial of its drug Codivir for use against coronavirus. On Monday, the Israeli research team that will support the Phase II trial applied for permission from the Helsinki Committee to move forward at the Barzilai Medical Center.

    The Phase II study, which will involve around 150 patients and is expected to launch in the next month, will also take place in Spain, Brazil and South Africa. According to Code Pharma CEO Zyon Ayni, the goal is to complete the trial within about three to six months and then already apply for emergency use authorization of the drug.

    In the first and second wave of the COVID-19 pandemic, many of the drugs with putative or proven antiviral mechanisms of action have not proven themselves to significantly prolong life expectancy,” said Prof. Shlomo Maayan, director of the Infectious Disease division at Barzilai. He is advising Code Pharma as it moves forward with Codivir but receives no financial or other compensation.

    “Codivir has a very good safety profile and a very impressive antiviral effect, both in laboratory conditions and in a phase I clinical trial in humans,” he said. “We eagerly await the results of the double-blind studies using Codivir. It may be a breakthrough in the field of antiviral therapy for early COVID-19 patients.”

    The Phase I trial was recently completed in Brazil at Casa de Saúde – Vera Cruz Hospital in São Paulo, Brazil, under the approval of the National Research Ethics Commission (CONEP). Twelve patients between the ages of 18 and 60 with mild to moderate coronavirus participated in the study.

    Seven of the volunteers were tested sequentially using a standard PCR swab test every two days from the time they began receiving the treatment, which like insulin is given subcutaneously – injection under the skin.

    Patients received two injections per day for 10 days.

    Maayan said that five of the patients showed a very profound decline in the viral load during the treatment. Codivir significantly suppressed viral replication in all patients with an antiviral effect noted as early as three days after the beginning of treatment.

    Moreover, the safety profile of the drug was very good. There were no significant side effects from the treatment itself, Ayni said, nor did those who received the drug show any signs of side effects that are very often associated with COVID-19 infections.

    Manuscripts describing these results have been submitted to a peer-reviewed journal.

    CODIVIR IS based on a short 16 amino-acid peptide derived from the HIV-1 integrase. It was first discovered by researchers at the Hebrew University, who are still involved with the company.

    “The initial idea was to eradicate HIV-infected cells,” the CEO explained, noting that the drug seemed to induce HIV cell death in pre-clinical trials. Around the time that the coronavirus pandemic was beginning, Code Pharma was testing the drug unofficially in HIV patients in the Congo.

    “One hospital there started administering it to COVID-19 patients, too, and they got completely better – some in hours and some in days,” Ayni said.

    The hospital then requested additional doses, which it administered in an unofficial clinical trial, where doctors divided and tracked patients who received Codivir and patients who did not. All of the patients were between the ages of 35 and 78 and were being treated in the intensive care unit – though he said the ICU in the Congo does not look like a Western ICU, meaning the patients were only receiving oxygen.

    “The doctor gave them the medication and saw that in only nine days, two patients completely recovered and the rest got much better and almost had no trace of the virus. Of the 15 people who did not receive the medication, 14 died.

    “It was very clear we were onto something, but we did not know what,” Ayni said.

    So, the company decided to conduct in-vitro studies at the well-respected Virology Research Services in London, with what Maayan described as “excellent results.”

    “We saw complete elimination of the virus in 90% to 100% of cells in less than 24 hours,” Ayni said, noting that the results play out slightly differently in people. However, one thing was clear to Code Pharma: The laboratory studies demonstrated a potent antiviral activity.

    The lab results are what led to the Brazil trial.

    The Phase II multinational trial will be double-blind and also evaluate Codivir in the treatment of mild to moderate cases.

    “The idea is that if the data we generated from Phase I with no controls repeats itself, this will be a significant achievement,” Maayan said. “If the results do not repeat themselves, then it is a no-go.

    “But with both the laboratory results and the Phase I trial so encouraging, it looks promising,” he said.

    Due to the high levels of COVID infection continuing around the world, the company is already preparing to submit emergency approval requests to several countries once the Phase II trial is complete, Ayni said. It is also preparing for mass production of Codivir at different sites worldwide.

    “The world is in need of an antiviral medication against COVID.”

    The tangled history of mRNA vaccines

    Hundreds of scientists had worked on mRNA vaccines for decades before the coronavirus pandemic brought a breakthrough.

    The tangled history of mRNA vaccines
    Hundreds of scientists had worked on mRNA vaccines for decades before the coronavirus pandemic brought a breakthrough.

    In late 1987, Robert Malone performed a landmark experiment. He mixed strands of messenger RNA with droplets of fat, to create a kind of molecular stew. Human cells bathed in this genetic gumbo absorbed the mRNA, and began producing proteins from it1.

    Realizing that this discovery might have far-reaching potential in medicine, Malone, a graduate student at the Salk Institute for Biological Studies in La Jolla, California, later jotted down some notes, which he signed and dated. If cells could create proteins from mRNA delivered into them, he wrote on 11 January 1988, it might be possible to “treat RNA as a drug”. Another member of the Salk lab signed the notes, too, for posterity. Later that year, Malone’s experiments showed that frog embryos absorbed such mRNA2. It was the first time anyone had used fatty droplets to ease mRNA’s passage into a living organism.

    Those experiments were a stepping stone towards two of the most important and profitable vaccines in history: the mRNA-based COVID-19 vaccines given to hundreds of millions of people around the world. Global sales of these are expected to top US$50 billion in 2021 alone.

    But the path to success was not direct. For many years after Malone’s experiments, which themselves had drawn on the work of other researchers, mRNA was seen as too unstable and expensive to be used as a drug or a vaccine. Dozens of academic labs and companies worked on the idea, struggling with finding the right formula of fats and nucleic acids — the building blocks of mRNA vaccines.

    Today’s mRNA jabs have innovations that were invented years after Malone’s time in the lab, including chemically modified RNA and different types of fat bubble to ferry them into cells (see ‘Inside an mRNA COVID vaccine’). Still, Malone, who calls himself the “inventor of mRNA vaccines”, thinks his work hasn’t been given enough credit. “I’ve been written out of history,” he told Nature.

    Inside an mRNA COVID vaccine: infographic that shows the innovations used in the mRNA and nanoparticle of the vaccine.

    Nik Spencer/Nature; Adapted from M. D. Buschmann et al. Vaccines 9, 65 (2021)

    The debate over who deserves credit for pioneering the technology is heating up as awards start rolling out — and the speculation is getting more intense in advance of the Nobel prize announcements next month. But formal prizes restricted to only a few scientists will fail to recognize the many contributors to mRNA’s medical development. In reality, the path to mRNA vaccines drew on the work of hundreds of researchers over more than 30 years.

    The story illuminates the way that many scientific discoveries become life-changing innovations: with decades of dead ends, rejections and battles over potential profits, but also generosity, curiosity and dogged persistence against scepticism and doubt. “It’s a long series of steps,” says Paul Krieg, a developmental biologist at the University of Arizona in Tucson, who made his own contribution in the mid-1980s, “and you never know what’s going to be useful”.

    The beginnings of mRNA

    Malone’s experiments didn’t come out of the blue. As far back as 1978, scientists had used fatty membrane structures called liposomes to transport mRNA into mouse3 and human4 cells to induce protein expression. The liposomes packaged and protected the mRNA and then fused with cell membranes to deliver the genetic material into cells. These experiments themselves built on years of work with liposomes and with mRNA; both were discovered in the 1960s (see ‘The history of mRNA vaccines’).

    The history of mRNA vaccines: A timeline that shows the key scientific innovations in the development of mRNA vaccines.

    Nik Spencer/Nature; Adapted from U. Şahin et al. Nature Rev. Drug Discov. 13, 759–780 (2014) and X. Hou et al. Nature Rev. Mater. (2021).

    Back then, however, few researchers were thinking about mRNA as a medical product — not least because there was not yet a way to manufacture the genetic material in a laboratory. Instead, they hoped to use it to interrogate basic molecular processes. Most scientists repurposed mRNA from rabbit blood, cultured mouse cells or some other animal source.

    That changed in 1984, when Krieg and other members of a team led by developmental biologist Douglas Melton and molecular biologists Tom Maniatis and Michael Green at Harvard University in Cambridge, Massachusetts, used an RNA-synthesis enzyme (taken from a virus) and other tools to produce biologically active mRNA in the lab5 — a method that, at its core, remains in use today. Krieg then injected the lab-made mRNA into frog eggs, and showed that it worked just like the real thing6.

    Both Melton and Krieg say they saw synthetic mRNA mainly as a research tool for studying gene function and activity. In 1987, after Melton found that the mRNA could be used both to activate and to prevent protein production, he helped to form a company called Oligogen (later renamed Gilead Sciences in Foster City, California) to explore ways to use synthetic RNA to block the expression of target genes — with an eye to treating disease. Vaccines weren’t on the mind of anyone in his lab, or their collaborators.

    RNA in general had a reputation for unbelievable instability,” says Krieg. “Everything around RNA was cloaked in caution.” That might explain why Harvard’s technology-development office elected not to patent the group’s RNA-synthesis approach. Instead, the Harvard researchers simply gave their reagents to Promega Corporation, a lab-supplies company in Madison, Wisconsin, which made the RNA-synthesis tools available to researchers. They received modest royalties and a case of Veuve Clicquot Champagne in return.

    Patent disputes

    Years later, Malone followed the Harvard team’s tactics to synthesize mRNA for his experiments. But he added a new kind of liposome, one that carried a positive charge, which enhanced the material’s ability to engage with the negatively charged backbone of mRNA. These liposomes were developed by Philip Felgner, a biochemist who now leads the Vaccine Research and Development Center at the University of California, Irvine.

    Despite his success using the liposomes to deliver mRNA into human cells and frog embryos, Malone never earned a PhD. He fell out with his supervisor, Salk gene-therapy researcher Inder Verma and, in 1989, left graduate studies early to work for Felgner at Vical, a recently formed start-up in San Diego, California. There, they and collaborators at the University of Wisconsin–Madison showed that the lipid–mRNA complexes could spur protein production in mice7.

    Then things got messy. Both Vical (with the University of Wisconsin) and the Salk began filing for patents in March 1989. But the Salk soon abandoned its patent claim, and in 1990, Verma joined Vical’s advisory board.

    Malone contends that Verma and Vical struck a back-room deal so that the relevant intellectual property went to Vical. Malone was listed as one inventor among several, but he no longer stood to profit personally from subsequent licensing deals, as he would have from any Salk-issued patents. Malone’s conclusion: “They got rich on the products of my mind.”

    Verma and Felgner categorically deny Malone’s charges. “It’s complete nonsense,” Verma told Nature. The decision to drop the patent application rested with the Salk’s technology-transfer office, he says. (Verma resigned from the Salk in 2018, following allegations of sexual harassment, which he continues to deny.)

    Malone left Vical in August 1989, citing disagreements with Felgner over “scientific judgment” and “credit for my intellectual contributions”. He completed medical school and did a year of clinical training before working in academia, where he tried to continue research on mRNA vaccines but struggled to secure funding. (In 1996, for example, he unsuccessfully applied to a California state research agency for money to develop a mRNA vaccine to combat seasonal coronavirus infections.) Malone focused on DNA vaccines and delivery technologies instead.

    In 2001, he moved into commercial work and consulting. And in the past few months, he has started publicly attacking the safety of the mRNA vaccines that his research helped to enable. Malone says, for instance, that proteins produced by vaccines can damage the body’s cells and that the risks of vaccination outweigh the benefits for children and young adults — claims that other scientists and health officials have repeatedly refuted.

    Manufacturing challenges

    In 1991, Vical entered into a multimillion-dollar research collaboration and licensing pact with US firm Merck, one of the world’s largest vaccine developers. Merck scientists evaluated the mRNA technology in mice with the aim of creating an influenza vaccine, but then abandoned that approach. “The cost and feasibility of manufacturing just gave us pause,” says Jeffrey Ulmer, a former Merck scientist who now consults with companies on vaccine-research issues.

    Researchers at a small biotech firm in Strasbourg, France, called Transgène, felt the same way. There, in 1993, a team led by Pierre Meulien, working with industrial and academic partners, was the first to show that an mRNA in a liposome could elicit a specific antiviral immune response in mice8. (Another exciting advance had come in 1992, when scientists at the Scripps Research Institute in La Jolla used mRNA to replace a deficient protein in rats, to treat a metabolic disorder9. But it would take almost two decades before independent labs reported similar success.)

    The Transgène researchers patented their invention, and continued to work on mRNA vaccines. But Meulien, who is now head of the Innovative Medicines Initiative, a public–private enterprise based in Brussels, estimated that he needed at least €100 million (US$119 million) to optimize the platform — and he wasn’t about to ask his bosses for that much for such a “tricky, high-risk” venture, he says. The patent lapsed after Transgène’s parent firm decided to stop paying the fees needed to keep it active.

    Meulien’s group, like the Merck team, moved to focus instead on DNA vaccines and other vector-based delivery systems. The DNA platform ultimately yielded a few licensed vaccines for veterinary applications — helping, for example, to prevent infections in fish farms. And just last month, regulators in India granted emergency approval to the world’s first DNA vaccine for human use, to help ward off COVID-19. But for reasons that are not completely understood, DNA vaccines have been slow to find success in people.

    Still, the industry’s concerted push around DNA technology has had benefits for RNA vaccines, too, argues Ulmer. From manufacturing considerations and regulatory experience to sequence designs and molecular insights, “many of the things that we learned from DNA could be directly applied to RNA”, he says. “It provided the foundation for the success of RNA.”

    Continuous struggle

    In the 1990s and for most of the 2000s, nearly every vaccine company that considered working on mRNA opted to invest its resources elsewhere. The conventional wisdom held that mRNA was too prone to degradation, and its production too expensive. “It was a continuous struggle,” says Peter Liljeström, a virologist at the Karolinska Institute in Stockholm, who 30 years ago pioneered a type of ‘self-amplifying’ RNA vaccine.

    “RNA was so hard to work with,” says Matt Winkler, who founded one of the first RNA-focused lab supplies companies, Ambion, in Austin, Texas, in 1989. “If you had asked me back [then] if you could inject RNA into somebody for a vaccine, I would have laughed in your face.”

    The mRNA vaccine idea had a more favourable reception in oncology circles, albeit as a therapeutic agent, rather than to prevent disease. Beginning with the work of gene therapist David Curiel, several academic scientists and start-up companies explored whether mRNA could be used to combat cancer. If mRNA encoded proteins expressed by cancer cells, the thinking went, then injecting it into the body might train the immune system to attack those cells.

    Curiel, now at the Washington University School of Medicine in St Louis, Missouri, had some success in mice10. But when he approached Ambion about commercialization opportunities, he says, the firm told him: “We don’t see any economic potential in this technology.”

    Another cancer immunologist had more success, which led to the founding of the first mRNA therapeutics company, in 1997. Eli Gilboa proposed taking immune cells from the blood, and coaxing them to take up synthetic mRNA that encoded tumour proteins. The cells would then be injected back into the body where they could marshal the immune system to attack lurking tumours.

    Gilboa and his colleagues at Duke University Medical Center in Durham, North Carolina, demonstrated this in mice11. By the late 1990s, academic collaborators had launched human trials, and Gilboa’s commercial spin-off, Merix Bioscience (later renamed to Argos Therapeutics and now called CoImmune), soon followed with clinical studies of its own. The approach was looking promising until a few years ago, when a late-stage candidate vaccine failed in a large trial; it has now largely fallen out of fashion.

    But Gilboa’s work had an important consequence. It inspired the founders of the German firms CureVac and BioNTech — two of the largest mRNA companies in existence today — to begin work on mRNA. Both Ingmar Hoerr, at CureVac, and Uğur Şahin, at BioNTech, told Nature that, after learning of what Gilboa had done, they wanted to do the same, but by administering mRNA into the body directly.

    There was a snowball effect,” says Gilboa, now at the University of Miami Miller School of Medicine in Florida.

    Start-up accelerator

    Hoerr was the first to achieve success. While at the University of Tübingen in Germany, he reported in 2000 that direct injections could elicit an immune response in mice12. He created CureVac (also based in Tübingen) that year. But few scientists or investors seemed interested. At one conference where Hoerr presented early mouse data, he says, “there was a Nobel prizewinner standing up in the first row saying, ‘This is completely shit what you’re telling us here — completely shit’.” (Hoerr declined to name the Nobel laureate.)

    Eventually, money trickled in. And within a few years, human testing began. The company’s chief scientific officer at the time, Steve Pascolo, was the first study subject: he injected himself13 with mRNA and still has match-head-sized white scars on his leg from where a dermatologist took punch biopsies for analysis. A more formal trial, involving tumour-specific mRNA for people with skin cancer, kicked off soon after.

    Şahin and his immunologist wife, Özlem Türeci, also began studying mRNA in the late 1990s, but waited longer than Hoerr to start a company. They plugged away at the technology for many years, working at Johannes Gutenberg University Mainz in Germany, earning patents, papers and research grants, before pitching a commercial plan to billionaire investors in 2007. “If it works, it will be ground-breaking,” Şahin said. He got €150 million in seed money.

    The same year, a fledgling mRNA start-up called RNARx received a more modest sum: $97,396 in small-business grant funding from the US government. The company’s founders, biochemist Katalin Karikó and immunologist Drew Weissman, both then at the University of Pennsylvania (UPenn) in Philadelphia, had made what some now say is a key finding: that altering part of the mRNA code helps synthetic mRNA to slip past the cell’s innate immune defences.

    Fundamental insights

    Karikó had toiled in the lab throughout the 1990s with the goal of transforming mRNA into a drug platform, although grant agencies kept turning down her funding applications. In 1995, after repeated rejections, she was given the choice of leaving UPenn or accepting a demotion and pay cut. She opted to stay and continue her dogged pursuit, making improvements to Malone’s protocols14, and managing to induce cells to produce a large and complex protein of therapeutic relevance15.

    In 1997, she began working with Weissman, who had just started a lab at UPenn. Together, they planned to develop an mRNA-based vaccine for HIV/AIDS. But Karikó’s mRNAs set off massive inflammatory reactions when they were injected into mice.

    She and Weissman soon worked out why: the synthetic mRNA was arousing16 a series of immune sensors known as Toll-like receptors, which act as first responders to danger signals from pathogens. In 2005, the pair reported that rearranging the chemical bonds on one of mRNA’s nucleotides, uridine, to create an analogue called pseudouridine, seemed to stop the body identifying the mRNA as a foe17.

    Few scientists at the time recognized the therapeutic value of these modified nucleotides. But the scientific world soon awoke to their potential. In September 2010, a team led by Derrick Rossi, a stem-cell biologist then at Boston Children’s Hospital in Massachusetts, described how modified mRNAs could be used to transform skin cells, first into embryonic-like stem cells and then into contracting muscle tissue18. The finding made a splash. Rossi was featured in Time magazine as one of 2010’s ‘people who mattered’. He co-founded a start-up, Moderna in Cambridge.

    Moderna tried to license the patents for modified mRNA that UPenn had filed in 2006 for Karikó’s and Weissman’s invention. But it was too late. After failing to come to a licensing agreement with RNARx, UPenn had opted for a quick payout. In February 2010, it granted exclusive patent rights to a small lab-reagents supplier in Madison. Now called Cellscript, the company paid $300,000 in the deal. It would go on to pull in hundreds of millions of dollars in sublicensing fees from Moderna and BioNTech, the originators of the first mRNA vaccines for COVID-19. Both products contain modified mRNA.

    RNARx, meanwhile, used up another $800,000 in small-business grant funding and ceased operations in 2013, around the time that Karikó joined BioNTech (retaining an adjunct appointment at UPenn).

    The pseudouridine debate

    Researchers still argue over whether Karikó and Weissman’s discovery is essential for successful mRNA vaccines. Moderna has always used modified mRNA — its name is a portmanteau of those two words. But some others in the industry have not.

    Researchers at the human-genetic-therapies division of the pharmaceutical firm Shire in Lexington, Massachusetts, reasoned that unmodified mRNA could yield a product that was just as effective if the right ‘cap’ structures were added and all impurities were removed. “It came down to the quality of the RNA,” says Michael Heartlein, who led Shire’s research effort and continued to advance the technology at Translate Bio in Cambridge, to which Shire later sold its mRNA portfolio. (Shire is now part of the Japanese firm Takeda.)

    Although Translate has some human data to suggest its mRNA does not provoke a concerning immune response, its platform remains to be proved clinically: its COVID-19 vaccine candidate is still in early human trials. But French drug giant Sanofi has been convinced of the technology’s promise: in August 2021, it announced plans to acquire Translate for $3.2 billion. (Heartlein left last year to found another firm in Waltham, Massachusetts, called Maritime Therapeutics.)

    CureVac, meanwhile, has its own immune-mitigation strategy, which involves altering the genetic sequence of the mRNA to minimize the amount of uridine in its vaccines. Twenty years of working on that approach seemed to be bearing fruit, with early trials of the company’s experimental vaccines for rabies19 and COVID-1920 both proving a success. But in June, data from a later-stage trial showed that CureVac’s coronavirus vaccine candidate was much less protective than Moderna’s or BioNTech’s.

    In light of those results, some mRNA experts now consider pseudouridine an essential component of the technology — and so, they say, Karikó’s and Weissman’s discovery was one of the key enabling contributions that merits recognition and prizes. “The real winner here is modified RNA,” says Jake Becraft, co-founder and chief executive of Strand Therapeutics, a Cambridge-based synthetic-biology company working on mRNA-based therapeutics.

    Not everyone is so certain. “There are multiple factors that may affect the safety and efficacy of an mRNA vaccine, chemical modification of mRNA is only one of them,” says Bo Ying, chief executive of Suzhou Abogen Biosciences, a Chinese company with an mRNA vaccine for COVID-19 now in late-stage clinical testing. (Known as ARCoV, the product uses unmodified mRNA.)

    Fat breakthrough

    As for linchpin technologies, many experts highlight another innovation that was crucial for mRNA vaccines — one that has nothing to do with the mRNA. It is the tiny fat bubbles known as lipid nanoparticles, or LNPs, that protect the mRNA and shuttle it into cells.

    This technology comes from the laboratory of Pieter Cullis, a biochemist at the University of British Columbia in Vancouver, Canada, and several companies that he founded or led. Beginning in the late 1990s, they pioneered LNPs for delivering strands of nucleic acids that silence gene activity. One such treatment, patisiran, is now approved for a rare inherited disease.

    After that gene-silencing therapy began to show promise in clinical trials, in 2012, two of Cullis’s companies pivoted to explore opportunities for the LNP delivery system in mRNA-based medicines. Acuitas Therapeutics in Vancouver, for example, led by chief executive Thomas Madden, forged partnerships with Weissman’s group at UPenn and with several mRNA companies to test different mRNA–LNP formulations. One of these can now be found in the COVID-19 vaccines from BioNTech and CureVac. Moderna’s LNP concoction is not much different.

    The nanoparticles have a mixture of four fatty molecules: three contribute to structure and stability; the fourth, called an ionizable lipid, is key to the LNP’s success. This substance is positively charged under laboratory conditions, which offers similar advantages to the liposomes that Felgner developed and Malone tested in the late 1980s. But the ionizable lipids advanced by Cullis and his commercial partners convert to a neutral charge under physiological conditions such as those in the bloodstream, which limits the toxic effects on the body.

    What’s more, the four-lipid cocktail allows the product to be stored for longer on the pharmacy shelf and to maintain its stability inside the body, says Ian MacLachlan, a former executive at several Cullis-linked ventures. “It’s the whole kit and caboodle that leads to the pharmacology we have now,” he says.

    By the mid-2000s, a new way to mix and manufacture these nanoparticles had been devised. It involved using a ‘T-connector’ apparatus, which combines fats (dissolved in alcohol) with nucleic acids (dissolved in an acidic buffer). When streams of the two solutions merged, the components spontaneously formed densely packed LNPs21. It proved to be a more reliable technique than other ways of making mRNA-based medicines.

    Once all the pieces came together, “it was like, holy smoke, finally we’ve got a process we can scale”, says Andrew Geall, now chief development officer at Replicate Bioscience in San Diego. Geall led the first team to combine LNPs with an RNA vaccine22, at Novartis’s US hub in Cambridge in 2012. Every mRNA company now uses some variation of this LNP delivery platform and manufacturing system — although who owns the relevant patents remains the subject of legal dispute. Moderna, for example, is locked in a battle with one Cullis-affiliated business — Arbutus Biopharma in Vancouver — over who holds the rights to the LNP technology found in Moderna’s COVID-19 jab.

    An industry is born

    By the late 2000s, several big pharmaceutical companies were entering the mRNA field. In 2008, for example, both Novartis and Shire established mRNA research units — the former (led by Geall) focused on vaccines, the latter (led by Heartlein) on therapeutics. BioNTech launched that year, and other start-ups soon entered the fray, bolstered by a 2012 decision by the US Defense Advanced Research Projects Agency to start funding industry researchers to study RNA vaccines and drugs. Moderna was one of the companies that built on this work and, by 2015, it had raised more than $1 billion on the promise of harnessing mRNA to induce cells in the body to make their own medicines — thereby fixing diseases caused by missing or defective proteins. When that plan faltered, Moderna, led by chief executive Stéphane Bancel, chose to prioritize a less ambitious target: making vaccines.

    That initially disappointed many investors and onlookers, because a vaccine platform seemed to be less transformative and lucrative. By the beginning of 2020, Moderna had advanced nine mRNA vaccine candidates for infectious diseases into people for testing. None was a slam-dunk success. Just one had progressed to a larger-phase trial.

    But when COVID-19 struck, Moderna was quick off the mark, creating a prototype vaccine within days of the virus’s genome sequence becoming available online. The company then collaborated with the US National Institute of Allergy and Infectious Diseases (NIAID) to conduct mouse studies and launch human trials, all within less than ten weeks.

    BioNTech, too, took an all-hands-on-deck approach. In March 2020, it partnered with New York-based drug company Pfizer, and clinical trials then moved at a record pace, going from first-in-human testing to emergency approval in less than eight months.

    Both authorized vaccines use modified mRNA formulated in LNPs. Both also contain sequences that encode a form of the SARS-CoV-2 spike protein that adopts a shape more amenable to inducing protective immunity. Many experts say that the protein tweak, devised by NIAID vaccinologist Barney Graham and structural biologists Jason McLellan at the University of Texas at Austin and Andrew Ward at Scripps, is also a prize-worthy contribution, albeit one that is specific to coronavirus vaccines, not mRNA vaccination as a general platform

    Some of the furore in discussions of credit for mRNA discoveries relates to who holds lucrative patents. But much of the foundational intellectual property dates back to claims made in 1989 by Felgner, Malone and their colleagues at Vical (and in 1990 by Liljeström). These had only a 17-year term from the date of issue and so are now in the public domain.

    Even the Karikó–Weissman patents, licensed to Cellscript and filed in 2006, will expire in the next five years. Industry insiders say this means that it will soon become very hard to patent broad claims about delivering mRNAs in lipid nanoparticles, although companies can reasonably patent particular sequences of mRNA — a form of the spike protein, say — or proprietary lipid formulations.

    Firms are trying. Moderna, the dominant player in the mRNA vaccine field, which has experimental shots in clinical testing for influenza, cytomegalovirus and a range of other infectious diseases, got two patents last year covering the broad use of mRNA to produce secreted proteins. But multiple industry insiders told Nature they think these could be challengeable.

    We don’t feel there’s a lot that is patentable, and certainly not enforceable,” says Eric Marcusson, chief scientific officer of Providence Therapeutics, an mRNA vaccines company in Calgary, Canada.

    Nobel debate

    As for who deserves a Nobel, the names that come up most often in conversation are Karikó and Weissman. The two have already won several prizes, including one of the Breakthrough Prizes (at $3 million, the most lucrative award in science) and Spain’s prestigious Princess of Asturias Award for Technical and Scientific Research. Also recognized in the Asturias prize were Felgner, Şahin, Türeci and Rossi, along with Sarah Gilbert, the vaccinologist behind the COVID-19 vaccine developed by the University of Oxford, UK, and the drug firm AstraZeneca, which uses a viral vector instead of mRNA. (Cullis’s only recent accolade was a $5,000 founder’s award from the Controlled Release Society, a professional organization of scientists who study time-release drugs.)

    Some also argue that Karikó should be acknowledged as much for her contributions to the mRNA research community at large as for her discoveries in the lab. “She’s not only an incredible scientist, she’s just a force in the field,” says Anna Blakney, an RNA bioengineer at the University of British Columbia. Blakney gives Karikó credit for offering her a speaking slot at a major conference two years ago, when she was still in a junior postdoc position (and before Blakney co-founded VaxEquity, a vaccine company in Cambridge, UK, focusing on self-amplifying-RNA technology). Karikó “is actively trying to lift other people up in a time when she’s been so under-recognized her whole career”.

    Although some involved in mRNA’s development, including Malone, think they deserve more recognition, others are more willing to share the limelight. “You really can’t claim credit,” says Cullis. When it comes to his lipid delivery system, for instance, “we’re talking hundreds, probably thousands of people who have been working together to make these LNP systems so that they’re actually ready for prime time.”

    “Everyone just incrementally added something — including me,” says Karikó.

    Looking back, many say they’re just delighted that mRNA vaccines are making a difference to humanity, and that they might have made a valuable contribution along the road. “It’s thrilling for me to see this,” says Felgner. “All of the things that we were thinking would happen back then — it’s happening now.”

    Nature 597, 318-324 (2021)


    Early COVID Care Experts Launches Online Hub for Early Treatment

    Early COVID Care Experts Launches Online Hub for Early Treatment
    TrialSite shares some important news with the community—the recent launch of, an online hub for early treatment advocacy by

    Early COVID Care Experts Launches Online Hub for Early Treatment

    TrialSite shares some important news with the community—the recent launch of, an online hub for early treatment advocacy by the Early COVID Care Experts (ECCE). This site offers guidance for clinicians, scientific evidence supporting early treatment, and resources to help patients find doctors who are willing to prescribe.

    Perhaps 90% or more of SARS-CoV-2 infections are mild-to-moderate in severity and for the duration of the pandemic passionate, dedicated physicians evangelized the importance of treating COVID-19 early on. Unfortunately to this day, the established protocol involves no care other than over-the-counter drugs and rest. Consequently, patients diagnosed with COVID-19 are sent home and instructed to come back to the hospital if conditions materially worsen. But how many of this type of scenario could be avoided with early care?

    At, those interested can learn about the history, safety, and current usage of effective drug treatments for COVID-19, and find COVID-expert doctors who are available either in person or by telemedicine to provide expert outpatient, early treatment for COVID patients.

    Early COVID Care Experts include prominent physicians dedicated to safe and effective early treatment options including Dr. Peter McCullough, Dr. Harvey Risch, Dr. George Fareed, and Dr. Ramin Oskoui.

    Call to Action: We invite you to visit their new site to review the evidence in support of COVID treatments, find guidance for clinicians, or see the latest from the Early COVID Care Experts. You may also email them at [email protected] for more information.

    Early COVID Care Experts | Hope Is Real

    Another dot to follow in understanding Covid and how to treat. Treat early and treat all, non vaxed as well as breakthroughs

    University of Virginia School of Medicine-led Study Reveals Cholesterol Links to AD Plaque Formation

    University of Virginia School of Medicine-led Study Reveals Cholesterol Links to AD Plaque Formation
    Does brain-manufactured cholesterol play a role in the development of Alzheimer’s disease? According to recently published research led by scientists

    Does brain-manufactured cholesterol play a role in the development of Alzheimer’s disease? According to recently published research led by scientists at the University of Virginia School of Medicine and collaborators, the cholesterol produced by astrocytes is necessary for controlling the production of amyloid-beta, a sticky protein that develops in the brains of patients with Alzheimer’s. Accumulating into insoluble plaques that “are a hallmark of the disease,” waves of biotech development efforts target these plaques for removing or preventing them in the first place—all in the quest to treat or prevent Alzheimer’s. The new findings help point to how and why plaques form in the first place and could indicate why genes associated with cholesterol could be linked to a heightened risk for the disease.

    Writing for the University of Virginia School of Medicine News, John Barney recently reported on the notable research breakthroughs. Dr. Heather A. Ferris, UVA Health’s Division of Endocrinology and Metabolism, went on the record, “This study helps us to understand why genes linked to cholesterol are so important to the development of Alzheimer’s disease.” She continued, “Our data point to the importance of focusing on the production of cholesterol in astrocytes and the transport to neurons as a way to reduce amyloid-beta and prevent plaques from ever being formed.”

    A brief breakdown of this research topic led by the University of Virginia School of Medicine follows.

    Why is cholesterol also good?

    Good cholesterol is produced by the human body to help produce hormones that execute other important functions in the case of good cholesterol.

    What’s the key breakthrough of this research?

    Cholesterol may also help control the production of amyloid-beta and indicate more clarity on the role of astrocytes in Alzheimer’s disease. While scientists have realized that during Alzheimer’s, a patient’s common brain cells undergo significant changes, they were not sure if this was due to 1) impact from the disease itself or 2) contributing to the disease. The University of Virginia School of Medicine News’ Barney writes the new study results indicate the latter.

    What is the finding?

    When astrocytes make and distribute cholesterol to brain cells (neurons), this leads to more amyloid-beta generation, which in turn causes plaque communication. This, of course, very well may lead to Alzheimer’s.

    What’s the difference between normal state & AD?

    Neurons have low amounts of cholesterol in normal conditions, which minimizes amyloid-beta accumulation. However, with the onset of Alzheimer’s, neurons cannot modulate amyloid-beta leading to plaque formation.

    What did the researchers demonstrate in a preclinical lab study with mice?

    By setting up a preclinical study using mice, the researchers found that if they inhibit the astrocytes’ cholesterol production, they “robustly” lowered amyloid-beta production in the mice.

    Could this experiment be reproduced in humans?

    Possibly, but it is too soon to know.

    What are some parting thoughts?

    Given that amyloid-beta generation is tightly controlled, this suggests it would play a vital role in brain cells, writes University of Virginia’s Barney. Consequently, doctors could potentially need to consider how to inhibit or eliminate amyloid-beta.

    Who funded the research?

    · National Institutes of Health (NIH)

    · Owens Family Foundation

    Lead Research/Investigator

    Dr. Heather A. Ferris, MD, Ph.D., UVA Health’s Division of Endocrinology and Metabolism

    For other research authors, see the source.

    Call to Action: These findings have been published in the scientific journal PNAS.

    Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol
    The accumulation of amyloid β (Aβ) in the brain appears to be a necessary event in the pathogenesis of Alzheimer’s disease (AD). However, processes linked to…

    SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability

    SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability
    COVID-19 patients may exhibit neuropsychiatric and neurological symptoms. We found that anxiety and cognitive impairment are manifested by 28-56% of…

    Stanford-led Study Demonstrates COVID-19 Hospitalized Patients Produce Self-Attacking Antibodies—Make a Case for Vaccination

    Stanford-led Study Demonstrates COVID-19 Hospitalized Patients Produce Self-Attacking Antibodies—Make a Case for Vaccination
    Stanford University investigators recently concluded in a study that 1 in 5 COVID-19 hospitalized patients develop new antibodies that attack their own

    Produce Self-Attacking Antibodies—Make a Case for Vaccination

    Stanford University investigators recently concluded in a study that 1 in 5 COVID-19 hospitalized patients develop new antibodies that attack their own tissue within a week of admission. Called autoantibodies, that is, antibodies directed at their own tissue or at substances their immune cells secrete into the blood, COVID-19 patients are far more likely to encounter this dynamic than those individuals without COVID-19. Autoantibodies potentially indicate the potential for autoimmune disease. The study results indicate that those that wind up hospitalized with COVID-19 “…may not be out of the woods,” suggests Stanford Medicine’s PJ Utz, lead researcher and professor of immunology and rheumatology.

    Published on September 14 in Nature Communications, the study team probed for autoantibodies in blood samples drawn during March and April of 2020 from 147 COVID-19 patients at the three university-affiliated hospitals in addition to a group of additional patients admitted to Kaiser Permanente. For the control group, the scientists included blood samples from additional donors.

    As reported in Stanford Medicine News, the research team both identified as well as measured levels of antibody targeting the virus in addition to autoantibodies and antibodies targeting cytokines, those proteins that immune cells secrete for communications and coordination.


    Not surprisingly, the researchers discovered that 60% of all hospitalized COVID-19 patients carried anti-cytokine antibodies as compared to 1o 15% of the healthy controls. The study authors indicate that this observation is more than likely associated with “immune-system overdrive triggered by virulent, lingering infection.” Professor Utz suggested, “In the fog of war, the abundance of cytokines may trip off the erroneous production of antibodies targeting them.”

    The research team observed new antibodies in 20% of the patients after a week of admittance. These additional antibodies were not present upon hospital admittance. Professor Utz commented, “In many cases, these autoantibody levels were similar to what you’d see in a diagnosed autoimmune disease.”

    But what triggers the presence of these autoantibodies? According to Utz, one of the following factors could be present:

    Immune response-driven increase in antibodies that previously were present but in low levels

    Inflammatory shock associated with SARS-CoV-2 infection triggers jump in previously undetectable levels of innate autoantibodies

    Exposure to viral materials that resemble the patient’s own proteins

    Extended SARS-Cov-2 infection triggers greater immune response—leading to broken pieces of viral particles—human immune system may identify viral pieces as novel

    Making the Case for Vaccination

    Why could the argument be made that the results bolster the case for vaccination? The COVID-19 vaccines only contain one protein (spike protein), which is the genetic instructions to produce the spike protein. The authors state in Stanford Medicine News that “With vaccination, the immune system is never exposed to—and potentially confused by—the numerous other novel viral proteins generated during infection.”

    Study Funding

    National Institute of Health (NIH)

    The Henry Gustav Floren Trust

    The Parker Institute for Cancer Immunotherapy

    Sean N. Parker Center

    Frank Quattrone and Denise Foderaro Family Research Fund

    Chan Zuckerberg Biohub

    the Allen Institute for Immunology

    CEND COVID Catalyst Fund

    Chen Family Research Fund

    Carreras Foundation

    Foundation for Pathobiochemistry and Molecular Diagnostics

    Universities Giessen

    Marburg Lung Center

    German Center for Lung Research and the Deutsche Forschungsgemeinschaft

    Next Steps

    Stanford Medicine reports that Professor Utz seeks to further investigate SARS-CoV-2 infected blood samples of those asymptomatic or individuals that experienced mild COVID-19. The research question: Is the “massive hyperactivation of the immune system” causing the trouble, or could it be “the mere molecular resemblance of SARS-CoV-2 proteins?”

    Lead Research/Investigator

    PJ Utz, MD, Professor of Medicine, Immunology and Rheumatology.

    Sarah Chang, Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine (Now at Genentech/Roche)

    Call to Action: Follow the link to the study in Nature Communications.

    New-onset IgG autoantibodies in hospitalized patients with COVID-19 - Nature Communications
    Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production.…

    Saudi Retrospective Study Compares Favipiravir & Hydroxychloroquine

    Saudi Retrospective Study Compares Favipiravir & Hydroxychloroquine
    Recently, a group of Saudi Arabian researchers from King Abdulaziz University and other academic medical centers in the nation investigated both

    Recently, a group of Saudi Arabian researchers from King Abdulaziz University and other academic medical centers in the nation investigated both Hydroxychloroquine (HCQ) and Favipiravir as possible COVID-19 treatments. Both drugs are used in many countries, including Saudi Arabia, during the pandemic for early-onset SARS-CoV-2 infection. Seeking to compare the effectiveness and safety of the two drugs, the investigational team, led by Aziza Al-Rafiah, conducted a retrospective cohort study evaluating the drugs’ impact on 508 patients admitted to King Faisal Medical Complex in Tarif, Saudi Arabia, from June 2020 to August 2020. The study authors indicate that both HCQ and Favipiravir appear to decrease mortality and need for oxygen, but a retrospective study such as this one has limitations. The safety signal for HCQ was stronger.


    During the first part of the pandemic in Saudi Arabia, health systems needed a rapid response, leveraging treatments that were thought to provide some benefit, including both HCQ and Favipiravir. Health care professionals used these treatments without collecting baseline data, from C-reactive protein (CRP) to D-dimer and lymphocyte count that could impact treatment allocation.

    The Study

    This retrospective study categorized patients into three cohorts including the following:

    Group # Patients %

    Favipiravir 244 55.8%

    HCQ 193 44.2%

    Neither 71 13.81%

    The Results

    The Saudi team reported recently that the Favipiravir group included a higher overall age of patient as well as greater comorbidity. While a majority of the patients were discharged by day 14 of the study (n = 303, 59.6%), 26 (36.6%) in the group that received neither medication, 154 (63.1%) in Favipiravir and 123 (63.7%) in the HCQ groups—the investigators reported a significant delta between groups (P<0.0001) as reported in Dovepress.

    But what about mortality rates? The team reported a mortality rate of 8.2% (n=20) in the Favipiravir group (mindful that this group had proportionally more elderly and reported comorbidity), and 7.3% (n=14) in the HCQ group of patients representing a significant delta between groups (P=0.048).

    Safety concerns were raised about HCQ last year. Meanwhile, Favipiravir, approved in Japan for influenza (stockpile), is also approved for COVID-19 in several nations from Russia to Thailand. 19.7% of the Favipiravir patients versus 7.8% of the HCQ patients experienced adverse effects with material differences between the groups (P>0.0001).

    The authors reported a majority of the side effects involved ALT and AST. A prolonged Q-T interval was documented solely in the HCQ group (2.6%).

    The Saudi authors performed a Cox regression model, declaring that only mechanical ventilation could predict mortality (HR: 16.598, 95% CI: 7.095-38.828, P<0.0001).

    Concerning discharge predictability, not one of the study drugs correlated with anticipating discharge. FPV vas HCQ)- (HR: 0.933, 95% CI: 0.729– 1.195, P = 0.5843), predictors of mortality were HCQ (vs FPV) (HR: 2.3, 95% CI: 0.994– 5.487, P = 0.0518). Kaplan–Meier survival curves showed improved survival time and discharged time among patients in the HCQ versus FPV group with an insignificant difference between them (P = 0.85, P = 0.06, respectively).


    Retrospective studies have several limitations well known but also can contribute to insight. The study was limited to patients hospitalized in one province of Saudi Arabia—the Taif province. Consequently, the researchers did not include a representative sampling of the entire population. While the investigators only used a dosing regimen for both HCQ and Favipiravir, multiple doses for safety evaluation are indicated.


    The authors wrote that both Favipiravir and HCQ demonstrate similar efficacy in decreasing mortality and the need for oxygen. While Favipiravir “likely has a more favorable safety profile regarding cardiac toxicity,” the Saudi investigators conclude on the need for large, randomized controlled clinical trials to confirm their findings in COVID-19 patients.

    Lead Research/Investigator

    Aziza Al-Rafiah, Ph.D., Corresponding Author, Assistant Professor, Department of Laboratory Technology

    Americans seem to have bad memories! This jab in every American policy is a continuation of Biden H1N1 debacle in 2010. Vaccine sites opening on every corner, Biden running around like chicken little, the administration following mopping up his mess. We are all going to die crap he's using now. Sooner than the sites went up they disappeared. That's who is setting policy! Wake up america!!!

    Time for American Health Agencies to Factor in Natural Immunity for Precision Vaccination

    Time for American Health Agencies to Factor in Natural Immunity for Precision Vaccination
    Why does the entire American society need a COVID-19 vaccine if evidence increasingly indicates natural immunity is just as if not superior in boosting

    Why does the entire American society need a COVID-19 vaccine if evidence increasingly indicates natural immunity is just as if not superior in boosting immunity? After all, by May 2021, a third of the U.S. population, estimated at 44% of adults aged 18-50, had already been infected, suggests Centers for Disease Control and Prevention (CDC) data. With the confluence of massive numbers of already infected persons on the one hand and mounting evidence as to superiority of natural immunity, why haven’t health agency decision-makers factored natural immunity into decision making associated with the prioritization of vaccination? Why can’t the CDC at least establish a protocol that those that have been infected wait at least eight months? Or why not follow the recommendation of Florian Krammer, Icahn School of Medicine, who suggested to the New York Times that it would be prudent to administer only one dose to individuals who have already recovered from a SARS-CoV-2 infection. Or there is the well-known Marty Makary, the outspoken Johns Hopkins University professor and MedPage Today editor who recently declared why vaccinate everyone—even those with immunity—when the focus should be on using them where they can save lives? The reality is that America’s health authorities are increasingly under the microscope for the decisions they are making. The CDC, Food and Drug Administration (FDA), and of course POTUS, and not surprisingly, the industry appears most certainly eager to just round up and vaccinate everyone, regardless if they have been previously infected and their subsequent natural immunity levels. Something is terribly off in America, and thankfully a talented journalist delved into the matter with the results published in the prominent The BMJ.

    A freelance journalist has taken up this topic up in a comprehensive piece published again in The BMJ. Jennifer Block digs deep into this matter, penning a comprehensive and compelling argument that the powers-that-be start investigating the infected population in more detail. It’s time for health agencies to do their job, not only studying natural immunity response strength but also durability. Ms. Block implies in her article that the current public health apparatus may be making an irrevocable mistake, leading up to what could be large-scale unnecessary safety risks combined with a perpetuation of health inequity issues as the current paradigm doesn’t leave much assistance to the world’s poorest countries.

    Block provides significant evidence that natural immunity must be taken seriously. She demonstrates while other countries at least attempt to factor in natural immunity into their analyses, it’s as if the concept didn’t exist in America.

    Of course, a counterargument is that America just isn’t good at tailored, data-driven approaches and that rather only a universal vaccination offers “a more quantifiable, predictable, reliable and feasible way to protect the population.”

    Hogwash! The entire movement of medicine moves to data-driven, precision, and personalized medicine, as we enter the age of data and directed value rather than the mass-produced generic treatments of yesteryear? Is convenience and a streamlined economy a reason to run roughshod over real data, true science, and possibly large numbers of people’s health?

    TrialSite recently reported that a number of prominent medical boards are now colluding to severely punish any licensed physician that dares utter negative work about the current vaccines or the vaccination program. TrialSite let it be known that these medical licensing bodies were essentially putting doctors on notice: forewarned—be quiet about the vaccine or risk one’s license and, therefore, their economic livelihood. Yet the very groups pushing the mass vaccination agenda don’t effectively use science themselves, while they accuse any critics of scientific blasphemy.

    Call to Action: Follow the link to read Ms. Block’s piece in The BMJ.

    Vaccinating people who have had covid-19: why doesn’t natural immunity count in the US?
    The US CDC estimates that SARS-CoV-2 has infected more than 100 million Americans, and evidence is mounting that natural immunity is at least as protective as…

    Interesting study, could this link explain long covid and adverse reactions to vaccine?

    Evidence of a possible link between herpes simplex and neurodegenerative diseases

    Evidence of a possible link between herpes simplex and neurodegenerative diseases
    A new study by researchers at University of Illinois Chicago suggests that when the protein optineurin, or OPTN, is present in cells it restricts the spread of…

    A new study by researchers at University of Illinois Chicago suggests that when the protein optineurin, or OPTN, is present in cells it restricts the spread of HSV-1, the herpes simplex virus type 1.

    In a "first of its kind" study, researchers also found a potential direct connection between neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), glaucoma, and the herpesvirus, said Dr. Deepak Shukla, the Marion H. Schenk Esq. Professor in Ophthalmology for Research of the Aging Eye, and vice chair for research at UIC.

    The research paper, "OPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection," led by Shukla, was published recently in the journal Nature Communications.

    Researchers sought to discover why HSV-1 can become fatal for individuals who are immunocompromised but not for healthy individuals. Herpesviruses naturally infect the central nervous system and can result in degenerative brain and eye disorders, as well as encephalitis. However, in most individuals, the virus is suppressed during a primary infection before it can significantly damage the central nervous system.

    The new research suggests why HSV-1 is suppressed: OPTN, a conserved autophagy receptor, selectively targets HSV-1 proteins to degradation by autophagy, explained Tejabhiram Yadavalli, a co-author of the study and visiting scholar at UIC's department of ophthalmology and visual science.

    "OPTN stops the virus from growing and it stops it by autophagy—engulfing the virus particles inside tiny vesicles called autophagosomes. The autophagy that happens is very selective. That has meaning for other viruses as well," Shukla said.

    The researchers believe the results from this study will apply to all eight different human herpesviruses.

    For the study, mice with removed OPTN genes were infected with ocular HSV-1. The virus growth was much higher in the brains of animals without OPTN, killing local neurons and eventually leading to animal death. This shows there is a faster degeneration of neurons when OPTN is not there. Additional studies are being planned to examine naturally occurring mutations in OPTN, such as the ones reported in glaucoma and ALS patients, and how they may affect neuronal health and HSV-1 infection, Shukla explained.

    Where you have mutated OPTN plus herpes, you have the recipe to create a disaster in terms of neurodegeneration," Shukla said.

    "The study also shows there is an impairment of immune response when there is a deficiency in OPTN. OPTN is needed to signal an influx of proper immune cells at the site of infection. When you don't have it, you have issues," said Chandrashekhar Patil, also a co-author of the study and a visiting scholar at UIC's department of ophthalmology and visual science.

    Some of those issues could include neurodegenerative disorders, which researchers believe further research may show.

    "We think we will have data to show other viruses, such as Epstein-Barr, Kaposi's sarcoma, varicella-zoster, are all going to share this mechanism because they share homologous proteins," Shukla said.

    Because the herpesvirus sits in neurons forever, there is speculation it is connected to neurodegenerative diseases. The immune system requires inflammation to constantly fight off the virus, and neurons have some degree of damage because of this continuous immune response, according to Dr. Tibor Valyi-Nagy, professor of pathology, director of neuropathology at UIC and research collaborator on the study.

    The study also showed that animals without OPTN and infected with HSV-1 after 30 days lost the ability to recognize objects. Shukla said this could be an indication that having HSV-1 along with a mutation of OPTN could accelerate neuronal damage, which would translate into cognitive impairment.

    "Part of our translational research can be how can we correct the problems with OPTN so that we don't have issues with neurodegeneration," Shukla said.

    Additional authors are Joshua Ames, Rahul Suryawanshi, James Hopkins, Alexander Agelidis, Chandrashekhar Patil and Brian Fredericks, all of UIC, and Henry Tseng of Duke University Medical Center.

    This research was supported by the National Institutes of Health and National Eye Institute grants (K08-EY021520-02, RO1 EY029426, P30 EY001792 and RO1 EY024710) as well as the Butner Pioneer Award, Duke Health Scholars and Research to Prevent Blindness unrestricted funds.

    More information: Joshua Ames et al, OPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection, Nature Communications (2021). DOI: 10.1038/s41467-021-25642-z

    Journal information: Nature Communications

    Our Most Reliable Pandemic Number Is Losing Meaning

    A new study suggests that almost half of those hospitalized with COVID-19 have mild or asymptomatic cases.

    Our Most Reliable Pandemic Number Is Losing Meaning
    A new study suggests that almost half of those hospitalized with COVID-19 have mild or asymptomatic cases.

    At least 12,000 Americans have already died from COVID-19 this month, as the country inches through its latest surge in cases. But another worrying statistic is often cited to depict the dangers of this moment: The number of patients hospitalized with COVID-19 in the United States right now is as high as it has been since the beginning of February. It’s even worse in certain places: Some states, including Arkansas and Oregon, recently saw their COVID hospitalizations rise to higher levels than at any prior stage of the pandemic. But how much do those latter figures really tell us?

    From the start, COVID hospitalizations have served as a vital metric for tracking the risks posed by the disease. Last winter, this magazine described it as “the most reliable pandemic number,” while Vox quoted the cardiologist Eric Topol as saying that it’s “the best indicator of where we are.” On the one hand, death counts offer finality, but they’re a lagging signal and don’t account for people who suffered from significant illness but survived. Case counts, on the other hand, depend on which and how many people happen to get tested. Presumably, hospitalization numbers provide a more stable and reliable gauge of the pandemic’s true toll, in terms of severe disease. But a new, nationwide study of hospitalization records, released as a preprint today (and not yet formally peer reviewed), suggests that the meaning of this gauge can easily be misinterpreted—and that it has been shifting over time.

    If you want to make sense of the number of COVID hospitalizations at any given time, you need to know how sick each patient actually is. Until now, that’s been almost impossible to suss out. The federal government requires hospitals to report every patient who tests positive for COVID, yet the overall tallies of COVID hospitalizations, made available on various state and federal dashboards and widely reported on by the media, do not differentiate based on severity of illness. Some patients need extensive medical intervention, such as getting intubated. Others require supplemental oxygen or administration of the steroid dexamethasone. But there are many COVID patients in the hospital with fairly mild symptoms, too, who have been admitted for further observation on account of their comorbidities, or because they reported feeling short of breath. Another portion of the patients in this tally are in the hospital for something unrelated to COVID, and discovered that they were infected only because they were tested upon admission. How many patients fall into each category has been a topic of much speculation. In August, researchers from Harvard Medical School, Tufts Medical Center, and the Veterans Affairs Healthcare System decided to find out.

    Researchers have tried to get at similar questions before. For two separate studies published in May, doctors in California read through several hundred charts of pediatric patients, one by one, to figure out why, exactly, each COVID-positive child had been admitted to the hospital. Did they need treatment for COVID, or was there some other reason for admission, like cancer treatment or a psychiatric episode, and the COVID diagnosis was merely incidental? According to the researchers, 40 to 45 percent of the hospitalizations that they examined were for patients in the latter group.

    Risks of Vaccines for Those Recovered from COVID-19

    Risks of Vaccines for Those Recovered from COVID-19
    Note that views expressed in this opinion article are the writer’s personal views and not necessarily those of TrialSite. There is recent research on the

    Risks of Vaccines for Those Recovered from COVID-19

    Note that views expressed in this opinion article are the writer’s personal views and not necessarily those of TrialSite.

    There is recent research on the fact that the COVID-19 vaccine is dangerous for those who have already had COVID-19 and have recovered with inferred robust, complete, and durable immunity. These patients were excluded from the FDA-approved clinical trials performed by Pfizer, Moderna, and J&J. From these trials, the safety profile was unknown when the products for approved for Emergency Use Authorization in 2020.

    There has been no study demonstrating clinical benefit with COVID-19 vaccination in those who have well documented or even suspected prior COVID-19 illness.

    A medical study of United Kingdom healthcare workers who had already had COVID-19 and then received the vaccine found that they suffered higher rates of side effects than the average population. Rachel K. Raw, et al., Previous COVID-19 infection but not Long-COVID-19 is associated with increased adverse events following BNT162b2/Pfizer vaccination, medRxiv (preprint), (last visited June 21, 2021).

    > Previous COVID-19 infection but not Long-COVID is associated with increased adverse events following BNT162b2/Pfizer vaccination

    The test group experienced more moderate to severe symptoms than the study group that did not previously have COVID-19. The symptoms included fever, fatigue, myalgia-arthralgia, and lymphadenopathy. Id. Raw found that in 974 individuals who received the BNT162b2/Pfizer vaccine, those with a prior history of SARS-CoV-2 or those who had positive antibodies at baseline had a higher rate of vaccine reactions than those who were COVID-19 naive.

    For a full review of the study, follow the link. Dr. Peter McCullough’s frequently contributes to American OutLoud Podcast Network.

    Previous COVID-19 infection, but not Long-COVID, is associated with increased adverse events following BNT162b2/Pfizer vaccination

    Human exposure to respiratory aerosols in a ventilated room: Effects of ventilation condition, emission mode, and social distancing

    Human exposure to respiratory aerosols in a ventilated room: Effects of ventilation condition, emission mode, and social distancing
    Airborne transmission of virus via respiratory aerosols plays an important role in the spread of infectious diseases in indoor environments. Ventilati…


    We evaluate effects of ventilation and social distancing on aerosol exposure.

    We study transport dynamics of exhaled aerosols in human breathing zone.

    Ventilation strategy notably affects the airborne infection risk.

    Buoyancy-driven airflow can cause elevated human exposure to viral aerosols.

    A 2 m social distance may not effectively reduce the risk of infectious aerosols.


    Airborne transmission of virus via respiratory aerosols plays an important role in the spread of infectious diseases in indoor environments. Ventilation and social distancing are two major control strategies to reduce the indoor airborne infection risk. However, there is a present lack of science-based information on how the human exposure to viral aerosols vary with ventilation condition and social distance. The objective of this study is to explore the transport patterns of respiratory aerosols in occupied spaces and assess the occupant exposure risk under different ventilation strategies, social distances and aerosol emission modes. The study results show that buoyancy-driven flow regime (can be found in many residential settings) can lead to a longer transmission distance and elevated exposure to viral aerosols than the mixing airflow, thereby causing higher cross-infection risk in indoor environments. The results also suggest that a 2 m (6 ft) social distance alone may not ensure control of indoor airborne infections.


    U.S. Covid cases finally start to dip from latest peak, but delta variant still on the rise in some states

    U.S. Covid cases finally start to dip from latest peak, but delta variant still on the rise in some states
    Covid case counts in the U.S. are showing signs of easing off their latest highs but remain elevated as the country heads into the fall season.


    The seven-day average of daily Covid cases is about 144,300 as of Sept. 12, down 12% over the past week and 14% from the most-recent peak in case counts on Sept. 1, when the country was reporting an average of roughly 167,600 cases per day.

    There are also some promising signs in Covid hospitalization and death tallies, which tend to lag case counts by a couple weeks or more.

    The pace of new infections is falling in some of the states that saw the earliest impact of the delta variant this past summer, while in states like West Virginia and Kentucky, the variant is still taking hold.