Virus World

Yet another experimental HIV vaccine has failed. The National Institute of Allergy and Infectious Diseases reported Wednesday that a phase 3 clinical trial of an HIV vaccine was stopped because the vaccine was ineffective at preventing infection. The vaccine was being developed by Janssen, the vaccine division of Johnson & Johnson. The Mosaico trial, which enrolled 3,900 volunteers in multiple countries, was halted after a scheduled data review by a data and safety monitoring board found there were roughly as many new HIV infections among people in the vaccine arm as in the placebo arm. The trial was studying the vaccine in cisgender men and transgender people who have sex with cisgender men and/or transgender people. “We are disappointed with this outcome and stand in solidarity with the people and communities vulnerable to and affected by HIV,” Penny Heaton, Janssen’s global therapeutic area head for vaccines, said in a statement. “We remain steadfast in our commitment to advancing innovation in HIV, and we hope the data from Mosaico will provide insights for future efforts to develop a safe and effective vaccine.” In 2021, a Phase 2b trial of a similar candidate HIV vaccine was halted when a data and safety monitoring board determined that it was not preventing infections. The Imbokodo trial was studying the vaccine in women in sub-Saharan Africa.

“For our research partners and others who have waged a decades-long effort to develop vaccines to end the HIV/AIDS pandemic, these results are disappointing,” Susan Buchbinder, co-chair of the Mosaico trial, said in a statement. “Although HIV continues to prove uniquely challenging for development of a vaccine, the HIV research community remains fully committed to doing just that, and each study brings us a step closer to this realization,” she said. Buchbinder is director of Bridge HIV, a grant-funded research unit at the San Francisco Department of Public Health, and a clinical professor at the University of California, San Francisco. The trial was conducted by the HIV Vaccine Clinical Trials Network based at the Fred Hutchinson Cancer Center in Seattle. Veteran HIV vaccine trialist Larry Corey acknowledged yet another setback in the decades-long quest to find an effective HIV vaccine. “HIV is a constantly changing and very challenging adversary. We can become disappointed when our best efforts don’t produce the results we’re looking for,” said Corey, principal investigator of the network’s leadership and operations center. “We have, however, come a long way and made many discoveries since the time when life expectancy was very short following an HIV diagnosis.” The vaccine was based on “mosaic” immunogens targeting HIV subtypes. The goal was to induce immune responses to a broad range of HIV strains. It was given in four injections over the course of a year. The vaccine used the same antigen delivery system employed by J&J’s Covid-19 vaccine, a common cold virus known as adenovirus 26. Volunteers were enrolled in the trial only after they were offered HIV pre-exposure prophylaxis, the antiretroviral drugs that can prevent infection. Those who accepted PrEP were steered towards services where they could access the drugs. People who did not want them, however, were considered for the study. Anyone in the trial who later changed their mind and wanted to use PrEP was also given access to the drugs, but remained in the trial.

At least five experimental HIV vaccines, tested over nine trials, have failed to show efficacy at the Phase 3 stage of development, said Mitchell Warren, executive director of AVAC, the AIDS Vaccine Advocacy Coalition. This latest failure hangs a big question mark over this field of research, he suggested. “I’m not sure we know exactly where the next big investment is going to come from because there’s not an obvious vaccine candidate in HIV that is next up in our efficacy pipeline,” Warren said. “This is another reason why this result is disappointing. This was the last true product in development. And the other activities in the field, which are very exciting … [are] quite upstream. Important upstream science, but not products that are going to be in efficacy trials anytime soon.” Stephaun Wallace, director of external relations for the HIV Vaccine Trials Network, noted work is being done on a candidate HIV vaccine using messenger RNA, the platform successfully used by Pfizer and its partner BioNTech as well as by Moderna to create their Covid-19 vaccines. The HIV work uses the Moderna platform. Exploration of the mRNA platform as a possible basis for an HIV vaccine is still in the safety testing phase, he said. Warren questioned, though, whether the answer is a different vaccine delivery system, suggesting the problem is probably the immune targets at which the various vaccines have aimed. He noted, for instance, that the J&J platform — adenovirus 26 — worked against Covid, but not against HIV. “These are the harsh reminders that it’s not that we don’t have great [vaccine] platforms,” he said. “Our challenge is figuring out exactly what is the target, what is the insert? … We have the vehicles. We don’t even know what passengers to put in the vehicles.” Wallace acknowledged the path ahead will be difficult, but said he remains optimistic that at some point, HIV vaccine efforts will meet success. “I’m pretty certain that with continued public support and interest in this area that we will see the day that an HIV vaccine is developed,” he said.

The National Institutes of Health has chosen Pfizer's antiviral drug Paxlovid as the first treatment it will study in patients who experience prolonged symptoms of COVID-19, known as "long COVID," under its RECOVER Initiative tasked with looking into the causes of the largely unexplained medical condition. The trial, which will start next year, will investigate whether portions of the COVID-19 virus remain in the body after infection, causing the long-lasting symptoms associated with long COVID that are wide-ranging, including cognitive impairment or lethargy.  The Duke Clinical Research Institute will oversee the trial, which will involve 1,700 patients 18 and up. Experts theorize that antivirals such as Paxlovid might be used to help treat long COVID symptoms and clear the coronavirus from a patient's system, according to a study description. Paxlovid, which has been used to treat mild and moderate COVID-19 already, has been named by physicians as a possible drug for treatment, though this will be the first time a study tests it on long COVID patients, per Reuters. The underlying causes of long COVID have mostly remained a mystery to experts. The NIH maintains a webpage compiling possible symptoms of long COVID, such as swelling in the legs or feet and loss of appetite. The Centers for Disease Control and Prevention estimated in June that nearly 1 in 5 adults in the United States who have had a COVID-19 infection continue to experience lingering symptoms after first contracting the virus. The trial is estimated to start on Jan. 17, 2023.

Novavax Inc's COVID-19 vaccine was 96% effective in preventing cases caused by the original version of the coronavirus in a late-stage trial conducted in the United Kingdom, the company said on Thursday, moving it a step closer to regulatory approval.  There were no cases of severe illness or deaths among those who got the vaccine, the company said, in a sign that it could stop the worse effects of new variants that have cropped up. The vaccine was 86% effective in protecting against the more contagious virus variant first discovered and now prevalent in the United Kingdom, for a combined 90% effectiveness rate overall based on data from infections of both versions of the coronavirus. Novavax shares jumped 22% in after-hours trading to $229. They were trading below $10 on Jan. 21, 2020, when the company announced it was developing a coronavirus vaccine. In a smaller trial conducted in South Africa - where volunteers were primarily exposed to another newer, more contagious variant widely circulating there and spreading around the world - the Novavax vaccine was 55% effective, based on people without HIV, but still fully prevented severe illness.  Novavax Chief Medical Officer Filip Dubovsky said the performance in South Africa suggests there may still be a case for using it in areas where the South African variant is dominant.

Novavax is also developing new formulations of its vaccine to protect against emerging variants and plans to initiate clinical testing of these shots in the second quarter of this year. Results from the final analysis of the UK trial were largely in line with interim data released in January. The company expects to use the data to submit for regulatory authorization in various countries. It is not clear when it will seek U.S. authorization or if regulators will require it to complete an ongoing trial in the United States. Novavax expects data from a 30,000-person trial in the United States and Mexico by early April. Dubovsky said that Novavax is still planning to file for authorization from UK regulators early in the second quarter of 2021.  The UK trial, which enrolled more than 15,000 people aged 18 to 84, assessed efficacy of the vaccine during a period with high transmission of the UK virus variant now circulating widely.

The shot’s effectiveness in the South Africa trial declined to around 49% when the analysis included data from HIV-positive participants. The vaccine could be cleared for use in the United States as soon as May if U.S. regulators decide the UK data is enough to make a decision. It could take a couple months longer if they insist on first seeing data from the U.S. trial, its chief executive told Reuters earlier this month. “Ultimately, they have to decide whether the data we can bring to the table is adequate or whether they would prefer to wait on data from our U.S. study,” Dubovsky said on Thursday. Novavax’s vaccine production plants should all be fully functional by April, executives said on a March investor call. The drugmaker expects to have tens of millions of doses stockpiled and ready to ship in the United States when it receives authorization, CEO Stanley Erck told Reuters.  Novavax plans to produce its two-shot vaccine at eight manufacturing locations, including the Serum Institute of India. If authorized, it would follow three COVID-19 vaccines previously approved for use in Britain from Pfizer and partner BioNTech, Moderna Inc and the AstraZeneca shot developed with Oxford University. The Maryland-based company has received $1.6 billion from the U.S. government in funding for the vaccine trial and to secure 100 million doses.

UK drug company says that while further research is needed, it did not expect it to delay regulatory approval in Europe.  AstraZeneca might have to run an additional global trial to assess the efficacy of its COVID-19 vaccine, after concerns were raised about the effectiveness of its jab. The British company’s chief executive Pascal Soriot was quoted as saying in a Bloomberg News report on Thursday that an additional study would be run to evaluate a lower dosage that performed better than a full amount in AstraZeneca’s studies. “Now that we’ve found what looks like a better efficacy we have to validate this, so we need to do an additional study,” Soriot was quoted as saying. Soriot said it would probably be another “international study, but this one could be faster because we know the efficacy is high, so we need a smaller number of patients”. The news comes as AstraZeneca, and its partner the University of Oxford, has faced questions about its success rate that some experts said could hinder its chances of getting speedy approval by United States and European Union’s regulators.

Several scientists have raised doubts about the robustness of results released on Monday showing the experimental vaccine was 90 percent effective in a sub-group of trial participants who, by error initially, received a half-dose followed by a full dose.  Soriot said he did not expect the additional trial to delay United Kingdom and European regulatory approvals. Clearance from the US Food and Drug Administration (FDA) may take longer though because the agency is unlikely to approve the vaccine based on studies carried out elsewhere, especially given the questions about the results, he said. Authorisation in some countries is still expected before the end of the year, he added. AstraZeneca research chief Mene Pangalos told Reuters on Monday that researchers had stumbled upon the half-dose regime by accident, saying a sub-group of the trial was given a smaller initial dose by mistake. Earlier he had said that the firm would start discussions with the FDA to change the design of its experimental COVID-19 vaccine trial to add the more-effective dosage regime...

AstraZeneca should still know by year-end whether its experimental vaccine protects people against coronavirus, as long as it is cleared to resume trials soon, its chief executive said on Thursday amid doubts over its rollout. Governments desperate to put an end to the COVID-19 pandemic which has caused more than 900,000 deaths and huge economic and social disruption during 2020 are pinning their hopes on a vaccine. However British drugmaker AstraZeneca suspended late-stage trials on its potential vaccine this week after an illness in a participant in Britain who was reported to be suffering from symptoms associated with transverse myelitis, a rare spinal inflammatory disorder. The World Health Organization (WHO) has flagged the AstraZeneca vaccine, which is being developed with the University of Oxford, as the most promising for coronavirus.

CEO Pascal Soriot said during an online event on Thursday that AstraZeneca (AZN.L) did not yet know the diagnosis of the participant who was ill, adding that it was not clear if the volunteer had transverse myelitis and more tests were needed. The diagnosis would be submitted to an independent safety committee and this would usually then say whether trials can be resumed, Soriot said, adding it was usual for such pauses. “It’s very common, actually, and many experts will tell you this,” Soriot said, adding: “The difference with other vaccine trials is, the whole world is not watching them, of course. They stop, they study, and they restart.” Shares in AstraZeneca fell on Wednesday after the trial halt raised doubts about the timeline for the vaccine’s rollout.

AstraZeneca would supply vaccines to countries at the same time to ensure a fair and equitable distribution, Soriot said, reiterating that the company was close to having capacity to produce 3 billion doses at sites set up around the world to prevent governments from restricting distribution. With up to 60,000 people set to participate in the study program, AstraZeneca’s CEO said the volume was typical of vaccine trials and large enough to spot rare side effects. “With this you are going to pick up very rare events.” he said, adding that a planned staggered launch, prioritizing at-risk groups, would provide further assurance for the masses that are set to be covered by government plans at a later stage. Serum Institute of India, one of AstraZeneca’s (AZN.L) development and production partners, said on Thursday it was joining the suspension, backtracking on remarks that it did not face any issues.

Transverse myelitis cases after a vaccination have been documented before, but concrete links between the condition and vaccinations have not been established, experts said. The U.S.-based Mayo Clinic concludes that the association so far is not strong enough to warrant limiting any vaccine. A 2009 review in the journal Lupus of nearly 40 years of English-language publications found 37 cases of transverse myelitis associated with hepatitis B vaccines, measles-mumps-rubella, diphtheria-tetanus-pertussis and others.  The vaccines remained on the market, Stephen Evans, a professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, said. Linking such an autoimmune response to a single factor like a vaccine is problematic, he said, given the number of immunological, hormonal or environmental factors at play. “It’s terribly difficult to be sure,” Evans said. 

RBC Capital Markets analyst Bryan Abrahams cautioned the trial participant’s condition must be thoroughly investigated. “Even a single case could possibly imply a rate or association higher in the study than what is normally observed sporadically” he wrote to investors, adding a one in 10,000 risk, if confirmed, would likely be unacceptable. BioNTech (BNTX.O), among the frontrunners in the vaccine race with partner Pfizer (PFE.N), echoed remarks by Soriot that clinical halts are a common feature of immunization trials. 

“Safety is a top priority,” its CEO Ugur Sahin told Reuters.

Passive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. Objective: To explore potential signals of efficacy of COVID-19 convalescent plasma. Design: Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma.

Multicenter, including 2,807 acute care facilities in the US and territories. Participants: Adult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome. Intervention: Transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion. Main Outcomes and Measures: Seven and thirty-day mortality.

The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units. Conclusions and Relevance: The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients.

Preprint of the study in medRxiv (August 12, 2020):

https://doi.org/10.1101/2020.08.12.20169359 

Initial trial to determine if monoclonal antibodies can shorten severity of COVID-19 in outpatients. Study aims to determine safety and efficacy of experimental monoclonal antibodies. A Phase 2 clinical trial will evaluate the safety and efficacy of potential new therapeutics for COVID-19, including an investigational therapeutic based on synthetic monoclonal antibodies (mAbs) to treat the disease. Researchers sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, are working with clinical sites to identify potential patient volunteers currently infected with SARS-CoV-2, the virus which causes COVID-19, who have mild to moderate disease not requiring hospitalization. They will be invited to take an experimental therapy or a placebo as part of a rigorously designed randomized clinical trial. The trial, which is known as ACTIV-2, also may investigate other experimental therapeutics later under the same trial protocol. If the investigational mAbs show promise, the study would expand from a Phase 2 to a Phase 3 trial to gather additional critical data from a larger pool of volunteers without delay. The trial will be led by the NIAID-funded AIDS Clinical Trials Group (ACTG) and will enroll participants at sites around the world.

ACTIV-2 was established as part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program instituted to speed development of the most promising treatments and vaccines. This study is also receiving support through Operation Warp Speed(link is external), the U.S. government’s multi-agency effort to develop, manufacture and distribute medical countermeasures to fight COVID-19. The design of the study is adaptive to enable maximum flexibility in the shortest time frame. If the experimental treatment appears effective in the first stage, the treatment can be advanced rapidly to testing in larger groups of volunteers. The study also can be adapted to test additional therapeutics. “We have seen encouraging, rapid results from other adaptive treatment trials for COVID-19,” said NIH Director Francis S. Collins, M.D., Ph.D. “Under ACTIV, specific therapeutics are being prioritized based on their likelihood for success. Prioritized therapeutics under ACTIV will use a master protocol that emphasizes flexibility, which enables these critical trials to be conducted without incurring delays when a treatment shows promise.”

The first therapeutic to be tested in this trial will be LY-CoV555, an investigational monoclonal antibody made by Eli Lilly and Company (Indianapolis, Indiana). LY-CoV555 emerged from Lilly’s collaboration with AbCellera Biologics (Vancouver, British Columbia). Antibodies are infection-fighting proteins produced by immune cells. So-called neutralizing antibodies target specific viruses or other pathogens. This antibody, which was discovered by AbCellera in collaboration with NIAID’s Vaccine Research Center, was isolated from a blood sample from a recovered COVID-19 patient. Copies of this antibody were then synthesized in a lab—the term “monoclonal” refers to these laboratory-manufactured antibodies. “Using an antibody generated by the immune system of a recovered COVID-19 patient gives us a jump start on finding a safe and effective therapeutic,” said NIAID Director Anthony S. Fauci, M.D. “Investigating a variety of different therapeutics, including monoclonal antibodies, will help ensure that we advance towards an effective treatment for people suffering from COVID-19 disease as quickly as possible.”...

Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison.

A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55).

In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936. opens in new tab; ISRCTN number, 50189673. opens in new tab.)

Original study available in New England J. Med. (July 17, 2020):

https://doi.org/10.1056/NEJMoa2021436

Hospitalized patients with COVID-19 receiving convalescent plasma did not gain a statistically significant benefit in time to clinical improvement in a small randomized trial conducted in Wuhan, China. But that may have been because the trial was stopped early, leaving it underpowered for many of the intended analyses. Among the 103 patients treated in the study -- barely half of the originally planned 200 -- more patients receiving convalescent plasma in addition to standard treatment experienced clinical improvement within 28 days compare with a group getting standard care only (51.9% vs 43.1%, respectively; HR 1.40, 95% CI 0.79-2.49, P=0.26), reported Zhong Liu, MD, PhD, of Chinese Academy of Medical Sciences and Peking Union Medical College, and colleagues.

However, in a subgroup analysis of patients with severe, but not life-threatening, disease, there was a significant difference in clinical improvement in the plasma group compared to controls (HR 2.15, 95% CI 1.07-4.32, P=0.03), the authors wrote in JAMA. Liu and colleagues explained that they had to give up enrolling patients in late March, when the outbreak in Wuhan petered out. Beginning March 24, no new cases were reported in the city where, just a few weeks earlier, hundreds were diagnosed every day. Had they succeeded in recruiting 200 patients, they estimated that the trial would have had 80% power to detect a benefit from the intervention. 

The group recommended a new, larger trial of convalescent plasma in patients with severe COVID-19 where sufficient numbers can be enrolled. Previously, a five-patient case series in China found beneficial effects of convalescent plasma among hospitalized COVID-19 patients, but an editorial warned the therapy is difficult to scale.

In addition, Liu and colleagues noted its effects have been varied, likely due to "no standardization or evidence-based rationale for donor selection, quality control of convalescent plasma, or recipient transfusion indications for convalescent plasma."

Original Study Published in JAMA (June 3, 2020):

https://doi.org/10.1001/jama.2020.10044

One of the first biotech companies to begin human trials of an experimental vaccine for the coronavirus is now ready to move onto the next phase of testing. On Thursday, Moderna announced that the Food and Drug Administration had cleared its application to proceed to a clinical trial involving about 600 people.

“The imminent Phase 2 study start is a crucial step forward,” Stéphane Bancel, Moderna’s chief executive, said in a statement. The main goal of this set of tests is to find out if the vaccine is safe and if positive results from the first few dozen volunteers in the first phase can be replicated in a much larger group. If it is successful, later studies, known as Phase 3 trials, will determine exactly how well the vaccine works. More than a dozen companies, including known vaccine producers like Johnson & Johnson, or Sanofi, are involved in a global race to develop a vaccine to tamp down the highly infectious coronavirus that has killed more than a quarter-million people around the world. Four Chinese companies have started testing their potential vaccines on humans, including CanSino Biologics, which announced the beginning of Phase 2 trials in early April. A few others, such as Pfizer and its German partner, BioNTech, are enrolling volunteers for combined Phase 1 and 2 trials.

Dr. Anthony Fauci, the nation’s leading expert on infectious diseases, has suggested that it would still take 12 to 18 months for a vaccine to be widely available to the public. There is no proven treatment, and many researchers and corporations around the world are pursuing remedies in addition to vaccines. Moderna’s vaccine candidate, called mRNA-1273, relies on genetic material known as messenger RNA, which carries the recipe for making proteins to tiny ribosome chefs inside cells. The vaccine is written with a very specific recipe — in this case for making the spike protein of the coronavirus.

The antiviral medicine remdesivir from Gilead Sciences failed to speed the improvement of patients in China with Covid-19 or prevent them from dying. according to results from a long-awaited clinical trial conducted in China. Gilead, however, said the data suggest a “potential benefit.”

A summary of the study results was inadvertently posted to the website of the World Health Organization and seen by STAT on Thursday, but then removed. “A draft manuscript was provided by the authors to WHO and inadvertently posted on the website and taken down as soon as the mistake was noticed. The manuscript is now undergoing peer review and we are waiting for a final version before WHO comments on it,” said WHO spokesperson Daniela Bagozzi. Gilead spokesperson Amy Flood said the company believes “the post included inappropriate characterization of the study.” Because the study was stopped early because it had too few patients, she said, it cannot “enable statistically meaningful conclusions.” However, she said, “trends in the data suggest a potential benefit for remdesivir, particularly among patients treated early in disease.” The data (for details, see screenshot below) will be closely scrutinized but are also likely imperfect.

The study was terminated prematurely, which could have affected the results. The context that would be provided by a full manuscript is missing, and the data have not been reviewed as normally occurs before publication. Many studies are being run to test remdesivir, and this one will not be the final word. Results are expected soon from a Gilead-run study in severe Covid-19 patients, although that study may be difficult to interpret because the drug is not compared to patients receiving only standard treatment. Encouraging data from patients in that study at the University of Chicago were described by researchers at a virtual town hall and obtained by STAT last week. However, unlike those data, these new results are from a randomized controlled trial, the medical gold standard....

The final study was published at the Lancet (April 29, 2020):

https://doi.org/10.1016/S0140-6736(20)31022-9

A randomized, controlled clinical trial to evaluate the safety and efficacy of the investigational antiviral remdesivir in hospitalized adults diagnosed with coronavirus disease 2019 (COVID-19) has begun at the University of Nebraska Medical Center (UNMC) in Omaha. The trial regulatory sponsor is the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. This is the first clinical trial in the United States to evaluate an experimental treatment for COVID-19, the respiratory disease first detected in December 2019 in Wuhan, Hubei Province, China.

The first trial participant is an American who was repatriated after being quarantined on the Diamond Princess cruise ship that docked in Yokohama, Japan and volunteered to participate in the study. The study can be adapted to evaluate additional investigative treatments and to enroll participants at other sites in the U.S. and worldwide. There are no specific therapeutics approved by the Food and Drug Administration (FDA) to treat people with COVID-19, the disease caused by the newly emergent SARS-CoV-2 virus (formerly known as 2019-nCoV). Infection can cause mild to severe respiratory illness, and symptoms can include fever, cough and shortness of breath. As of February 24, the World Health Organization (WHO) has reported 77,262 confirmed cases of COVID-19 and 2,595 deaths in China and 2,069 cases of COVID-19 and 23 deaths in 29 other countries. There have been 14 confirmed COVID-19 cases reported in the United States and an additional 39 cases among persons repatriated to the United States, according to the Centers for Disease Control and Prevention (CDC)

Remdesivir, developed by Gilead Sciences Inc., is an investigational broad-spectrum antiviral treatment. It was previously tested in humans with Ebola virus disease and has shown promise in animal models for treating Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), which are caused by other coronaviruses. “We urgently need a safe and effective treatment for COVID-19. Although remdesivir has been administered to some patients with COVID-19, we do not have solid data to indicate it can improve clinical outcomes,” said NIAID Director and U.S. Coronavirus Task Force member Anthony S. Fauci, M.D. “A randomized, placebo-controlled trial is the gold standard for determining if an experimental treatment can benefit patients.”

With the study only meeting one of its two primary endpoints, the result leaves scope to question how Pfizer will fare against AstraZeneca and Sanofi.  Pfizer has halted a pivotal trial of its respiratory syncytial virus (RSV) vaccine candidate early for efficacy, positioning the Big Pharma to file for approval by the end of the year. But with the study only meeting one of its two primary endpoints, the top-line result leaves scope to question how Pfizer will fare against AstraZeneca and Sanofi’s rival antibody. At the preplanned interim efficacy analysis, Pfizer linked the administration of its bivalent RSV prefusion vaccine candidate RSVpreF, also known as PF-06928316, during pregnancy to a significant reduction in the rate of severe medically attended lower respiratory tract illness (MA-LRTI) in newborns. The efficacy against severe MA-LRTI was 81.8% through the first 90 days of life, falling to 69.4% over the six-month follow-up period. The result was enough for the study to meet one of its co-primary endpoints. However, the study came up short against the second co-primary endpoint, which looked at the effect of RSVpreF on the rate of all severities of MA-LRTI. Pfizer called the 57.1% efficacy for MA-LRTI over the first 90 days of life clinically meaningful. But the figure, which slipped to 51.3% over the six-month follow-up period, wasn’t statistically significant and may suggest AstraZeneca and Sanofi’s antibody nirsevimab has an advantage over RSVpreF. The company plans to release secondary endpoint data later that includes impact on hospitalized patients, Pfizer CEO Albert Borla said during a Nov. 1 earnings call. “When you look at this dramatic effect on the severe infections, it seems very reasonable to project that we will have a dramatic impact in lowering hospitalizations,” Borla said, referring to the study.

It's estimated that more than 177,000 older adults are hospitalized from RSV in the U.S. each year, and 14,000 of them die, the CEO said.    While Pfizer is working to protect newborns from RSV using a maternal vaccine, AstraZeneca and Sanofi are developing a long-acting antibody that is administered to infants. In a phase 3 clinical trial, the Big Pharma partners linked nirsevimab to 74.5% efficacy against medically attended RSV-associated lower respiratory tract infection.  When asked about how RSVpreF could stack up to AstraZeneca and Sanofi’s RSV antibody for infants, Angela Hwang, Pfizer’s chief commercial officer and president of global biopharmaceuticals business, said Pfizer is the only company that has both an adult vaccine as well as the maternal vaccine in development. She said most infant RSV deaths are in those younger than six months old, citing 102,000 infant deaths reported worldwide each year. “So you really need that protection from day one,” Hwang said, which is where the company believes it can stand out. “Literally, from the moment of birth you have protection, and duration of protection throughout the six months, which is what we've shown in our clinical trials,” Hwang said. “While obviously, it's great to have many different options, I think that the option that we have with our vaccine is truly a unique one.”  Pfizer is hot on the heels of AstraZeneca and Sanofi, which have secured a recommendation for approval of nirsevimab in the EU but are yet to get the nod in the U.S. A filing for FDA approval of the breakthrough-designated RSVpreF is planned for this year.  With GSK halting enrollment in studies of its maternal RSV vaccine candidate, Pfizer, which said RSVpreF was well tolerated with no safety concerns for both the vaccinated individuals and their newborns, has a clear run at the vaccine market. But AstraZeneca and Sanofi are addressing the same unmet need from a different angle, suggesting RSVpreF will face competition from deep-pocketed rivals.

Pfizer Press Release (Nov. 1, 2022):

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-positive-top-line-data-phase-3-global 

J&J's HIV vaccine, using the same technology as its COVID vaccine, failed to meet its goal of reducing the chance of HIV infection by 50%. An HIV vaccine using the same basic technology as Johnson & Johnson’s Covid shot failed to prevent infection, the company said Tuesday, dealing yet another blow to efforts to create a vaccine against the virus.  The study, called Imbokodo, enrolled 2,600 women in southern Africa who were at very high risk of HIV infection. J&J and its partners, including the National Institutes of Health and the Bill & Melinda Gates Foundation, launched the study in 2017 and announced that all participants had received either a vaccine or a placebo last year. The goal of the vaccine was not to completely prevent infection, but to reduce the chance of infection by half. “If a vaccine is 50% efficacious it can curb the future of the HIV pandemic,” said Paul Stoffels, J&J’s chief scientific officer and, before that, an HIV researcher. He said that the actual efficacy seen was 25.2%, meaning those that received the vaccine had their odds of becoming infected reduced that much compared to the placebo group 24 months after the first dose. That difference was not statistically significant, indicating that it is possible the result is due to chance. A second study, called Mosaico, that is testing a somewhat different vaccine regimen in men who have sex with men and transgender people in the Americas and Europe, will continue. 

“The development of a safe and effective vaccine to prevent HIV infection has proven to be a formidable scientific challenge,” Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, said in a statement. “Although this is certainly not the study outcome for which we had hoped, we must apply the knowledge learned from the Imbokodo trial and continue our efforts to find a vaccine that will be protective against HIV.” Scientists have been trying for decades to develop an HIV vaccine. After a Merck vaccine failed to prove effective in 2007, researchers looked back at the data and found it raised the risk of people developing the disease. Hopes were buoyed by a 2009 study in Thailand, which showed limited but significant efficacy, reducing the rate of infection by about 30%. But last year, an effort combining vaccines from Sanofi and GlaxoSmithKline also failed to prove effective.  J&J had repeatedly expressed optimism about its vaccine. In 2015, Johan Van Hoof, who leads J&J’s vaccine R&D, pointed to data showing that, in animals, the vaccine could reduce infection by 90%, “suggesting it might be a real breakthrough with regard to a future HIV vaccine.” On calls with financial analysts in 2020 and 2021, Stoffels listed the HIV project among the company’s vaccine efforts, calling it “very encouraging.” When the trial began five years ago, Fauci had said “the development and delivery of a preventive HIV vaccine that is safe and at least moderately effective would help bring about a durable end to the HIV/AIDS pandemic.” Imbokodo means “rock” in isiZulu, and refers to a proverb about women’s strength and the need for community. In the study, 63 of 1,109 volunteers in the placebo group developed HIV, while 51 of the 1,079 volunteers who received the vaccine developed HIV. That difference leaves a great deal of uncertainty as to whether there was an effect. The 95% confidence interval, used by researchers to define a range of likely outcomes, ranged from -10.5% to 49.3%. However, J&J said in its release that no vaccine-related safety issues were identified. Stoffels told STAT that it was clear the vaccine did not increase the risk of HIV.  Larry Corey, the principal investigator of the HIV Trials Network, which helped run the study, and a professor at the Fred Hutchinson Cancer Research Center in Seattle, said that he saw the result as a disappointment but also a sign of progress. It had been hoped that non-neutralizing antibodies – those that bound to the virus but did not entirely stop infectivity – would be enough to slow the rate of HIV infection, he said, but it is beginning to appear that vaccine developers will need to figure out how to generate antibodies that neutralize the virus.

“It is telling us that non-neutralizing antibodies are not decreasing acquisition and maybe demonstrates how difficult and different HIV is than Covid-19,” Corey said. Like the Covid-19 vaccine that Johnson & Johnson developed, this HIV vaccine delivers genetic code for proteins to a recipient’s cells using a type of virus called an adenovirus, which then makes proteins that the immune system learns to recognize and attack. The strain of adenovirus used, called Ad26, is also used in Johnson & Johnson’s experimental vaccine against respiratory syncytial virus, which can be very serious in infants.  The HIV vaccine regimen tested repeated dosing. It was given four times, and included genetic code for a “mosaic” of proteins from different strains of the HIV virus. Patients also received soluble protein injections at the third and fourth visit. The ongoing Mosaico study – the one in the Americas and Europe – uses a different mixture of soluble proteins at the vaccination visits three and four. Stoffels said that this is one reason that the vaccine might perform better in that study. Another is that the volunteers in the Mosaico study are at lower risk of infection, which may make the vaccine’s work less difficult. Corey also said there was hope Mosaico would succeed where Imbokodo failed. He said that the new formulation had led, in earlier studies, to higher levels of antibodies against HIV. Stoffels said that he doesn’t believe that the result should color people’s feelings about J&J’s adenovirus vaccine platform, which, he pointed out, has proven effective against Covid-19 and Ebola. (In Covid-19, the broad use of the vaccine also was linked to a rare but severe side effect that involves both the formation of clots and excessive bleeding. That side effect is so rare even large clinical trials might not detect it.) “It shows again that the HIV virus is a very special virus, very unique, escaping the immune system and finding its way to infect people and it’s very difficult to mount immunity against acquisition of HIV,” Stoffels said. But researchers will continue to try. Moderna recently began human trials of an HIV vaccine that relies on the mRNA technology behind its Covid vaccines. Corey pointed out that even under Covid lockdowns, women in the study still had a 4% chance of contracting HIV. That underscores the need for a vaccine, he said. “Vaccines really do make a difference when you have an effective vaccine, look at what happened with Covid,” Corey said. “I think we can’t give up.”

NIH- and BARDA-funded trial will enroll up to 30,000 volunteers. The Phase 3 trial of another investigational coronavirus disease 2019 (COVID-19) vaccine has begun enrolling adult volunteers. The randomized, placebo-controlled trial will enroll approximately 30,000 people at approximately 115 sites in the United States and Mexico. It will evaluate the safety and efficacy of NVX-CoV2373, a vaccine candidate developed by Novavax, Inc., of Gaithersburg, Maryland. Novavax is leading the trial as the regulatory sponsor. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, are funding the trial.  “Addressing the unprecedented health crisis of COVID-19 has required extraordinary efforts on the part of government, academia, industry and the community,” said NIAID Director Anthony S. Fauci, M.D. “The launch of this study — the fifth investigational COVID-19 vaccine candidate to be tested in a Phase 3 trial in the United States — demonstrates our resolve to end the pandemic through development of multiple safe and effective vaccines.”

The trial is being conducted in collaboration with Operation Warp Speed(link is external) (OWS), a multi-agency collaboration overseen by HHS and the Department of Defense that aims to accelerate development, manufacture and distribution of medical countermeasures for COVID-19. Some of the U.S. trial sites participating are part of the NIAID-supported COVID-19 Prevention Network(link is external) (CoVPN). The CoVPN includes existing NIAID-supported clinical research networks with infectious disease expertise and was designed for rapid and thorough evaluation of vaccine candidates and monoclonal antibodies for preventing COVID-19. Volunteers will be asked to give informed consent prior to their participation in the trial. They will be grouped into two cohorts: individuals 18 through 64 years old and those aged 65 and older, with a goal of enrolling at least 25% of all volunteers who are 65 years old or older. Trial organizers also are emphasizing recruitment of people who are at higher risk of severe COVID-19 disease, including those who are Black (including African Americans), Native American, or of Latino or Hispanic ethnicity, and people who have underlying health conditions such as obesity, chronic kidney disease or diabetes.  “We’ve come this far, this fast, but we need to get to the finish line,” said NIH Director Francis S. Collins, M.D., Ph.D. “That will require multiple vaccines using different approaches to ensure everyone is protected safely and effectively from this deadly disease.”  After providing a baseline nasopharyngeal and blood sample, participants will be assigned at random to receive an intramuscular injection of either the investigational vaccine or a saline placebo. Randomization will be in a 2:1 ratio with two volunteers receiving the investigational vaccine for each one who receives placebo. Because the trial is blinded, neither investigators nor participants will know who is receiving the candidate vaccine. A second injection will be administered 21 days after the first. Participants will be followed closely for potential vaccine side effects and will be asked to provide blood samples at specified time points after each injection and during the following two years. Scientists will analyze the blood samples to detect and quantify immune responses to SARS-CoV-2, the virus that causes COVID-19. Of note, specialized assays will be used to distinguish between immunity as a result of natural infection and vaccine-induced immunity. The trial’s primary endpoint is to determine whether NVX-CoV2373 can prevent symptomatic COVID-19 disease seven or more days after the second injection relative to placebo.

Novavax’s investigational vaccine, NVX-CoV2373, is made from a stabilized form of the coronavirus spike protein using the company’s recombinant protein nanoparticle technology. The purified protein antigens in the vaccine cannot replicate and cannot cause COVID-19. The vaccine also contains a proprietary adjuvant, MatrixM™. Adjuvants are additives that enhance desired immune system responses to vaccine. NVX-CoV2373 is administered in liquid form and can be stored, handled and distributed at above-freezing temperatures (35° to 46°F). A single vaccine dose contains 5 micrograms (mcg) of protein and 50 mcg of adjuvant.  In animal tests, NVX-CoV2373 vaccination produced antibodies that blocked the coronavirus spike protein from binding to the cell surface receptors targeted by the virus, preventing viral infection. In results(link is external) of a Phase 1 clinical trial published in the New England Journal of Medicine, NVX-CoV2373 was generally well-tolerated and elicited higher levels of antibodies than those seen in blood samples drawn from people who had recovered from clinically significant COVID-19. NVX-CoV2373 also is being evaluated in a Phase 2b trial in South Africa, now fully enrolled with 4,422 volunteers, and data from a Phase 1/2 continuation trial in the United States and Australia is expected as early as first quarter 2021. Novavax also recently completed enrollment of more than 15,000 volunteers in a Phase 3 trial of the candidate vaccine in the United Kingdom, which is also testing two injections of 5 mcg of protein and 50 mcg of Matrix-M adjuvant administered 21 days apart. An independent Data and Safety Monitoring Board (DSMB) will provide oversight to ensure the safe and ethical conduct of the study. All Phase 3 clinical trials of candidate vaccines supported through OWS are overseen by a common DSMB developed in consultation with the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative.

A large, United Kingdom-based Phase 2/3 study testing a Covid-19 vaccine being developed by AstraZeneca has been restarted, according to a statement from the company. News that the trial is resuming comes four days after the disclosure that it had been paused because of a suspected serious adverse reaction in a participant.  A spokesperson for AstraZeneca told STAT that at this point, only the trial in the U.K. has been resumed. The company is also conducting Phase 2/3 or Phase 3 trials in the U.S., Brazil, and South Africa.  “The Company will continue to work with health authorities across the world and be guided as to when other clinical trials can resume to provide the vaccine broadly, equitably and at no profit during this pandemic,” the spokesperson, Michele Meixell, wrote in an email.

Saturday’s statement from AstraZeneca said the independent U.K. investigation into the event has concluded and it advised the Medicines Health Regulatory Authority, Britain’s equivalent of the Food and Drug Administration, that it was safe to resume the trial. The MHRA concurred and gave the green light for the trial to restart. The illness that triggered the international pause, which occurred in a woman who was in the vaccine arm of the U.K. trial, has not been officially disclosed, though AstraZeneca CEO Pascal Soriot told a group of investors on Wednesday that her symptoms were consistent with transverse myelitis, a serious condition involving inflammation of the spinal cord that can cause muscle weakness, paralysis, pain and bladder problems. The AstraZeneca statement said information about the illness the woman suffered cannot be disclosed. Oxford University, where the vaccine was developed, said in a separate statement that the nature of the illness cannot be revealed “for reasons of participant confidentiality.” As part of the review process, independent boards overseeing trials of a number of other Covid-19 vaccines were analyzing their own data, looking for cases. There are at least 35 vaccines in clinical trials around the world, nine of which are in Phase 3, the final stage of testing.

It’s not uncommon for clinical trials to be paused. This is the second known hold of studies of the AstraZeneca vaccine. A woman in the U.K. trial was diagnosed with multiple sclerosis in July, but that event, which triggered the first pause, was deemed not to be related to the vaccine. An AstraZeneca spokesperson previously described the decision as a “routine action which has to happen whenever there is a potentially unexplained illness” in a trial. Still, the pause drew extraordinary attention because of the urgent need for progress on Covid-19 vaccines in the midst of the pandemic.

The antiviral drug remdesivir has been one of the few treatments that's seemed to help curb death rates in COVID-19 patients so ill that they need a ventilator. But a new study finds the drug might not be as effective for 'moderate' cases of COVID-19—patients hospitalized and perhaps needing oxygen to breathe, but not requiring a ventilator. The study of nearly 600 such patients found that those who got a five-day course of remdesivir had a "statistically significant difference in clinical status compared to standard care, but the difference was of uncertain clinical importance," according to researchers led by Dr. Diana Brainard of Gilead Sciences, which makes remdesivir. One infectious disease expert believes the findings may temper the excitement that first emerged around remdesivir.

"This study highlights that remdesivir clearly isn't a path-breaking drug when it comes to the treatment of COVID-19, as its benefits are marginal," said Dr. Amesh Adalja, a senior scholar at the Johns Hopkins Center for Health Security in Baltimore. He believes the findings "underscore the need to develop antivirals and other therapies that can meaningfully impact the trajectory of COVID-19 patients." Gilead is currently seeking U.S. Food and Drug Administration approval for remdesivir, which is available now on an emergency basis for hospitalized patients with severe COVID-19. If the FDA approves it, however, the drug would gain wider use. Remdesivir works by blocking the virus from copying itself. Trials of the drug showed that it can cut recovery time from COVID-19 by nearly a third in people with severe COVID-19. But what about more moderate coronavirus cases? To find out, Brainard's group looked at 584 hospitalized patients who received either five days of remdesivir administered intravenously; 10 days on the same regimen, or standard care without remdesivir. Patients averaged 57 years of age and 61% were men. More than half had heart disease and 40% were diabetic. All of the patients had moderate COVID-19, which was defined as the presence of pneumonia evidenced on lung scans along with low blood oxygen levels. As reported Aug. 21 in the Journal of the American Medical Association, 28 days after treatment began, four patients (2%) in the standard care group had died, compared to three (2%) who got 10 days of remdesivir and two (1%) who got the five-day regimen. At 11 days, a statistical benefit in terms of a "better clinical status" on a 7-point scale was only seen among those who got five days of remdesivir: This group had a 65% higher odds of an improved outcome compared to those who got standard care, the researchers said. Still, improvements were not dramatic and of "uncertain clinical importance," Brainard's team noted.

According to Adalja, more study is needed and "there may still be a role for remdesivir in certain patient subgroups in which the benefits may be more apparent." Dr. Matthew Heinz is a hospital physician and internist from Tucson, Ariz. Reading over the report, he agreed that while remdesivir may help some patients with severe COVID-19, "there was [only] a small benefit for the ones taking the five-day course" in this study of people with moderate illness. Heinz offered up one more caveat: the drug's hefty price tag. In late June, Gilead announced that it would charge U.S. hospitals $3,120 for a five-day course of remdesivir in a patient with private insurance. Remdesivir "is very costly, and not every hospital is able to consistently stock it," Heinz said, and before hospitals rush to buy the drug, "more study is definitely required."

Original study published in JAMA (August 21, 2020):

https://doi.org/10.1001/jama.2020.16349

The trial shows the vaccine "may be a potential winner, but efficacy and safety studies need to continue,” one expert said. A potential Covid-19 vaccine from the biotech company Novavax showed a promising immune response in a small, early trial, but not without a high rate of mostly mild side effects. The results, published Tuesday, are the latest encouraging sign in the global effort to develop a vaccine for the novel coronavirus, which has killed nearly 700,000 people around the world. But the Novavax data, much like results recently published by Moderna and AstraZeneca, are too preliminary to draw any conclusions about how well the vaccine might protect against Covid-19, experts said. “It’s a small number of people in each arm, and the study wasn’t designed to demonstrate efficacy, which are the standard caveats for a Phase 1 trial,” said Edward Belongia, an epidemiologist and vaccine researcher at the Marshfield Clinic Research Institute in Wisconsin. “Having said that, it looks very promising — at least as promising if not more so than the other vaccines we’ve looked at.” The data were published on a preprint server, meaning they have not yet been peer-reviewed.

Novavax enrolled about 130 healthy volunteers in its trial and gave them either a placebo or one of four escalating doses of its vaccine. Everyone who received the vaccine developed neutralizing antibodies against SARS-CoV-2, which may help prevent infection. The best responses came from volunteers who received two injections of Novavax’s vaccine three weeks apart, plus an adjuvant meant to boost its effects. After 35 days, those participants had neutralizing antibody levels that, on average, were roughly four times higher than what was seen in a group of 32 patients who had recovered from the disease. About 80% of those volunteers had side effects at the site of injection, including pain and tenderness. More than 60% had other side effects, mostly headaches, muscle pain, and fatigue. Most reactions were mild or moderate, but eight patients had side effects that were graded severe; Novavax said none required hospitalization. All of the reactions resolved after a few days, and none was life-threatening. The study, conducted in Australia, recruited a roughly even number of men and women between the ages of 18 and 59. Volunteers were about 79% white, 15% Hispanic, 13% Asian, 6% Indigenous, and 2% Black. The median age was 31....

Preprint of the study available at medRxiv (August 4, 2020):

https://www.medrxiv.org/content/10.1101/2020.08.05.20168435v1

The investigational vaccine was developed by the biotechnology company Moderna and the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. The trial is to be conducted at nearly 100 US research sites, according to Moderna. The first Phase 3 clinical trial of a coronavirus vaccine in the United States began Monday. The investigational vaccine was developed by the biotechnology company Moderna and the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. The trial is to be conducted at nearly 100 US research sites, according to Moderna. The first patient was dosed at a site in Savannah, Georgia. The trial is expected to enroll about 30,000 adult volunteers and evaluates the safety of the Moderna/NIH vaccine and whether it can prevent symptomatic Covid-19 after two doses, among other outcomes. Volunteers will receive either two 100 microgram injections of the vaccine or a placebo about 28 days apart. Investigators and participants will not know who has received the vaccine.

Results from a Phase 1 trial of the vaccine published earlier this month in the New England Journal of Medicine found it induced immune responses in all of the volunteers and was generally safe. It had mild side effects, including fatigue, chills, headache, muscle pain, pain at the injection site. A Phase 1 study typically studies a small number of people and focuses on whether a vaccine is safe and elicits an immune response. In Phase 2, the clinical study is expanded and the vaccine is given to people who have characteristics -- such as age and physical health -- similar to those for whom the new vaccine is intended, according to the US Centers for Disease Control and Prevention. In Phase 3, the vaccine is given to thousands of people and tested for efficacy and again for safety. The Moderna/NIH vaccine is one of 25 in clinical trials around the world, according to the World Health Organization. Moderna is one of several companies that received support from Operation Warp Speed, the federal government's Covid-19 vaccine program. On Sunday, Moderna announced it had received an additional $472 million from the Biomedical Advanced Research and Development Authority for Phase 3 study and development of its Covid-19 vaccine, bringing the total to $955 million.

See also NIH Press Release (July 27, 2020):

https://www.nih.gov/news-events/news-releases/phase-3-clinical-trial-investigational-vaccine-covid-19-begins

The study showed that vaccinated volunteers made more neutralizing antibodies than have been seen in most patients who have recovered from Covid-19. Moderna's Covid-19 vaccine led patients to produce antibodies that can neutralize the novel coronavirus that causes the disease, though it caused minor side effects in many patients, according to the first published data from an early-stage trial of the experimental shot. The results were published Tuesday in the New England Journal of Medicine. Moderna had previously released some results in a press release, but many experts said they were not sufficient to draw many conclusions. Even now, many are withholding judgment.

“It certainly is a good beginning,” said Betty Diamond, director at the Feinstein Institutes for Medical Research, who was not involved in the trial. “There are certainly lots of things we don’t know yet right now.” The study, which was run by the National Institutes of Health, showed that volunteers who received the vaccine made more neutralizing antibodies than have been seen in most patients who have recovered from Covid-19. But a second injection, four weeks after the first, was required before the vaccine produced a dramatic immune response. “The hallmark of a vaccine is one that can actually mimic natural infection and induce the kind of response that you would get with natural infection. And it looks like, at least in this limited, small number of individuals, that is exactly what’s happening,” said Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, the NIH branch that conducted the trial. “The data really look quite good,” he added. “There were no serious adverse events.”

The data roughly mirror the results from a similar vaccine being produced by Pfizer and BioNTech, which were released July 1. Moderna posted a listing on clinicaltrials.gov, a government registry, that says it will start a Phase 3 study in 30,000 patients on July 27. Pfizer and BioNTech said they plan to start their own large study by the end of the month. There are 23 vaccines in human clinical trials against the virus, SARS-CoV-2, according to the World Health Organization, with more set to begin testing soon. In a statement, Moderna CEO Stéphane Bancel called the data “encouraging,” saying they “represent an important step forward” in the development of the vaccine, called mRNA-1273. “We are committed to advancing the clinical development of mRNA-1273 as quickly and safely as possible while investing to scale up manufacturing so that we can help address this global health emergency,” Bancel said....

Original study available at New England J. Medicine (July 14, 2020):

https://doi.org/10.1056/NEJMoa2022483

NOTE: THIS PUBLICATION HAS BEEN RETRACTED BY THE AUTHORS

Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation)....

We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

Published in  The Lancet (May 22, 2020):

https://doi.org/10.1016/S0140-6736(20)31180-6

The closely watched drug has moved markets in the past few weeks following the release of several studies that painted a mixed picture of its effectiveness. Gilead Sciences Inc on Wednesday said its experimental antiviral drug remdesivir helped improve outcomes for patients with COVID-19, and provided data suggesting it worked better when given earlier in the course of infection.

The closely watched drug has moved markets in the past few weeks following the release of several studies that painted a mixed picture of its effectiveness. On Wednesday, broader markets again rose on the data and Gilead shares jumped 2.4%. Gilead provided information on two clinical trials underway. The company said a study being conducted by the National Institute of Allergy and Infectious Diseases (NIAIS) met its main goal in helping patients with COVID-19, the disease caused by the novel coronavirus. Results from that trial have been highly anticipated because it compares how patients who received remdesivir fared versus patients who did not. The lead researcher on that trial told Reuters on Friday that results could come by mid-May, with preliminary findings possible even earlier. More detailed information on that study will be provided at a later date, Gilead said. Gilead also provided data on a study that it has conducted in dozens of medical centers, which does not compare the use of remdesivir against a placebo. In that trial, Gilead said 62% of patients treated early with remdesivir were discharged from the hospital, compared with 49% of patients who were treated late.

"This is good news for Gilead and the market," Jefferies analyst Michael Yee said in a research note. The trial included 397 patients and evaluated the safety and efficacy of five-day and 10-day dosing regimens of remdesivir in hospitalized patients with severe manifestations of COVID-19. "The study demonstrates the potential for some patients to be treated with a five-day regimen, which could significantly expand the number of patients who could be treated with our current supply of remdesivir," said Merdad Parsey, chief medical officer at Gilead Sciences, in a statement....

Official Press Release (April 29, 2020):

https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19

A mix of legacy drugmakers and small startups have stepped forward with plans to develop vaccines or treatments that target the infection caused by the novel coronavirus.

COVID-19, which was first detected in December in Wuhan, China, has sickened more than 100,000 people worldwide and killed at least 3,400. There are no Food and Drug Administration-approved vaccines or therapies for the disease.

In the U.S., the companies that are initiating development have received funding from two organizations: the Biomedical Advanced Research and Development Authority (BARDA), which is a division of the Department of Health and Human Services, and the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health. Some companies have received funding from Coalition for Epidemic Preparedness Innovations (CEPI), a global organization based in Oslo. Other companies are funding trials by themselves or through partnerships with other life sciences companies. 

Here are some of the companies developing treatments or vaccines in the U.S. for COVID-19:

Company: Gilead Sciences

Type: Treatment

Stage: Phase 3 clinical trials

Name: remdesivir

Background: Gilead is a longtime drug maker that is best known for developing the first major cure for hepatitis-C in Sovaldi, a therapy that changed the standard of care for that disease but also kicked off the national debate about drug pricing. The company has experience developing and marketing HIV drugs, including Truvada for pre-exposure prophylaxis (PrEP), its preventive HIV medicine. Along with U.S. trials, Gilead is conducting a randomized, controlled clinical trial in Wuhan, testing remdesivir as a treatment for mild to moderate forms of pneumonia in people with the virus. The trial was given the go-ahead by China’s Food and Drug Administration in February.

Clinical trials:

1. On Feb. 21, the National Institute of Allergy and Infectious Diseases started enrolling patients in a randomized, double-blind, placebo-controlled Phase 3 trial evaluating 394 hospitalized patients with COVID-19 at up to 50 sites worldwide. The trial is expected to conclude April 1, 2023. Sites include the National Institutes of Health in Bethesda, Md., (not recruiting), the University of Nebraska Medical Center in Omaha (recruiting), the University of Texas Medical Branch in Galveston (not recruiting), and Providence Sacred Heart Medical Center in Spokane (recruiting).

The scourge of the influenza virus devastates health and claims many lives worldwide each year. It is especially daunting because vaccines are only protective when they are well matched to the strains circulating in the population. But now, a team led by researchers at the Icahn School of Medicine at Mount Sinai is getting closer to a universal flu vaccine using a novel approach they've developed called chimeric hemagglutinin (cHA).

A protein on the surface of influenza viruses, hemagglutinin, shepherds the virus into host cells. Hemagglutinin is comprised of a 'head' (variable) and a 'stalk' (varies less from strain to strain). Thus, Icahn School of Medicine researchers, led by Peter Palese, Ph.D., Professor and Chair of Microbiology and Florian Krammer, Ph.D., Professor of have focused their efforts on developing a vaccine against the stalk portion of this protein. Their study, undertaken in collaboration with PATH, an international nonprofit, the Cincinnati Children's Hospital Medical Center, the Duke Early Phase Clinical Research Unit, and the University of Chicago, involved testing of several cHA-based vaccination regimens to see if they would induce antibodies that provide broad protection against influenza virus infections. The results were published this month in The Lancet Infectious Diseases.

The diverse research team including Adolfo García-Sastre, Ph.D., Professor of Microbiology and Director of the Global Health and Emerging Pathogens Institute at Icahn; Bruce Innis, M.D., Leader, Respiratory Infections and Maternal Immunizations at PATH; and Patrick Wilson, Ph.D., Professor of Medicine at the University of Chicago, have investigated whether several potential cHA-based vaccines might induce antibodies that would target the stalk of group 1 hemagglutinin-expressing influenza viruses. An adjuvant, an ingredient that boosts the effectiveness of vaccines, was also part of the testing process. Vaccine regimens examined included: 1) a group receiving a chimeric H8/1 hemagglutinin-based live attenuated vaccine followed by a boost with a non-adjuvanted chimeric H5/1 hemagglutinin-based inactivated vaccine (IIV), and 2) the same regimen but with the IIV having an adjuvant called AS03, and 3) a prime-boost regimen including an adjuvanted cH8/1 IIV prime followed by an adjuvanted cH5/1 IIV boost.

The researchers found that the IIV, but not the live attenuated vaccine, induced a significant antibody response after the prime, with a strong increase in anti-H1 stalk titers. All vaccine regimens induced detectable H1 stalk antibody responses after receiving boosts. "The vaccine induced a broad antibody response which was not only cross-reactive for currently circulating human influenza virus but also to avian and bat influenza virus subtypes," said Florian Krammer. "It was surprising to find that the inactivated formulation with adjuvant induced a very strong anti-stalk response already after the prime suggesting that one vaccination might be enough to induce protection against pandemic influenza viruses yet to arise. The results indicate that we are moving towards a universal influenza virus vaccine, but these are still interim results. Additional results will be available upon completion of the study at the end of 2019."...

Published in the Lancet Infectious Diseases (Open Access):

https://doi.org/10.1016/S1473-3099(19)30393-7