Virus World

The investigational vaccine known as mRNA-1273 was 94.1% efficacious in preventing symptomatic coronavirus disease 2019 (COVID-19), according to preliminary results from a Phase 3 clinical trial reported in the New England Journal of Medicine. The vaccine also demonstrated efficacy in preventing severe COVID-19. Investigators identified no safety concerns and no evidence of vaccine-associated enhanced respiratory disease (VAERD). The vaccine was co-developed by Moderna, Inc., a biotechnology company based in Cambridge, Massachusetts, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Moderna(link is external) and NIAID previously shared initial results from the COVE trial. On Dec. 18, 2020, the FDA issued an Emergency Use Authorization(link is external) allowing Moderna to make the vaccine available for the prevention of COVID-19 in adults in the United States. The trial was led by principal investigators Lindsey R. Baden, M.D. of Brigham and Women’s Hospital in Boston, Hana M. El-Sahly, M.D. of Baylor College of Medicine in Houston, and Brandon Essink, M.D., of Meridian Clinical Research. The trial was implemented under the U.S. government’s Operation Warp Speed program and supported by NIAID and the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response.

The trial began on July 27, 2020, and enrolled 30,420 adult volunteers at clinical research sites across the United States. Volunteers were randomly assigned 1:1 to receive either two 100 microgram (mcg) doses of the investigational vaccine or two shots of saline placebo 28 days apart. The average age of volunteers is 51 years. Approximately 47% are female, 25% are 65 years or older and 17% are under the age of 65 with medical conditions placing them at higher risk for severe COVID-19. Approximately 79% of participants are white, 10% are Black or African American, 5% are Asian, 0.8% are American Indian or Alaska Native, 0.2% are Native Hawaiian or Other Pacific Islander, 2% are multiracial, and 21% (of any race) are Hispanic or Latino. From the start of the trial through Nov. 25, 2020, investigators recorded 196 cases of symptomatic COVID-19 occurring among participants at least 14 days after they received their second shot. One hundred and eighty-five cases (30 of which were classified as severe COVID-19) occurred in the placebo group and 11 cases (0 of which were classified as severe COVID-19) occurred in the group receiving mRNA-1273. The incidence of symptomatic COVID-19 was 94.1% lower in those participants who received mRNA-1273 as compared to those receiving placebo.  Investigators observed 236 cases of symptomatic COVID-19 among participants at least 14 days after they received their first shot, with 225 cases in the placebo group and 11 cases in the group receiving mRNA-1273. The vaccine efficacy was 95.2% for this secondary analysis. There were no concerning safety issues with vaccination, according to the authors. Local reactions to the vaccine were generally mild. About 50% of participants receiving mRNA-1273 experienced moderate-to-severe side effects — such as fatigue, muscle aches, joint pain and headache — after the second dose, which resolved in most volunteers within two days.

Investigators also observed no evidence of VAERD among those who received mRNA-1273. This rare complication was seen in individuals vaccinated with a whole-inactivated respiratory syncytial virus (RSV) vaccine in the 1960s, before there was a capacity to define protein structures and measure immune responses with precision. VAERD can occur when a vaccine induces an immune response that is not strong enough to protect against infection. Although mRNA-1273 is highly efficacious in preventing symptomatic COVID-19, there is not yet enough available data to draw conclusions as to whether the vaccine can impact SARS-CoV-2 transmission. Preliminary trial data suggests there may be some degree of prevention of asymptomatic infection after a single dose. Additional analyses are underway of the incidence of asymptomatic infection and viral shedding post-infection to understand the vaccine’s impact on infectiousness. The authors concluded by discussing the unprecedented efficiency of the candidate vaccine’s development, noting, “this process demonstrates what is possible in the context of motivated collaboration among key sectors of society, including academia, government, industry, regulators and the larger community.”

Findings Published in NEJM (Dec. 30, 2020):

https://doi.org/10.1056/NEJMoa2035389

Final results from Pfizer Inc's COVID-19 vaccine trial showed its shot had a 95% success rate and two months of safety data, paving the way for the drugmaker to apply for an emergency U.S. authorization within days, it said on Wednesday. The efficacy rate of the vaccine developed by Pfizer and its German partner BioNTech is the highest of any candidate in late-stage clinical trials so far, and experts said it was a significant achievement in the race to end the pandemic. Pfizer said 170 volunteers in its trial involving over 43,000 people contracted COVID-19 but 162 of them had only been given a placebo, meaning the vaccine was 95% effective. Of the 10 people who had severe COVID-19, one had received the vaccine. “A first in the history of mankind: less than a year from the sequence of the virus to the large-scale clinical trial of a vaccine, moreover based on a whole new technique,” said Enrico Bucci, biologist at Temple University in Philadelphia. “Today is a special day.”

Pfizer said it expected the U.S. Food and Drug Administration’s vaccine advisory committee to review and discuss the data in a public meeting that will likely be held in December. The final analysis comes a week after initial results from the trial showed the vaccine was more than 90% effective. Moderna Inc on Monday released preliminary data for its vaccine, showing 94.5% effectiveness. The better-than-expected results from the two vaccines, both developed with new messenger RNA (mRNA) technology, have raised hopes for an end to a pandemic that has killed more than 1.3 million people and wreaked havoc upon economies and daily life. “These are extraordinary results, and the safety data look good,” said David Spiegelhalter, a professor and expert in risk and evidence communication at the University of Cambridge. “It would be interesting to see what adverse reactions were reported by the group getting the placebo, since that gives an idea of how much of the adverse effects are due to the vaccination process, and how much is due to the vaccine itself.” Global shares edged higher on Wednesday as Pfizer’s trial results more than offset concerns around the stubbornly high global infection rate. Pfizer shares rose 2.9% when U.S. markets opened while BioNTech jumped 4%.

While some groups such as healthcare workers will be prioritized in the United States for vaccinations this year, it will be months before large-scale rollouts begin. Distribution of a Pfizer shot is complicated by the need to store it at ultra-cold temperatures of -70 degrees Celsius. It can, however, be kept in a normal fridge for up to five days, or up to 15 days in a thermal shipping box. Moderna’s vaccine can be stored for up to six months at -20C though it is expected to be stable for 30 days at normal fridge temperatures of 2 to 8 degrees Celsius (36°-46°F). 

Pfizer said the efficacy of the vaccine was consistent across different age and ethnic groups, a sign that the immunization could be employed broadly around the world. Efficacy in adults over 65 years was over 94%. “The 94% protection for older people is key. This is the evidence we needed to ensure that the most vulnerable people are protected,” said Andrew Hill, senior visiting research fellow at the University of Liverpool’s department of pharmacology.  Pfizer said its two-dose vaccine, BNT162b2, was well-tolerated and that side effects were mostly mild to moderate, and cleared up quickly. It said the only severe adverse events experienced by volunteers were fatigue and headaches. Out of 8,000 participants, 2% had headaches after the second dose while 3.8% experienced fatigue. Older adults tended to report fewer and milder adverse events. For its trial, Moderna named five severe side effects experienced by at least 2% of those who received its shot: fatigue at 9.7%, muscle pain at 8.9%, joint pain at 5.2%, headache at 4.5%, pain at 4.1% and redness around the injection site at 2%....

Pfizer Press Release (November 18, 2020):

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine

The trial is expected to enroll and test the vaccine in up to 10,000 participants aged between 18 and 84 years over the next four to six weeks.

• Novavax Inc on Thursday started a late-stage trial of its experimental Covid-19 vaccine in partnership with the UK government’s Vaccines Taskforce, sending the company’s shares up 6% after the bell.
• The trial is expected to enroll and test the vaccine in up to 10,000 participants aged between 18 and 84 years over the next four to six weeks.
• Data from the trial will support regulatory submissions for license in the UK, EU and other countries, the company said.

Novavax on Thursday started a late-stage trial of its experimental Covid-19 vaccine in partnership with the UK government’s Vaccines Taskforce, sending the company’s shares up 6% after the bell. The trial is expected to enroll and test the vaccine in up to 10,000 participants aged between 18 and 84 years over the next four to six weeks. Data from the trial will support regulatory submissions for license in the UK, EU and other countries, the company said The study has two main goals, the first occurrence of PCR-confirmed symptomatic Covid-19 at least 7 days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2. The second main goal is first occurrence of PCR-confirmed symptomatic moderate or severe Covid-19 at least 7 days after the second study vaccination in volunteers who have not been previously infected with the virus The trial will enroll at least 25% of participants over the age of 65 and prioritize groups most affected by the Covid-19, the company said.

Company's release available at (Sept. 24, 2020):

https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-3-efficacy-trial-covid-19-vaccine-united

Patients admitted with COVID-19 at select hospitals may now volunteer to enroll in a clinical trial to test the safety and efficacy of a potential new treatment for the disease. The Phase 3 randomized, controlled trial is known as ACTIV-3, and as a “master protocol,” it is designed to expand to test multiple different kinds of monoclonal antibody treatments. It also can enroll additional volunteers in the middle of the trial, if a specific investigational treatment shows promise. The new study is one of four ongoing or planned trials in the National Institutes of Health’s. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, a public-private partnership to speed development of the most promising treatments and vaccine candidates. It also is 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 trial will take place at select hospitals around the world that are part of existing clinical trial networks. They include the lead network, the International Network of Strategic Initiatives in Global HIV Trials (INSIGHT), operated by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health. Collaborating clinical trial networks include the Prevention and Early Treatment of Acute Lung Injury network (PETAL) and Cardiothoracic Surgical Trials Network (CTSN), supported by the NIH’s National Heart, Lung and Blood Institute through the Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS) program, and the U.S. Department of Veterans Affairs Medical Centers. ACTIV-3 uses an adaptive two-stage Phase 3 protocol design. The ACTIV-3 trial can be modified to test additional experimental therapeutics and flexibly allow novel therapeutics to enter at either stage 1 or stage 2. In addition, if a treatment appears to be safe and effective in the initial stage after review by an independent data and safety monitoring board (DSMB), the investigational therapeutic proceeds to stage 2 testing, where more volunteers are enrolled. If an investigational therapeutic is unsafe or not likely to be effective, it will be dropped...

The initial stage of the ACTIV-3 clinical trial aims to enroll approximately 300 volunteers who have been hospitalized with mild to moderate COVID-19 with fewer than 13 days of symptoms. Once their COVID-19 infections have been confirmed and they have consented to take part in the study, participants will be randomly assigned to receive either an intravenous (IV) infusion of LY-CoV555 or a saline placebo infusion. Participants also will receive standard care for COVID-19, including the antiviral remdesivir. After five days, participants’ symptoms will be assessed, as will their need for supplemental oxygen, mechanical ventilation, or other supportive care. Volunteers will be followed for 90 days after enrollment and will receive regular examinations and have blood samples taken periodically during this time to analyze their response to the investivational therapeutic. Data collected on the fifth day of the volunteers’ participation will determine whether the investigational therapeutic will be administered to a larger group of volunteers. If LY-CoV555 appears to be safe and appears to be effective, the trial will enroll an additional 700 participants. It also will begin enrolling more severely ill participants, such as those with organ failure requiring mechanical support, or COVID-19-associated dysfunction of organs other than the lungs. The primary endpoint of the trial is the participants’ sustained recovery for 14 days after release from the hospital. The principal investigator of ACTIV-3 is Jens Lundgren, M.D., of the University of Copenhagen and Rigshospitalet. Leads of the participating networks include James Neaton, Ph.D., of the INSIGHT network, Taylor Thompson, M.D., of the PETAL network, Annetine Gelijns, Ph.D., and Alan Moskowitz, M.D., of the CTSN, and Rachel Ramoni, D.M.D., Sc.D., of the U.S. Department of Veterans Affairs. To ensure that the trial is being conducted in a safe and effective manner, an independent DSMB will oversee the trial and conduct periodic reviews of the accumulating data...

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently.

Methods

In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety.

Results

A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.

Conclusions

A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728. opens in new tab.)

Published in NEJM (Dec. 10, 2020): 

https://doi.org/10.1056/NEJMoa2034577

Moderna said Monday that its coronavirus vaccine candidate is 94.5% effective in fighting the virus, per an initial analysis released by the company.

Why it matters: The Moderna vaccine — alongside Pfizer's similarly effective candidate — provides another dash of hope that the pandemic currently raging across the world could be tamed by next year.

The state of play: Moderna's study, done in collaboration with the National Institute of Health, looked at 30,000 participants — with half receiving a placebo.

• In 95 cases of COVID-19 that developed among participants, 90 were taking the placebo.
• Of the 11 people who contracted "severe" COVID-19 infections, all were taking a placebo.
• Moderna reports there are no significant safety concerns so far.
• The company also said that the vaccine could be stored at refrigerator temperatures for up to a month — compared to Pfizer's vaccine candidate, which requires ultra-cold conditions.

What they're saying: "It’s extremely good news. If you look at the data, the numbers speak for themselves," said Dr. Anthony Fauci, per the Washington Post.

• "I describe myself as a realist, but I’m fundamentally a cautious optimist. I felt we’d likely get something less than this. … I said certainly a 90-plus-percent effective vaccine is possible, but I wasn’t counting on it."

The big picture: The Moderna vaccine was part of the federal government's Operation Warp Speed acceleration project, and the company received about $2.5 billion to back its research and development.

• Pfizer, on the other hand, funded its own vaccine research but did commit to an Operation Warp Speed deal to speed potential distribution.

Worth noting: Like Pfizer's announcement last week, Moderna's details on its vaccine candidate came in the form of a press release.

• The data has not been peer-reviewed and its effectiveness could change as the study progresses, but Moderna says they plan to submit to a peer-reviewed publication when the study is complete.
• Pfizer CEO Albert Bourla said that his company had avoided such specificity about effectiveness given that the numbers could continue changing as its trial continues.

Moderna's press release (Nov. 16, 2020):

https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy

The Covid-19 vaccine trial designed by Pfizer Inc. and its German partner BioNTech SE may allow them to find whether their shot works before their fastest-moving rivals. The companies plan a first look after a mere 32 coronavirus infections have accumulated in their massive 44,000-person trial. That case total could be reached as soon as Sept. 27, according to Airfinity Ltd., a London-based analytics firms tracking vaccine trials. Pfizer has also given itself four chances to get a preliminary result, before reaching the final goal of 164. Some trial experts say the company appears to be looking for a leg up in a race against frontrunners such as Moderna Inc. and AstraZeneca Plc to be first with a vaccine. “I’ve never seen a trial where there were four interim analyses; that may be the Olympic record,” said Eric Topol, editor-in-chief of Medscape, a website offering clinical information for health-care professionals, and director of the Scripps Research Translational Institute in La Jolla, California. “It’s obvious why it is being done: so you can just keep looking at the data to try to win a race.”

A wide range of symptoms and severity makes the evaluation of Covid-19 vaccines tricky. The U.S. Food and Drug Administration has said that to be approved, vaccines should cut the number of symptomatic cases by half. Yet documents released by the drugmakers show each has its own approach to defining which symptoms count, and when to count them. Big drug studies usually allow a panel of monitors to get an early peek at the data once or twice before the planned end. The panel can stop the trial early if a treatment is judged overwhelmingly effective -- or alternatively, a total dud. Four early looks may give Pfizer an “easy route” to making sure it has results soon, said Marie-Paule Kieny, a former World Health Organization official who’s now a research director at the French health-science institute Inserm. “It seems that there are different levels of stringency,” she said in an interview. “I wouldn’t say that Pfizer-BioNTech comes out as a star of stringency.” Moderna, working with the U.S. National Institute of Allergy and Infectious Diseases, won’t dive in until 53 cases have occurred; its ultimate goal is to make a judgment at 151 diagnoses. Cancer powerhouse AstraZeneca, collaborating with the University of Oxford, will take its first look at 75 cases, and not again until the trial is complete with 150.

“All trials have set the bar quite low for what they test against,” said Rasmus Bech Hansen, Airfinity’s chief executive officer. Pfizer’s trial was designed to evaluate its vaccine candidate “as fast as possible,” said Amy Rose, a spokeswoman, in an email. The company has worked with government scientists to develop best practices for testing and based its schedule for interim analyses on the vaccine’s “strong profile” in early human trials and animal tests, she said. Moderna’s plan was agreed upon with U.S. regulators, and the company has been open about the numbers since before the trial began in late July, spokesman Ray Jordan said in an email. Case totals for interim analysis were based on probabilities of success and “were not selected based on timeframes,” he said. AstraZeneca said its trials are conducted under regulatory oversight and its plans have evolved over time to make sure they produce robust information in a timely way. All the companies said their trials will continue beyond points such as a preliminary readout or potential authorization. Pfizer says its study will likely yield conclusive results in October. None of the drugmakers will likely know whether their vaccines lower hospitalizations until February, according to Airfinity. But it’s the earlier assessments that have observers most concerned.

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