Virus World

Antibody levels stayed elevated in the 90 days after people received the second dose of Moderna’s COVID-19 vaccine, raising hopes that the prophylactic can provide protection for one year. With Moderna and Pfizer, in partnership with BioNTech, showing mRNA vaccines provide protection against symptomatic COVID-19 in the short term, attention has turned to durability. The full picture of the durability of protection will only become clear over time, but immunogenicity data from the phase 1/2 trial of Moderna’s mRNA-1273 offer encouragement.  In a letter to The New England Journal of Medicine, scientists at the National Institute of Allergy and Infectious Diseases and other research centers presented updated data on 34 people who received the 100-μg dose of mRNA-1273 in the early-phase trial. The phase 3 trial used the same 100-μg dose. The researchers tracked a slight decline in levels of binding and neutralizing antibodies over the 90 days after the administration of the second dose. However, the geometric mean titers for both types of antibody remained above the median of a panel of 41 convalescent COVID-19 patients. The median time from diagnosis of contributors to the convalescent panel was 34 days. 

Researchers are yet to show what immune characteristics an individual needs to be protected against the coronavirus, limiting our ability to infer the real-world consequences of the antibody increases associated with any vaccine. However, the authors of the NEJM letter said the data show mRNA-1273 “has the potential to provide durable humoral immunity.” Analysts concurred with that assessment.    In a note to investors, analysts at Jefferies wrote, “mRNA-1273 induced neutralizing antibody levels stay relatively high and decline only modestly over the initial 3 months suggesting the trajectory of protection from symptomatic disease could last for at least 6 mos (though unclear), so an annual boost would seem good." The NEJM update also touched on the safety of the vaccine. No serious adverse events were seen in the small trial, and no new adverse events deemed related to the vaccine occurred after Day 57.  Moderna shared details of the NEJM letter alongside an update on its effort to scale up production. As previously disclosed, Moderna expects to make around 20 million doses available in the U.S. by the end of the year. That early delivery is set to be followed by the shipment of up to 125 million vaccines globally in the first quarter. The U.S. will get around 80% of the vaccines available in the first quarter...

Research cited published in NEJM (December 3, 2020):

https://doi.org/10.1056/NEJMc2032195

Pfizer and BioNTech are under a white-hot spotlight because their vaccine, by design, is likely to be the first to have any efficacy data. The announcement is both good news and bad news. Umer Raffat, a senior managing director at the investment bank Evercore ISI, wrote in an analyst note that the fact that Pfizer hasn’t conducted an interim analysis was “a good thing” because it means that, based on the details of the trial protocol, the vaccine had not failed to prevent more than 77% of Covid cases, the benchmark for success at this early juncture. But it also suggests that cases of Covid are being reported less frequently among participants in the Pfizer study than in the U.S. as a whole. That means that the study is progressing more slowly than Pfizer and its partner, BioNTech, originally expected. In August, Pfizer had thought that the first interim analysis could occur as early as September. Pfizer and BioNTech are under a white-hot spotlight because their Covid-19 vaccine, by design, is likely to be the first to have any efficacy data. But that first analysis will come when there have been a total of only 32 cases of Covid-19 across the company’s entire 42,000-volunteer study. It would be considered to be positive, Pfizer has said, if six or fewer of those 32 cases occurred in the group that received the vaccine, with the rest occurring in the group that received the placebo. The trial is expected to continue until 150 of the volunteers in the study have had Covid-19.

Pfizer CEO Albert Bourla set the goal of having a Covid-19 vaccine ready by October this spring, in what appeared to be a bid both to combat the pandemic and to make a statement about the company’s research prowess. Pfizer is in the midst of spinning off older, slower-growing parts of the company in a merger with Mylan, which will leave Bourla running a firm whose future will depend heavily on its research laboratories and the prospects of its experimental drugs.  The vaccine itself is expected to be a significant but not huge financial opportunity. Analysts at SVB Leerink estimate sales could peak at $3.5 billion in 2021, and then stabilize at $1.4 billion a year. In its third-quarter earnings, also announced Tuesday, Pfizer reported profits of $2.2 billion on sales of $12.1 billion. But the October time frame has put Pfizer squarely in the political maelstrom of the U.S. election, as President Trump repeatedly predicted that a vaccine would be available before Election Day. It has been clear for months that other companies developing Covid-19 vaccines, including Moderna, AstraZeneca, and Johnson & Johnson, had no chance of hitting that mark.

On Oct. 6, the Food and Drug Administration released new guidance on safety data that would be required before it would consider clearing a vaccine through an emergency use authorization, or EUA, its fastest path to making a vaccine available. The agency told drug makers not to file for an EUA until at least half the patients in their studies have been followed for two months. In an Oct. 16 public letter, Bourla confirmed that this would prevent Pfizer from filing for an EUA until the third week of November. At an advisory panel of outside experts the FDA held last week, the agency signaled that it was not certain it would grant an EUA for a vaccine until a sufficient amount of data had been accumulated to more fully understand the safety and efficacy of a vaccine prospect.

Moderna’s coronavirus vaccine could potentially induce as strong an immune response in older people as it does in younger adults, a small study published Tuesday in the New England Journal of Medicine found. The study found the vaccine triggered a response almost as strong in people over 56 as in adults between the ages of 18 and 55. Older people are at higher risk for severe illness from COVID-19, according to the Centers for Disease Control and Prevention. The Moderna study was conducted by researchers at Emory University and tested the vaccine in groups of 20 people, including one made up of people aged 56-70 and one of people 71 and over. According to the study, their response was similar to previous findings among age groups between 18-55. 

“These interim results are very encouraging,” Evan Anderson, a professor of infectious disease at Emory University Medical School and lead author on the paper, said in a statement. “While there is still a lot of work to do before we have a vaccine that is proven to be safe and effective against COVID-19, this study provides critical information about the safety of the vaccine. Importantly, the vaccine resulted in a robust immune response. Moderna is one of a handful of companies working on a vaccine and is now in phase three clinical trials in the United States. 

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

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

Moderna, the first company to start US clinical trials of a Covid-19 vaccine, on Thursday finished enrolling all 30,000 of its participants. All 30,000 have received their first shot, and most of them have also received the required second shot. The company's president says it's now on track to apply to the US Food and Drug Administration for authorization to put the vaccine on the market in early December "if all the stars align."  Dr. Stephen Hoge, Moderna's president, said enrolling 30,000 participants is "just a milestone -- it's not the mission." Half of the participants received the vaccine and half received a placebo, or a shot of saline that does nothing. The participants receive a second shot four weeks later.

NIH-led study of mRNA vaccine supports advance to Phase 3 human trials. Two doses of an experimental vaccine to prevent coronavirus disease 2019 (COVID-19)  induced robust immune responses and rapidly controlled the coronavirus in the upper and lower airways of rhesus macaques exposed to SARS-CoV-2, report scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.  SARS-CoV-2 is the virus that causes COVID-19. The candidate vaccine, mRNA-1273, was co-developed by scientists at the NIAID Vaccine Research Center and at Moderna, Inc., Cambridge, Massachusetts. The animal study results published online today in the New England Journal of Medicine complement recently reported interim results from an NIAID-sponsored Phase 1 clinical trial of mRNA-1273. The candidate mRNA-1273 vaccine is manufactured by Moderna.

In this study, three groups of eight rhesus macaques received two injections of 10 or 100 micrograms (µg) of mRNA-1273 or a placebo. Injections were spaced 28 days apart. Vaccinated macaques produced high levels of neutralizing antibodies directed at the surface spike protein used by SARS-CoV-2 to attach to and enter cells. Notably, say the investigators, animals receiving the 10-µg or 100-µg dose vaccine candidate produced neutralizing antibodies in the blood at levels well above those found in people who recovered from COVID-19. The experimental vaccine also induced Th1 T-cell responses but not Th2 responses. Induction of Th2 responses has been associated with a phenomenon called vaccine-associated enhancement of respiratory disease (VAERD). Vaccine-induced Th1 responses have not been associated with VAERD for other respiratory diseases. In addition, the experimental vaccine induced T follicular helper T-cell responses that may have contributed to the robust antibody response.

Four weeks after the second injection, all the macaques were exposed to SARS-CoV-2 via both the nose and the lungs. Remarkably, after two days, no replicating virus was detectable in the lungs of seven out of eight of the macaques in both vaccinated groups, while all eight placebo-injected animals continued to have replicating virus in the lung. Moreover, none of the eight macaques vaccinated with 100 µg of mRNA-1273 had detectable virus in their noses two days after virus exposure. This is the first time an experimental COVID-19 vaccine tested in nonhuman primates has been shown to produce such rapid viral control in the upper airway, the investigators note. A COVID-19 vaccine that reduces viral replication in the lungs would limit disease in the individual, while reducing shedding in the upper airway would potentially lessen transmission of SARS-CoV-2 and consequently reduce the spread of disease, they add. 

Original study published in New England J. of Medicine (July 28, 2020):

https://doi.org/10.1056/NEJMoa2024671 

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