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mRNA-1273

COVID-19 Vaccine Appears Well-Tolerated and Effective in Developing Antibodies in Small Study of Older Adults

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Bandage after vaccine
Credit: iStock/BackyardProduction

It’s been truly breathtaking to watch the progress being made on a daily basis to develop safe and effective vaccines for SARS-CoV-2, the novel coronavirus that causes COVID-19. Indeed, months sooner than has ever been possible for a newly emerging infection, several promising vaccines are already working their way through Phase 3 studies, the final stage of clinical evaluation. I remain optimistic that we will have one or more vaccines that prove to be safe and effective by January 2021.

But, as encouraging as the early data have been, uncertainty has remained over whether vaccines that appear safe and effective in developing antibodies in younger adults will work as well in older people, too. It’s a critical issue given that older individuals also are at greater risk for severe or life-threatening illness if they do get sick from COVID-19.

So, I’m pleased to highlight some recent findings, published in the New England Journal of Medicine [1], from an early Phase 1 clinical trial that was expanded to include 40 adults over age 55. While we eagerly await the results of ongoing and larger studies, these early data suggest that an innovative COVID-19 vaccine co-developed by NIH’s Vaccine Research Center (VRC), in partnership with Moderna Inc., Cambridge, MA, is both well tolerated and effective in generating a strong immune response when given to adults of any age.

The centerpiece of the vaccine in question, known as mRNA-1273, is a small, non-infectious snippet of messenger RNA (mRNA). When this mRNA is injected into muscle, a person’s own body will begin to make the key viral spike protein. As the immune system detects this spike protein, it spurs the production of antibodies that may help to fend off the novel SARS-CoV-2.

Earlier findings from the NIH-supported phase 1 human clinical trial found mRNA-1273 was safe and effective in generating a vigorous immune response in people ages 18 to 55, when delivered in two injections about a month apart. Based on those findings, a large Phase 3 clinical trial is currently enrolling 30,000 volunteers, with results expected in the next few weeks [2]. But, given that immune response to many other vaccines tends to grow weaker with age, how well would this new COVID-19 vaccine work for older individuals?

To find out, a team at Kaiser Permanente Washington Health Research Institute, Seattle, and Emory University School of Medicine, Atlanta, expanded the initial Phase 1 trial to include 20 healthy volunteers ages 56 to 70 and another 20 healthy volunteers ages 71 and older. Ten volunteers in each of the two older age groups received a lower dose of the vaccine (25 micrograms) in two injections given about a month apart. The other 10 in each age group received a higher dose (100 micrograms), given on the same schedule.

Here’s what they found:

• No volunteers suffered serious adverse events. The most common adverse events were mild-to-moderate in severity and included headache, fatigue, muscle aches, chills and pain at the injection site. Those symptoms occurred most often after the second dose and in individuals receiving the higher dose of 100 micrograms.

• Volunteers showed a rapid production of protective antibodies against the spike protein following immunization. After the second injection, all participants showed a strong immune response, with production of robust binding and neutralizing antibodies against SARS-CoV-2.

• The higher dose of 100 micrograms safely produced a stronger immune response compared to the lower dose, supporting its use in larger clinical studies.

• Most importantly, the immune response observed in these older individuals was comparable to that seen previously in younger adults.

The researchers will continue to follow the volunteer trial participants of all ages for about a year to monitor the vaccine’s longer-term effects. But these findings provided support for continued testing of this promising vaccine in older adults in the ongoing Phase 3 clinical trial.

There are currently four SARS-CoV-2 vaccines in phase 3 clinical trials in the United States (though two are currently on hold). Trials of two more vaccines are expected start in the next month or two.

It is not known whether all of these vaccines will have the same vigorous immune response in older individuals that has been demonstrated for this one. But if more than one of these vaccines turns out to be safe and effective, it will be important to know about the response in various populations, so that distribution to high-risk groups can be planned accordingly.

References:

[1] Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. Anderson EJ, Rouphael NG, Widge AT, Jackson LA, Roberts PC, Makhene M, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott AB, Flach B, Lin BC, Doria-Rose NA, O’Dell S, Schmidt SD, Corbett KS, Swanson PA 2nd, Padilla M, Neuzil KM, Bennett H, Leav B, Makowski M, Albert J, Cross K, Edara VV, Floyd K, Suthar MS, Martinez DR, Baric R, Buchanan W, Luke CJ, Phadke VK, Rostad CA, Ledgerwood JE, Graham BS, Beigel JH; mRNA-1273 Study Group. N Engl J Med. 2020 Sep 29.

[2] “Phase 3 clinical trial of investigational vaccine for COVID-19 begins.” National Institutes of Heath. July 27, 2020

Links:

Coronavirus (COVID-19) (NIH)

COVID-19 Prevention Network (National Institute of Allergy and Infectious Diseases/NIH)

Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)

Moderna, Inc. (Cambridge, MA)

Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) (ClinicalTrials.gov)

NIH Support: National Institute of Allergy and Infectious Diseases


Researchers Publish Encouraging Early Data on COVID-19 Vaccine

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Diagram of how mRNA vaccine works
Credit: NIH

People all around the globe are anxiously awaiting development of a safe, effective vaccine to protect against the deadly threat of coronavirus disease 2019 (COVID-19). Evidence is growing that biomedical research is on track to provide such help, and to do so in record time.

Just two days ago, in a paper in the New England Journal of Medicine [1], researchers presented encouraging results from the vaccine that’s furthest along in U.S. human testing: an innovative approach from NIH’s Vaccine Research Center (VRC), in partnership with Moderna Inc., Cambridge, MA [1]. The centerpiece of this vaccine is a small, non-infectious snippet of messenger RNA (mRNA). Injecting this mRNA into muscle will spur a person’s own body to make a key viral protein, which, in turn, will encourage the production of protective antibodies against SARS-CoV-2—the novel coronavirus that causes COVID-19.

While it generally takes five to 10 years to develop a vaccine against a new infectious agent, we simply don’t have that time with a pandemic as devastating as COVID-19. Upon learning of the COVID-19 outbreak in China early this year, and seeing the genome sequence of SARS-CoV-2 appear on the internet, researchers with NIH’s National Institute of Allergy and Infectious Diseases (NIAID) carefully studied the viral instructions, focusing on the portion that codes for a spike protein that the virus uses to bind to and infect human cells.

Because of their experience with the original SARS virus back in the 2000s, they thought a similar approach to vaccine development would work and modified an existing design to reflect the different sequence of the SARS-CoV-2 spike protein. Literally within days, they had created a vaccine in the lab. They then went on to work with Moderna, a biotech firm that’s produced personalized cancer vaccines. All told, it took just 66 days from the time the genome sequence was made available in January to the start of the first-in-human study described in the new peer-reviewed paper.

In the NIH-supported phase 1 human clinical trial, researchers found the vaccine, called mRNA-1273, to be safe and generally well tolerated. Importantly, human volunteers also developed significant quantities of neutralizing antibodies that target the virus in the right place to block it from infecting their cells.

Conducted at Kaiser Permanente Washington Health Research Institute, Seattle; and Emory University School of Medicine, Atlanta, the trial led by Kaiser Permanente’s Lisa Jackson involved healthy adult volunteers. Each volunteer received two vaccinations in the upper arm at one of three doses, given approximately one month apart.

The volunteers will be tracked for a full year, allowing researchers to monitor their health and antibody production. However, the recently published paper provides interim data on the phase 1 trial’s first 45 participants, ages 18 to 55, for the first 57 days after their second vaccination. The data revealed:

• No volunteers suffered serious adverse events.

• Optimal dose to elicit high levels of neutralizing antibody activity, while also protecting patient safety, appears to be 100 micrograms. Doses administered in the phase 1 trial were either 25, 100, or 250 micrograms.

• More than half of the volunteers reported fatigue, headache, chills, muscle aches, or pain at the injection site. Those symptoms were most common after the second vaccination and in volunteers who received the highest vaccine dose. That dose will not be used in larger trials.

• Two doses of 100 micrograms of the vaccine prompted a robust immune response, which was last measured 43 days after the second dose. These responses were actually above the average levels seen in blood samples from people who had recovered from COVID-19.

These encouraging results are being used to inform the next rounds of human testing of the mRNA-1273 vaccine. A phase 2 clinical trial is already well on its way to recruiting 600 healthy adults.This study will continue to profile the vaccine’s safety, as well as its ability to trigger an immune response.

Meanwhile, later this month, a phase 3 clinical trial will begin enrolling 30,000 volunteers, with particular focus on recruitment in regions and populations that have been particularly hard hit by the virus.

The design of that trial, referred to as a “master protocol,” had major contributions from the Accelerating COVID-19 Therapeutic Interventions and Vaccine (ACTIV) initiative, a remarkable public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies. Now, a coordinated effort across the U.S. government, called Operation Warp Speed, is supporting rapid conduct of these clinical trials and making sure that millions of doses of any successful vaccine will be ready if the vaccine proves save and effective.

Results of this first phase 3 trial are expected in a few months. If you are interested in volunteering for these or other prevention trials, please check out NIH’s new COVID-19 clinical trials network.

There’s still a lot of work that remains to be done, and anything can happen en route to the finish line. But by pulling together, and leaning on the very best science, I am confident that we will be able rise to the challenge of ending this pandemic that has devastated so many lives.

Reference:

[1] A SARS-CoV-2 mRNA Vaccine—Preliminary Report. Jackson LA, Anderson EJ, Rouphael NG, Ledgerwood JE, Graham BS, Beigel JH, et al. NEJM. 2020 July 14. [Publication ahead of print]

Links:

Coronavirus (COVID-19) (NIH)

Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)

Moderna, Inc. (Cambridge, MA)

Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) (ClinicalTrials.gov)

NIH Launches Clinical Trials Network to Test COVID-19 Vaccines and Other Prevention Tools,” NIAID News Release, NIH, July 8, 2020.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

Explaining Operation Warp Speed (U.S. Department of Health and Human Services, Washington, DC)

NIH Support: National Institute of Allergy and Infectious Diseases


To Beat COVID-19, Social Distancing is a Must

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Teleworking with family at home
gettyimages/SDI Productions

Even in less challenging times, many of us try to avoid close contact with someone who is sneezing, coughing, or running a fever to avoid getting sick ourselves. Our attention to such issues has now been dramatically heightened by the emergence of a novel coronavirus causing a pandemic of an illness known as COVID-19.

Many have wondered if we couldn’t simply protect ourselves by avoiding people with symptoms of respiratory illness. Unfortunately, the answer is no. A new study shows that simply avoiding symptomatic people will not go far enough to curb the COVID-19 pandemic. That’s because researchers have discovered that many individuals can carry the novel coronavirus without showing any of the typical symptoms of COVID-19: fever, dry cough, and shortness of breath. But these asymptomatic or only mildly ill individuals can still shed virus and infect others.

This conclusion adds further weight to the recent guidance from U.S. public health experts: what we need most right now to slow the stealthy spread of this new coronavirus is a full implementation of social distancing. What exactly does social distancing mean? Well, for starters, it is recommended that people stay at home as much as possible, going out only for critical needs like groceries and medicines, or to exercise and enjoy the outdoors in wide open spaces. Other recommendations include avoiding gatherings of more than 10 people, no handshakes, regular handwashing, and, when encountering someone outside of your immediate household, trying to remain at least 6 feet apart.

These may sound like extreme measures. But the new study by NIH-funded researchers, published in the journal Science, documents why social distancing may be our best hope to slow the spread of COVID-19 [1]. Here are a few highlights of the paper, which looks back to January 2020 and mathematically models the spread of the coronavirus within China:

• For every confirmed case of COVID-19, there are likely another five to 10 people with undetected infections.
• Although they are thought to be only about half as infectious as individuals with confirmed COVID-19, individuals with undetected infections were so prevalent in China that they apparently were the infection source for 86 percent of confirmed cases.
• After China established travel restrictions and social distancing, the spread of COVID-19 slowed considerably.

The findings come from a small international research team that included NIH grantee Jeffrey Shaman, Columbia University Mailman School of Public Health, New York. The team developed a computer model that enabled researchers to simulate the time and place of infections in a grid of 375 Chinese cities. The researchers did so by combining existing data on the spread of COVID-19 in China with mobility information collected by a location-based service during the country’s popular 40-day Spring Festival, when travel is widespread.

As these new findings clearly demonstrate, each of us must take social distancing seriously in our daily lives. Social distancing helped blunt the pandemic in China, and it will work in other nations, including the United States. While many Americans will likely spend weeks working and studying from home and practicing other social distancing measures, the stakes remain high. If this pandemic isn’t contained, this novel coronavirus could well circulate around the globe for years to come, at great peril to us and our loved ones.

As we commit ourselves to spending more time at home, progress continues to be made in using the power of biomedical research to combat this novel coronavirus. A notable step this week was the launch of an early-stage human clinical trial of an investigational vaccine, called mRNA-1273, to protect against COVID-19 [2]. The vaccine candidate was developed by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and their collaborators at the biotechnology company Moderna, Inc., Cambridge, MA.

This Phase 1 NIAID-supported trial will look at the safety of the vaccine—which cannot cause infection because it is made of RNA, not the whole coronavirus—in 45 healthy adults. The first volunteer was injected this past Monday at Kaiser Permanente Washington Health Research Institute, Seattle. If all goes well and larger follow-up clinical studies establish the vaccine’s safety and efficacy, it will then be necessary to scale up production to make millions of doses. While initiating this trial in record time is reason for hope, it is important to be realistic about all of the steps that still remain. If the vaccine candidate proves safe and effective, it will likely take at least 12–18 months before it would be widely available.

In the meantime, social distancing remains one of the best weapons we have to slow the silent spread of this virus and flatten the curve of the COVID-19 pandemic. This will give our health-care professionals, hospitals, and other institutions more valuable time to prepare, protect themselves, and aid the many people whose lives may be on the line from this coronavirus.

Importantly, saving lives from COVID-19 requires all of us—young, old and in-between—to take part. Healthy young people, whose risk of dying from coronavirus is not zero but quite low, might argue that they shouldn’t be constrained by social distancing. However, the research highlighted here demonstrates that such individuals are often the unwitting vector for a dangerous virus that can do great harm—and even take the lives of older and more vulnerable people. Think about your grandparents. Then skip the big gathering. We are all in this together

References:

[1] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, Shaman J. Science. 16 March 2020. [Preprint ahead of publication]

[2] NIH clinical trial of investigational vaccine for COVID-19 begins. NIH News Release, March 16, 2020.

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Coronavirus (COVID-19) (Centers for Disease Control and Prevention, Atlanta)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences