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COVID-19 vaccine

Is One Vaccine Dose Enough After COVID-19 Infection?

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COVID-19 vaccination record card
Credit: iStock/Bill Oxford

For the millions of Americans now eligible to receive the Pfizer or Moderna COVID-19 vaccines, it’s recommended that everyone get two shots. The first dose of these mRNA vaccines trains the immune system to recognize and attack the spike protein on the surface of SARS-CoV-2, the virus that causes COVID-19. The second dose, administered a few weeks later, boosts antibody levels to afford even better protection. People who’ve recovered from COVID-19 also should definitely get vaccinated to maximize protection against possible re-infection. But, because they already have some natural immunity, would just one shot do the trick? Or do they still need two?

A small, NIH-supported study, published as a pre-print on medRxiv, offers some early data on this important question [1]. The findings show that immune response to the first vaccine dose in a person who’s already had COVID-19 is equal to, or in some cases better, than the response to the second dose in a person who hasn’t had COVID-19. While much more research is needed—and I am definitely not suggesting a change in the current recommendations right now—the results raise the possibility that one dose might be enough for someone who’s been infected with SARS-CoV-2 and already generated antibodies against the virus.

These findings come from a research team led by Florian Krammer and Viviana Simon, Icahn School of Medicine at Mount Sinai, New York. The researchers reasoned that for folks whose bodies have already produced antibodies following a COVID-19 infection, the first shot might act similarly to the second one in someone who hadn’t had the virus before. In fact, there was some anecdotal evidence suggesting that previously infected people were experiencing stronger evidence of an active immune response (sore arm, fever, chills, fatigue) than never-infected individuals after getting their first shots.

What did the antibodies show? To find out, the researchers enlisted the help of 109 people who’d received their first dose of mRNA vaccines made by either Pfizer or Moderna. They found that those who’d never been infected by SARS-CoV-2 developed antibodies at low levels within 9 to 12 days of receiving their first dose of vaccine.

But in 41 people who tested positive for SARS-CoV-2 antibodies prior to getting the first shot, the immune response looked strikingly different. They generated high levels of antibodies within just a few days of getting the vaccine. Compared across different time intervals, previously infected people had immune responses 10 to 20 times that observed in uninfected people. Following their second vaccine dose, it was roughly the same story. Antibody levels in those with a prior infection were about 10 times greater than the others.

Both vaccines were generally well tolerated. But, because their immune systems were already in high gear, people who were previously infected tended to have more symptoms following their first shot, such as pain and swelling at the injection site. They also were more likely to report other less common symptoms, including fatigue, fever, chills, headache, muscle aches, and joint pain.

Though sometimes it may not seem like it, COVID-19 and the mRNA vaccines are still relatively new. Researchers haven’t yet been able to study how long these vaccines confer immunity to the disease, which has now claimed the lives of more than 500,000 Americans. But these findings do suggest that a single dose of the Pfizer or Moderna vaccines can produce a rapid and strong immune response in people who’ve already recovered from COVID-19.

If other studies support these results, the U.S. Food and Drug Administration (FDA) might decide to consider whether one dose is enough for people who’ve had a prior COVID-19 infection. Such a policy is already under consideration in France and, if implemented, would help to extend vaccine supply and get more people vaccinated sooner. But any serious consideration of this option will require more data. It will also be up to the expert advisors at FDA and Centers for Disease Control and Prevention (CDC) to decide.

For now, the most important thing all of us can all do to get this terrible pandemic under control is to follow the 3 W’s—wear our masks, wash our hands, watch our distance from others—and roll up our sleeves for the vaccine as soon as it’s available to us.

Reference:

[1] Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. Krammer F et al. medRxiv. 2021 Feb 1.

Links:

COVID-19 Research (NIH)

Krammer Lab (Icahn School of Medicine at Mount Sinai, New York, NY)

Simon Lab (Icahn School of Medicine at Mount Sinai)

NIH Support: National Institute of Allergy and Infectious Diseases


ACTIV Update: Making Major Strides in COVID-19 Therapeutic Development

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NIH ACTIV
Credit: NIH

Right now, many U.S. hospitals are stretched to the limit trying to help people battling serious cases of COVID-19. But as traumatic as this experience still is for patients and their loved ones, the chances of surviving COVID-19 have in fact significantly improved in the year since the start of the pandemic.

This improvement stems from several factors, including the FDA’s emergency use authorization (EUA) of a number of therapies found to be safe and effective for COVID-19. These include drugs that you may have heard about on the news: remdesivir (an antiviral), dexamethasone (a steroid), and monoclonal antibodies from the companies Eli Lilly and Regeneron.

Yet the quest to save more lives from COVID-19 isn’t even close to being finished, and researchers continue to work intensively to develop new and better treatments. A leader in this critical effort is NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, a public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies.

ACTIV was founded last April to accelerate drug research that typically requires more than a decade of clinical ups and downs to develop a safe, effective therapy. And ACTIV has indeed moved at unprecedented speed since its launch. Cutting through the usual red tape and working with an intense sense of purpose, the partnership took a mere matter of weeks to set up its first four clinical trials. Beyond the agents mentioned above that have already been granted an EUA, ACTIV is testing 15 additional potential agents, with several of these already demonstrating promising results.

Here’s how ACTIV works. The program relies on four expert “working groups” with specific charges:

Preclinical Working Group: Shares standardized preclinical evaluation resources and accelerate testing of candidate therapies and vaccines for clinical trials.

Therapeutics Clinical Working Group: Prioritizes therapeutic agents for testing within an adaptive master protocol strategy for clinical research.

Clinical Trial Capacity Working Group: Has developed and organized an inventory of clinical trial capacity that can serve as potential settings in which to implement effective COVID-19 clinical trials.

Vaccines Working Group: Accelerates the evaluation of vaccine candidates.

To give you just one example of how much these expert bodies have accomplished in record time, the Therapeutics Clinical Working Group got to work immediately evaluating some 400 candidate therapeutics using multiple publicly available information sources. These candidates included antivirals, host-targeted immune modulators, monoclonal antibodies (mAb), and symptomatic/supportive agents including anticoagulants. To follow up on even more new leads, the working group launched a COVID-19 Clinical & Preclinical Candidate Compound Portal, which remains open for submissions of therapeutic ideas and data.

All the candidate agents have been prioritized using rigorous scoring and assessment criteria. What’s more, the working group simultaneously developed master protocols appropriate for each of the drug classes selected and patient populations: outpatient, inpatient, or convalescent.

Through the coordinated efforts of all the working groups, here’s where we stand with the ACTIV trials:

ACTIV-1: A large-scale Phase 3 trial is enrolling hospitalized adults to test the safety and effectiveness of three medicines (cenicriviroc, abatacept, and infliximab). They are called immune modulators because they help to minimize the effects of an overactive immune response in some COVID-19 patients. This response, called a “cytokine storm,” can lead to acute respiratory distress syndrome, multiple organ failure, and other life-threatening complications.

ACTIV-2: A Phase 2/3 trial is enrolling adults with COVID-19 who are not hospitalized to evaluate the safety of multiple monoclonal antibodies (Lilly’s LY-CoV555, Brii Biosciences’s BRII-196 and BRII-198, and AstraZeneca’s AZD7442) used to block or neutralize the SARS-CoV-2 virus. The Lilly monoclonal antibody LY-CoV555 received an EUA for high risk non-hospitalized patients on November 9, 2020 and ACTIV-2 continued to test the agent in an open label study to further determine safety and efficacy in outpatients. Another arm of this trial has just started, testing inhaled, easy-to-administer interferon beta-1a treatment in adults with mild-to-moderate COVID-19 who are not hospitalized. An additional arm will test the drug camostat mesilate, a protease inhibitor that can block the TMPRSS2 host protein that is necessary for viral entry into human cells.

ACTIV-3: This Phase 3 trial is enrolling hospitalized adults with COVID-19. This study primarily aims to evaluate safety and to understand if monoclonal antibodies (AstraZeneca’s AZD7442, BRII-196 and BRII-198, and the VIR-7831 from GSK/Vir Biotechnology) and potentially other types of therapeutics can reduce time to recovery. It also aims to understand a treatment’s effect on extrapulmonary complications and respiratory dysfunction. Lilly’s monoclonal antibody LY-CoV555 was one of the first agents to be tested in this clinical trial and it was determined to not show the same benefits seen in outpatients.

ACTIV-4: This trial aims to determine if various types of blood thinners, including apixaban, aspirin, and both unfractionated (UF) and low molecular weight (LMW) heparin, can treat adults diagnosed with COVID-19 and prevent life-threatening blood clots from forming. There are actually three Phase 3 trials included in ACTIV-4. One is enrolling people diagnosed with COVID-19 but who are not hospitalized; a second is enrolling patients who are hospitalized; and a third is enrolling people who are recovering from COVID-19. ACTIV-4 has already shown that full doses of heparin blood thinners are safe and effective for moderately ill hospitalized patients.

ACTIV-5: This is a Phase 2 trial testing newly identified agents that might have a major benefit to hospitalized patients with COVID-19, but that need further “proof of concept” testing before they move into a registrational Phase 3 trial. (In fact, another name for this trial is the “Big Effect Trial”.) It is testing medicines previously developed for other conditions that might be beneficial in treatment of COVID-19. The first two agents being tested are risankizumab (the result of a collaboration between Boehringer-Ingelheim), which is already FDA-approved to treat plaque psoriasis, and lenzilumab, which is under development by Humanigen to treat patients experiencing cytokine storm as part of cancer therapy.

In addition to trials conducted under the ACTIV partnership, NIH has prioritized and tested additional therapeutics in “ACTIV-associated trials.” These are NIH-funded, randomized, placebo-controlled clinical trials with one or more industry partners. Here’s a table with a comprehensive list.

Looking a bit further down the road, we also seek to develop orally administered drugs that would potentially block the replication ability of SARS-CoV-2, the coronavirus that causes COVID-19, in the earliest stages of infection. One goal would be to develop an antiviral medication for SARS-CoV-2 that acts similarly to oseltamivir phosphate (Tamiflu®), a drug used to shorten the course of the flu in people who’ve had symptoms for less than two days and to prevent the flu in asymptomatic people who may have been exposed to the influenza virus. Yet another major long-term effort of NIH and its partners will be to develop safe and effective antiviral medications that work against all coronaviruses, even those with variant genomes. (And, yes, such drugs might even cure the common cold!)

So, while our ACTIV partners and many other researchers around the globe continue to harness the power of science to end the devastating COVID-19 pandemic as soon as possible, we must also consider the lessons learned this past year, in order to prepare ourselves to respond more swiftly to future outbreaks of coronaviruses and other infectious disease threats. Our work is clearly a marathon, not a sprint.

Links:

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

COVID-19 Research (NIH)

Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)

Pull Up a Chair with Dr. Freire: The COVID Conversations (Foundation for the National Institutes of Health, Bethesda, MD)

SARS-COV-2 Antiviral Therapeutics Summit Report, November 2020 (NIH)


Mapping Which Coronavirus Variants Will Resist Antibody Treatments

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Antibodies Binding to RBD
Caption: The antibody LY-CoV016 (purple) is bound to RBD. This “escape map” indicates where in the viral RBD new mutations are most likely to make LY-CoV016 less effective (red). It also shows places where mutations are least likely to affect antibody binding (white) and where mutations can’t persist because they’d disrupt RBD’s ability to function (gray). Credit: Adapted from TN Starr, Science, 2021.

You may have heard about the new variants of SARS-CoV-2—the coronavirus that causes COVID-19—that have appeared in other parts of the world and have now been detected in the United States. These variants, particularly one called B.1.351 that was first identified in South Africa, have raised growing concerns about the extent to which their mutations might help them evade current antibody treatments and highly effective vaccines.

While researchers take a closer look, it’s already possible in the laboratory to predict which mutations will help SARS-CoV-2 evade our therapies and vaccines, and even to prepare for the emergence of new mutations before they occur. In fact, an NIH-funded study, which originally appeared as a bioRxiv pre-print in November and was recently peer-reviewed and published in Science, has done exactly that. In the study, researchers mapped all possible mutations that would allow SARS-CoV-2 to resist treatment with three different monoclonal antibodies developed for treatment of COVID-19 [1].

The work, led by Jesse Bloom, Allison Greaney, and Tyler Starr, Fred Hutchinson Cancer Center, Seattle, focused on the receptor binding domain (RBD), a key region of the spike protein that studs SARS-CoV-2’s outer surface. The virus uses RBD to anchor itself to the ACE2 receptor of human cells before infecting them. That makes the RBD a prime target for the antibodies that our bodies generate to defend against the virus.

In the new study, researchers used a method called deep mutational scanning to find out which mutations positively or negatively influence the RBD from being able to bind to ACE2 and/or thwart antibodies from striking their target. Here’s how it works: Rather than waiting for new mutations to arise, the researchers created a library of RBD fragments, each of which contained a change in a single nucleotide “letter” that would alter the spike protein’s shape and/or function by swapping one amino acid for another. It turns out that there are more than 3,800 such possible mutations, and Bloom’s team managed to make all but a handful of those versions of the RBD fragment.

The team then used a standard laboratory approach to measure systematically how each of those single-letter typos altered RBD’s ability to bind ACE2 and infect human cells. They also measured how those changes affected three different therapeutic antibodies from recognizing and binding to the viral RBD. Those antibodies include two developed by Regeneron (REGN10933 and REGN10987), which have been granted emergency use authorization for treatment of COVID-19 together as a cocktail called REGN-COV2. They also looked at an antibody developed by Eli Lilly (LY-CoV016), which is now in phase 3 clinical trials for treating COVID-19.

Based on the data, the researchers created four mutational maps for SARS-CoV-2 to escape each of the three therapeutic antibodies, as well as for the REGN-COV2 cocktail. Their studies show most of the mutations that would allow SARS-CoV-2 to escape treatment differed between the two Regeneron antibodies. That’s encouraging because it indicates that the virus likely needs more than one mutation to become resistant to the REGN-COV2 cocktail. However, it appears there’s one spot where a single mutation could allow the virus to resist REGN-COV2 treatment.

The escape map for LY-CoV016 similarly showed a number of mutations that could allow the virus to escape. Importantly, while some of those changes might impair the virus’s ability to cause infection, most of them appeared to come at little to no cost to the virus to reproduce.

How do these laboratory data relate to the real world? To begin to explore this question, the researchers teamed up with Jonathan Li, Brigham and Women’s Hospital, Boston. They looked at an immunocompromised patient who’d had COVID-19 for an unusually long time and who was treated with the Regeneron cocktail for 145 days, giving the virus time to replicate and acquire new mutations.

Viral genome data from the infected patient showed that these maps can indeed be used to predict likely paths of viral evolution. Over the course of the antibody treatment, SARS-CoV-2 showed changes in the frequency of five mutations that would change the makeup of the spike protein and its RBD. Based on the newly drawn escape maps, three of those five are expected to reduce the efficacy of REGN10933. One of the others is expected to limit binding by the other antibody, REGN10987.

The researchers also looked to data from all known circulating SARS-CoV-2 variants as of Jan. 11, 2021, for evidence of escape mutations. They found that a substantial number of mutations with potential to allow escape from antibody treatment already are present, particularly in parts of Europe and South Africa.

However, it’s important to note that these maps reflect just three important antibody treatments. Bloom says they’ll continue to produce maps for other promising therapeutic antibodies. They’ll also continue to explore where changes in the virus could allow for escape from the more diverse set of antibodies produced by our immune system after a COVID-19 infection or vaccination.

While it’s possible some COVID-19 vaccines may offer less protection against some of these new variants—and recent results have suggested the AstraZeneca vaccine may not provide much protection against the South African variant, there’s still enough protection in most other current vaccines to prevent serious illness, hospitalization, and death. And the best way to keep SARS-CoV-2 from finding new ways to escape our ongoing efforts to end this terrible pandemic is to double down on whatever we can do to prevent the virus from multiplying and spreading in the first place.

For now, emergence of these new variants should encourage all of us to take steps to slow the spread of SARS-CoV-2. That means following the three W’s: Wear a mask, Watch your distance, Wash your hands often. It also means rolling up our sleeves to get vaccinated as soon as the opportunity arises.

Reference:

[1] Prospective mapping of viral mutations that escape antibodies used to treat COVID-19.
Starr TN, Greaney AJ, Addetia A, Hannon WW, Choudhary MC, Dingens AS, Li JZ, Bloom JD.
Science. 2021 Jan 25:eabf9302.

Links:

COVID-19 Research (NIH)

Bloom Lab (Fred Hutchinson Cancer Center, Seattle)

NIH Support: National Institute of Allergy and Infectious Diseases


A Double Thumbs Up

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VP Visit
It was an honor welcoming the 49th Vice President of the United States Kamala Harris to NIH on January 26, 2021. She received her second dose of the Moderna COVID-19 vaccine at the NIH Clinical Center in a livestreamed event. All was a thumbs up afterwards. The NIH community thanks Vice President Harris for her kind words and looks forward to her future visits to the NIH campus. Credit: NIH


Following COVID-19 Vaccines Across the United States

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Vaccine Tracker

Recently, there is a new and very hopeful COVID-19 number for everyone to track: the total number of vaccine doses that have been administered in the United States. If 80 percent of Americans roll up their sleeves in the coming months and accept COVID-19 vaccinations, we can greatly slow the spread of the novel coronavirus in our communities and bring this horrible pandemic to an end in 2021.

So far, more than 20 million people in our country have received one or two doses of either the Pfizer or Moderna vaccine. While this number is lower than initially projected for a variety of logistical reasons, we’re already seeing improvements in the distribution system that has made it possible to get close to 1 million doses administered per day.

If you want to keep track of the vaccine progress in your state over the coming weeks, it’s now pretty easy to do online. A fine resource is the vaccine information on the Centers for Disease Control and Prevention (CDC) COVID Data Tracker. It offers an interactive state-by-state map, as well as data on vaccinations in long-term care facilities. Keep in mind that there’s a delay of three to five days in reporting actual vaccinations from the states.

There’s also a lot of useful information on the Johns Hopkins Coronavirus Resource Center’s Vaccine Tracker. Posting the daily updates is a team, led by William Moss, that draws on the expertise of data scientists, analysts, programmers, and researchers. The Hopkins team gathers its vaccination data from each state’s official dashboard, webpages, press releases, or wherever cumulative numbers are reported. Not all states publish the same vaccine information, and that’s what can make the Vaccine Tracker so challenging to compile.

The Hopkins team now presents on its homepage the top 10 U. S. states and territories to vaccinate fully the highest percentage of their residents. With another click, there’s also a full rundown of vaccine administration by state and territory, plus the District of Columbia. The site also links to lots of other information about COVID-19—including cases, testing, contact tracing, and an interactive tool about vaccine development.

In uncertain times, knowledge can be a source of comfort. That’s what makes these interactive COVID-19 resources so helpful and empowering. They show that, with time, safe and effective COVID-19 vaccines will indeed coming to everyone. I hope that you will accept your vaccine, like I did when given the opportunity. However, until we get to the point where most Americans are immunized, we must stay vigilant and keep up our tried-and-true public health measures such as wearing masks, limiting physical interactions (especially indoors), and washing our hands.

Links:

COVID-19 Research (NIH)

CDC COVID Data Tracker (Centers for Disease Control and Prevention, Atlanta)

Coronavirus Resource Center (Johns Hopkins University School of Medicine)

William Moss (Johns Hopkins University, Baltimore)

International Vaccine Access Center (Johns Hopkins Bloomberg School of Public Health, Baltimore)



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