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Tuberculosis: An Ancient Disease in Need of Modern Scientific Tools

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Two men, one holds an award
Caption: Here I am with Paul Farmer, who was a strong voice for improving TB prevention and treatments in resource-scarce settings, when he came to NIH in 2007 to deliver my institute’s James C. Hill Memorial Lecture. Credit: NIH

Although COVID-19 has dominated our attention for the past two years, tuberculosis (TB), an ancient scourge, remains a dominating infectious disease globally, with an estimated 10 million new cases and more than 1.3 million deaths in 2020. TB disproportionately afflicts the poor and has long been the leading cause of death in people living with HIV.

Unfortunately, during the global COVID-19 pandemic, recent gains in TB control have been stalled or reversed. We’ve seen a massive drop in new TB diagnoses, reflecting poor access to care and an uptick in deaths in 2020 [1].

We are fighting TB with an armory of old weapons inferior to those we have for COVID-19. The Bacillus Calmette–Guérin (BCG) vaccine, the world’s only licensed TB vaccine, has been in use for more than 100 years. While BCG is somewhat effective at preventing TB meningitis in children, it provides more limited durable protection against pulmonary TB in children and adults. More effective vaccination strategies to prevent infection and disease, decrease relapse rates, and shorten durations of treatment are desperately needed to reduce the terrible global burden of TB.

In this regard, over the past five years, several exciting research advances have generated new optimism in the field of TB vaccinology. Non-human primate studies conducted at my National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center and other NIAID-funded laboratories have demonstrated that effective immunity against infection is achievable and that administering BCG intravenously, rather than under the skin as it currently is given, is highly protective [2].

Results from a phase 2 trial testing BCG revaccination in adolescents at high risk of TB infection suggested this approach could help prevent TB [3]. In addition, a phase 2 trial of an experimental TB vaccine based on the recombinant protein M72 and an immune-priming adjuvant, AS01, also showed promise in preventing active TB disease in latently infected adults [4].

Both candidates are now moving on to phase 3 efficacy trials. The encouraging results of these trials, combined with nine other candidates currently in phase 2 or 3 studies [5], offer new hope that improved vaccines may be on the horizon. The NIAID is working with a team of other funders and investigators to analyze the correlates of protection from these studies to inform future TB vaccine development.

Even with these exciting developments, it is critical to accelerate our efforts to enhance and diversify the TB vaccine pipeline by addressing persistent basic and translational research gaps. To this end, NIAID has several new programs. The Immune Protection Against Mtb Centers are taking a multidisciplinary approach to integrate animal and human data to gain a comprehensive understanding of the immune responses required to prevent TB infection and disease.

This spring, NIAID will fund awards under the Innovation for TB Vaccine Discovery program that will focus on the discovery and early evaluation of novel TB vaccine candidates with the goal of diversifying the TB vaccine pipeline. Later this year, the Advancing Vaccine Adjuvant Research for TB program will systematically assess combinations of TB immunogens and adjuvants. Finally, NIAID’s well-established clinical trials networks are planning two new clinical trials of TB vaccine candidates.

As we look to the future, we must apply the lessons learned in the development of the COVID-19 vaccines to longstanding public health challenges such as TB. COVID-19 vaccine development was hugely successful due to the use of novel vaccine platforms, structure-based vaccine design, community engagement for rapid clinical trial enrollment, real-time data sharing with key stakeholders, and innovative trial designs.

However, critical gaps remain in our armamentarium. These include the harnessing the immunology of the tissues that line the respiratory tract to design vaccines more adept at blocking initial infection and transmission, employing thermostable formulations and novel delivery systems for resource-limited settings, and crafting effective messaging around vaccines for different populations.

As we work to develop better ways to prevent, diagnose, and treat TB, we will do well to remember the great public health icon, Paul Farmer, who tragically passed away earlier this year at a much too young age. Paul witnessed firsthand the devastating consequences of TB and its drug resistant forms in Haiti, Peru, and other parts of the world.

In addition to leading efforts to improve how TB is treated, Paul provided direct patient care in underserved communities and demanded that the world do more to meet their needs. As we honor Paul’s legacy, let us accelerate our efforts to find better tools to fight TB and other diseases of global health importance that exact a disproportionate toll among the poor and underserved.

References:

[1] Global tuberculosis report 2021. WHO. October 14, 2021.

[2] Prevention of tuberculosis in macaques after intravenous BCG immunization. Darrah PA, Zeppa JJ, Maiello P, Hackney JA, Wadsworth MH,. Hughes TK, Pokkali S, Swanson PA, Grant NL, Rodgers MA, Kamath M, Causgrove CM, Laddy DJ, Bonavia A, Casimiro D, Lin PL, Klein E, White AG, Scanga CA, Shalek AK, Roederer M, Flynn JL, and Seder RA. Nature. 2020 Jan 1; 577: 95–102.

[3] Prevention of M. tuberculosis Infection with H4:IC31 vaccine or BCG revaccination. Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F,Bilek N., Mabwe S, Makhethe L, Erasmus M, Toefy A, Mulenga H, Hanekom WA, et al. N Engl J Med 2018; 379:138-149.

[4] Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, Scriba TJ, Akite EJ, Ayles HM, et al.

[5] Pipeline Report 2021: Tuberculosis Vaccines. TAG. October 2021.

Links:

Tuberculosis (National Institute of Allergy and Infectious Diseases/NIH)

NIAID Strategic Plan for Tuberculosis Research

Immune Mechanisms of Protection Against Mycobacterium tuberculosis Centers (IMPAc-TB) (NIAID)

Partners in Health (Boston, MA)

[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the seventh in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]


Discussing the Need for Reliable Antibody Testing for COVID-19

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At Home with Ned Sharpless

There’s been a great deal of discussion about whether people who recover from coronavirus disease 2019 (COVID-19), have neutralizing antibodies in their bloodstream to guard against another infection. Lots of interesting data continue to emerge, including a recent preprint from researchers at Sherman Abrams Laboratory, Brooklyn, NY [1]. They tested 11,092 people for antibodies in May at a local urgent care facility and found nearly half had long-lasting IgG antibodies, a sign of exposure to the novel coronavirus SARS-CoV-2, the cause of COVID-19. The researchers also found a direct correlation between the severity of a person’s symptoms and their levels of IgG antibodies.

This study and others remind us of just how essential antibody tests will be going forward to learn more about this challenging pandemic. These assays must have high sensitivity and specificity, meaning there would be few false negatives and false positives, to tell us more about a person’s exposure to SARS-CoV-2. While there are some good tests out there, not all are equally reliable.

Recently, I had a chance to discuss COVID-19 antibody tests, also called serology tests, with Dr. Norman “Ned” Sharpless, Director of NIH’s National Cancer Institute (NCI). Among his many talents, Dr. Sharpless is an expert on antibody testing for COVID-19. You might wonder how NCI got involved in COVID-19 testing. Well, you’re going to find out. Our conversation took place while videoconferencing, with him connecting from North Carolina and me linking in from my home in Maryland. Here’s a condensed transcript of our chat:

Collins: Ned, thanks for joining me. Maybe we should start with the basics. What are antibodies anyway?

Sharpless: Antibodies are proteins that your body makes as part of the learned immune system. It’s the immunity that responds to a bacterium or a virus. In general, if you draw someone’s blood after an infection and test it for the presence of these antibodies, you can often know whether they’ve been infected. Antibodies can hang around for quite a while. How long exactly is a topic of great interest, especially in terms of the COVID-19 pandemic. But we think most people infected with coronavirus will make antibodies at a reasonably high level, or titer, in their peripheral blood within a couple of weeks of the infection.

Collins: What do antibodies tell us about exposure to a virus?

Sharpless: A lot of people with coronavirus are infected without ever knowing it. You can use these antibody assays to try and tell how many people in an area have been infected, that is, you can do a so-called seroprevalence survey.

You could also potentially use these antibody assays to predict someone’s resistance to future infection. If you cleared the infection and established immunity to it, you might be resistant to future infection. That might be very useful information. Maybe you could make a decision about how to go out in the community. So, that part is of intense interest as well, although less scientifically sound at the moment.

Collins: I have a 3D-printed model of SARS-CoV-2 on my desk. It’s sort of a spherical virus that has spike proteins on its surface. Do the antibodies interact with the virus in some specific ways?

Sharpless: Yes, antibodies are shaped like the letter Y. They have two binding domains at the head of each Y that will recognize something about the virus. We find antibodies in the peripheral blood that recognize either the virus nucleocapsid, which is the structural protein on the inside; or the spikes, which stick out and give coronavirus its name. We know now that about 99 percent of people who get infected with the virus will develop antibodies eventually. Most of those antibodies that you can detect to the spike proteins will be neutralizing, which means they can kill the virus in a laboratory experiment. We know from other viruses that, generally, having neutralizing antibodies is a promising sign if you want to be immune to that virus in the future.

Collins: Are COVID-19 antibodies protective? Are there reports of people who’ve gotten better, but then were re-exposed and got sick again?

Sharpless: It’s controversial. People can shed the virus’s nucleic acid [genetic material], for weeks or even more than a month after they get better. So, if they have another nucleic acid test it could be positive, even though they feel better. Often, those people aren’t making a lot of live virus, so it may be that they never stopped shedding the virus. Or it may be that they got re-infected. It’s hard to understand what that means exactly. If you think about how many people worldwide have had COVID-19, the number of legitimate possible reinfection cases is in the order of a handful. So, it’s a pretty rare event, if it happens at all.

Collins: For somebody who does have the antibodies, who apparently was previously infected, do they need to stop worrying about getting exposed? Can they can do whatever they want and stop worrying about distancing and wearing masks?

Sharpless: No, not yet. To use antibodies to predict who’s likely to be immune, you’ve got to know two things.

First: can the tests actually measure antibodies reliably? I think there are assays available to the public that are sufficiently good for asking this question, with an important caveat. If you’re trying to detect something that’s really rare in a population, then any test is going to have limitations. But if you’re trying to detect something that’s more common, as the virus was during the recent outbreak in Manhattan, I think the tests are up to the task.

Second: does the appearance of an antibody in the peripheral blood mean that you’re actually immune or you’re just less likely to get the virus? We don’t know the answer to that yet.

Collins: Let’s be optimistic, because it sounds like there’s some evidence to support the idea that people who develop these antibodies are protected against infection. It also sounds like the tests, at least some of them, are pretty good. But if there is protection, how long would you expect it to last? Is this one of those things where you’re all set for life? Or is this going to be something where somebody’s had it and might get it again two or three years from now, because the immunity faded away?

Sharpless: Since we have no direct experience with this virus over time, it’s hard to answer. The potential for this cell-based humoral immunity to last for a while is there. For some viruses, you have a long-lasting antibody protection after infection; for other viruses, not so much.

So that’s the unknown thing. Is immunity going to last for a while? Of course, if one were to bring up the topic of vaccines, that’s very important to know, because you would want to know how often one would have to give that vaccine, even under optimal circumstances.

Collins: Yes, our conversation about immunity is really relevant to the vaccines we’re trying to develop right now. Will these vaccines be protective for long periods of time? We sure hope so, but we’ve got to look carefully at the issue. Let’s come back, though, to the actual performance of the tests. The NCI has been right in the middle of trying to do this kind of validation. How did that happen, and how did that experience go?

Sharpless: Yes, I think one might ask: why is the National Cancer Institute testing antibody kits for the FDA? It is unusual, but certainly not unheard of, for NCI to take up problems like this during a time of a national emergency. During the HIV era, NCI scientists, along with others, identified the virus and did one of the first successful compound screens to find the drug AZT, one of the first effective anti-HIV therapies.

NCI’s Frederick National Lab also has a really good serology lab that had been predominantly working on human papillomavirus (HPV). When the need arose for serologic testing a few months ago, we pivoted that lab to a coronavirus serology lab. It took us a little while, but eventually we rounded up everything you needed to create positive and negative reference panels for antibody testing.

At that time, the FDA had about 200 manufacturers making serology tests that hoped for approval to sell. The FDA wanted some performance testing of those assays by a dispassionate third party. The Frederick National Lab seemed like the ideal place, and the manufacturers started sending us kits. I think we’ve probably tested on the order of 20 so far. We give those data back to the FDA for regulatory decision making. They’re putting all the data online.

Collins: How did it look? Are these all good tests or were there some clunkers?

Sharpless: There were some clunkers. But we were pleased to see that some of the tests appear to be really good, both in our hands and those of other groups, and have been used in thousands of patients.

There are a few tests that have sensitivities that are pretty high and specificities well over 99 percent. The Roche assay has a 99.8 percent specificity claimed on thousands of patients, and for the Mt. Sinai assay developed and tested by our academic collaborators in a panel of maybe 4,000 patients, they’re not sure they’ve ever had a false positive. So, there are some assays out there that are good.

Collins: There’s been talk about how there will soon be monoclonal antibodies directed against SARS-CoV-2. How are those derived?

Sharpless: They’re picked, generally, for appearing to have neutralizing activity. When a person makes antibodies, they don’t make one antibody to a pathogen. They make a whole family of them. And those can be individually isolated, so you can know which antibodies made by a convalescent individual really have virus-neutralizing capacity. That portion of the antibody that recognizes the virus can be engineered into a manufacturing platform to make monoclonal antibodies. Monoclonal means one kind of antibody. That approach has worked for other infectious diseases and is an interesting idea here too.

Collins: I can say a bit about that, because we are engaged in a partnership with industry and FDA called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). One of the hottest ideas right now is monoclonal antibodies, and we’re in the process of devising a master protocol, one for outpatients and one for inpatients.

Janet Woodcock of Operation Warp Speed tells me 21 companies are developing monoclonal antibodies. While doing these trials, we’d love to do comparisons, which is why it’s good to have an organization like ACTIV to bring everybody together, making sure you’re using the same endpoints and the same laboratory measures. I think that, maybe even by late summer, we might have some results. For people who are looking at what’s the next most-hopeful therapeutic option for people who are really sick with COVID-19, so far we have remdesivir. It helps, but it’s not a home run. Maybe monoclonal antibodies will be the next thing that really gives a big boost in survival. That would be the hope.

Ned, let me ask you one final question about herd, or group, immunity. One hears a bit about that in terms of how we are all going to get past this COVID-19 pandemic. What’s that all about?

Sharpless: Herd immunity is when a significant portion of the population is immune to a pathogen, then that pathogen will die out in the population. There just aren’t enough susceptible people left to infect. What the threshold is for herd immunity depends on how infectious the virus is. For a highly infectious virus, like measles, maybe up to 90 percent of the population must be immune to get herd immunity. Whereas for other less-infectious viruses, it may only be 50 percent of the population that needs to be immune to get herd immunity. It’s a theoretical thing that makes some assumptions, such as that everybody’s health status is the same and the population mixes perfectly every day. Neither of those are true.

How well that actual predictive number will work for coronavirus is unknown. The other thing that’s interesting is a lot of that work has been based on vaccines, such as what percentage do you have to vaccinate to get herd immunity? But if you get to herd immunity by having people get infected, so-called natural herd immunity, that may be different. You would imagine the most susceptible people get infected soonest, and so the heterogeneity of the population might change the threshold calculation.

The short answer is nobody wants to find out. No one wants to get to herd immunity for COVID-19 through natural herd immunity. The way you’d like to get there is with a vaccine that you then could apply to a large portion of the population, and have them acquire immunity in a more safe and controlled manner. Should we have an efficacious vaccine, this question will loom large: how many people do we need to vaccinate to really try and protect vulnerable populations?

Collins: That’s going to be a really critical question for the coming months, as the first large-scale vaccine trials get underway in July, and we start to see how they work and how successful and safe they are. But I’m also worried seeing some reports that 1 out of 5 Americans say they wouldn’t take a vaccine. It would be truly a tragedy if we have a safe and effective vaccine, but we don’t get enough uptake to achieve herd immunity. So, we’ve got some work to do on all fronts, that’s for sure.

Ned, I want to thank you for sharing all this information about antibodies and serologies and other things, as well as thank you for your hard work with all your amazing NCI colleagues.

Sharpless: Thanks for having me.

Reference:
[1] SARS-CoV-2 IgG Antibody Responses in New York City. Reifer J, Hayum N, Heszkel B, Klagsbald I, Streva VA. medRxiv. Preprint posted May 26, 2020.

Links:

Coronavirus (COVID-19) (NIH)

At NCI, A Robust and Rapid Response to the COVID-19 Pandemic. Norman E. Sharpless. Cancer Currents Blog. April 17, 2020 (National Cancer Institute/NIH)

Serological Testing for SARS-CoV-2 Antibodies (American Medical Association, Chicago)

COVID-19 Antibody Testing Primer (Infectious Diseases Society of America, Arlington, VA)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (NIH)


Will Warm Weather Slow Spread of Novel Coronavirus?

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Summer gear and a face mask
Credit: Modified from iStock/energyy

With the start of summer coming soon, many are hopeful that the warmer weather will slow the spread of SARS-CoV-2, the novel coronavirus that causes COVID-19. There have been hints from lab experiments that increased temperature and humidity may reduce the viability of SARS-CoV-2. Meanwhile, other coronaviruses that cause less severe diseases, such as the common cold, do spread more slowly among people during the summer.

We’ll obviously have to wait a few months to get the data. But for now, many researchers have their doubts that the COVID-19 pandemic will enter a needed summertime lull. Among them are some experts on infectious disease transmission and climate modeling, who ran a series of sophisticated computer simulations of how the virus will likely spread over the coming months [1]. This research team found that humans’ current lack of immunity to SARS-CoV-2—not the weather—will likely be a primary factor driving the continued, rapid spread of the novel coronavirus this summer and into the fall.

These sobering predictions, published recently in the journal Science, come from studies led by Rachel Baker and Bryan Grenfell at Princeton Environmental Institute, Princeton, NJ. The Grenfell lab has long studied the dynamics of infectious illnesses, including seasonal influenza and respiratory syncytial virus (RSV). Last year, they published one of the first studies to look at how our warming climate might influence those dynamics in the coming years [2].

Those earlier studies focused on well-known human infectious diseases. Less clear is how seasonal variations in the weather might modulate the spread of a new virus that the vast majority of people and their immune systems have yet to encounter.

In the new study, the researchers developed a mathematical model to simulate how seasonal changes in temperature might influence the trajectory of COVID-19 in cities around the world. Of course, because the virus emerged on the scene only recently, we don’t know very much about how it will respond to warming conditions. So, the researchers ran three different scenarios based on what’s known about the role of climate in the spread of other viruses, including two coronaviruses, called OC43 and HKU1, that are known to cause common colds in people.

In all three scenarios, their models showed that climate only would become an important seasonal factor in controlling COVID-19 once a large proportion of people within a given community are immune or resistant to infection. In fact, the team found that, even if one assumes that SARS-CoV-2 is as sensitive to climate as other seasonal viruses, summer heat still would not be enough of a mitigator right now to slow its initial, rapid spread through the human population. That’s also clear from the rapid spread of COVID-19 that’s currently occurring in Brazil, Ecuador, and some other tropical nations.

Over the longer term, as more people develop immunity, the researchers suggest that COVID-19 may likely fall into a seasonal pattern similar to those seen with diseases caused by other coronaviruses. Long before then, NIH is working intensively with partners from all sectors to make sure that safe, effective treatments and vaccines will be available to help prevent the tragic, heavy loss of life that we’re seeing now.

Of course, climate is just one key factor to consider in evaluating the course of this disease. And, there is a glimmer of hope in one of the group’s models. The researchers incorporated the effects of control measures, such as physical distancing, with climate. It appears from this model that such measures, in combination with warm temperatures, actually might combine well to help slow the spread of this devastating virus. It’s a reminder that physical distancing will remain our best weapon into the summer to slow or prevent the spread of COVID-19. So, keep wearing those masks and staying 6 feet or more apart!

References:

[1] Susceptible supply limits the role of climate in the early SARS-CoV-2 pandemic. Baker RE, Yang W, Vecchi GA, Metcalf CJE, Grenfell BT. Science. 2020 May 18. [Online ahead of print.]

[2] Epidemic dynamics of respiratory syncytial virus in current and future climates. Baker RE, Mahmud AS, Wagner CE, Yang W, Pitzer VE, Viboud C, Vecchi GA, Metcalf CJE, Grenfell BT.Nat Commun. 2019 Dec 4;10(1):5512.

Links:

Coronavirus (COVID-19) (NIH)

Bryan Grenfell (Princeton University, Princeton, NJ)

Rachel Baker (Princeton University, Princeton, NJ)


The Challenge of Tracking COVID-19’s Stealthy Spread

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Floating SARS-CoV-2 particles
Credit: CDC/ Alissa Eckert, MS; Dan Higgins, MAMS

As our nation looks with hope toward controlling the coronavirus 2019 disease (COVID-19) pandemic, researchers are forging ahead with efforts to develop and implement strategies to prevent future outbreaks. It sounds straightforward. However, several new studies indicate that containing SARS-CoV-2—the novel coronavirus that causes COVID-19—will involve many complex challenges, not the least of which is figuring out ways to use testing technologies to our best advantage in the battle against this stealthy foe.

The first thing that testing may help us do is to identify those SARS-CoV-2-infected individuals who have no symptoms, but who are still capable of transmitting the virus. These individuals, along with their close contacts, will need to be quarantined rapidly to protect others. These kinds of tests detect viral material and generally analyze cells collected via nasal or throat swabs.

The second way we can use testing is to identify individuals who’ve already been infected with SARS-CoV-2, but who didn’t get seriously ill and can no longer transmit the virus to others. These individuals may now be protected against future infections, and, consequently, may be in a good position to care for people with COVID-19 or who are vulnerable to the infection. Such tests use blood samples to detect antibodies, which are blood proteins that our immune systems produce to attack viruses and other foreign invaders.

A new study, published in Nature Medicine [1], models what testing of asymptomatic individuals with active SARS-CoV-2 infections may mean for future containment efforts. To develop their model, researchers at China’s Guangzhou Medical University and the University of Hong Kong School of Public Health analyzed throat swabs collected from 94 people who were moderately ill and hospitalized with COVID-19. Frequent in-hospital swabbing provided an objective, chronological record—in some cases, for more than a month after a diagnosis—of each patient’s viral loads and infectiousness.

The model, which also factored in patients’ subjective recollections of when they felt poorly, indicates:

• On average, patients became infectious 2.3 days before onset of symptoms.
• Their highest level of potential viral spreading likely peaked hours before their symptoms appeared.
• Patients became rapidly less infectious within a week, although the virus likely remains in the body for some time.

The researchers then turned to data from a separate, previously published study [2], which documented the timing of 77 person-to-person transmissions of SARS-CoV-2. Comparing the two data sets, the researchers estimated that 44 percent of SARS-CoV-2 transmissions occur before people get sick.

Based on this two-part model, the researchers warned that traditional containment strategies (testing only of people with symptoms, contact tracing, quarantine) will face a stiff challenge keeping up with COVID-19. Indeed, they estimated that if more than 30 percent of new infections come from people who are asymptomatic, and they aren’t tested and found positive until 2 or 3 days later, public health officials will need to track down more than 90 percent of their close contacts and get them quarantined quickly to contain the virus.

The researchers also suggested alternate strategies for curbing SARS-CoV-2 transmission fueled by people who are initially asymptomatic. One possibility is digital tracing. It involves creating large networks of people who’ve agreed to install a special tracing app on their smart phones. If a phone user tests positive for COVID-19, everyone with the app who happened to have come in close contact with that person would be alerted anonymously and advised to shelter at home.

The NIH has a team that’s exploring various ways to carry out digital tracing while still protecting personal privacy. The private sector also has been exploring technological solutions, with Apple and Google recently announcing a partnership to develop application programming interfaces (APIs) to allow voluntary digital tracing for COVID-19 [3], The rollout of their first API is expected in May.

Of course, all these approaches depend upon widespread access to point-of-care testing that can give rapid results. The NIH is developing an ambitious program to accelerate the development of such testing technologies; stay tuned for more information about this in a forthcoming blog.

The second crucial piece of the containment puzzle is identifying those individuals who’ve already been infected by SARS-CoV-2, many unknowingly, but who are no longer infectious. Early results from an ongoing study on residents in Los Angeles County indicated that approximately 4.1 percent tested positive for antibodies against SARS-CoV-2 [4]. That figure is much higher than expected based on the county’s number of known COVID-19 cases, but jibes with preliminary findings from a different research group that conducted antibody testing on residents of Santa Clara County, CA [5].

Still, it’s important to keep in mind that SARS-CoV-2 antibody tests are just in the development stage. It’s possible some of these results might represent false positives—perhaps caused by antibodies to some other less serious coronavirus that’s been in the human population for a while.

More work needs to be done to sort this out. In fact, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which is our lead institute for infectious disease research, recently launched a study to help gauge how many adults in the U. S. with no confirmed history of a SARS-CoV-2 infection have antibodies to the virus. In this investigation, researchers will collect and analyze blood samples from as many as 10,000 volunteers to get a better picture of SARS-CoV-2’s prevalence and potential to spread within our country.

There’s still an enormous amount to learn about this major public health threat. In fact, NIAID just released its strategic plan for COVID-19 to outline its research priorities. The plan provides more information about the challenges of tracking SARS-CoV-2, as well as about efforts to accelerate research into possible treatments and vaccines. Take a look!

References:

[1] Temporal dynamics in viral shedding and transmissibility of COVID-19. He X, Lau EHY, Wu P, Deng X, Wang J, Hao X, Lau YC, Wong JY, Guan Y, Tan X, Mo X, Chen Y, Liao B, Chen W, Hu F, Zhang Q, Zhong M, Wu Y, Zhao L, Zhang F, Cowling BJ, Li F, Leung GM. Nat Med. 2020 Apr 15. [Epub ahead of publication]

[2] Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. Li, Q. et al. N. Engl. J. Med. 2020 Mar 26;382, 1199–1207.

[3] Apple and Google partner on COVID-19 contact tracing technology. Apple news release, April 10, 2020.

[4] USC-LA County Study: Early Results of Antibody Testing Suggest Number of COVID-19 Infections Far Exceeds Number of Confirmed Cases in Los Angeles County. County of Los Angeles Public Health News Release, April 20, 2020.

[5] COVID-19 Antibody Seroprevalence in Santa Clara County, California. Bendavid E, Mulaney B, Sood N, Sjah S, Ling E, Bromley-Dulfano R, Lai C, Saavedra-Walker R, Tedrow J, Tversky D, Bogan A, Kupiec T, Eichner D, Gupta R, Ioannidis JP, Bhattacharya J. medRxiv, Preprint posted on April 14, 2020.

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (NIAID)

NIAID Strategic Plan for COVID-19 Research, FY 2020-2024

NIH Support: National Institute of Allergy and Infectious Diseases


Can Smart Phone Apps Help Beat Pandemics?

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Crowd of people with connection symbols.
iStock/peterhowell

In recent weeks, most of us have spent a lot of time learning about coronavirus disease 2019 (COVID-19) and thinking about what’s needed to defeat this and future pandemic threats. When the time comes for people to come out of their home seclusion, how will we avoid a second wave of infections? One thing that’s crucial is developing better ways to trace the recent contacts of individuals who’ve tested positive for the disease-causing agent—in this case, a highly infectious novel coronavirus.

Traditional contact tracing involves a team of public health workers who talk to people via the phone or in face-to-face meetings. This time-consuming, methodical process is usually measured in days, and can even stretch to weeks in complex situations with multiple contacts. But researchers are now proposing to take advantage of digital technology to try to get contact tracing done much faster, perhaps in just a few hours.

Most smart phones are equipped with wireless Bluetooth technology that creates a log of all opt-in mobile apps operating nearby—including opt-in apps on the phones of nearby people. This has prompted a number of research teams to explore the idea of creating an app to notify individuals of exposure risk. Specifically, if a smart phone user tests positive today for COVID-19, everyone on their recent Bluetooth log would be alerted anonymously and advised to shelter at home. In fact, in a recent paper in the journal Science, a British research group has gone so far to suggest that such digital tracing may be valuable in the months ahead to improve our chances of keeping COVID-19 under control [1].

The British team, led by Luca Ferretti, Christophe Fraser, and David Bonsall, Oxford University, started their analyses using previously published data on COVID-19 outbreaks in China, Singapore, and aboard the Diamond Princess cruise ship. With a focus on prevention, the researchers compared the different routes of transmission, including from people with and without symptoms of the infection.

Based on that data, they concluded that traditional contact tracing was too slow to keep pace with the rapidly spreading COVID-19 outbreaks. During the three outbreaks studied, people infected with the novel coronavirus had a median incubation period of about five days before they showed any symptoms of COVID-19. Researchers estimated that anywhere from one-third to one-half of all transmissions came from asymptomatic people during this incubation period. Moreover, assuming that symptoms ultimately arose and an infected person was then tested and received a COVID-19 diagnosis, public health workers would need at least several more days to perform the contact tracing by traditional means. By then, they would have little chance of getting ahead of the outbreak by isolating the infected person’s contacts to slow its rate of transmission.

When they examined the situation in China, the researchers found that available data show a correlation between the roll-out of smart phone contact-tracing apps and the emergence of what appears to be sustained suppression of COVID-19 infection. Their analyses showed that the same held true in South Korea, where data collected through a smart phone app was used to recommend quarantine.

Despite its potential benefits in controlling or even averting pandemics, the British researchers acknowledged that digital tracing poses some major ethical, legal, and social issues. In China, people were required to install the digital tracing app on their phones if they wanted to venture outside their immediate neighborhoods. The app also displayed a color-coded warning system to enforce or relax restrictions on a person’s movements around a city or province. The Chinese app also relayed to a central database the information that it had gathered on phone users’ movements and COVID-19 status, raising serious concerns about data security and privacy of personal information.

In their new paper, the Oxford team, which included a bioethicist, makes the case for increased social dialogue about how best to employ digital tracing in ways the benefit human health. This is a far-reaching discussion with implications far beyond times of pandemic. Although the team analyzed digital tracing data for COVID-19, the algorithms that drive these apps could be adapted to track the spread of other common infectious diseases, such as seasonal influenza.

The study’s authors also raised another vital point. Even the most-sophisticated digital tracing app won’t be of much help if smart phone users don’t download it. Without widespread installation, the apps are unable to gather enough data to enable effective digital tracing. Indeed, the researchers estimate that about 60 percent of new COVID-19 cases in a community would need to be detected–and roughly the same percentage of contacts traced—to squelch the spread of the deadly virus.

Such numbers have app designers working hard to discover the right balance between protecting public health and ensuring personal rights. That includes NIH grantee Trevor Bedford, Fred Hutchinson Cancer Research Center, Seattle. He and his colleagues just launched NextTrace, a project that aims to build an opt-in app community for “digital participatory contact tracing” of COVID-19. Here at NIH, we have a team that is actively exploring the kind of technology that could achieve the benefits without unduly compromising personal privacy.

Bedford emphasizes that he and his colleagues aren’t trying to duplicate efforts already underway. Rather, they want to collaborate with others help to build a scientifically and ethically sound foundation for digital tracing aimed at improving the health of all humankind.

Reference:

[1] Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing. Ferretti L, Wymant C, Kendall M, Zhao L, Nurtay A, Abeler-Dörner L, Parker M, Bonsall D, Fraser C. Science. 2020 Mar 31. [Epub ahead of print]

Links:

Coronavirus (COVID-19) (NIH)

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

NextTrace (Fred Hutchinson Cancer Research Center, Seattle)

Bedford Lab (Fred Hutchinson Cancer Research Center)

NIH Support: National Institute of General Medical Sciences


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