public health
Tuberculosis: An Ancient Disease in Need of Modern Scientific Tools
Posted on by Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases
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.]
COVID-19 Infected Many More Americans in 2020 than Official Tallies Show
Posted on by Dr. Francis Collins
At the end of last year, you may recall hearing news reports that the number of COVID-19 cases in the United States had topped 20 million. While that number came as truly sobering news, it also likely was an underestimate. Many cases went undetected due to limited testing early in the year and a large number of infections that produced mild or no symptoms.
Now, a recent article published in Nature offers a more-comprehensive estimate that puts the true number of infections by the end of 2020 at more than 100 million [1]. That’s equal to just under a third of the U.S. population of 328 million. This revised number shows just how rapidly this novel coronavirus spread through the country last year. It also brings home just how timely the vaccines have been—and continue to be in 2021—to protect our nation’s health in this time of pandemic.
The work comes from NIH grantee Jeffrey Shaman, Sen Pei, and colleagues, Columbia University, New York. As shown above in the map, the researchers estimated the percentage of people who had been infected with SARS-CoV-2, the novel coronavirus that causes COVID-19, in communities across the country through December 2020.
To generate this map, they started with existing national data on the number of coronavirus cases (both detected and undetected) in 3,142 U.S. counties and major metropolitan areas. They then factored in data from the Centers for Disease Control and Prevention (CDC) on the number of people who tested positive for antibodies against SARS-CoV-2. These CDC data are useful for picking up on past infections, including those that went undetected.
From these data, the researchers calculated that only about 11 percent of all COVID-19 cases were confirmed by a positive test result in March 2020. By the end of the year, with testing improvements and heightened public awareness of COVID-19, the ascertainment rate (the number of infections that were known versus unknown) rose to about 25 percent on average. This measure also varied a lot across the country. For instance, the ascertainment rates in Miami and Phoenix were higher than the national average, while rates in New York City, Los Angeles, and Chicago were lower than average.
How many people were potentially walking around with a contagious SARS-CoV-2 infection? The model helps to answer this, too. On December 31, 2020, the researchers estimate that 0.77 percent of the U.S. population had a contagious infection. That’s about 1 in every 130 people on average. In some places, it was much higher. In Los Angeles, for example, nearly 1 in 40 (or 2.42 percent) had a SARS-CoV-2 infection as they rang in the New Year.
Over the course of the year, the fatality rate associated with COVID-19 dropped, at least in part due to earlier diagnosis and advances in treatment. The fatality rate went from 0.77 percent in April to 0.31 percent in December. While this is great news, it still shows that COVID-19 remains much more dangerous than seasonal influenza (which has a fatality rate of 0.08 percent).
Today, the landscape has changed considerably. Vaccines are now widely available, giving many more people immune protection without ever having to get infected. And yet, the rise of the Delta and other variants means that breakthrough infections and reinfections—which the researchers didn’t account for in their model—have become a much bigger concern.
Looking ahead to the end of 2021, Americans must continue to do everything they can to protect their communities from the spread of this terrible virus. That means getting vaccinated if you haven’t already, staying home and getting tested if you’ve got symptoms or know of an exposure, and taking other measures to keep yourself and your loved ones safe and well. These measures we take now will influence the infection rates and susceptibility to SARS-CoV-2 in our communities going forward. That will determine what the map of SARS-CoV-2 infections will look like in 2021 and beyond and, ultimately, how soon we can finally put this pandemic behind us.
Reference:
[1] Burden and characteristics of COVID-19 in the United States during 2020. Pei S, Yamana TK, Kandula S, Galanti M, Shaman J. Nature. 2021 Aug 26.
Links:
COVID-19 Research (NIH)
Sen Pei (Columbia University, New York)
Jeffrey Shaman (Columbia University, New York)
Tracking the Evolution of a ‘Variant of Concern’ in Brazil
Posted on by Dr. Francis Collins
By last October, about three out of every four residents of Manaus, Brazil already had been infected with SARS-CoV-2, the virus that causes COVID-19 [1]. And yet, despite hopes of achieving “herd immunity” in this city of 2.2 million in the Amazon region, the virus came roaring back in late 2020 and early 2021 to cause a second wave of illness and death [2]. How is this possible?
The answer offers a lesson in viral evolution, especially when an infectious virus such as SARS-CoV-2 replicates and spreads through a population largely unchecked. In a recent study in the journal Science, researchers tied the city’s resurgence of SARS-CoV-2 to the emergence and rapid spread of a new SARS-CoV-2 “variant of concern” known as P.1 [3]. This variant carries a unique constellation of mutations that allow it not only to sneak past the human immune system and re-infect people, but also to be about twice as transmissible as earlier variants.
To understand how this is possible, consider that each time the coronavirus SARS-CoV-2 makes copies of itself in an infected person, there’s a chance a mistake will be made. Each mistake can produce a new variant that may go on to make more copies of itself. In most cases, those random errors are of little to no consequence. This is evolution in action.
But sometimes a spelling change can occur that benefits the virus. In the special case of patients with suppressed immune systems, the virus can have ample opportunity to accrue an unusually high number of mutations. Variants carrying beneficial mutations can make more copies of themselves than other variants, allowing them to build their numbers and spread to cause more infection.
At this advanced stage of the COVID-19 pandemic, such rapidly spreading new variants remain cause for serious concern. That includes variants such as B.1.351, which originated in South Africa; B.1.1.7 which emerged in the United Kingdom; and now P.1 from Manaus, Brazil.
In the new study, Nuno Faria and Samir Bhatt, Imperial College London, U.K., and Ester Cerdeira Sabino, Universidade de Sao Paulo, Brazil, and their colleagues sequenced SARS-CoV-2 genomes from 184 patient samples collected in Manaus in November and December 2020. The research was conducted under the auspices of the Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE), a project focused on viral genomics and epidemiology for public health.
Those genomic data revealed the P.1 variant had acquired 17 new mutations. Ten were in the spike protein, which is the segment of the virus that binds onto human cells and the target of current COVID-19 vaccines. In fact, the new work reveals that three of these spike protein mutations make it easier for the P.1 spike to bind the human ACE2 receptor, which is SARS-CoV-2’s preferred entry point.
The first P.1 variant case was detected by genomic surveillance on December 6, 2020, after which it spread rapidly. Through further evolutionary analysis, the team estimates that P.1 must have emerged, undetected for a brief time, in mid-November 2020.
To understand better how the P.1 variant led to such an explosion of new COVID-19 cases, the researchers developed a mathematical model that integrated the genomic data with mortality data. The model suggests that P.1 may be 1.7 to 2.4 times more transmissible than earlier variants. They also estimate that a person previously infected with a variant other than P.1 will have only 54 percent to 79 percent protection against a subsequent infection with P.1.
The researchers also observed an increase in mortality following the emergence of the P.1 variant. However, it’s not yet clear if that’s an indication P.1 is inherently more deadly than earlier variants. It’s possible the increased mortality is related primarily to the extra stress on the healthcare system in Manaus from treating so many people with COVID-19.
These findings are yet another reminder of the importance of genomic surveillance and international data sharing for detecting and characterizing emerging SARS-CoV-2 variants quickly. It’s worth noting that at about the same time this variant was detected in Brazil, it also was reported in four individuals who had traveled to Brazil from Japan. The P.1 variant continues to spread rapidly across Brazil. It has also been detected in more than 37 countries [4], including the United States, where it now accounts for more than 1 percent of new cases [5].
No doubt you are wondering what this means for vaccines, such as the Pfizer and Moderna mRNA vaccines, that have been used to immunize (at least one dose) over 140 million people in the United States. Here the news is encouraging. Serum from individuals who received the Pfizer vaccine had titers of neutralizing antibodies that were only slightly reduced for P.1 compared to the original SARS-CoV-2 virus [6]. Therefore, the vaccine is predicted to be highly protective. This is another example of a vaccine providing more protection than a natural infection.
The United States has made truly remarkable progress in combating COVID-19, but we must heed this lesson from Manaus: this terrible pandemic isn’t over just yet. While the P.1 variant remains at low levels here for now, the “U.K. variant” B.1.1.7 continues to spread rapidly and now is the most prevalent variant circulating in the U.S., accounting for 44 percent of new cases [6]. Fortunately, the mRNA vaccines also work well against B.1.1.7.
We must continue to do absolutely everything possible, individually and collectively, to prevent these new SARS-CoV-2 variants from slowing or even canceling the progress made over the last year. We need to remain vigilant for just a while longer, while encouraging our friends, neighbors, and loved ones to get vaccinated.
References:
[1] Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Buss, L. F., C. A. Prete, Jr., C. M. M. Abrahim, A. C. Dye, V. H. Nascimento, N. R. Faria and E. C. Sabino et al. (2021). Science 371(6526): 288-292.
[2] Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. Sabino EC, Buss LF, Carvalho MPS, Prete Jr CCA, Crispim MAE, Fraiji NA, Pereira RHM, Paraga KV, Peixoto PS, Kraemer MUG, Oikawa MJ, Salomon T, Cucunuba ZM, Castro MC, Santos AAAS, Nascimento VH, Pereira HS, Ferguson NM, Pybus OG, Kucharski A, Busch MP, Dye C, Faria NR Lancet. 2021 Feb 6;397(10273):452-455.
[3] Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Faria NR, Mellan TA, Whittaker C, Claro IM, Fraiji NA, Carvalho MDPSS, Pybus OG, Flaxman S, Bhatt S, Sabino EC et al. Science. 2021 Apr 14:eabh2644.
[4] GRINCH Global Report Investigating novel coronavirus haplotypes. PANGO Lineages.
[5] COVID Data Tracker. Variant Proportions. Centers for Disease Control and Prevention.
[6] Antibody evasion by the P.1 strain of SARS-CoV-2. Dejnirattisai W, Zhou D, Supasa P, Liu C, Mongkolsapaya J, Ren J, Stuart DI, Screaton GR, et al. Cell. 2021 Mar 30:S0092-8674(21)00428-1.
Links:
COVID-19 Research (NIH)
Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE)
Nuno Faria (Imperial College, London, U.K.)
Samir Bhatt (Imperial College)
Ester Cerdeira Sabino (Universidade de Sao Paulo, Brazil)
NIH Support: National Institute of Allergy and Infectious Diseases
Following COVID-19 Vaccines Across the United States
Posted on by Dr. Francis Collins
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)
Face Coverings Could Save 130,000 American Lives from COVID-19 by March
Posted on by Dr. Francis Collins
The coronavirus disease 2019 (COVID-19) pandemic has already claimed the lives of more than 230,000 Americans, the population of a mid-sized U.S. city. As we look ahead to winter and the coming flu season, the question weighing on the minds of most folks is: Can we pull together to contain the spread of this virus and limit its growing death toll?
I believe that we can, but only if each of us gets fully engaged with the public health recommendations. We need all Americans to do the right thing and wear a mask in public to protect themselves and their communities from spreading the virus. Driving home this point is a powerful new study that models just how critical this simple, low-cost step will be this winter and through the course of this pandemic [1].
Right now, it’s estimated that about half of Americans always wear a mask in public. According to the new study, published in Nature Medicine, if this incomplete rate of mask-wearing continues and social distancing guidelines are not adhered to, the total number of COVID-19 deaths in the United States could soar to more than 1 million by the end of February.
However, the model doesn’t accept that we’ll actually end up at this daunting number. It anticipates that once COVID mortality reaches a daily threshold of 8 deaths per 1 million citizens, U.S. states would re-instate limits on social and economic activity—as much of Europe is now doing. If so, the model predicts that by March, such state-sanctioned measures would cut the projected number of deaths in half to about 510,000—though that would still add another 280,000 lives lost to this devastating virus.
The authors, led by Christopher Murray, Institute of Health Metrics and Evaluations, University of Washington School of Medicine, Seattle, show that we can do better than that. But doing better will require action by all of us. If 95 percent of people in the U.S. began wearing masks in public right now, the death toll would drop by March from the projected 510,000 to about 380,000.
In other words, if most Americans pulled together to do the right thing and wore a mask in public, this simple, selfless act would save more than 130,000 lives in the next few months alone. If mask-wearers increased to just 85 percent, the model predicts it would save about 96,000 lives across the country.
What’s important here aren’t the precise numbers. It’s the realization that, under any scenario, this pandemic is far from over, and, together, we have it within our power to shape what happens next. If more people make the decision to wear masks in public today, it could help to delay—or possibly even prevent—the need for future shutdowns. As such, the widespread use of face coverings has the potential to protect lives while also minimizing further damage to the economy and American livelihoods. It’s a point that NIH’s Anthony Fauci and colleagues presented quite well in a recent commentary in JAMA [2].
As we anxiously await the approved vaccines for COVID-19 and other advances in its prevention and treatment, the life-saving potential of face coverings simply can’t be overstated. I know that many people are tired of this message, and, unfortunately, mask-wearing has been tangled up in political perspectives at this time of deep divisions in our country.
But think about it in the same way you think about putting on your seat belt—a minor inconvenience that can save lives. I’m careful to wear a mask outside my home every time I’m out and about. But, ultimately, saving lives and livelihoods as we head into these winter months will require a collective effort from all of us.
To do so, each of us needs to follow these three W’s: Wear a mask. Watch your distance (stay 6 feet apart). Wash your hands often.
References:
[1] Modeling COVID-19 scenarios for the United States. IHME COVID-19 Forecasting Team. Nat Med. 2020 Oct 23.
[2] Preventing the spread of SARS-CoV-2 with masks and other “low-tech” interventions. Lerner AM, Folkers, GK, Fauci AS. JAMA. 2020 October 26.
Links:
Coronavirus (COVID-19) (NIH)
Institute for Health Metrics and Evaluations (University of Washington School of Medicine, Seattle)
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