Anthony Fauci, MD, is that rare individual “who really needs no introduction.” And while his recent throw of the first ball for the Washington Nationals' season opener fell short of the mound, he delivered a perfect pitch as keynote speaker for the American Association for Cancer Research's virtual meeting on “Covid-19 and Cancer,” July 20.
Director of National Institute of Allergy and Infectious Diseases, Fauci has devoted his entire 52 years-and-counting career to the National Institutes of Health (NIH) and has made contributions that are both extensive and extraordinary.
“His laboratory and clinical team recognized that polyarteritis nodosa and Wegener's granulomatosis and related diseases were in fact autoimmune diseases that could be successfully treated with dexamethasone and cyclophosphamide,” said David A. Tuveson, MD, PhD, President-Elect of AACR and Director of Cold Spring Harbor Laboratory Cancer Center, in opening remarks. “The curing of these formerly highly disabling and occasionally fatal diseases is recognized as one of the most important contributions in the history of rheumatology.”
Fauci's laboratory also discovered critical features regarding the pathogenicity of HIV. “In particular, the concept of dormant or latent viruses that [establish] persistent antigen-presenting cells, including macrophages and follicular dendritic cells, eventually leading to the depletion of both CD4-positive T cells and follicular dendritic cells, and collectively causing extreme hypogammaglobulinemia, which contributes to the profound immune suppression and late stage HIV,” detailed Tuveson.
“Dr. Fauci has led national and international efforts to manage outbreaks of Ebola, SARS, MERS, tuberculosis, swine flu, and many others. He is credited for listening to and working with AIDS' activists to productively introduce combination therapy for HIV patients. Dr. Fauci has advised six successive presidents of the United States. Most recently, he has been an important member of the President's task force against COVID-19, an appointment for which President Trump should be congratulated, and that is much appreciated by all humans in the U.S. and beyond.”
In his presentation, “Coronavirus Infections: More Than Just the Common Cold,” Fauci offered both concerning reality and an underpinning of hope. Of primary concern to those in oncology, Fauci said that because of the COVID-19-related “total country lockdown that we and other nations have experienced...the next decade could actually result in 10,000 or more excess deaths from breast and colorectal cancer because of the reductions in routine screening.”
Beyond the realm of clinical care, the COVID-19 pandemic has caused great disruption throughout the cancer research community, “... shuttering many labs and slowing down cancer clinical trial operations,” he lamented.
Fauci's History Lesson
In an expansive look-back, Fauci explained that prior to SARS and MERS, there were four coronaviruses that were responsible for about 15-30 percent of the recurrent common colds that we all get. “However, the issue of the possibility of a coronavirus being a pandemic came upon us in 2002 with the severe acute respiratory syndrome (SARS), and then again, in 2012 with MERs.”
SARS, the first entry into the realization of the pandemic potential of coronaviruses, started in the Guangdong province of China in November of 2002, “with what was described as an atypical pneumonia,” recalled Fauci. When infected person No. 1 stayed in a Hong Kong hotel, 19 more people were infected. From that starting point, SARS travelled around the world.
It was “...the beginning of the pandemic of SARS, because within a period of time from November 2002 to July 2003, there were over 8,000 cases and close to 800 deaths,” he said. “There were some substantial differences between this SARS coronavirus and what we refer to as SARS-CoV-2 in the moment. The outbreak was contained by a number of strategies: isolation, infection control, quarantine, travel advisory, screening at airport. And, in fact, it was clear that, although this was transmissible relatively easily from person to person, it did not have the absolute overwhelming efficiency and capability of spreading from human to human,” said Fauci.
“Measures like physical separation, mask wearing, [and] quarantine actually turned the outbreak around. By the time we got to June and July of 2003, there were essentially no cases. In essence, the outbreak was controlled by purely public health measures without any drugs and without any vaccines.”
Fast forward 10 years to 2012, Middle Eastern respiratory syndrome (MERS), another pandemic-potential novel coronavirus, emerged in Saudi Arabia. “Of note, MERS is still smoldering up to this day,” said Fauci. “However, the number of cases is relatively small and outbreaks are typically well-controlled.”
The Problem at Hand
“So let's go to where we are today with the SARS-CoV-2,” said Fauci. “The name of the disease is COVID-19 for coronavirus disease, 2019. The name of the virus is SARS-CoV-2, because of its close phylogenetic proximity to the original SARS-CoV-1.
“So here we are with close to 14 million cases [18,322,926 as of August 3] globally and 580,000-plus deaths [694,268 as of August 3], thus far, with essentially no end in sight. The United States has been hit harder than any country in the world with the most cases [4,827,843 as of August 3] and the most deaths [158,495 as of August 3].”
Fauci continued with a slide-illustrated look at some of the aspects of this infection. “First the virology,” he began. “It's a betacoronavirus, the same subgenus as the original SARS virus. It's a positive-sense, single-stranded RNA. It has a number of structural proteins, the most important of which is the S protein or the spike protein, which allows the virus to attach to, fuse with, and enter the host cell via the ACE2 cellular receptor.
“Transmission is respiratory route, direct person-to-person, usually in close contact, which is why we ask that people maintain a 6 foot distance... But there's considerable interest now in the relative role of aerosol transmission, namely with droplets less than 5 micrometers. It is unclear the extent to which this is responsible for spread, but most [researchers] feel that it has some impact on spread. The virus is detected in a number of bodily fluids, but their role in transmission is uncertain. Animals can be infected, but again, their role in transmission is uncertain. An important bit of knowledge that has just been confirmed is that about 20-45 percent of individuals who are infected are without symptoms. This is very important, when one thinks of tracking transmission, particularly contact tracing.”
Fauci noted that clinical presentation strongly resembles an influenza or flu-like syndrome. Those infected often experience fever, cough, fatigue, anorexia, shortness of breath, myalgias, and the loss of smell and taste, which actually precedes the onset of respiratory symptoms.
“The thing I'm most impressed with is, of all the viruses that I've been dealing with over the last several decades, COVID-19's extraordinarily wide spectrum of disease,” said Fauci. “Twenty to 45 percent of people are completely asymptomatic, while others can be pre-symptomatic in their spread. There's a range of mild illness—people who need to stay home for a few days—but also people who are in bed for weeks and have post-viral syndromes, people who require hospitalizations and oxygen, intensive care, intubation, ventilation, and then [some who experience] death. So it's extraordinary.”
Fauci recounted that older individuals are more susceptible to the disease than younger counterparts, but reminded that people of any age with certain underlying medical conditions are at high risk for severe illness.
“That includes chronic kidney disease, obstructive pulmonary disease, any immunocompromised host such as with solid organ transplantation, obesity, heart conditions, diabetes, sickle cell disease,” he listed. “And then there's underlying medical conditions that may confirm an increased risk...such as the use of glucocorticoids, pregnancy, hypertension, HIV infection, etc. If you look at the age-associated race and ethnicity distribution of COVID-19 hospitalization rate, you see a disproportionately high rate of hospitalization among minority communities, such as blacks, Hispanics, LatinX, American Indians, and Alaskan natives.”
The manifestations of severe disease vary from patient to patient, said Fauci. While acute respiratory distress syndrome is the most typical, “... there are also manifestations of hyperinflammation with cardiac injury, including arrhythmias and cardiomyopathy, renal disease, neurological disease, hypercoagulability, and anything from a stroke involving a major vessel to microthrombi in venules. And then there's an interesting multi-system inflammatory syndrome in children, which we're now learning more about, which strikingly resembles what we've seen with Kawasaki syndrome.”
Testing, Therapeutics, Prevention, Vaccines
The “typical test” for SARS-CoV-2 virus is a molecular test using PCR, said Fauci. Another more recently introduced test looks for antigen, such as the spike protein.
“One can scale up much more readily with antigen tests,” he explained. “And then finally there are tests for the antibody to determine if you've actually been exposed and infected. The durability of any antibody response is being tracked, but as of now it is really quite unclear how long these antibodies last. This is something that is going to be followed very closely.”
Moving on to sorely needed therapeutics, Fauci mentioned there are several broad spectrum antivirals being tested, and a number of ongoing studies are investigating the utility of convalescent plasma, as well as hyperimmune globulin, derived from the convalescent plasma. He was encouraging about by the usefulness of repurposed drugs, like remdesivir, “...which essentially all related studies have shown to be effective.”
The New England Journal of Medicine reported in May that one study showed patients who received remdesivir had a 32 percent faster time to recovery than those who received placebo (2020; doi: 10.1056/NEJMoa2007764). Results also suggested a survival benefit. Studies are also being conducted into the use of immune-based therapies to dampen inflammatory response, as well as monoclonal antibodies directed specifically against the virus, Fauci noted.
“Let me take a minute to tell you about the dexamethasone investigative study, which was the first randomized, placebo-controlled trial in COVID-19 in hospitalized patients,” offered Fauci. “In over 1,000 individuals studied in 10 countries, the results were significant and showed a modest [about 32%] but definite decrease in the time to recovery.
“Another study from the UK, a randomized placebo-controlled trial, looked at patients in the hospital on ventilators or receiving oxygen compared to individuals with early disease (N Engl J Med 2020; doi: 10.1056/NEJMoa2021436). It was very clear that dexamethasone, given at 6 mg a day for up to 10 days, had a significant impact on decreasing mortality in the patients on ventilators and those requiring oxygen. But it did not have a positive effect, and maybe even a negative effect, in people with early disease. This finding goes along with our understanding of the pathogenesis of this infection, wherein early on you want to block the virus, but you want to keep the inflammatory and immunological response intact. Whereas later in the disease...you have a lot of aberrant inflammatory response that you want to dampen down, and which the dexamethasone certainly did.”
The NIH has initiated a panel which is responsible for keeping an online living document on treatment guidelines for COVID-19. “The data are uploaded regularly, depending on the evolution and the availability of new data from clinical trials,” detailed Fauci. “One can access this by just linking onto covid19treatmentguidelines.nih.gov.
The final leg of Fauci's COVID-19 run around the bases slid into a discussion on prevention, and the public health measures that remain broadly applicable.
“The bottom line, common denominator is physical distancing,” said an adamant Fauci. “This can be accomplished by stay-at-home orders, closing or modifying school schedules, bans on public gatherings, and travel restrictions, followed by aggressive case identification and contact tracing.”
He also stressed the importance of “common sense personal preventative measures,” including diligent handwashing, avoiding close contact and maintaining 6 feet of distance, covering the mouth and the nose with a mask or a cloth, and personal and respiratory hygiene encompassing covering sneezes and coughs, avoiding face touching, and regular cleaning of inanimate objects.
“With regard to vaccines, we at NIH have taken a strategic approach,” said Fauci. “We are supporting, directly or indirectly, a number of candidates using different platforms, but we have tried to harmonize the approach so that even with multiple candidates with multiple platforms, there is a common protocol that is, in many respects, quite similar one to the other. They have a common data safety monitoring board, common primary and secondary endpoints, as well as laboratory data that's compatible and interchangeable.”
Fauci listed three major platforms that are being pursued and in various trial phases: Nucleic acid platform being developed by Moderna, BioNTech, and Pfizer; viral vectors being developed by University of Oxford, AstraZeneca, Janssen, Johnson & Johnson, and Merck; and protein subunits being developed by Novavax, GSK, and Sanofi.
“There is no statement as to what is better than the other,” said Fauci. “A phase I trial which showed some very promising data was published online just a few days ago in the New England Journal of Medicine (2020; doi: 10.1056/NEJMoa2022483). It showed in 45 individuals that even the moderate dose of this MRNA platform induced very robust neutralizing antibodies that were at the same level or greater than what you would see with convalescent serum. This is really very good news because one of the tenets of vaccinology is that you'd like to get a vaccine that induces a response that's comparable to response that's induced by natural infection. And it looks like that is actually the case right here.”
The address ended all too quickly as Fauci said, “Let me close by showing a slide of a paper that was written 12 years ago by my colleagues and me.” They titled it “Emerging Infections: A Perpetual Challenge,” a truth that is unfolding today (Lancet Infect Dis 2008;8(11):710-719).
“We've always had emerging infectious diseases. We have them now, and we will continue to have them in the future,” said Fauci. “So just as emerging infections provide for us a perpetual challenge, we need to be perpetually prepared.”
Valerie Neff Newitt is a contributing writer.