By Deborah Borfitz

July 21, 2020 | In his opening keynote address at the American Association for Cancer Research virtual meeting on COVID-19 and cancer yesterday, Anthony Fauci, M.D., head of the National Institute of Allergy and Infectious Diseases, stayed true to his reputation as a beacon of knowledge and truth in the battle against a confounding viral foe. He provided a historical perspective on coronavirus infections before diving into the current pandemic with close to 14 million cases globally, 583,294 deaths, and “essentially no end in sight.”

The U.S. has been “hit harder than any other country in the world,” says Fauci, with 3.4 million of those cases claiming 135,235 lives. A relatively small percentage of those diagnosed with COVID-19 have severe (14%) or critical (5%) disease. The case-fatality rate has been pegged at 2.3% but is more likely 1% or less if all asymptomatic people are factored into the equation.

Unlike any virus he has dealt with over the last several decades, COVID-19 has caused an “extraordinarily wide spectrum of disease” with between 20% and 45% of infected individuals being completely asymptomatic, Fauci says. On the other end of the spectrum are folks 85 years and up where the rate of severe disease per 100,000 population is almost 600. In between are people who might have mild illness keeping them home for a few days to others in bed for weeks with a post-viral syndrome.

With regards to cancer, one big concern is the COVID-19-related reductions in screening because of the country-wide lockdown, Fauci says. Over the next decade, the consequence could be 10,000 or more excess deaths from breast and colorectal cancer.

Same and Different

“Human coronaviruses are not just a human infection,” he points out, “since bats and other intermediate hosts are important reservoirs.” Coronaviruses were associated primarily with recurrent common colds prior to November 2002, when the first severe acute respiratory syndrome (SARS) coronavirus revealed its pandemic potential. SARS started in the Guangdong province of China, where a single individual infected 19 others at a hotel in Hong Kong and, from there, the virus spread to more than 8,000 people throughout the world.

By the following July, after 774 people had perished, SARS “essentially disappeared,” he notes. Unlike SARS-CoV-2, the virus responsible for COVID-19, the first coronavirus pandemic was contained by isolation, physical separation and mask-wearing, quarantine, travel advisories, and airport screenings. Although easily transmissible, it did not have the “absolute overwhelming efficiency and capability of spreading human to human” as SARS-CoV-2. “The outbreak was controlled purely by public health measures, without any drugs or vaccines.”

A decade later, Middle Eastern respiratory syndrome (MERS) emerged in Saudi Arabia. Like SARS, it originated in bats but instead of spreading to civet cats—served at festive meals in China—it jumped to camels before infecting humans, Fauci says. Although the fatality rate was about 35%, versus 10% for SARS, about 80% of the 2,519 cases were confined to Saudi Arabia. “MERS is still smoldering [there] up to this day.”

SARS-CoV-2 is a beta coronavirus, in the same subgenus as SARS and several bat coronaviruses, Fauci continues. It’s a positive-sense single-strand RNA virus and has a number of structural proteins, the most important of which is the S (aka “spike”) protein that allows the virus entry into a host cell via the ACE2 cellular receptor. It has a respiratory route of transmission, person to person, usually through close contact.

Clinical Realities

In addition to respiratory droplets that generally drop three to six feet from where they were expelled, most scientists believe aerosol transmission of droplets less than 5 micrometers also has some impact, says Fauci. The virus is detectable in a number of bodily fluids, and animals can also be infected, but both have an uncertain role in transmission.

Clinically, COVID-19 has protean manifestations strongly resembling influenza: fever, cough, fatigue, anorexia, shortness of breath and myalgias. “What’s interesting and reported consistently now are loss of smell and taste, which precedes the onset of respiratory symptoms,” Fauci says.

In addition to older adults, people at any age with certain underlying medical conditions are at higher risk of severe illness, he continues. These include people with chronic kidney disease, chronic obstructive pulmonary disease, any immunocompromised state (e.g., solid organ transplantation), obesity, heart disease, diabetes, and sickle cell disease. There is also less-firm evidence that other conditions may also confer increased risk, notably use of glucocorticoids, pregnancy, hypertension, and HIV infection.

When looking at age-associated rates of COVID-19 hospitalizations by ethnicity, it is clear that minority communities (blacks, Hispanics, Latinx, American Indians and Alaskan natives) are also disproportionately affected, he adds.

Manifestations of severe disease are also protean, most typically acute respiratory distress syndrome but also hyperinflammation, acute cardiac injury, arrhythmias, cardiomyopathy, renal disease, neurological diseases, and hypercoagulability, says Fauci. A multisystem inflammatory syndrome seen in children “strikingly resembles” Kawasaki syndrome.

COVID-19 testing is typically a molecular assay that detects genetic materials from the virus, he continues. Recently introduced antigen tests, such as those looking for the spike protein, could allow testing to “scale up much more readily.” The big unknown with antibody tests, to determine who has been infected, is durability of the antibody response.

Treatments, Prevention and Vaccines

Among the list of experimental treatments for COVID-19 are remdesivir, broad-spectrum anti-viral agents, convalescent plasma, and hyperimmune immunoglobulin (derived from convalescent plasma), says Fauci, as well as the repurposed drug hydroxychloroquine “that pretty much all studies have shown to be ineffective.” Still under study are the HIV treatment lopinavir/ritonavir, as well as immune-based therapies that dampen the inflammatory response and monoclonal antibodies directed specifically at the SARS-CoV-2 virus.

Remdesivir was the first to be tested in a randomized, placebo-controlled trial (RCT) among more than 1,000 hospitalized COVID-19 patients across 10 countries. “The results showed a modest but definite [32%] decrease in the time to recovery,” Fauci shares. In another RCT in the U.K., dexamethasone given at a dose of 6 mg. per day for up to 10 days had a significant impact on decreasing mortality—by 35% among hospitalized patients on ventilators and 20% among those receiving oxygen. “But it did not have a positive effect, and may even have a negative effect, in people with early disease.”

The findings align with understanding of the pathogenesis of infection, say Fauci. “Early on, you want to block the virus but keep the inflammatory/immunological response intact, whereas later in disease there is not really that much viral activity perhaps but you have a lot of aberrant inflammatory response that you want to dampen down.”

The National Institutes of Health (NIH) stays current with data from clinical trials as it becomes available, Fauci says. A panel of experts will be responsible for maintaining a “living document” online as treatment guidelines for COVID-19.

In terms of prevention, the common denominator among all applicable public health measures—stay-at-home orders, closing or modifying school schedules, bans on public gatherings, and travel restrictions—is physical distancing, he stresses. Personal prevention measures include commonsense (and oft-repeated) approaches such as diligent handwashing, avoiding close contact, wearing a mask, and regularly cleaning inanimate objects.

The NIH is being strategic about vaccine development, directly or indirectly supporting multiple candidates using different platforms, Fauci says. Its harmonized approach uses a common protocol across studies, including the same data and safety monitoring board and primary and secondary endpoints as well as laboratory data that is compatible and interchangeable.

Three major platforms are in the mix: nucleic acid (mRNA), a path being pursued by Pfizer and BioNTech as well as Moderna; viral vector, where the University of Oxford, AstraZeneca, Janssen, Johnson & Johnson and Merck are focusing their efforts; and protein subunit, the strategy of Novavax and a partnership between GlaxoSmithKline and Sanofi.

Temporally speaking, Moderna’s mRNA-1273 vaccine candidate is ahead of the pack with a phase III trial launching at the end of July, Fauci says. In the phase I trial, it was found to be safe and immunogenic in 45 healthy volunteers ages 18 to 55. Results published (DOI: DOI: 10.1056/NEJMoa2022483) in the New England Journal of Medicine only days ago.

“Even at a moderate dose, it produced robust neutralizing antibodies that were at a level, or greater, than what you would see with convalescent serum. That’s very good news, because one of the tenets of vaccinology is you like to get a vaccine that induces response comparable to the response induced by natural infection.”

As Fauci wrote in a paper published in Lancet Infectious Diseases 12 years ago (DOI: 10.1016/S1473-3099(08)70256-1), emerging infections are “a perpetual challenge.” They have always existed and always will, he says, “so we need to be perpetually prepared.”