“The speed and efficiency with which these highly efficacious [coronavirus 2019 (COVID-19)] vaccines were developed and their potential for saving millions of lives are due to an extraordinary, multidisciplinary effort involving basic, preclinical, and clinical science that has been under way, out of the spotlight, for decades before the unfolding of the COVID-19 pandemic,” said Anthony S. Fauci, MD, who delivered this year’s Martin Memorial Lecture Monday morning, October 25. Dr. Fauci is Director, National Institute of Allergy and Infectious Diseases, Bethesda, MD,
In his lecture, COVID-19 in 2021: Lessons Learned and Remaining Challenges, Dr. Fauci explained the development of the COVID-19 vaccines, which he called the true “scientific success story of the outbreak”; identified similarities between the COVID-19 pandemic and other virus outbreaks; and provided an overview of medical management of SARS-CoV-2.
Historical perspective
“When we first heard about this puzzling disease in January of 2020, I wrote a ‘Viewpoint’ in the Journal of the American Medical Association, and I entitled it ‘Coronavirus infections—more than the common cold.’ I was not at all trying to be facetious with that title,” Dr. Fauci said. “I wanted to point out that we had known about and been involved with coronaviruses literally for decades before COVID-19.”
In fact, it was 2002 when clinicians and the general public had the first known and recognized experience with a pandemic coronavirus—severe acute respiratory syndrome (SARS). Then, 10 years later, in 2012, scientific investigators encountered Middle East respiratory syndrome (MERS)—also considered a pandemic coronavirus, according to Dr. Fauci.
“Now, fast-forward to the present time, and we have a third novel coronavirus. As of October 11, there have been almost 240 million cases globally with just short of 5 million deaths,” he said. “The U.S. has been one of the countries that has been most severely hit by this pandemic, with over 44 million cases and now exceeding 700,000 deaths.”
Virology and medical management
After giving an overview of the epidemiology of the COVID-19 pandemic, Dr. Fauci summarized the virology of SARS-CoV-2. “The transmission is now well studied; it is by exposure to infectious respiratory fluids with inhalation of not only respiratory droplets, but also the inhalation of aerosol particles that get deposited on the mucous membranes in the mouth, nose, and eyes. We know, after a year and three-quarters, that transmission is much less common through contact with contaminated surfaces such as fomites.” The risk is greatest, he noted, in enclosed spaces with poor ventilation and during activities, such as exercise and signing, with prolonged indoor exposure.
“With regard to the transmission, very uniquely among viruses, at least one-third of the patients with SARS-CoV-2 infections never develop symptoms,” Dr. Fauci said. “And very importantly, between 50 to 60 percent of all SARS-CoV-2 infections are transmitted by someone who is without symptoms—35 percent from pre-symptomatic individuals, 24 percent from individuals who never develop symptoms.”
Generally speaking, for patients who do present with symptoms (including fever, cough, fatigue, anorexia, shortness of breath, myalgias, and so on), about 80 percent are mild to moderate, and about 15 to 20 percent are severe and critical, leading to a case fatality rate of 2.3 percent overall. Individuals with an increased risk for severe COVID-19 illness are older adults, particularly those over 75 years of age, as well as anyone at any age who has underlying medical conditions, including severe obesity, diabetes, chronic lung disease, heart disease, and others. “The manifestation of severe COVID-19 is dominated by acute respiratory distress syndrome, “ added Dr. Fauci. “And other organ systems such as neurological, cardiovascular, and kidney injury can occur, as well as other pathogenic processes.”
The medical management of the SARS-CoV-2-infected patient can involve multiple approaches, starting with controlling the symptoms, which can be conducted as an outpatient regimen. This stage is sometimes followed by end-organ support, which requires hospitalization for mechanical ventilation, dialysis, and other organ system support.
Another pathway for managing COVID-19 involves antivirals and immunomodulators, which includes two major approaches. “First, target the virus itself, and this generally needs to be done early. There is a drug, Remdesivir, which must be administered intravenously and has been approved by the FDA,” he said, noting that monoclonal antibodies also have been shown to be highly effective when given early in the course of the disease.
According to Dr. Fauci, when an individual advances to late disease, it is important to moderate the aberrant inflammatory response with drugs as “simple” as dexamethasone, but also with newer drugs such as Tocilizumab and Baricitinib, which interfere with various stages of the inflammatory and immune response.
A new program that the National Institutes of Health launched in June will support the development of additional antiviral drugs to fight COVID-19 infection in its early stages. “One of the initiatives that has recently been launched involves the identification of vulnerable targets in the SARS-CoV-2 replication cycle and [the development] of drugs to inhibit these vulnerable targets very similar to what was done so successfully with antiretroviral drugs for [the human immunodeficiency virus],” Dr. Fauci said.
The program, called the Antiviral Program for Pandemics, aims to catalyze the development of new medicines to combat COVID-19 and to prepare for other pandemic threats. This program is two-tiered: development, taking already existing drugs and furthering their development to determine their capability against SARS-CoV-2; and discovery, with the design of new molecules to aim at the various vulnerable targets, which will likely require several years of work, Dr. Fauci said.
Vaccine efficacy
“Many people feel that in 11 months, we went from the sequence of the virus to effective and safe vaccines going into the arms of individuals, and that this was done at greater speed than ever experienced,” said Dr. Fauci, noting that although that observation is true, these vaccinations were actually developed with the help of decades of evidence-based research.
“When SARS-CoV-2 came along, investigators were well-prepared to immediately use the knowledge over the previous several years to develop and apply the precise mutations to stabilize that spike protein in the optimal, prefusion confirmation, which was highly immunogenic,” he said. “Now, that had to be married with the right vaccine platform, some of which we are familiar with and some of which are new. Originally, we had live, attenuated, and killed vaccines, and now we have platforms like genetic immunization, viral vectors, recombinant proteins, and nanoparticles.”
According to Dr. Fauci, the story of the mRNA vaccine goes back approximately 16 years to when researchers showed that if you modify an mRNA molecule so that it doesn’t trigger a key inflammatory pathway, which would nullify its potential as a vaccine, you could overcome that hurdle and pave the way for current vaccine platforms.
“In the U.S. now, after hundreds of millions of doses have been administered, even in the era of the Delta variant, a person that has been vaccinated has a reduced risk of an infection that is five-fold, a reduced risk of hospitalization that is more than 10-fold, and a reduced risk of death that is more than 10-fold,” Dr. Fauci said.
“However, along came several variants.” The Delta variant comprises more than 99 percent of all the isolates in the U.S. and is seen in more than 173 countries throughout the world. “Why is it so important? Its transmissibility is extraordinary, much greater than any of the other variants. And the viral loads in the upper airway are up to 1,000 times greater than other variants,” he said.
“When you look at the vaccine effectiveness in the U.S., when you get to six to eight months, it diminishes in all the cohort studies. The real troublesome data are coming from Israel because, now in a predominated fully vaccinated population during the Delta wave, we’re seeing new PCR [polymerase chain reaction]-positive infections and severe COVID cases indicating waning immunity, which brings up the topic of booster shots for SARS-CoV-2 vaccines.”
Research suggests that when an individual receives a booster after two doses of an mRNA vaccine, he or she receives a major enhancement of neutralizing titers. “In fact, in Israel, which is about a month ahead of us with this, it shows that the rate of infection following a boost was lower by 11-fold compared to the non-booster group and the rate of severe illness was diminished by a factor of almost 20-fold with the booster.”
The real question that is going to remain is whether the booster is “sort of a bonus” or a necessity. “The thinking now is leaning much more toward the fact that the booster shot may actually be part of the original vaccine regimen, so that it is not just a booster for waning efficiency, and likely should be part of the overall, primary regimen,” Dr. Fauci said.
Dr. Fauci also underscored the role the U.S. needs to play in ensuring that countries with limited resources are receiving COVID-19 vaccines.
“Even as we talk about boosters, we still have a major responsibility for those parts of the world that are not as fortunate to have the accessibility or resources. So, at the same time that you talk about boosts, you’ve got to talk about the responsibility of getting the rest of the world vaccinated, and the U.S. takes that very seriously,” Dr. Fauci said.
“Finally, the race is on—namely, the race of getting as many people vaccinated as we can to outstrip the virus, which is highly transmissible,” he said. “We still have about 68 million people in this country who are not vaccinated, and we will prevent another surge if we successfully vaccinate the overwhelming proportion of the population of this country.”
This and other Clinical Congress 2021 sessions are available to registered attendees for on-demand viewing for a full year following Congress on the virtual meeting platform.