The days are long, but the years are short.” This bittersweet saying, which is often shared with new parents, may apply to everyone who has been living through the COVID-19 pandemic—although what we’re experiencing is almost entirely bitter and not at all sweet. Over the past 12 months, SARS-CoV-2, an RNA virus that carries a mere 29,903 nucleotides, has devastated our communities, disabling economies and taking far too many lives. However, as we hit the grim one-year anniversary of COVID-19, we may anticipate a measure of relief.

On January 7, 2020, the virus that causes COVID-19 was isolated by Chinese health authorities. They determined that COVID-19, a new respiratory illness that had been circulating for about a month, was associated with a novel coronavirus. Initially, the virus behind COVID-19 was dubbed 2019-nCoV; later, it was named SARS-CoV-2.

The first death was confirmed in Wuhan, China, on January 9. By January 12, Chinese researchers had posted the viral genomic sequence, allowing researchers to arm for battle. On January 13 and 15, the first cases were reported outside China—in Thailand and Japan, respectively. And the first confirmed case of SARS-CoV-2 infection in the United States was reported just days later—on January 20.

Subsequently, SARS-CoV-2 drove a fast-spreading contagion, one that surged wherever opportunities presented themselves. All the while, however, scientists hoping to contribute to countermeasures kept working at full tilt, especially scientists in vaccine production. For example, the novel mRNA vaccines produced by Pfizer/BioNTech and Moderna progressed from concept to FDA approval in less than a year—an absolutely staggering accomplishment.

In the early days of the pandemic, researchers loaded car trunks with the hard-to-find RNA extraction kits that their clinical lab neighbors desperately needed. More recently, collaborations have seen scientists banding together to provide space, supplies, personnel, or whatever else was needed to keep the data pouring in.

As the world marks this COVID-19 one-year anniversary, GEN offers this review of the progress that is being made against the pandemic. Our focus is on a handful of pressing questions, some of which concern scientific and technical developments, and some of which pertain to business issues.

What do our genes have to do with SARS-CoV-2 infection?

As the wide range of symptoms of COVID-19 began to unfold—from lung infections to loss of taste and smell—and as vast differences in disease severity among people became apparent, COVID-19’s complexity started to come into focus. As researchers started investigating the virus, others rushed to tackle the problem from another direction—identifying the host factors that determine the course of an infection.

Understanding the genetic basis for an individual’s COVID-19 susceptibility and severity could be key to understanding the pandemic on multiple levels, not only to explain the depth and breadth of COVID-19 symptoms, but also to identify novel antiviral targets that are important for the virus to set up an infection and replicate. In the future, people may be able to gain a sense of their risk. For example, if a specific immune profile is determined to increase risk for severe infection, patients could be stratified into high- and low-risk categories upon entering the hospital.

Work led by Neville Sanjana, PhD, core faculty member at the New York Genome Center, used a genome-wide CRISPR screen to systematically knock out all human genes to identify genetic modifications that make lung cells more resistant to SARS-CoV-2 infection. His group’s findings revealed individual genes and regulatory networks that are exploited by SARS-CoV-2. Suppressing these genes and networks could confer resistance to viral infection.

Several large international working groups have been established to uncover the genetic basis for the susceptibility and severity of COVID-19. For example, the COVID-19 Host Genetics Initiative, organized by Andrea Ganna, PhD, research fellow in medicine at Massachusetts General Hospital, and other researchers in Boston, now includes researchers from more than 50 countries.

A similar effort, the COVID Human Genetic Effort, was established by Jean-Laurent Casanova, MD, PhD, professor at the Rockefeller University, and Helen Su, MD, PhD, chief of the human immunological diseases section at the National Institute of Allergy and Infectious Diseases. The first results were published by the Casanova lab in September in twin Science papers. The research highlighted the role of interferons (IFNs) in severe COVID cases. More specifically, disruption of IFN-1 might be a factor for developing life-threatening COVID-19.

The Casanova lab also found that autoantibodies to IFN-1 were present in 13.7% of severe COVID-19 cases, a seminal result that other labs, such as the Yale University lab led by Akiko Iwasaki, PhD, are following up. By investigating the host, science may uncover the mystery of why some people get very sick and die, while others don’t even know they are infected.

What does the worldwide tracking of SARS-CoV-2’s RNA reveal?

As soon as genome sequences of SARS-CoV-2 were available, researchers at Nextstrain—an open-source project to harness the scientific and public health potential of pathogen genome data—started their analysis. Nextstrain’s initial goal was to study flu strains, but the mission now includes other pathogens including Zika virus, West Nile virus, and Ebola virus.

Analysis of the genetic variants of SARS-CoV-2 map
Analysis of the genetic variants of SARS-CoV-2 circulating among COVID-19 patients in Europe, performed by researchers at the University of Basel, ETH Zürich, and the SeqCOVID-Spain consortium. Tools that illustrate the number of sequences found in a location (represented by the diameter of the circles), or the phylogenetic tree, prove useful to many working on the pandemic, from genetic epidemiologists to public health specialists. [Nextstrain, Mapbox, OpenStreetMap]
SARS-CoV-2 is replicated by an RNA-dependent RNA polymerase that is error prone and poor at proofreading. Consequently, SARS-CoV-2 diverges into varied forms that contain different mutations. But the significance of these genetic changes, and their potential impact on public health measures such as vaccination, is still an open question. Multiple media reports have erroneously suggested that certain viral “strains” are more transmissible, more virulent, or less responsive to vaccines, at times sparking unnecessary concern.

Emma Hodcroft, PhD, a postdoctoral researcher at the University of Basel, tells GEN that such language is not accurate. She explains that the word “strains” is not appropriate when talking about SARS-CoV-2, because the virus is simply not that diverged yet.

Some genome variants have become widespread in certain populations. In Europe, where hundreds of variants are currently circulating, one variant, 20A.EU1, has become prevalent. Hodcroft, who led a study on the variant, cautions that nobody should jump to conclusions. “There is currently no evidence the new variant’s spread is due to a mutation that increases transmission or impacts clinical outcome,” she insists.

In the Hodcroft-led study, which was posted on the medRxiv preprint server, the authors present the idea that the variant’s expansion may have been due, in part, to loosening travel restrictions and social distancing measures last summer.

Will our immune systems protect us from reinfection?

The first example of reinfection in the United States was confirmed through genomic analysis of the viral sequence and described in a paper that appeared last October in The Lancet Infectious Diseases. Although only a handful of cases like this are known, more widespread viral genome sequencing may uncover more cases.

In a commentary that accompanied the article, Akiko Iwasaki noted that the key goal for the future is “to ascertain the level and specificity of antibody to spike protein at the time of reinfection, to determine immune correlate of protection.” Indeed, understanding the body’s immune response to COVID-19 is important not only to understand whether reinfections are an important factor in the pandemic, but also to inform public health measures such as the optimal frequency of vaccinations.

Two papers published back to back in Science Immunology brought good news in October. Protective antibodies were present in recovered COVID-19 patients for three to four months, offering hope that people will have some level of lasting antibody protection against reinfection. To advance this work, the National Cancer Institute launched the NCI Serological Sciences Network for COVID19 (SeroNet)—a large nationwide effort to characterize the immune response to COVID-19.

What are the prospects for a broader anti-COVID-19 armamentarium?

Last October, the U.S. Food and Drug Administration (FDA) approved the first treatment for COVID-19. This treatment, which consists of an antiviral drug called remdesivir (Veklury), may be used in combination with baricitinib (Olumiant), an anti-inflammatory drug that gained FDA approval as a remdesivir partner in November.

Many other drugs, both novel and repurposed, are in development. And several vaccines look promising. As of this article’s preparation, in mid-December, two mRNA vaccines have already been authorized by the FDA for use.

Less certain is the timing of an EUA or full approval for AstraZeneca/University of Oxford’s AZD1222. AstraZeneca announced preliminary positive Phase III results on November 23 based on two trials averaging 70% efficacy. But in the higher-efficacy trial (90%), a dosing error occurred.

Also on track for approvals are a pair of antibody treatments—Regeneron Pharmaceuticals’ two-antibody “cocktail” REGEN-COV2 (formerly REGN-COV2) and Eli Lilly’s bamlanivimab (LY-CoV555). The FDA on November 21 authorized emergency use of REGEN-COV2, a few days after granting an EUA for bamlanivimab. Both are indicated for adults and youths ages 12 years and older with mild-to-moderate COVID-19, based on positive clinical data. However, both have shown disappointing results in hospitalized COVID-19 patients.

How much has been projected in sales for leading vaccines and drugs?

Geoffrey C. Porges
Geoffrey C. Porges
Sr. Analyst, SVB Leerink

Projected sales run into the billions of dollars. Geoffrey C. Porges, MBBS, director of therapeutics research and a senior research analyst at SVB Leerink, on November 10 projected sales for Pfizer/BioNTech’s BNT162b2 of $4.6 billion worldwide in 2021. He said sales will slide as other vaccines and drugs reach the market, to $2.8 billion by 2023, then between $1.2 billion and $1.6 billion between 2026 and 2029.

Moderna’s mRNA-1273 could generate more than $5 billion a year, Michael J. Yee, equity analyst with Jefferies, wrote November 18 in an investor note: “If the company sold 500 [million] at $20/dose, that would be $10 [billion] in revenue over 2021–2022 and way higher than consensus of $3 [billion]-plus in 2021.”

Michael J. Yee
Analyst, Jefferies

Last September, in a discussion of leading COVID-19 drugs, Morningstar analyst Karen Andersen projected that Regeneron’s REGEN-COV2 could generate $6 billion in annual sales in 2021. Porges lowered his 2021 forecast for REGEN-COV2 sales in November by $500 million, to $1.3 billion, following the disappointing data in hospitalized COVID-19 patients. He expects annual sales for the antibody cocktail will decline to $646 million by 2023 and $352 million two years later.

Karen Andersen
Karen Andersen
Analyst, Morningstar

As for remdesivir, Andersen has projected $3 billion in sales in 2021. The drug generated $873 million in the third quarter of 2020, below analysts’ estimates of $960 million, according to Refinitiv IBES data quoted by Reuters. Porges has projected that remdesivir sales will climb to $7.7 billion by 2022, then dip to between $6 billion and $7 billion each year after.

How have the United States and the European Union sought to accelerate development of COVID-19 vaccines and drugs?

The Trump administration in May launched Operation Warp Speed, designed to support development and delivery of 300 million vaccine doses by January 2021. Through Warp Speed, the U.S. government committed about $11.2 billion toward 7 vaccines and $1.85 billion toward 11 drugs, according to the Biomedical Advanced Research and Development Authority (BARDA).

In Europe, the European Medicines Agency (EMA) has developed rapid formal review procedures related to COVID-19. Scientific advice letters to developers of treatments and vaccines seeking guidance and direction on the best methods and study designs are generated within 20 days, compared with the regular 40–70-day timeframe. The 20-day timeframe also applies to review time for pediatric investigation plans for new drugs and vaccines.

The EMA carries out rolling reviews assessing data supporting marketing authorization applications (MAAs). Several rolling review cycles can be carried out during evaluation of one product as data emerges, with each cycle requiring about two weeks, depending on the amount of data being assessed. Once the data is considered complete, developers can submit formal marketing authorization applications. Reviews may be expedited for “products of major interest for public health” such as COVID-19 drugs and vaccines. Specifically, COVID-19 reviews have been shortened from 210 to under 150 days.

How have vaccine and drug developers addressed manufacturing?

Pfizer and BioNTech have projected that in 2021 they will manufacture 1.3 billion doses; Moderna has projected that it will manufacture 500 million to 1 billion doses. AstraZeneca has said it is building a global supply capacity of 3 billion doses.

Among the makers of COVID-19 drugs, Gilead Sciences stated October 22 that it planned to manufacture more than 2 million treatment courses by the end of 2020, to be followed in 2021 by “several million” courses. Eli Lilly has indicated that it will manufacture bamlanivimab through a partnership with Samsung Biologics. Regeneron is partnering with Roche to manufacture REGEN-COV2.

How much will the leading vaccines and drugs cost?

BioNTech chief strategy officer Ryan Richardson told the Financial Times’ Global Pharmaceutical and Biotechnology Conference on November 10 that BNT162b2 will be priced “well below typical market rates,” with pricing to differ depending on where in the world it is being marketed.

The U.S. government paid $19.50 per dose when it purchased an initial order of 100 million doses for $1.95 billion under Operation Warp Speed. The contract included a government option to buy 500 million additional doses at an undisclosed price.

Stéphane Bancel
CEO, Moderna

Moderna CEO Stéphane Bancel said August 5 that his company had signed “smaller volume agreements” pricing mRNA-1273 at between $32 and $37 per dose—between $64 and $74 for a full two-vaccination treatment course. “Larger-volume agreements under discussion will be at a lower price for higher volumes,” Bancel added.

AstraZeneca has said it intends to supply AZD1222 at cost—$3 to $5 per dose—until the pandemic ends.

Regeneron has said it has not set a price for REGEN-COV2. In July, the government awarded Regeneron a $450 million contract to manufacture and supply the cocktail. The company expects to have 2.4-g doses ready for about 300,000 patients by the end of January—which would value the government contract at $1,500 a dose.

In October, Eli Lilly charged $1,250 a vial for bamlanivimab to the U.S. government. At the time, the government agreed to buy an initial 300,000 vials of the antibody therapy over two months for $375 million, with an option to buy another 650,000 vials for up to an additional $812.5 million through June 2021.

“We still think that pricing for vaccines will deteriorate rapidly as supply and the number of vaccines increases throughout 2021, and that demand beyond 2022 is very difficult to predict,” Andersen said. “That’s because we don’t know whether the virus will become endemic, although it likely will, and we don’t know how long the vaccines will last [or whether] annual boosters [will be needed].”

Previous articleMonoclonal Antibodies: Developers Explore New Territories
Next articleLeroy Hood: Reflections on a Legendary Career