Zoe Berg and Ryan Chiao, photo editors

For Yale researchers, the pandemic meant a daunting checklist of breakthroughs to achieve: dissecting COVID-19’s toll on the body, devising accurate and accessible COVID-19 testing and designing vaccines and drugs against COVID-19. In the two years since Yale reported its first case, researchers have done all that and more.

The first step to demystifying the virus was to establish a library of COVID-19 patient samples. In March 2020, this biorepository was developed through a key partnership between the School of Medicine, School of Public Health and Yale New Haven Hospital — together, the team called themselves “Yale IMPACT.”

Yale IMPACT sought to address the demand for a robust bank of COVID-19 biosamples. The three main groups providing patient samples were health care workers, community members and hospitalized patients. The project quickly began supporting scientists through critical COVID-19 research, providing the foundation for numerous discoveries to come. 

“These samples … with the cooperation and commitment of this cohort, continue to contribute to our knowledge of the natural immune response to this virus, waning of natural antibodies and re-infection as well as the immune interactions of the virus in healthy, but continuously exposed, individuals,” Melissa Campbell, a clinical fellow at Yale who led the health care worker arm of the initiative, wrote in an email to the News in 2020.

COVID-19 in the body

Although COVID-19 is primarily a respiratory illness, two Yale studies suggested that COVID-19 could invade the brain. These findings, published in September 2020, showed that immune responses to the virus in the central nervous system could occur independently from the rest of the body — making direct infection of brain cells possible.

According to the researchers, this neuroinvasion could explain the neurological symptoms — such as loss of smell or taste — that had been found in 40 to 60 percent of COVID-19 patients. The independence of the immune response also suggested a need for brain-specific treatments for COVID-19. These two studies were led by Sterling Professor of Immunobiology and Molecular, Cellular and Developmental Biology Akiko Iwasaki.

Another question researchers sought to answer was why men were more likely to die from COVID-19 than women. In August 2020, the Iwasaki Lab — recognizing a dearth of research on the biological basis for this sex difference — published a study comparing the immune responses of men and women infected with the coronavirus.

The study found that men resorted to a more pro-inflammatory response — mediated by the immune molecules called cytokines — earlier in COVID-19’s course than women. Women were better at harnessing T cells, immune cells that halt the virus’ spread by killing infected cells, among other roles. It was found that in the long run, a weaker T-cell response was associated with worse disease outcomes in men, and stronger cytokine responses predicted worse disease progression in women.

According to Takehiro Takahashi — an associate research scientist in the Iwasaki lab and first author of the study — this was the first study to show that sex differences in immune responses to COVID-19 were significant and could be behind variation in clinical outcomes. These findings suggested that COVID-19 treatments for men and women may need to differ.

Building on this discovery, the Iwasaki Lab collaborated with the Caroline Johnson Lab on a study linking metabolism to sex-specific COVID-19 outcomes. The researchers found that kynurenic acid, a metabolic molecule, could serve as an effective predictor of COVID-19 outcomes. In males, the molecule was found to be negatively correlated with T cell responses while being positively correlated with age and inflammatory cytokines — thereby potentially underlying the poorer outcomes observed in men. These correlations were not found in women.

Iwasaki then approached professor of genetics and computer science Smita Krishnaswamy with a sample of immune cells from COVID-19 patients. Using Krishnaswamy’s tool, Multiscale PHATE, a Yale study published Feb. 28 found that certain immune cell types were more abundant in people who died from COVID-19 versus those who survived the infection. Specifically, the immune cells granulocytes and monocytes had a strong association with COVID-19 mortality.

According to Krishnaswamy, running Multiscale PHATE on a patient’s immune cells could guide doctors to the best path of treatment. The tool was able to predict mortality with 83 percent accuracy when applied to COVID-19 patients’ immune cell samples. Iwasaki said that treatment targeting these “rogue” immune system factors could be useful in preventing COVID-19-related fatalities.

Fighting COVID

In February 2021, knowledge of the shape of the SARS-CoV-2 genome deepened thanks to a study led by Rafael Tavares GRD ’21 and Nicholas Huston GRD ’23, mentored by Sterling professor of molecular, cellular and developmental biology and professor of chemistry Anna Marie Pyle.

Tavares and Huston found that a part of the genome that encodes proteins was highly folded. While most of the studies at that time focused on the virus’ spike protein, Pyle’s team decided that determination of where the virus was most highly folded could inform development of diagnostic testing and treatment.

From here, the next step was to identify the regions of folded genomic RNA that were the most vulnerable to attack — what Pyle called the virus’ “Achilles’ heel.” This new knowledge of the SARS-CoV-2 genome structure had major implications for how COVID-19 was tested for and treated, according to Pyle.

In March 2021, a novel COVID-19 drug was developed using molecular sculpting. Born from a collaboration between the Jorgensen, Anderson, Miller, Isaacs and Lindenbach labs at Yale, this new drug was designed to target the enzyme called Mpro. 

According to Sterling professor of chemistry William Jorgensen, choosing to target this enzyme was one of the new drug’s main advantages. While antibodies and vaccines targeted the cell membrane protein spike — which mutates rapidly — the drug’s targeted mutates at a much slower rate.

“The search for new and effective direct-acting antivirals against COVID-19 must be pursued alongside global vaccination efforts to provide a therapeutic strategy for patients that do not mount an immune response to SARS-CoV-2 for a variety of reasons,” M.D./Ph.D. student Maya Deshmukh GRD ’25, one of the study’s authors, wrote to the News.

A study published in February 2021 found that prescribing anticoagulants could be effective in preventing COVID-19 deaths. Patients who took preventative doses of anticoagulants — drugs that prevent blood clotting — within the first 24 hours of being hospitalized with COVID-19, had a mortality rate that was 30 percent lower than patients who did not.

Under Iwasaki’s leadership, a study found that a Yale-designed RNA-based antiviral could bring hope to immunocompromised patients. Published November 2021, this research found that SLR14, a short antiviral RNA molecule, could stimulate the innate immune system in the body’s fight against COVID-19, thereby protecting against all variants of the virus known at the time.

According to Iwasaki, this antiviral could be a new treatment for immunocompromised patients, and was relatively easy-to-manufacture and inexpensive — ideal for countries with limited access to vaccines.

As vaccines became widely available across the country in the spring of 2021, numerous Yale studies investigated their effectiveness against COVID-19.

In March 2021, a study looked at the effect of the Pfizer vaccine on COVID-19 rates in two Connecticut nursing homes. According to associate professor of epidemiology and medicine Sunil Parikh, the study’s senior author, nursing homes represented the “epicenter” of the COVID-19 pandemic in the United States and worldwide. The study found that the Pfizer vaccine led to ‘significantly lower’ case rates in nursing homes.

“Vaccines are often less effective in the elderly, and particularly those with multiple comorbidities,” Parikh wrote in an email to the News. “We wanted to assess just how effective these novel mRNA vaccines would be in this demographic.”

In October 2021, a Yale study found that messenger RNA vaccines, such as Pfizer’s and Moderna’s, effectively neutralized most variants of SARS-CoV-2. The study, led by Iwasaki and associate professor of epidemiology Nathan Grubaugh, demonstrated that variations in antibody production between individuals underscored the importance of booster shots. 

In January, an exciting study was published on a novel nasal vaccine against COVID-19. Guided by Iwasaki, Tianyang Mao GRD ’23 and infectious disease fellow Benjamin Israelow were the co-first authors of the study. According to Mao, the nasal vaccines were developed to address a weakness in current COVID-19 vaccines: while highly effective at preventing severe illness and hospitalization, mRNA vaccines were less effective at preventing infection and transmission of the virus.

The nasal vaccine was designed to trigger specific antibodies to attack the virus at the onset of infection, when the virus was expected to be in the respiratory tract, thereby neutralizing the virus and preventing its replication. This vaccine, when combined with an mRNA vaccine, could decrease the incidence of COVID-19 infections, even after exposure to COVID-19. This study was conducted in mice.

“We are also enthusiastic about ultimately moving into clinical trials with human patients to test the safety and tolerability of our boosting strategy and assess the actual efficacy of our vaccines, perhaps within a household context,” Mao said.

Iwasaki and professor of medicine, epidemiology and public health Harlan Krumholz also embarked on a year-long study — set to end in May — on the effect of vaccination on long COVID symptoms. Iwasaki had stumbled upon fascinating results from a poll in the Survivor Corps Facebook group — 40 percent of respondents had experienced an improvement in their long COVID symptoms after their first dose of the vaccine. 

Tracking COVID-19 

Early on in the pandemic, nasopharyngeal (NP) swabs were the standard method available for SARS-CoV-2 detection. Yet, the swabs were uncomfortable for many people, and supply chain bottlenecks drastically limited testing capacity.

SalivaDirect started as a preprint released in April 2020 with Anne Wyllie — a research scientist at the Yale School of Public Health — as the lead author. The study found that saliva was more sensitive to SARS-CoV-2 detection than specimens collected using nasopharyngeal swabs. 

With the saliva method, people could spit into a cup and mail it or drop it off at a testing site. This had the potential to greatly increase the country’s testing capacity. It also minimized risk faced by healthcare workers performing the tests — according to Wyllie, many individuals undergoing NP collection would cough or sneeze due to having the collection stick up their nose, further exposing workers to the virus.

“Saliva testing solves many problems,” Iwasaki said. “Saliva requires no swabs or viral transport media, both of which are in short supply. It also does not require a trained medical professional. [Nasopharyngeal] swab collection requires training and PPE, and is not always reliable if the swabs are not collected properly.”

Further supporting the saliva-based method, the Iwasaki Lab found that saliva viral load was a better predictor of COVID-19 mortality than NP viral load. The study found that greater levels of saliva viral load were correlated with increasing levels of COVID-19 severity. 

A successful partnership with the NBA led to the U.S. Food and Drug Administration (FDA) granting an Emergency Use Authorization for SalivaDirect in August 2020. The FDA then authorized SalivaDirect for pooled COVID-19 testing after the team published a study supporting the expansion of SARS-CoV-2 testing capacity via pooling. By analyzing five samples at once, only one test would be needed if the whole pool tested negative, while individual retesting would only be required if there was a positive result.

Yale researchers developed another novel COVID-19 detection method — a wearable COVID-19 exposure detection device. Assistant professor of epidemiology Krystal Pollitt worked with professor of chemical and environmental engineering Jordan Peccia’s lab to develop the FreshAir Clip — a small, silicone passive sampler that picks up aerosolized viral particles, which can then be analyzed via PCR to determine levels of exposure to SARS-CoV-2.

According to Pollitt, this device could be used as a COVID-19 surveillance monitoring tool on a larger scale, especially for high-risk groups. The “novel low cost and portable nature of the FreshAir Clip” could help determine the location of viral hotspots, Darryl Angel GRD ’25, a doctoral student in the Peccia lab, said. Peccia also led weekly analyses of New Haven’s wastewater as a reliable early-warning measure of COVID-19’s trajectory and surges.

The first COVID-19 case in New Haven was identified on March 14, 2020.