Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia.

Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw a few conclusions, such as: there was no “Patient Zero”, at least here.

According to sequence analysis in the paper, multiple early introductions of SARS-CoV-2 into Georgia occurred, probably coming from Asia, weeks before the first officially reported case in March 2020. The authors suggest that the early focus on returning international travelers was misplaced, as opposed to broader testing of patients with COVID-19 symptoms.

“SARS-CoV-2 was likely spreading within the state for approximately three weeks prior to detection in either diagnostic or sequencing data,” the authors write.

Tree showing relationships between SARS-CoV-2 genetic sequences from Georgia and other states/countries

In Georgia, the subclade, or swarm of related viruses, that was dominant early on (called 19B) disappeared by the end of April, eclipsed by variants carrying the D614G mutation. This was an early hint – even before the emergence of B117/Alpha and other variants such as Delta and Omicron — that SARS-CoV-2 would evolve through competition.

Similarly, sequence analysis from Washington state – the site of the first COVID-19 case identified in the United States — has shown that the first official case did not lead directly to the initial wave of infections there. The first wave actually fizzled out as a result of public health interventions, but other undetected infections in Washington in February 2020 led to sustained downstream transmission.

The co-first authors of the Viral Evolution paper are Emory infectious disease specialist Ahmed Babiker and graduate student Michael Martin, with co-authors from the Centers of Disease Control and Prevention. The paper analyzes sequences from Emory Healthcare patients along with previously available sequences.

In a few cases, scientists attempted to trace relationships between infected patients who had recently travelled to other countries (Italy, Switzerland) or other states (Louisiana, Colorado), but the available data did not confirm all of those connections.

Keep in mind that SARS-CoV-2 testing was very limited at the start of the pandemic, because of short supplies as well as FDA policy. More extensive virus sequencing efforts at Emory did not begin until mid-March 2020. With respect to viruses, we only see what we look for, and scientists can’t analyze samples they don’t have. If more samples were available from January or February, what would we find? Also, this paper’s analysis does not include any (known) samples from a February 2020 funeral in Albany, GA that was considered a “super-spreader event.”

Two years later, has SARS-CoV-2 genomic surveillance improved? Piantadosi says that her team’s paper should be viewed in combination with their recent paperon the detection of the first Omicron case in Georgia, a woman who became sick in November 2021 while visiting Cape Town, South Africa.

“That’s an example of where we did better,” Piantadosi says. “It does speak to how much surveillance has improved. We were conducting routine surveillance – not focusing on returning travelers.”

In the Omicron case, the woman in question first went to a community testing site, and those samples were not available for sequence analysis.

Piantadosi says that “we’ve achieved Phase I” – in that large hospitals or health systems such as Emory are collecting SARS-CoV-2 sequences, and the state Department of Public Health and large diagnostic services companies are also doing so. But as more SARS-CoV-2 testing is performed at home – generally a good thing for convenience and public health — surveillance for new variants needs to continue, she says.

Posted on March 3, 2022 by Quinn Eastman in Uncategorized Leave a comment

Report on first Omicron case detected in GA

The first Omicron case detected in Georgia through SARS-CoV-2 genomic surveillance probably became infected during a visit to Cape Town, South Africa, according to a recent case report in Clinical Infectious Diseases.

The patient was a woman in her 30s, who was fully vaccinated with Pfizer/BioNTech twice, then a booster in October 2021 – about six weeks before becoming sick. She had a negative PCR test shortly before traveling back to Georgia but developed symptoms around the time of her return flight.

The woman was diagnosed with COVID-19 at the end of November, a few days after her return to Georgia — just after Omicron was declared a Variant of Concern by the WHO.

This single case report is not representative of the overall severity of Omicron, which is generating a large number of infections, burdening hospitals in Georgia and elsewhere. The patient experienced muscle aches, nausea, fatigue and cough, but did not have a fever or shortness of breath and did not require hospitalization.

The lead authors of the case report were Marybeth Sexton, chief quality officer for the Emory Clinic, and infectious disease specialist Jesse Waggoner. The senior author was viral geneticist Anne Piantadosi.

The authors note: “Identifying this case required eliciting an appropriate travel history and being able to identify and perform sequencing for COVID patients in the community, since the patient had mild symptoms and did not seek clinical care.”

To speed detection of SARS-CoV-2 variants such as Omicron, the case report contains information about how to customize the “Spike SNP” PCR assay to give results within a few hours, rather than waiting for full viral sequencing taking 72 hours.

With the help of virologist Mehul Suthar’s lab, the authors were also able to report that the patient developed high levels of antiviral antibodies capable of neutralizing the Omicron variant. Currently available booster shots can elicit measurable antiviral antibody activity (see our recent post Thrice is nice), but actual Omicron infection generates way more.

Posted on January 20, 2022 by Quinn Eastman in Immunology Leave a comment

Booster COVID-19 vaccine vs Omicron: thrice is nice

A third dose of an mRNA COVID-19 vaccine is necessary to give someone robust neutralizing antibody activity against the Omicron variant, according to data from Emory researchers posted on the preprint server Biorxiv.

The findings support public health efforts to promote booster vaccination as a measure to fight Omicron, which is currently overwhelming hospitals around the world. They also explain why more breakthrough infections are occurring with the Omicron variant in people who have been vaccinated twice, and are in line with what other investigators have observed.

Compared with the 2020 Wuhan strain, the Omicron variant of SARS-CoV2 has more than 30 mutations in the viral spike protein, which is the primary target of neutralizing antibodies generated by vaccination.

“Our findings highlight the need for a third dose to maintain an effective antibody response for neutralizing the Omicron variant,” says lead author Mehul Suthar, a virologist based at Emory Vaccine Center and Yerkes National Primate Research Center.

Vaccinated individuals who develop breakthrough Omicron infections are likely to experience less severe symptoms, and it is possible for Omicron to infect people even after receiving a booster, Suthar notes. Still, a majority of patients now coming into hospitals continue to be those who are unvaccinated.

In the preprint, Emory researchers tested blood samples from people who participated in Pfizer/BioNTech or Moderna vaccine studies in the laboratory for their ability to smother SARS-CoV-2 variants in culture. The preprint does not include clinical outcomes from infection, and also does not cover other aspects of vaccine-induced antiviral immunity, such as T cells.

In people who were vaccinated twice with mRNA vaccines, either Pfizer/BioNTech or Moderna, none showed measurable neutralizing antibody activity against Omicron six months after vaccination. But 90 percent displayed some neutralizing activity against Omicron a few weeks after a third dose.

Posted on January 6, 2022 by Quinn Eastman in Immunology Leave a comment

Social isolation and the adolescent brain

We can’t read Emory neuroscientist Shannon Gourley’s papers on social isolation in adolescent mice, without thinking about how the COVID-19 pandemic is affecting children and teenagers. Much of the experimental work was completed before the pandemic began. Still, in the future, researchers will be studying the effects of the pandemic on children, in terms of depression and anxiety, or effects on relationships and education. They could look to neuroscience studies such as Gourley’s for insights into brain mechanisms.

What will the social isolation of the pandemic mean for developing brains?

In the brain, social isolation interferes with the pruning of dendritic spines, the structures that underly connections between neurons. One might think that more dendritic spines are good, but the brain is like a sculpture taking shape – the spines represent processes that are refined as humans and animals mature.

Mice with a history of social isolation have higher spine densities in regions of the brain relevant to decision-making, such as the prefrontal cortex, the Emory researchers found.

In a recently published review, Gourley and her co-authors, former graduate student Elizabeth Hinton and current MD/PhD Dan Li, say that more research is needed on whether non-social enrichment, such as frequent introduction of new toys, can compensate for or attenuate the effects of social isolation.

This research is part of an effort to view adolescent mental health problems, such as depression, obesity or substance abuse, through the prism of decision-making. The experiments distinguish between goal-oriented behaviors and habits. For humans, this might suggest choices about work/school, food, or maybe personal hygiene. But in a mouse context, this consists of having them poke their noses in places that will get them tasty food pellets, while they decode the information they have been given about what to expect.

Posted on August 25, 2021 by Quinn Eastman in Uncategorized Leave a comment

COVID-triggered autoimmunity may be mostly temporary

In people with severe COVID-19, the immune system goes temporarily berserk and generates a wide variety of autoantibodies: proteins that are tools for defense, but turned against the body’s own tissues.

During acute infection, COVID-19 patients’ immune systems resemble those of people with diseases such as lupus or rheumatoid arthritis. However, after the storm passes, the autoantibodies decay and are mostly removed from the body over time, according to a study of a small number of patients who were hospitalized and then recovered.

In a preprint posted on medRxiv, Emory immunologists provide a view of the spectrum of what COVID-generated autoantibodies react against, both during acute infection and later. Note: the results have not yet been published in a peer-reviewed journal.

The findings on COVID-19-triggered autoimmunity may have implications for both the treatment of acute infection and for long-haulers, in whom autoantibodies are suspected of contributing to persistent symptoms such as fatigue, skin rashes and joint pain.

During acute infection, testing for autoantibodies may enable identification of some patients who need early intervention to head off problems later. In addition, attenuation of autoantibody activity by giving intravenous immunoglobulin (IVIG) – an approach that has been tested on a small scale — may help resolve persistent symptoms, the Emory investigators suggest.

Researchers led by Ignacio Sanz, MD and Frances Eun-Hyung Lee, MD, isolated thousands of antibody-secreting cells from 7 COVID-19 patients who were in ICUs at Emory hospitals. They also looked for markers of autoimmunity in a larger group of 52 COVID-19 ICU patients.

Posted on August 24, 2021 by Quinn Eastman in Uncategorized Leave a comment

Multiple myeloma patients display weakened antibody responses to mRNA COVID vaccines

A new study reports weakened antibody responses to COVID-19 mRNA vaccines among most patients with multiple myeloma, a form of bone-marrow cancer associated with an immunocompromised state.

The research, published in the journal Leukemia, was carried out at the Institute for Myeloma and Bone Cancer Research (IMBCR) in California, in collaboration with Emory infectious diseases fellow Samuel Stampfer, MD, PhD.

Patients with smoldering myeloma, not requiring treatment, all achieved a good response to COVID-19 vaccination, whereas less than half of patients with active myeloma requiring treatment did. Specifically, only 45 percent of active patients fully responded to the mRNA vaccines, whereas less than a quarter showed a partial response and one-third did not respond to the vaccines above background antibody levels.

Serum samples from 103 multiple myeloma patients were obtained prior to vaccination and 2-3 weeks after administration of the first and second vaccines, and compared to a group of age‑matched healthy controls. Predictors of reduced antibody responses to the vaccines included: older age, impaired renal function, low lymphocyte counts, reduced uninvolved antibody levels, past first line of treatment, and those not in complete remission. Nearly two-thirds of patients who received the Moderna vaccine responded to a level thought to be clinically significant, whereas only approximately a quarter who received the Pfizer vaccine did.

“Based on these data, myeloma patients may need to continue social distancing following COVID-19 vaccination, and postvaccine antibody tests may help guide decisions regarding supplementary vaccination or antibody prophylaxis for this vulnerable population,” says Stampfer, who co-designed the clinical study, under the guidance of senior author James Berenson, MD, the Scientific and Medical Director of IMBCR.

“This study highlights the importance of recognizing the limitations of current vaccination approaches to COVID-19 for immunocompromised patients, and that new approaches will have to be developed to improve their protection from this dangerous infection,” Berenson says. “It also suggests that there may be clinically significant differences in the effectiveness of different COVID-19 vaccines for immune compromised patients. Until these advances occur, it means that myeloma patients will need to remain very careful even if they have been vaccinated through wearing their masks and avoiding contact with unvaccinated individuals.”.

Posted on July 30, 2021 by Quinn Eastman in Cancer, Immunology Leave a comment

Neutrophils flood lungs in severe COVID-19

“First responder” cells called neutrophils are the dominant type of immune cells flooding the airways of people with severe COVID-19, according to a recent analysis of African-American patients in Emory hospitals.

The findings were posted on the preprint server Biorxiv prior to peer review.

Neutrophils are the most abundant immune cells in the blood, and usually the first to arrive at the site of a bacterial or viral infection. But in the lungs of severe COVID-19 patients, neutrophils camp out and release tissue-damaging enzymes, the new research shows. They also produce inflammatory messengers that induce more neutrophils to come to the lungs.

Lung inflammation photo from NIEHS. Most of these dense small cells are neutrophils

This circulating cell type enters the lung and initiates a self-sustaining hyper-inflammation that leads to acute respiratory distress syndrome (ARDS), the leading cause of mortality in COVID-19, says lead author Eliver Ghosn assistant professor of medicine at Emory University School of Medicine.

“Our findings reveal novel therapeutic targets, and developing tactics to intervene could benefit severe patients in the ICU, particularly those that are most vulnerable,” Ghosn says. “We compared our lung data with matching blood samples for all the patients, and we were able to identify the subtype of neutrophils in the blood that is most likely to infiltrate the lungs of severe patients and cause ARDS.”

Somewhat counter-intuitively, Emory researchers had difficulty detecting SARS-CoV-2 infected cells in the upper airways of hospitalized patients. This result, consistent with findings by others, may explain why antiviral drugs such as remdesivir are ineffective once systemic inflammation has gained momentum; lung injury comes more from the influx of immune cells, such as neutrophils, rather than viral infection itself.

When Ghosn and his colleagues began examining immune cells in COVID-19, they found that almost all of the hospitalized patients they encountered were African-American. This highlights the racial disparities of the COVID-19 pandemic, especially in Georgia, and Ghosn’s team decided to “lean in” and focus on African-Americans. They collaborated closely with Eun-Hyung Lee’s lab at Emory to collect samples from hospitalized patients.

“We believe these results can have broader implications and be applied to other demographics that suffer from similar lung pathology,” Ghosn says.

Posted on July 12, 2021 by Quinn Eastman in Uncategorized Leave a comment

More evidence for autoantibodies in severe COVID-19

A recent paper from Emory pathologist Cheryl Maier and colleagues provides more evidence for autoantibodies in critically ill COVID-19 patients. Autoantibodies are signs that the immune system attacking the body itself, and are features of diseases such as lupus and rheumatoid arthritis. They have been proposed as an explanation for the severity of some acute COVID-19 cases, as well as continued symptoms in long COVID.

Generally, antibodies are a good thing, and a major goal of COVID-19 vaccination is to drive the immune system to generate protective antibodies against the coronavirus. With autoantibodies and COVID, the idea is that intense inflammation coming from viral infection is causing immune cells to become confused. Not every COVID-19 patient’s immune system goes off the rails, but the train wreck seems to happen more often in COVID-19.

Last year, immunologist Ignacio Sanz’s lab at Emory demonstrated that patients with severe COVID-19 display signs of immune dysregulation similar to those seen in lupus. A follow-up preprint found the suspected autoantibodies, and several other labs have observed autoantibodies in COVID-19 that may be sabotaging antiviral responses or perturbing blood clotting. Now, an active topic of investigation is whether the autoantibodies last longer or don’t diminish as quickly in long COVID. Stay tuned.

This image has an empty alt attribute; its file name is MaierC.jpg — Cheryl Maier, MD, PhD

However, in the current paper in Cell Reports Medicine, autoantibodies were also found in most control samples from intensive care unit patients with pneumonia or sepsis, who are experiencing a state of systemic inflammation comparable to severe COVID-19.

“It’s a reminder that autoantibodies are not necessarily unique to COVID,” Maier says. “They may be more dramatic in COVID, but we see autoantibodies associated with other severe diseases too.”

Maier is medical director for Emory’s Special Coagulation Laboratory, and her team came to the autoimmunity question from a side angle. They were investigating blood clots and hyperviscosity in COVID-19 patients, and wanted to check whether high concentrations of antibodies might be an explanation. Antibodies are proteins, after all, and if someone’s blood is full of them, they thicken it.

Posted on June 3, 2021 by Quinn Eastman in Immunology Leave a comment

COVID-19 vaccine-generated antibodies last at least 6 months

How long does COVID-19 vaccine-generated immunity last? New laboratory results provide a partial answer to that question.

Antibodies generated by a currently available COVID-19 vaccine declined over time, but remained at high levels in 33 study participants 6 months after vaccination, according to data published Tuesday in the New England Journal of Medicine.

The results could begin to inform public health decisions about COVID-19 booster vaccinations and how frequently people should receive them. In older study participants, antiviral antibody activity tended to decay more rapidly than in those aged 18-55.

From Doria-Rose et al (2021). Note that neutralizing antibody activity was (on average) higher at day 209 than on day 29, when the second vaccine dose was administered. It takes two weeks for the immune system to kick into high gear after the second shot.

Emory Vaccine Center’s Mehul Suthar, co-lead author of the brief report, said that the “correlates of protection” are not yet known from COVID-19 vaccine studies – that is, what levels of antiviral antibodies are needed to fend off infection. Other forms of immunity, such as T cells, could be contributing to antiviral protection as well.

He cautioned that the decay in antibody activity over time – not surprising in itself – may combine with increased prevalence of emerging SARS-CoV-2 variants that may allow viruses to escape the immune system’s pressure.

“Still, these are encouraging results,” Suthar says. “We are seeing good antibody activity, measured three different ways, six months after vaccination. There are differences between age groups, which are consistent with what we know from other studies.”

The findings come from analysis of samples from the Moderna mRNA-1273 phase I clinical trial, which began last year. Reports of clinical outcomes from Pfizer/BioNTech also indicate that their vaccine remains effective after six months.

Posted on April 7, 2021 by Quinn Eastman in Immunology Leave a comment

Strengthening SARS-CoV-2 genomic surveillance: support from CDC, private foundations

As part of an effort to strengthen genomic surveillance for emerging strains of SARS-CoV-2, the Centers for Disease Control and Prevention (CDC) has awarded a contract to Emory University researchers to characterize viral variants circulating in Georgia.

The two-year contract is part of the SPHERES (SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology and Surveillance) initiative, with roughly $620,000 in total costs. The principal investigator is Anne Piantadosi, MD, PhD, assistant professor of pathology and laboratory medicine, with co-investigator Mehul Suthar, PhD, assistant professor of pediatrics (infectious diseases).

Both Piantadosi and Suthar are affiliated with Emory University School of Medicine and Emory Vaccine Center. Additional Emory partners include assistant professor of medicine Ahmed Babiker, MBBS, assistant professor of medicine Jesse Waggoner, MD and assistant professor of biology Katia Koelle, PhD.

“We are analyzing SARS-CoV-2 genomes from patients in Georgia to understand the timing and source of virus introduction into our community,” Piantadosi says. “We want to know whether there have been population-level changes in the rates of viral spread, and whether there are associations between viral genotype, viral phenotype in vitro, and clinical phenotype or clinical outcome.”

Posted on February 5, 2021 by Quinn Eastman in Immunology, Uncategorized 1 Comment

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