Northwestern researchers continue investigation on all aspects of COVID-19 pandemic

Northwestern Medicine scientists continue to investigate all aspects of the COVID-19 pandemic: from molecular mechanisms of infection, to child hospitalization and single-dose vaccine response.

One dose not enough for previously infected

Thomas McDade, PhD, professor of Medical Social Sciences, was senior author of the study published in EClinical Medicine.

One dose of an mRNA vaccine administered to patients previously infected with COVID-19 generated antibody responses of varying strength, according to a Northwestern Medicine study published in EClinical Medicine.

These findings suggest that one dose is not enough for people previously infected with COVID-19, according to Thomas McDade, PhD, professor of Medical Social Sciences and senior author of the study.

Prior exposure to SARS-CoV-2 does not guarantee a robust antibody response to the first dose of current mRNA vaccines."

Thomas McDade, PhD, Professor, Weinberg College of Arts and Sciences

Investigators sampled patients from a large Northwestern study that employed a home-based antibody test, requiring just a single drop of blood from a simple finger prick. Participants were analyzed in three groups: those previously recovered from confirmed COVID-19, those seropositive for prior infection with no acute diagnostic positive test and people who were seronegative for SARS-CoV-2 prior to vaccination.

Measures included anti-SARS-Cov-2 spike receptor binding antibody concentrations and the subsequent ability of those antibodies to neutralize spike protein binding to the angiotensin-converting enzyme (ACE2) receptor, the primary route through which SARS-CoV-2 enters human cells.

According to the study, patients with confirmed COVID-19 exhibited a robust response to a single vaccine dose, but individuals who were merely seropositive — possibly the result of a mild or asymptomatic infection — demonstrated a generally weaker response to a single dose of vaccine.

These findings suggest caution when assuming immunological "priming" for people previously infected with COVID-19. If their case was mild, then a single dose of mRNA vaccine may not give them full protection. Given there are few methods to accurately measure the severity of COVID-19 infection beyond hospitalization, patients previously infected with COVID-19 should be given two shots to be safe, according to McDade.

"In order to ensure maximum protection against emerging variants, two doses are advisable," McDade said.

The investigators plan to continue follow-up with this patient cohort, aiming to identify the frequency of re-infection and vaccine breakthrough infections — findings that could prove useful as dangerous variants crop up and spread, according to McDade.

This study was supported by National Science Foundation grant 2035114 and National Institutes of Health grant 3UL1TR001422-06S4.

Antiviral mechanisms fight COVID-19

Judd Hultquist, PhD, assistant professor of Medicine in the Division of Infectious Disease, was a co-author of the study published in Molecular Cell.

A small group of interferon-stimulated proteins help determine the efficiency of SARS-CoV-2 replication, according to a study published in Molecular Cell.

These findings highlight host determinants of COVID-19 severity and offer potential therapeutic strategies, according to Judd Hultquist, PhD, assistant professor of Medicine in the Division of Infectious Disease and a co-author of the study.

"We found that the body has a large number of antiviral proteins that can protect against SARS-CoV-2 — some of these even appear to provide broad antiviral protection as they have been previously found to protect against other viruses like HIV and the influenza virus," Hultquist said. "However, SARS-CoV-2 appears to have defensive strategies that help to protect it from some of these factors."

Interferons are signaling proteins released by several cell types in response to the presence of nearby pathogens. Release of interferons triggers the innate immune response, but advanced age and conditions such as cardiovascular disease or obesity can blunt the innate immune response. Proper functioning of the innate immune response is critical to preventing severe disease in COVID-19 patients, according to Hultquist.

In the current study, investigators examined which genes are activated in response to interferon stimulation in human airway epithelial cells. Next, investigators measured the activity of these proteins in inhibiting SARS-CoV-2 replication.

Hultquist and his collaborators found that a small subset of interferon-stimulated proteins helped control viral infection by inhibiting entry into cells and preventing viral RNA synthesis. However, the virus has countermeasures.

One protein, BST2, helps prevent SARS-CoV-2 from leaving cells and spreading throughout the body. It's directly counteracted by the viral protein Orf7a, nullifying its function. BST2 also plays a role in the antiviral response to HIV infection, but is counteracted by the HIV protein Vpu.

These findings highlight possible therapeutic pathways, said Hultquist, including restoring BST2 function.

"Ultimately, we hope these results help define the factors that underlie a genetic predisposition to severe COVID-19 while also providing new potential targets for therapeutic development," Hultquist said. "In the future, we want to begin exploring the molecular mechanisms that make these antiviral factors work to see if they can be applied more generally to invoke protection against a broad array of pathogenic viruses."

This study was funded by National Institutes of Health grants UL1 TR002389, UL1 TR001422 and P30 CA060553.

Lower COVID-19 hospitalization rate for children

Yuan Luo, PhD, associate professor of Preventive Medicine in the Division of Health and Biomedical Informatics, was senior author of the study published in Frontiers in Pediatrics.

The national COVID-19 hospitalization rate for children was 20-fold smaller than the rate for adults through April 2021, according to a study published in Frontiers in Pediatrics.

Timing of hospitalizations were similar between children and adults, helping rule out child-to-adult transmission as a major source of infection as observed in some other respiratory diseases, according to Yuan Luo, PhD, associate professor of Preventive Medicine in the Division of Health and Biomedical Informatics and senior author of the study.

"This study was conceived at a time when there was suspicion that children’s infections and hospitalization may significantly impact adults," said Luo, who is also a professor at the McCormick School of Engineering and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. "So the much lower hospitalization rates for children, as well as the lack of clear evidence of pediatric trends preceding adult trends speak against that suspicion, though more detailed data and analysis would shed more light on this subject."

Investigators evaluated COVID-19 hospitalizations reported to the U.S. Department of Health and Human Services from July 2020 through April 2021. Using census population estimates, the study authors calculated weekly hospitalizations per 100,000 children and adults, both nationally and by region.

Overall, they found a weekly median of 906 hospitalizations for children and 38,675 hospitalizations for adults, 1.2 per 1000,000 children and 15.1 per 100,000 adults. Using a univariate change point analysis, they identified peaks in hospitalizations, finding adult and child hospitalizations sharply rose the week of October 23, and peaked during the first two weeks of January.

The lack of a clear lead in the timing of pediatric hospitalizations compared to those of adults, suggests that child-to-adult transmission happens less often with COVID-19 when compared to other respiratory illnesses, such as flu or cold. However, this does not mean children are safe — pediatric illness from COVID-19 continues to rise so approval of vaccines for under-12s and vigilant surveillance may facilitate efforts to reduce childhood COVID-19, said Meghan Hutch, a student in the Driskill Graduate Program in Life Sciences (DGP) and lead author of the study.

"As national efforts continue to concentrate on vaccinating teenagers and adults, it is not clear how COVID-19 may continue to affect the younger, pediatric population and impact our national efforts to achieve heard immunity," Hutch said. "Additionally, with the rise of the Delta variant, continued monitoring of disease activity, especially in our vulnerable, unvaccinated populations, is crucial in guiding our management and response to the pandemic."

Source:
Journal reference:

Demonbreun, A.R., et al. (2021) Comparison of IgG and neutralizing antibody responses after one or two doses of COVID-19 mRNA vaccine in previously infected and uninfected individuals. EClinical Medicine. doi.org/10.1016/j.eclinm.2021.101018.

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