Tag Archives: Antibodies

Experimental decoy provides long-term protection from SARS-Cov-2 infection

31 May, 2023 Admin Leave a comment

Reviewed by Danielle Ellis, B.Sc.May 30 2023

An experimental “decoy” provided long-term protection from infection by the pandemic virus in mice, a new study finds.

Led by researchers at NYU Grossman School of Medicine, the work is based on how the virus that causes COVID-19, SARS-CoV-2, uses its spike protein to attach to a protein on the surface of the cells that line human lungs. Once attached to this cell surface protein, called angiotensin converting enzyme 2 (ACE2), the virus spike pulls the cell close, enabling the virus to enter the cell and hijack its machinery to make viral copies.

Earlier in the pandemic, pharmaceutical companies designed monoclonal antibodies to glom onto the spike and neutralize the virus. Treatment of patients soon after infection was successful in preventing hospitalization and death. However the virus rapidly evolved through random genetic changes (mutations) that altered the spike’s shape enough to evade even combinations of therapeutic monoclonal antibodies. Thus, such antibodies, which neutralized early variants, became about 300 times less effective against more recent delta and omicron variants.

Published online this week in the Proceedings of the National Academy of Sciences, the study describes an alternative approach from which the virus cannot escape. It employs a version of ACE2, the surface protein to which the virus attaches, which, unlike the natural, cell-bound version, is untethered from the cell surface. The free-floating “decoy” binds to the virus by its spikes so that it can no longer attach to ACE2 on cells in airways. Unlike the monoclonal antibodies, which are shaped to interfere with a certain spike shape, the decoy mimics the spike’s main target, and the virus cannot easily evolve away from binding to ACE2 and still invade cells.

Treatment with the decoy, either by injection or droplets in the nose, protected 100 percent of the study mice when they were infected in the lab with an otherwise lethal dose of SARS-CoV-2. The decoy lowered the virus load in the mice by 100,000-fold, while mice exposed to a non-active control treatment died. Decoy treatment of mice that were already infected with SARS-CoV-2 caused a rapid drop in viral levels and return to health. This suggests that the decoy could be effective as a therapy post-infection, similar to monoclonal antibodies, the researchers say.

What is remarkable about our study is that we delivered the decoy using a harmless, adeno-associated virus or AAV vector, a type of gene therapy that has been found in previous studies to be safe for use in humans. The viral vector instructs cells in the body to produce the decoy so that the mouse or person is protected long-term, without the need for continual treatment.”

Nathanial Landau, PhD, senior study author, professor, Department of Microbiology at NYU Langone Health

Administered with the vector, says Landau, the treatment caused cells, not only to make the decoy, but to continue making it for several months, and potentially for years.

Importantly, vaccines traditionally include harmless parts of a virus they are meant to protect against, which trigger a protective immune response should a person later be exposed. Vaccines are less effective, however, if a person’s immune system has been compromised, by diseases like cancer or in transplant patients treated with drugs that suppress the immune response to vaccination. Decoy approaches could be very valuable for immunocompromised patients globally, adds Landau.

Future pandemics

For the new study, the research team made key changes to a free ACE2 receptor molecule, and then fused the spike-binding part of it to the tail end of an antibody with the goal of strengthening its antiviral effect. Attaching ACE2 to the antibody fragment to form what the team calls an “ACE2 microbody” increases the time that the molecule persists in tissues (its half-life). The combination also causes the molecules to form dimers, mirror-image molecular pairs that increase the strength with which the decoy attaches to the viral spike.

Whether administered via injection into muscle, or through droplets in the nasal cavity, the study’s AAV vectors provided mice with long-lasting protection COVID infection, including the current Omicron variants.

The approach promises to be effective even if another coronavirus, a type of virus common in birds and bats or apes, were to be transferred to humans in the future, an event termed “zoonosis.” As long as the future virus also uses ACE2 to target cells, the decoy would be ready for “off-the-shelf” soon after an outbreak. If the virus were to somehow switch its receptor a different protein on the surface of lung cells, the decoy could be modified to target the new virus, says Landau.

Along with Landau, the study authors were Takuya Tada and Julia Minnee in the Department of Microbiology at NYU Grossman School of Medicine. The study was supported by a grant from the National Institutes of Health.

Source:

NYU Langone Health / NYU Grossman School of Medicine

Journal reference:

Tada, T., et al. (2023) Vectored immunoprophylaxis and treatment of SARS-CoV-2 infection in a preclinical model. PNAS. doi.org/10.1073/pnas.2303509120.

Microbiology

First-in-human nanoparticle HIV vaccine induces broad and publicly targeted helper T cell responses

25 May, 2023 Admin Leave a comment

Reviewed by Lily Ramsey, LLMMay 25 2023

Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.

Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.

We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”

Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study

However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.

“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.

The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.

McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.

Findings from the study include:

Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.

This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.

Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).

Source:

Fred Hutchinson Cancer Center

Journal reference:

Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine. doi.org/10.1126/scitranslmed.adf3309.

Microbiology

Mouse study offers clues to developing an effective vaccine for Klebsiella bacteria

19 May, 2023 Admin Leave a comment

Reviewed by Danielle Ellis, B.Sc.May 18 2023

A mouse study at Washington University School of Medicine in St. Louis points to data that could be key to developing an effective vaccine for the bacterium Klebsiella pneumoniae. The bug is often resistant to antibiotics, making it difficult to treat in some.

In the U.S., the bacterium Klebsiella pneumoniae is a common cause of urinary tract infection, bloodstream infection and pneumonia. While infections with the bacterium can be easily treated in some, Klebsiella has a dangerous flip side: It also is frequently resistant to antibiotics, making it extraordinarily difficult to treat in others. About half of people infected with a hypervirulent, drug-resistant strain of the bacterium die.

Scientists are working on vaccines for Klebsiella, but the optimal vaccine design is still unknown. However, a new study in mice by scientists at Washington University School of Medicine in St. Louis and Omniose, a St. Louis startup company specializing in vaccine production, provides critical data that could be key to developing an effective vaccine for Klebsiella. The findings, published in PLoS Pathogens, are a step toward taming the superbug.

When you think about the bugs that can be resistant to almost all antibiotics — the scary superbugs in the news — a lot of them are strains of Klebsiella. For a long time, the bacterium wasn’t even a pressing issue. But now it is, due to an explosion in antibiotic-resistant Klebsiella. Our goal is to diminish Klebsiella’s superbug status by developing a vaccine before hypervirulent or resistant strains sicken and kill even more people.”

David A. Rosen, MD, PhD, study’s senior author, assistant professor of pediatrics and of molecular microbiology at Washington University

Hypervirulent Klebsiella strains have spread globally, often causing community-acquired infections.

In the U.S., Klebsiella infections primarily occur in health-care facilities where medically vulnerable patients are immunocompromised, require long courses of antibiotics to treat other conditions, have chronic diseases, or are elderly people or newborns. “But now we’re seeing the emergence of hypervirulent strains dangerous enough to cause serious disease or death among healthy people in the community,” Rosen said.

Most concerning among scientists are the strains of Klebsiella impervious to carbapenems, a class of broad-spectrum antibiotics used to treat the most severe bacterial infections. For this reason, the World Health Organization and the U.S. Centers for Disease Control and Prevention have identified carbapenem-resistant Klebsiella as an urgent threat to public health.

The rod-shaped bacterium is immobile and, like chocolate-covered candies, encapsulated in sugar coatings. In the new study, researchers created two experimental vaccines based on two different sugars, or polysaccharides, on Klebsiella’s surface: the terminal sugars on lipopolysaccharide, called O-antigen, and a capsular polysaccharide, or K-antigen. Since sugars by themselves tend to produce weak immune responses, the researchers linked each of the sugars to a protein to boost the immune response, creating so-called conjugate vaccines. Sugar-protein conjugate vaccines have proven successful in combating several bacteria including Streptococcus pneumoniae, the most common cause of pneumonia. Historically, this connection between the sugar and protein carrier has been achieved using synthetic chemistry in a test tube; however, the vaccines created for this study are called bioconjugate vaccines, because the researchers connected the sugar to the protein all within an engineered bacteria system.

Once the vaccines were created, the researchers tested the experimental bioconjugate vaccines’ ability to protect mice from disease caused by Klebsiella.

“It turned out that the capsule vaccine was far superior to the O-antigen vaccine,” said the study’s first author, Paeton Wantuch, PhD, a postdoctoral associate in Rosen’s lab. “Mice that received the capsule vaccine were significantly more likely to survive Klebsiella infection in their lungs or their bloodstream than mice that received the O-antigen vaccine.”

Both vaccines elicited high levels of antibodies against their respective targets. But the antibodies against the O-antigen just weren’t as effective as the ones against the capsule. In some strains of Klebsiella, the O-antigen may be obscured by other sugars, so the antibodies that target the O-antigen cannot make contact with their target.

“Our findings suggest that we may also need to include the capsule-based antigens in vaccine formulations developed against Klebsiella,” Rosen said. “This is why it’s so important for us to continue studying antibody-antigen interactions in the different strains, with the goal of identifying the ideal vaccine composition for clinical trials soon. The need has never been more imperative, especially as Klebsiella’s drug-resistant, hypervirulent strains become stronger, bolder and more dangerous to human health.”

Source:

Washington University School of Medicine

Journal reference:

Wantuch, P. L., et al. (2023) Area-deprivation, social care spending and the rates of children in care proceedings in local authorities in Engl Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains of Klebsiella pneumoniae. PLOS Pathogens. doi.org/10.1371/journal.ppat.1011367.

Microbiology

Novel antibodies target human receptors to neutralize SARS-CoV-2 variants and future sarbecoviruses

17 May, 2023 Admin Leave a comment

By Neha MathurMay 17 2023Reviewed by Lily Ramsey, LLM

In a recent study published in the Nature Microbiology Journal, researchers generated six human monoclonal antibodies (mAbs) that prevented infection by all human angiotensin-converting enzyme 2 (ACE2) binding sarbecoviruses tested, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, Delta and Omicron.

They targeted the hACE2 epitope that binds to the SARS-CoV-2 spike (S) glycoprotein rather than targeting the S protein, which all previous therapeutic mAbs for SARS-CoV-2 targeted.

Study: Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies. Image Credit: paulista/Shutterstock.com

Background

The emergence of new variants of SARS-CoV-2, especially Omicron sublineages, made all therapeutic mAbs targeting SARS-CoV-2 S obsolete.

Any new S-targeting mAb therapy will also probably have limited utility because SARS-CoV-2 will continue to adapt to human antibodies. Ideally, mAbs developed in anticipation of future pandemics caused by sarbecoviruses should be resilient to mutations that arise in them.

About the study

In the present study, researchers developed hACE2-binding mAbs that blocked infection by pseudotypes of all tested sarbecoviruses at potencies matching SARS-CoV-2 S targeting therapeutic mAbs. The binding affinity of these mAbs to hACE2 was in the nanomolar to picomolar range.

To develop these mAbs, researchers used the KP and Av AlivaMab mouse strains that generate a human Kappa (κ) light chain and Kappa (κ) and Lambda (λ) light chains carrying antibodies, respectively.

They immunized these mice with monomeric and dimeric recombinant hACE2 extracellular domains. Fusion to the fraction, crystallizable (Fc) portion of human immunoglobulin G1 (IgG1) rendered them dimeric.

Further, the team generated hybridomas from mice using sera that inhibited SARS-CoV-2 pseudotyped viruses. They used enzyme-linked immunosorbent assay (ELISA) to screen hybridoma supernatants for hACE2-binding mAbs.

Furthermore, the researchers tested the ability of the six most potent mAbs to inhibit Wuhan-hu-1 S pseudotyped infection in Huh-7.5 target cells.

The team purified chimeric mAbs from the hybridoma culture supernatants and used a SARS-CoV-2 pseudotype assay to reconfirm their antiviral activity. They also sequenced the human Fab variable regions, VH and VL.

The team cloned V_H and V_L domains from the six most potent chimeric human-mouse mAbs into a human IgG1 expression vector to generate fully human anti-hACE2 mAbs.

They used single-particle cryo-electron microscopy (cryo-EM) to delineate the structural basis for broad neutralization of anti-hACE2 mAbs.

Specifically, they determined the structure of soluble hACE2 bound to the antigen-binding fragment (Fab) of 05B04, one of the most potent mAbs unaffected by naturally occurring human ACE2 variations.

Finally, the researchers tested these hACE2 mAbs in an animal model and determined their pharmacokinetic behavior.

Results

The researchers identified 82 hybridomas expressing hACE2-binding mAbs, of which they selected ten based on their potency in inhibiting pseudotyped virus infection of Huh-7.5 cells.

These ten mAbs were 1C9H1, 4A12A4, 05B04, 2C12H3, 2F6A6, 2G7A1, 05D06, 05E10, 05G01 and 05H02. Four of the five mAbs from the KP AlivaMab mice, viz., 05B04, 05E10, 05G01, and 05D06, shared identical complementarity-determining regions (CDRs). Conversely, AV AlivaMab mice-derived mAbs were diverse.

While allosteric inhibition of hACE2 activity by the mAbs was theoretically feasible, such inhibition did not occur.

Also, the anti-hACE2 mAbs did not affect hACE2 internalization or recycling, suggesting that the anti-hACE2 mAbs would unlikely undergo accelerated target-dependent clearance from the circulation during in vivo use.

These two findings confirmed that these mAbs would not have harmful side effects based on their target specificity.

In addition, the anti-hACE2 mAbs showed favorable pharmacokinetics and no ill effects on the hACE2 knock-in mice. When used prophylactically in hACE2 knock-in mice, these mAbs conferred near-sterilizing protection against lung SARS-CoV-2 infection.

Moreover, they presented a high genetic barrier to the acquisition of resistance by SARS-CoV-2.

The six anti-hACE2 mAbs also inhibited infection by pseudotyped SARS-CoV-2 variants, Delta, and Omicron, with similar potency, i.e., half maximal inhibitory concentration (IC₅₀) values ranging between 8.2 ng ml⁻¹ and 197 ng ml⁻¹.

A cryo-EM structure of the 05B04-hACE2 complex at 3.3 Å resolution revealed a 05B04 Fab bound to the N-terminal helices of hACE2.

05B04-mediated inhibition of ACE2-binding sarbecoviruses through molecular mimicry of SARS-CoV-2 receptor-binding domain (RBD) interactions, providing high binding affinity to hACE2 despite the smaller binding footprint on hACE2.

None of the four most potent mAbs affected hACE2 enzymatic activity or induced the internalization of hACE2 localized on the host cell surface. Thus, based on their target specificity, these mAbs shall not have deleterious side effects.

Though these anti-ACE2 antibodies could effectively inhibit sarbecovirus infection in humans, the fact that the antibodies target a host receptor molecule rather than the SARS-CoV-2 S protein will necessitate their testing in terms of safety, efficacy, and pharmacological behavior in primate models before human clinical trials.

Conclusions

SARS-CoV-2 might evolve and start using receptors other than ACE2, creating another genetic hurdle to overcome for researchers working on the development of SARS-CoV-2 therapeutics.

However, the human anti-hACE2 mAbs engineered in this study showed exceptional breadth and potency in inhibiting infection by hACE2-utilizing sarbecoviruses.

Thus, they represent a long-term, ‘resistance-proof’ prophylaxis and treatment for SARS-CoV-2, even for future outbreaks of SARS-like coronaviruses.

In addition, these mAbs might prove particularly useful for susceptible patients like those with immunodeficiency and in which vaccine-induced protective immunity is unattainable or difficult to attain.

Journal reference:

Zhang, F. et al. (2023) “Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies”, Nature Microbiology. doi: 10.1038/s41564-023-01389-9. https://www.nature.com/articles/s41564-023-01389-9

Microbiology

Anticoronavirals: the development of COVID-19 therapies and the challenges that remain

8 May, 2023 Admin Leave a comment

By Neha MathurMay 8 2023Reviewed by Danielle Ellis, B.Sc.

In a recent article published in Nature Microbiology, researchers highlighted the pace of development of coronavirus disease 2019 (COVID-19) therapies during the pandemic and the challenges that hinder the widespread availability of anticoronavirals.

*Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com*

Background

COVID-19 is the third coronavirus disease in the past 20 years after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). While the two predecessors caused severe mortality, they did not cause a pandemic. On the contrary, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a pandemic, and by 21 February 2023, it had caused more than 757 million confirmed cases, including >6.8 million deaths worldwide.

Vaccines and monoclonal antibody (mAb) treatments for COVID-19 became available within a year of the pandemic. Yet, there is a substantial need for more effective therapeutics to treat unvaccinated and immunocompromised patients and those whose vaccine immunity waned over time.

About the study

In this study, the authors highlighted four stages of SARS-CoV-2 infection that require different therapeutic interventions as critical for identifying COVID-19 therapeutic targets. At stage 1, when viral replication begins inside the host, oral or intravenous administration of monoclonal antibodies and antiviral therapies are effective. However, an ideal time for prophylactic administration of vaccines is Stage 0 preceding the infection.

Clinical trials have established that mAbs and antivirals effectively combat COVID-19 when administered up to 10 days after symptom onset and within three to five days following the onset of symptoms, respectively. COVID-19 patients in stage 2 develop viral pneumonia, cough and fever, lung inflammation causing shortness of breath, and lung aberrations, such as ground glass opacities.

The most serious is stage 3 characterized by a hyperinflammatory state or acute respiratory distress syndrome (ARDS). Some patients might also develop coagulation disorders or shock or systemic inflammatory response syndrome (SIRS). Thus, at stage 3, a patient needs antiviral drugs and immunomodulatory therapy.

Stage 4 represents post-COVID-19 conditions when patients experience hyperinflammatory illnesses, e.g., multi-system inflammatory syndrome in children (MISC), following acute SARS-CoV-2 infection. Unfortunately, possible preventative measures and treatment for post-acute sequelae of SARS-CoV-2 (PASC) are not fully understood. It is a growing area of unmet medical need; thus, extensive research efforts are ongoing to classify PASC, which might be a conglomeration of several syndromes, and determine its cause(s).

The National Institutes of Health (NIH) Treatment Guidelines Panel makes recommendations for the treatment and prevention of COVID-19. Early in the pandemic, clinicians used azithromycin and hydroxychloroquine as a possible COVID-19 treatment for hospitalized patients based on in vitro evidence of their synergistic effect on SARS-CoV-2 infection. Later, clinical trials found this combination ineffective. Similarly, the NIH panel did not specify recommendations for empirical antimicrobials.

The NIH rejected giving vitamin/mineral supplements, e.g., zinc, for hospitalized COVID-19 patients. On the contrary, they recommended prompt use of supplemental oxygenation and high-flow nasal cannula in patients with ARDS. In the absence of effective treatments, clinical recommendations by NIH continue to change and evolve.

Early drug repurposing efforts targeted nucleotide prodrugs, e.g., remdesivir (or GS-5734), AT-527, favipiravir, and molnupiravir (or MK-4482). However, only three antivirals received full Emergency Use Authorization (EUA) approval from the United States Food and Drug Administration (US-FDA), remdesivir, molnupiravir, and nirmatrelvir.

Pre-clinical characterization of remdesivir for other coronaviruses, pharmacokinetic and safety evaluation in humans in a failed clinical trial for Ebola virus, all acquired before the beginning of the COVID-19 pandemic, enabled rapid progression of remdesivir.

A phase 3 study conducted among patients in outpatient facilities and nursing facilities showed that remdesevir administration within seven days of symptom onset decreased hospitalization risk by 87%. Thus, its approval extended to high-risk non-hospitalized patients as well. Currently, phase 1b/2a study for inhaled remdesivir, and pre-clinical evaluation of an oral prodrug based on remdesivir is ongoing.

Another randomized phase III trial evaluated ivermectin, metformin, and fluvoxamine, all repurposed drug candidates, for early COVID-19 treatment of overweight or obese adults. Earlier pivotal efficacy and clinical studies found that molnupiravir provided no clinical benefit in hospitalized COVID-19 patients.

Conversely, the MOVe-OUT outpatient study demonstrated that treatment initiated within five days of symptom onset reduced the hospitalization risk or death. Accordingly, molnupiravir attained an EUA in the US on in late 2021 for treatment of mild-to-moderately ill COVID-19 patients at high risk of progression to severe disease. However, an outpatient study suggested that molnupiravir might augment SARS-CoV-2 evolution in immunocompromised individuals.

In the USA, multiple initiatives have been undertaken to identify candidate agents that may be repurposed as COVID-19 drugs. For instance, the Bill and Melinda Gates Foundation launched the Therapeutics Accelerator in March 2020, wherein they adopted a three-way approach to test approved drugs, screen drug repositories, and evaluate novel small molecules, including mAbs against SARS-CoV-2.

Encouragingly, apilimod, a PIKfyve kinase inhibitor developed for treating autoimmune diseases, is being tested for COVID-19 in clinical studies. Likewise, multiple clinical trials are ongoing for camostat mesilate, an inhibitor of transmembrane protease serine 2 (TMPRSS2), an approved chronic pancreatitis treatment in Japan.

Among anti-inflammatory and immunomodulating drugs, dexamethasone, a corticosteroid, baricitinib, a Janus kinase (JAK) inhibitor, and tocilizumab have received FDA approval. Among mAb therapies, casirivimab with imdevimab and bamlanivimab with etesevimab, Sotrovimab, Bebtelovimab, Tixagevimab–cilgavimab have received FDA approval. However, as SARS-CoV-2 continues to evolve, changes in the spike protein led to EUAs being withdrawn for all mAb therapies due to loss of efficacy.

Conclusions

There is a vast knowledge gap regarding COVID-19 pathogenesis. Despite the absence of a viral reservoir, severe disease persists for weeks or even months after COVID-19 recovery. Another intriguing area of investigation is why autoantibodies increase over time during COVID-19. In February 2022, the government of the United States of America (USA) started a flagship program, RECOVER, to understand, prevent and treat COVID-19-related long-term health effects.

Amid decreasing vaccine uptake and waning efficacy of mAbs as SARS-CoV-2 mutates, there is a need for new, safe, and effective COVID-19 therapies for population-level deployment and the potential to reduce resistance development. Researchers need to accelerate research targeting small molecule candidates that would mechanistically target the conserved region of SARS-CoV-2 and not become ineffective across mutant strains.

To be prepared for another pandemic, a large repository of small molecules that have already progressed through early pre-clinical and clinical evaluation is needed to develop drugs, like remdesivir, developed in a short span of two years.

More importantly, research efforts should continue to advance the development of antivirals for other pathogens, including coronaviruses, in preparation for the next pandemic.

Journal reference:

Toussi, S. et al. (2023) “Therapeutics for COVID-19”, Nature Microbiology, 8(5), pp. 771-786. doi: 10.1038/s41564-023-01356-4. https://www.nature.com/articles/s41564-023-01356-4

Microbiology

Long COVID: Cedars-Sinai Researchers Find COVID-19 Vaccine Produces Antibodies Far Longer Than Expected

27 April, 2023 Admin Leave a comment

Findings show people with long COVID-19 respond differently to COVID-19 vaccines.

A new study by investigators from the Smidt Heart Institute at Cedars-Sinai suggests long COVID-19 might be caused by a dysfunction of the immune system.

The study, published in the journal BMC Infectious Diseases, found that after people with long COVID-19 received the COVID-19 vaccine, they produced antibodies against the virus that causes COVID-19 for months longer than expected.

When a person has an infection, the immune system typically responds by making antibodies that block germs from entering cells. Vaccines imitate an infection so that the body’s immune system knows to release certain antibodies when it comes across a virus. In both cases, the immune system eventually stops creating antibodies when the suspected infection is gone.

“There’s general consensus that some level of aberrant immune response happens in long COVID-19, and this study adds to the evidence to suggest this is true,” said Catherine Le, MD, co-director of the Cedars-Sinai COVID-19 Recovery Program and a senior author of the study.

Long COVID-19, a condition in which people experience COVID-19-related symptoms three months or more after initial infection with the virus that causes COVID-19, is estimated to affect 65 million people worldwide. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction such as confusion and forgetfulness. Some symptoms can have debilitating effects.

To study the immune response of people with long COVID-19, investigators analyzed blood samples from 245 people diagnosed with long COVID-19 and 86 people who had COVID-19 and fully recovered. All the study participants had received either one or two doses of a COVID-19 vaccine regimen.

“We examined one part of the immune system response, the production of antibodies, which is mediated by immune cells called B-cells,” Le explained.

Specifically, the investigators looked at two types of antibodies that attack the virus that causes COVID-19. One of these is called the spike protein antibody, which attacks a protein on the exterior of the virus. The other is the nucleocapsid antibody, which attacks the part of the virus that allows it to replicate.

The investigators found that people who were diagnosed with long COVID-19 produced higher levels of spike protein and nucleocapsid antibodies than people without long COVID-19. Eight weeks after receiving a dose of the COVID-19 vaccine, antibody levels in people without long COVID-19 began to decrease, as was expected. People with long COVID-19, however, continued to have elevated antibody levels, especially of nucleocapsid antibodies.

“What you would expect after getting a COVID-19 vaccination is a jump in your spike protein antibody levels, but you wouldn’t expect a significant increase in nucleocapsid antibody levels,” said Susan Cheng, MD, MPH, the Erika J. Glazer Chair in Women’s Cardiovascular Health and Population Science, director of the Institute for Research on Healthy Aging in the Department of Cardiology at the Smidt Heart Institute, and a senior author of the study. “You would also expect these levels to eventually decrease and not persist for so long after vaccination.”

Although this study shows that long COVID-19 affects the immune system, it’s too soon to draw firm conclusions from these findings, according to the study’s authors.

“Theoretically, the production of these antibodies could mean that people are more protected from infection,” Le said. “We also need to investigate if the elevated immune response corresponds with severity or number of long COVID-19 symptoms.”

Investigators are continuing to study blood samples from people with long COVID-19. They are hoping to identify a measurable molecule that could be used to diagnose long COVID-19 and better understand the biological processes that cause it.

Reference: “Post-COVID-19 conditions alter a person’s immune response” by Sandy Joung, Brittany Weber, Min Wu, Yunxian Liu, Amber B. Tang, Matthew Driver, Sarah Sternbach, Timothy Wynter, Amy Hoang, Denisse Barajas, Yu Hung Kao, Briana Khuu, Michelle Bravo, Hibah Masoom, Teresa Tran, Nancy Sun, Patrick G. Botting, Brian L. Claggett, John C. Prostko, Edwin C. Frias, James L. Stewart, Jackie Robertson, Alan C. Kwan, Mariam Torossian, Isabel Pedraza, Carina Sterling, Caroline Goldzweig, Jillian Oft, Rachel Zabner, Justyna Fert-Bober, Joseph E. Ebinger, Kimia Sobhani, Susan Cheng and Catherine N. Le, 16 February 2023, BMC Infectious Diseases.
DOI: 10.1186/s12879-023-08060-y

Other Cedars-Sinai investigators who worked on the study include Sandy Joung; Min Wu; Yunxian Liu, PhD; Matthew Driver; Sarah Sternbach; Timothy Wynter; Amy Hoang; Denisse Barajas; Yu Hung Kao; Briana Khuu; Michelle Bravo; Hibah Masoom; Teresa Tran; Nancy Sun; Patrick G. Botting; Jackie Robertson; Alan C. Kwan, MD; Mariam Torossian, MD; Isabel Pedraza, MD; Carina Sterling, NP; Caroline Goldzweig, MD; Jillian Oft, MD; Rachel Zabner, MD; Justyna Fert-Bober, PhD; Joseph E. Ebinger, MD; and Kimia Sobhani, PhD.

Funding: The study was funded by Cedars-Sinai, the Erika J. Glazer Family Foundation, Sapient Bioanalytics, LLC, and the National Institutes of Health (award numbers K23-HL153888 and R01-HL131532).

Cedars-Sinai Medical Center

Microbiology

Bioengineered drug candidate can counter S. aureus infection in early tests

24 April, 2023 Admin Leave a comment

Reviewed by Emily Henderson, B.Sc.Apr 24 2023

Researchers at NYU Grossman School of Medicine and Janssen Biotech, Inc. have shown in early tests that a bioengineered drug candidate can counter infection with Staphylococcus aureus – a bacterial species widely resistant to antibiotics and a major cause of death in hospitalized patients.

Experiments demonstrated that SM1B74, an antibacterial biologic agent, was superior to a standard antibiotic drug at treating mice infected with S. aureus, including its treatment-resistant form known as MRSA.

Published online April 24 in Cell Host & Microbe, the new paper describes the early testing of mAbtyrins, a combination molecule based on an engineered version of a human monoclonal antibody (mAb), a protein that clings to and marks S. aureus for uptake and destruction by immune cells. Attached to the mAb are centyrins, small proteins that prevent these bacteria from boring holes into the human immune cells in which they hide. As the invaders multiply, these cells die and burst, eliminating their threat to the bacteria.

Together, the experimental treatment targets ten disease-causing mechanisms employed by S. aureus, but without killing it, say the study authors. This approach promises to address antibiotic resistance, say the researchers, where antibiotics kill vulnerable strains first, only to make more space for others that happen to be less vulnerable until the drugs no longer work.

To our knowledge, this is the first report showing that mAbtyrins can drastically reduce the populations of this pathogen in cell studies, and in live mice infected with drug-resistant strains so common in hospitals. Our goal was to design a biologic that works against S. aureus inside and outside of cells, while also taking away the weapons it uses to evade the immune system.”

Victor Torres, PhD, Lead Study Author, the C.V. Starr Professor of Microbiology and director of the NYU Langone Health Antimicrobial-Resistant Pathogen Program

One-third of the human population are carriers of S. aureus without symptoms, but those with weakened immune systems may develop life-threatening lung, heart, bone, or bloodstream infections, especially among hospitalized patients.

Inside out

The new study is the culmination of a five-year research partnership between scientists at NYU Grossman School of Medicine and Janssen to address the unique nature of S. aureus.

The NYU Langone team together with Janssen researchers, published in 2019 a study that found that centyrins interfere with the action of potent toxins used by S. aureus to bore into immune cells. They used a molecular biology technique to make changes in a single parental centyrin, instantly creating a trillion slightly different versions of it via automation. Out of this “library,” careful screening revealed a small set of centyrins that cling more tightly to the toxins blocking their function.

Building on this work, the team fused the centyrins to a mAb originally taken from a patient recovering from S. aureus infection. Already primed by its encounter with the bacteria, the mAb could label the bacterial cells such that they are pulled into bacteria-destroying pockets inside of roving immune cells called phagocytes. That is unless the same toxins that enable S. aureus to drill into immune cells from the outside let it drill out of the pockets to invade from the inside.

In a “marvel of bioengineering,” part of the team’s mAbtyrin serves as the passport recognized by immune cells, which then engulf the entire, attached mAbtyrin, along with its centyrins, and fold it into the pockets along with bacteria. Once inside, the centyrins block the bacterial toxins there. This, say the authors, sets their effort apart from antibody combinations that target the toxins only outside of cells.

The team made several additional changes to their mAbtyrin that defeat S. aureus by, for instance, activating chain reactions that amplify the immune response, as well by preventing certain bacterial enzymes from cutting up antibodies and others from gumming up their action.

In terms of experiments, the researchers tracked the growth of S. aureus strains commonly occurring in US communities in the presence of primary human immune cells (phagocytes). Bacterial populations grew almost normally in the presence of the parental antibody, slightly less well in the presence of the team’s engineered mAb, and half as fast when the mAbtyrin was used.

In another test, 98% of mice treated with a control mAb (no centyrins) developed bacteria-filled sores on their kidneys when infected with a deadly strain of S. aureus, while only 38% of mice did so when treated with the mAbtyrin. Further, when these tissues were removed and colonies of bacteria in them counted, the mice treated with the mAbtyrin had one hundred times (two logs) fewer bacterial cells than those treated with a control mAb.

Finally, the combination of small doses of the antibiotic vancomycin with the mAbtyrin in mice significantly improved the efficacy of the mAbtyrin, resulting in maximum reduction of bacterial loads in the kidneys and greater than 70% protection from kidney lesions.

“It is incredibly important,” said Torres, “that we find new ways to boost the action of vancomycin, a last line of defense against MRSA.”

Along with Torres, authors from the Department of Microbiology at NYU Langone were Rita Chan, Ashley DuMont, Keenan Lacey, Aidan O’Malley, and Anna O’keeffe. The study authors included 13 scientists from Janssen Research & Development (for details see the study manuscript).

This work was supported by Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, under the auspices of an exclusive license and research collaboration agreement with NYU. Torres has recently received royalties and consulting compensation from Janssen and related entities. These interests are being managed in accordance with NYU Langone policies and procedures.

Source:

NYU Langone Health / NYU Grossman School of Medicine

Journal reference:

Buckley, P. T., et al. (2023). Multivalent human antibody-centyrin fusion protein to prevent and treat Staphylococcus aureus infections. Cell Host & Microbe. doi.org/10.1016/j.chom.2023.04.004.

Microbiology

A creative new approach to make vaccine against norovirus

12 April, 2023 Admin Leave a comment

Reviewed by Emily Henderson, B.Sc.Apr 11 2023

Every year, norovirus causes hundreds of millions of cases of food poisoning -; and the deaths of at least 50,000 children -; yet there exists no real way to control it. The virus has proven exceptionally difficult to study in the lab, and scientists have struggled to develop effective vaccines and drugs.

A new study at Washington University School of Medicine in St. Louis describes a creative way to make a vaccine against norovirus by piggybacking on the highly effective vaccines for rotavirus, an unrelated virus that also causes diarrhea.

The researchers created an experimental rotavirus-norovirus combo vaccine by adding a key protein from norovirus to a harmless strain of rotavirus. Mice that received the experimental vaccine produced neutralizing antibodies against both rotavirus and norovirus. The study, available online in Proceedings of the National Academy of Sciences, outlines an innovative approach to preventing one of the most common and intractable viral infections.

Pretty much everyone has had norovirus at some point. You go out to eat, and the next thing you know you’re vomiting and having diarrhea. You will recover, but it’s going to be a rough three days or so. For kids in the developing world who don’t have access to clean water, though, it can be deadly. The rotavirus vaccines work really well, and there are already global distribution systems set up for them, so based on that, we saw an opportunity to finally make some headway against norovirus.”

Siyuan Ding, PhD, senior author, assistant professor of molecular microbiology

Before the first rotavirus vaccines were rolled out in 2006, half a million children around the world died every year of diarrhea caused by rotavirus infection. Now, the number is estimated to be about 200,000 -; still high but a huge improvement. Four rotavirus vaccines are in use around the world. All are live-virus vaccines, meaning they are based on weakened forms of rotavirus capable of triggering an immune response but not of making people sick.

Human norovirus, on the other hand, has stymied scientific investigation for decades. It doesn’t infect mice or rats or any other ordinary lab animals, so the kinds of experiments that led to the development of rotavirus vaccines have been impossible to replicate with norovirus.

Ding and colleagues -; including first author Takahiro Kawagishi, PhD, a staff scientist in Ding’s lab, and co-corresponding author Harry B. Greenberg, MD, a professor emeritus of medicine at Stanford University -; came up with the idea of using rotavirus to bypass the technical difficulties of working with norovirus. They worked with a laboratory strain of rotavirus as a stand-in for one of the approved rotavirus vaccines, which are proprietary.

The researchers inserted the gene for the protein that forms the outer surface of human norovirus into the genome of the rotavirus lab strain. Then, they administered the modified rotavirus to immunocompromised infant mice by mouth, the same way rotavirus vaccines are given to children. They took blood and fecal samples four, six and eight weeks later. Nine weeks after the initial immunization, the researchers gave the mice a booster by injection and took samples again a week later.

A strong antibody response was evident in the blood of nine of 11 mice tested, and in the intestines of all 11 mice. Even better, some of the antibodies from the blood and the intestines were able to neutralize both viruses in human “mini-gut” cultures in a dish. Such cultures, also known as organoids, are grown from human stem cells and replicate the surface of the human gut.

“Traditionally, vaccine studies have focused on the antibody response in the blood, because we understand that part of the immune response the best,” Ding said. “But norovirus and rotavirus are gut viruses, so antibodies in the blood are less important than the ones in the intestines in terms of fighting off these viruses. The fact that we saw a strong antibody response in the intestines is a good sign.”

The next step is to show that animals immunized with the experimental vaccine are less likely to get sick or die from norovirus. Ding has such experiments underway.

The power of this study is that it outlines a novel approach that could accelerate vaccine development for a variety of troublesome organisms that cause diarrhea, especially in resource-limited countries where many of these infections occur.

“There are a lot of intestinal pathogens out there for which we don’t have good treatments or vaccines,” Ding said. “In principle, we could put a gene from any organism that infects the intestinal tract into the rotavirus vaccine to create a bivalent vaccine. We’d have to find the right targets to produce a good immune response, of course, but the principle is simple.

“As basic scientists, we rarely get the chance to actually move something forward into the clinic,” Ding continued. “We study what the virus does and how the host responds at a basic level. This is a rare opportunity for our work to affect human health directly and make people’s lives better.”

Source:

Washington University School of Medicine

Journal reference:

Kawagishi, T., et al. (2023). Mucosal and systemic neutralizing antibodies to norovirus induced in infant mice orally inoculated with recombinant rotaviruses. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2214421120.

Microbiology

Nasal SARS-CoV-2 vaccine outperforms existing vaccines in preclinical trial

7 April, 2023 Admin Leave a comment

By Bhavana KunkalikarApr 6 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent study published in the journal Nature Microbiology, researchers assess the role of the live-attenuated vaccine (LAV) sCPD9 in inducing systemic and mucosal immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants.

Study: Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Image Credit: TopMicrobialStock / Shutterstock.com

Introduction

Coronavirus disease 2019 (COVID-19) vaccines, currently administered through the intramuscular route, effectively stimulate the production of neutralizing antibodies, effector and central memory T-cells, germinal center B-cells, long-lived plasma cells, and nasal-resident CD8+ T-cells. The intramuscular route has lower efficacy in promoting long-lasting mucosal immunoglobulin A (IgA) and IgG responses, as well as pulmonary tissue-resident memory cell responses.

Notably, mucosal antibodies are important in reducing viral infectivity and transmission at the site of entry. Tissue-resident memory cells have faster recall responses and can recognize cognate antigens earlier due to their local positioning.

About the study

In the present study, researchers compare the immune responses and preclinical efficacy of the Pfizer-BioNTech BNT162b2 messenger ribonucleic acid (mRNA) COVID-19 vaccine, adenovirus-vectored spike vaccine Ad2-spike, and LAV sCPD9 in Syrian hamsters.

The efficiency and mechanism of action of the evaluated vaccines were evaluated in a heterologous SARS-CoV-2 Delta variant challenge condition. To this end, Syrian hamsters received one vaccine dose and were exposed to the SARS-CoV-2 Delta variant 21 days after vaccination to evaluate its effectiveness. Hamsters were administered two vaccine doses 21 days apart and were later infected with the virus 14 days after booster administration.

Histopathology was used to examine challenged hamsters and determine any lung damage caused by infection. Single-cell RNA sequencing (scRNA-seq) was performed on lung specimens to establish a correlation between inflammation levels and cellular responses.

The humoral responses of hamsters were assessed by analyzing their sera collected before and after vaccination and determining their neutralizing ability against SARS-CoV-2 variants at different time points.

Results

All vaccinations protected hamsters from weight loss induced by SARS-CoV-2 infection. However, the vaccines did not provide complete protection against SARS-CoV-2 Delta infection after a single dose, as viral RNA was still present in the respiratory tract. The sCPD9 vaccine was the only tested vaccine that successfully reduced replicating viral titers to undetectable levels within two days post-challenge (dpc).

The overall efficacy of the SARS-CoV-2 vaccine was enhanced through prime-boost vaccination. Despite a significant reduction after prime-boost vaccination, all groups exhibited detectable viral RNA in oropharyngeal specimens and lungs. Nevertheless, sCPD9-based vaccination was more effective in decreasing viral RNA levels.

Vaccinated animals exhibited a significant reduction in replication-competent vial levels in their lungs two days post-challenge (dpc). Only the sCPD9 booster vaccine effectively reduced replicating virus proportions below the detection threshold, irrespective of whether the entire vaccination series was heterologous or homologous.

Furthermore, sCPD9 was highly effective in preventing inflammation and pneumonia after a single vaccination. This was demonstrated by the reduced levels of consolidated lung areas, along with lower scores for bronchitis, edema, and lung inflammation.

Animals with different vaccination schedules showed more significant bronchial hyperplasia. Prime-boost regimens showed a similar trend, with the mRNA vaccine displaying better histological outcomes with a homologous boost.

Homologous sCPD9 prime-boost vaccination offered better lung protection against inflammation. Both heterologous and homologous sCDP9 vaccinated hamsters exhibited reduced inflammation- and infection-related genes in their lung transcriptome.

Sera from sCPD9 vaccine recipients showed higher neutralization capacity against the ancestral SARS-CoV-2 variant B.1 compared to other groups. The sCPD9 sera effectively neutralized the Beta and Delta variants, as well as the Omicron BA.1 sublineage.

The neutralization capacity against Omicron BA.1 was reduced in all cohorts, with sCPD9 sera associated with significant neutralization. Neutralizing antibodies increased over time in all cohorts by five dpc due to challenge infection.

Hamsters that received the sCPD9 or mRNA vaccine, along with the prime-only vaccination, produced more neutralizing antibodies than those that only received the prime-only vaccination. Booster vaccination improved the serum neutralization capacity for various variants, with Omicron BA.1 exhibiting the highest neutralization evasion capacity among the tested variants.

Hamsters vaccinated with mRNA+sCDP9 and prime-boost sCDP9 produced notable IgG antibody responses against the SARS-CoV-2 spike, nucleocapsid protein, and open reading frame (ORF)-3a. Comparatively, hamsters vaccinated with prime-boost mRNA and Ad2 only exhibited IgG reactivity against the spike protein.

Conclusions

The study findings presented a comparison of vaccines across different platforms, including a novel LAV that provided better protection against SARS-CoV-2 infection than other types of COVID-19 vaccines. Importantly, these findings on enhanced immunity through heterologous prime-boost vaccination align with other recent studies that utilize systemic priming and intranasal boosting with Ad-2 vector or mRNA vaccines.

Anti-SARS-CoV-2 IgA levels in the nasal mucosa are significantly higher among sCPD9-vaccinated animals. Animals vaccinated with sCPD9 showed significant improvement in protection against virus replication, lung inflammation, and tissue damage. Animals that received sCPD9 had a broader antigen recognition, likely due to the key features of LAV.

Journal reference:

Nouailles, G., Adler, J. M., Pennitz, P., et al. (2023). Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Nature Microbiology 1-15. doi:10.1038/s41564-023-01352-8

Microbiology

The Immunity Puzzle: Why Viruses Like COVID-19 Can Reinfect Hosts, Evade the Immune Response

6 April, 2023 Admin Leave a comment

Using a tool called VirScan, Brigham investigators found that people produced shared antibody responses to certain regions of the virus, likely leading to selective pressure and new variants that can repeatedly escape detection by prior immunity.

The human body is capable of creating a vast, diverse repertoire of antibodies—the Y-shaped sniffer dogs of the immune system that can find and flag foreign invaders. Despite our ability to create a range of antibodies to target viruses, humans create antibodies that target the same viral regions again and again, according to a new study led by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, and Harvard Medical School. These “public epitopes” mean that the generation of new antibodies is far from random and that a virus may be able to mutate a single amino acid to reinfect a population of previously immune hosts. The team’s findings, which have implications for our understanding of immunity and public health, will be published today (April 6) in the journal Science.

“Our research may help explain a lot of the patterns we’ve seen during the COVID-19 pandemic, especially in terms of re-infection,” said corresponding author Stephen J. Elledge, PhD, the Gregor Mendel Professor of Genetics at the Brigham and HMS. “Our findings could help inform immune predictions and may change the way people think about immune strategies.”

Before the team’s study, there were hints, but no clear evidence, that people’s immune systems didn’t target sites on a viral protein at random. In isolated examples, investigators had seen recurrent antibody responses across individuals—people recreating antibodies to home in on the same viral protein location (known as an epitope). But the study by Elledge and colleagues helps explain the extent and underlying mechanisms of this phenomenon.

The team used a tool the Elledge lab developed in 2015 called VirScan, which can detect thousands of viral epitopes — sites on viruses that antibodies recognize and bind to — and give a snapshot of a person’s immunological history from a single drop of blood. For the new study, the researchers used VirScan to analyze 569 blood samples from participants in the U.S., Peru, and France. They found that recognition of public epitopes — viral regions recurrently targeted by antibodies — was a general feature of the human antibody response. The team mapped 376 of these commonly targeted epitopes, uncovering exactly where antibodies bind their targets. The team found that antibodies recognized public epitopes through germline-encoded amino acid binding (GRAB) motifs—regions of the antibodies that are particularly good at picking out one specific amino acid. So, instead of randomly choosing a target, human antibodies tend to focus on regions where these amino acids are available for binding, and thus repeatedly bind the same spots.

A small number of mutations can help a virus avoid detection by these shared antibodies, allowing the virus to reinfect populations that were previously immune.

“We find an underlying architecture in the immune system that causes people, no matter where in the world they live, to make essentially the same antibodies that give the virus a very small number of targets to evade in order to reinfect people and continue to expand and further evolve,” said lead author Ellen L. Shrock, PhD, of the Elledge lab.

Interestingly, the team notes that nonhuman species produce antibodies that recognize different public epitopes from those that humans recognize. And, while it is more likely for a person to produce antibodies against a public epitope, some people do produce rarer antibodies, which may more effectively protect them from reinfection. These insights could have important implications for treatments developed against COVID-19, such as monoclonal antibodies, as well as for vaccine design.

“The more unique antibodies may be a lot harder to evade, which is important to consider as we think about the design of better therapies and vaccines,” said Elledge.

Reference: “Germline-encoded amino acid-binding motifs drive immunodominant public antibody responses” by Shrock EL et al., 6 April 2023, Science.
DOI: 10.1126/science.adc9498
Funding: This research was supported by the SARS-CoV-2 Viral Variants Program and the Value of Vaccine Research Network, the MassCPR, the National Institutes of Health (1P01AI165072, K99DE031016, AI139538, AI169619, AI170715, and AI170580), the National Science Foundation (Graduate Research Fellows Program), Pemberton-Trinity Fellowship, Sir Henry Wellcome Fellowship (201387/Z/16/Z), Jane Coffin Childs Postdoctoral Fellowship, Burroughs Wellcome Career Award in Medical Sciences. Elledge is an Investigator with the Howard Hughes Medical Institute.

Disclosures: Elledge and co-author Tomasz Kula are founders of TSCAN Therapeutics and ImmuneID. Elledge is a founder of MAZE Therapeutics and Mirimus, and serves on the scientific advisory board of Homology Medicines, TSCAN Therapeutics, MAZE Therapeutics, none of which impact this work. Shrock was a consultant for ImmuneID. Elledge and Kula are inventors on a patent application filed by the Brigham and Women’s Hospital (US20160320406A) that covers the use of the VirScan library to identify pathogen antibodies in blood.

Brigham and Women’s Hospital

Microbiom

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Results

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