Natural killer cells can help control virus in primate model of HIV/AIDS

A combination immunotherapy of IL-21 and IFN-alpha, when added to antiviral therapy, is effective in generating highly functional natural killer cells that can help control and reduce SIV (simian immunodeficiency virus) in animal models. This finding, from Yerkes National Primate Research Center scientists in collaboration with Institut Pasteur, could be key for developing additional treatment options to control HIV/AIDS.

The results were published in Nature Communications.

Antiviral therapy (ART) is the current leading treatment for HIV/AIDS, and is capable of reducing the virus to undetectable levels, but is not a cure and is hampered by issues such as cost, adherence to medication treatment plan and social stigma.

To reduce reliance on ART, the Yerkes, Emory and Institut Pasteur research team worked with 16 SIV-positive, ART-treated rhesus macaques. In most nonhuman primates (NHPs), including rhesus macaques, untreated SIV infection progresses to AIDS-like disease and generates natural killer (NK) cells with impaired functionality. In contrast, natural primate hosts of SIV do not progress to AIDS-like disease. Determining why natural hosts do not progress or how to stop the progression is a critical step in halting HIV in humans.

The researchers compared ART-only treated animals with animals that received ART, IL-21 and IFN-alpha to evaluate how the ART plus combination immunotherapy affected the amount of virus in the animals’ tissues.

“Our results indicate ART plus combo-treated rhesus monkeys showed enhanced antiviral NK cell responses,” says first author Justin Harper, PhD, a senior research specialist and manager of the Paiardini research lab. “These robust NK cell responses helped clear cells in the lymph nodes, which are known for harboring the virus and enabling its replication and, therefore, the virus’ persistence. Targeting areas where the virus seeks refuge and knowing how to limit replication facilitate controlling HIV.”

HIV treatment has historically focused on the role of T cells in immunity, so harnessing NK cells opens up different avenues.

“This proof-of-concept study in rhesus monkeys, which progress to AIDS-like disease in the absence of ART, demonstrates how certain NK cell activities can contribute to controlling the virus,” says Mirko Paiardini, PhD, an associate professor of pathology and laboratory Medicine at Emory University and a researcher at Yerkes. “This opens the door to designing additional treatment strategies to induce SIV and HIV remission in the absence of ART, and, ultimately, reducing the burden HIV is to individuals, families and the world.”

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

Emory MVA COVID-19 Vaccine Safe and Effective in Animal Models

Researchers at Yerkes National Primate Research Center, Emory University, have developed a COVID-19 vaccine that has proven safe and effective in mice and monkeys. Results from this National Institute of Allergy and Infectious Diseases (NIAID)-funded study were published online Thursday, Feb. 4 in Immunity.

The Emory MVA COVID-19 vaccine induces protective immunity with the platform of modified vaccinia Ankara (MVA), a harmless version of a poxvirus that is well-known for its use in HIV/AIDS vaccines. Like the Moderna and Pfizer COVID-19 vaccines, the Emory MVA COVID-19 vaccine induces strong neutralizing antibodies, which support the immune system’s ability to fight infections. The Emory MVA COVID-19 vaccine also induces killer CD8 T cells, providing a multi-pronged approach to halting SARS-CoV-2.

In addition, the Emory researchers say the vaccine is easily adaptable to address disease variants and can be used in combination with existing vaccines to improve their ability to combat variants and has the potential to be equally effective with a single dose.

Lead researcher Rama Amara, PhD, built the Emory MVA COVID-19 vaccine based on his more than 20 years of experience working with MVA and animal models to develop an HIV/AIDS vaccine. He and his Yerkes-based research team tested two MVA SARS-CoV-2 vaccines in mice. One of them, MVA/S, used the complete spike protein of coronavirus to induce strong neutralizing antibodies and a strong killer CD8 T cell response against SARS-CoV-2.

“Generating neutralizing antibodies is an important component of a successful COVID-19 vaccine because the antibodies can block the virus from entering the body’s cells,” says Amara, Charles Howard Candler professor of microbiology and immunology at Emory University School of Medicine and a researcher in Yerkes’ Division of Microbiology and Immunology and Emory Vaccine Center. “It’s as important to activate CD8 T cells that can clear infected cells, so this allows us to approach halting the virus two ways simultaneously. The CD8 T cells also provide ongoing value because they are key to working against other variants of the virus, especially if antibodies fail.”

Posted on February 4, 2021 by Quinn Eastman in Immunology Leave a comment

SARS-CoV-2 culture system using human airway cells

Journalist Roxanne Khamsi had an item in Wired highlighting how virologists studying SARS-CoV-2 and its relatives have relied on Vero cells, monkey kidney cells with deficient antiviral responses.

Vero cells are easy to culture and infect with viruses, so they are a standard laboratory workhorse. Unfortunately, they may have given people the wrong idea about the controversial drug hydroxychloroquine, Khamsi writes.

In contrast, Emory virologist Mehul Suthar’s team recently published a Journal of Virology paper on culturing SARS-CoV-2 in primary human airway epithelial cells, which are closer to the cells that the coronavirus actually infects “out on the street.”

Effect of interferon-beta on SARS-CoV-2 in primary human epithelial airway cells. Green = SARS-CoV-2, Red = F-actin, Blue = Hoechst (DNA). Courtesy of Abigail Vanderheiden

The Emory researchers found that airway cells are permissive to SARS-CoV-2 infection, but mount a weak antiviral response lacking certain interferons (type I and type III). Interferons are cytokines, part of the immune system’s response to viral infection. They were originally named for their ability to interfere with viral replication, but they also rouse immune cells and bolster cellular defenses.

In SARS-CoV-2 infection, the “misdirected” innate immune response is dominated instead by inflammatory and fibrosis-promoting cytokines, something others have observed as well.

“Early administration of type I or III IFN could potentially decrease virus replication and disease,” the authors conclude. We note that an NIH-supported clinical trial testing a type I interferon (along with remdesivir) for COVID-19 just started.

The first author of the paper is IMP graduate student Abigail Vanderheiden. As with a lot of recent SARS-CoV-2 work, this project included contributions from several labs at Emory: Arash Grakoui’s, Steve Bosinger’s, Larry Anderson’s, and Anice Lowen’s, along with help from University of Texas Medical Branch at Galveston.

Posted on August 9, 2020 by Quinn Eastman in Immunology Leave a comment

In current vaccine research, adjuvants are no secret

Visionary immunologist Charlie Janeway was known for calling adjuvants – vaccine additives that enhance the immune response – a “dirty little secret.”

Charlie Janeway, MD, in a hat he wore often

Janeway’s point was that foreign antigens, by themselves, were unable to stimulate the components of the adaptive immune system (T and B cells) without signals from the innate immune system. Adjuvants facilitate that help.

By now, adjuvants are hardly a secret, looking at some of the research that has been coming out of Emory Vaccine Center. This week, an analysis by Ali Ellebedy, now at Washington University St Louis, and colleagues showed that in healthy volunteers, the AS03 adjuvant boosted otherwise poor immune responses to a limited dose of the exotic avian flu H5N1, recruiting both memory and naïve B cells. More on that here.

The Moderna SARS-CoV-2 vaccine, which has shown some activity in a small clinical trial here at Emory, has its own kind of adjuvant, since it’s made of both innate-immune-stimulating mRNA and clothed in lipid nanoparticles. Extra adjuvants may come into play later, either with this vaccine or others.

A question we’ve seen many people asking, and discussed on Twitter etc is this: how long does the immunity induced by a SARS-CoV-2 vaccine last? How can we make the immune cells induced by a vaccine stick around for a long time? Read more

Posted on July 15, 2020 by Quinn Eastman in Immunology Leave a comment

Study finds ‘important implications’ to understanding immunity against COVID-19

New research from Emory University indicates that nearly all people hospitalized with COVID-19 develop virus-neutralizing antibodies within six days of testing positive. The findings will be key in helping researchers understand protective immunity against SARS-CoV-2 and in informing vaccine development.

The test that Emory researchers developed also could help determine whether convalescent plasma from COVID-19 survivors can provide immunity to others, and which donors’ plasma should be used.

The antibody test developed by Emory and validated with samples from diagnosed patients has demonstrated that not all antibody tests are created equal – and that neutralizing antibodies, which provide immunity, have specific characteristics. Emory’s study focused on those neutralizing antibodies, which can stop the virus from infecting other cells.

The findings are now available on MedRxiv, the preprint server for health sciences, and are not yet peer-reviewed.

In the study, researchers looked at antibodies against the receptor-binding domain (RBD), part of the spike protein on the outside of the virus. The RBD is what grips on to human cells and allows the virus to enter them. The researchers focused on antibodies against the RBD because the sequence of the RBD in SARS-CoV-2 distinguishes it from other coronaviruses that cause the common cold.

The receptor-binding domain, or RBD, is what grips on to human cells and allows the virus to enter them.

The initial 44 patient blood samples used in this study were from patients being treated for COVID-19 at Emory University Hospital and Emory University Hospital Midtown.

“These findings have important implications for our understanding of protective immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of much-needed vaccines,” says Mehul S. Suthar, PhD, co-lead author and assistant professor of pediatrics at Emory University School of Medicine and Emory Vaccine Center. This study serves as the initial step in a much larger serology effort.

Posted on May 28, 2020 by Wayne Drash in Immunology Leave a comment

Stem-like CD8 T cells stay in lymph nodes/spleen

In a mouse model of chronic viral infection, there are very few virus-specific killer T cells in the blood, Emory Vaccine Center scientists report in a new paper in PNAS. This has implications for efforts to enhance cancer immunotherapy, because in both chronic viral infection and cancer, the same types of exhausted T cells accumulate.

CD8 T cells in lymphoid tissue (spleen) – from Im et al Nature (2016)

Vaccine Center director Rafi Ahmed’s lab has learned a great deal about exhausted T cells by studying the LCMV (lymphocytic choriomeningitis virus) model. In this situation, virus-specific CD8 T cells accumulate in lymph nodes and in other organs, without circulating in the blood, because they acquire a residency program, the PNAS authors write. Postdoc Sejin Im’s 2016 paper defined these “stem-like” cells – he is the first author of the new one as well.

A related phenomenon can be seen in the Kissick lab’s recent paper on immune “outposts” in kidney and other urologic tumors. The stem-like cells stay within the tumor and give rise to similar progeny. One consequence may be that treatments aimed at reactivating those cells need to get inside the tumor.

Posted on February 10, 2020 by Quinn Eastman in Immunology Leave a comment

Transition to exhaustion: clues for cancer immunotherapy

Research on immune cells “exhausted” by chronic viral infection provides clues on how to refine cancer immunotherapy. The results were published Tuesday, Dec. 3 in Immunity.

Scientists at Emory Vaccine Center, led by Rafi Ahmed, PhD, have learned about exhausted CD8 T cells, based on studying mice with chronic viral infections. In the presence of persistent virus or cancer, CD8 T cells lose much of their ability to fight disease, and display inhibitory checkpoint proteins such as PD-1 on their surfaces. PD-1 is targeted by cancer immunotherapy drugs, such as pembrolizumab and nivolumab, which allow CD8 T cells to regain their ability to attack and kill infected cells and cancers.

Those drugs are now FDA-approved for several types of cancer, yet some types of tumors do not respond to them. Studying exhausted CD8 T cells can help us understand how to better draw the immune system into action against cancer or chronic infections.

In previous research, Ahmed’s lab found that exhausted cells are not all alike, and the diversity within the exhausted T cell pool could explain variability in responses to cancer immunotherapy drugs. Specifically, they observed that a population of “stem-like” cells proliferated in response to PD-1-blocking drugs, while a more differentiated population of exhausted cells stayed inactive. The stem-like cells are responsible for maintaining the exhausted T cell population, but cannot kill virus-infected or tumor cells on their own.

The current paper defines a transitional stage in between the stem-like and truly exhausted cells. The truly exhausted cells are marked by a molecule called CD101, and are unable to migrate to sites of infection and contain lower amounts of proteins needed to kill infected or tumor cells.

“The transitional cells are not completely exhausted,” says postdoctoral fellow Will Hudson, PhD, first author of the Immunity paper. “They are still capable of proliferating and performing their ‘killer cell’ functions. In our experiments, they contribute to viral control.”

The transitional cells, lacking CD101, could be a good marker for response to PD-1 blocking drugs, Hudson says. Enhancing the proliferation or survival of these cells, or preventing their transition to lasting exhaustion, may be a novel therapeutic strategy for cancer. Read more

Posted on December 3, 2019 by Quinn Eastman in Immunology Leave a comment

Hope Clinic part of push to optimize HIV vaccine components

Ten years ago, the results of the RV144 trial– conducted in Thailand with the help of the US Army — re-energized the HIV vaccine field, which had been down in the dumps. It was the first vaccine clinical trial to ever demonstrate any efficacy in preventing HIV. The Hope Clinic of Emory Vaccine Center has been involved in efforts to build on the RV144 trial’s promising results. These early-stage studies have been optimizing the best vaccine components and techniques for larger vaccine efficacy trials, some of which are now underway.

Nadine Rouphael, interim director of the Hope Clinic, was first author on a recent paper in Journal of Clinical Investigation, reporting a multi-center study from the HIV Vaccine Trials Network. HVTN is headquartered at the Fred Hutchinson Cancer Research Center in Seattle and supported by the National Institute of Allergy and Infectious Diseases.

“Our study shows that there are tools available to us now to improve on the immunogenicity seen in RV144, which may lead to better efficacy in future field trials,” Rouphael says. (See statement on the HVTN 105 study here.) Read more

Posted on October 11, 2019 by Quinn Eastman in Immunology Leave a comment

Antibody diversity mutations come from a vast genetic library

Vaccine scientists want to nudge the immune system into producing antibodies that will protect us from infection. In doing so, they are playing with fire – in a limited way. With every healthy antibody response, a process of internal evolution takes place among B cells, the immune cells that produce antibodies. It’s called “somatic hypermutation.”

In the lymph nodes, individual B cells undergo an accelerated rate of mutation. It’s as if those B cells’ DNA were being cooked with radiation or mutagenic chemicals – but only in a few genes. Then the lymph nodes select the B cells with high-affinity antibodies.

Gordon Dale, a just-defended graduate student from Joshy Jacob’s lab in Emory Vaccine Center, has a new paper in Journal of Immunology that sheds light on how somatic hypermutation takes place in both mice and humans.

In particular, Dale and Jacob found that the mutations that occur in human and mouse antibody genes are not random. They appear to borrow information from gene segments that are leftovers from the process of assembling antibody DNA in B cells.

In a mix and match process called VDJ recombination, B cells use one of many V, D, and J segments to form their antibody genes. What Dale and Jacob were looking at occurs after the VDJ step, when B cells get stimulated as part of an immune response.

They analyzed the patterns of mutations in human and mouse antibody genes, and found that mutations tend to come together, in a way that suggests that they are being copied from leftover V segments. They call this pattern “tem Read more

Posted on August 5, 2019 by Quinn Eastman in Immunology Leave a comment

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