Now Emory, Harvard and Case Western Reserve scientists have identified a gene activity signature that may explain why the vaccine regimen in the RV144 study was protective in some individuals, while other HIV vaccine studies were not successful.
The researchers think that this signature, observed in immune cells in the blood after vaccination, could be used to design future vaccines that will have a better chance of providing protection against HIV infection.
“We may not need to take ‘shots in the dark’, when testing vaccine platforms or adjuvants for efficacy,” says senior author Rafick-Pierre Sekaly, PhD. “Instead, we can now identify adjuvants and/or vaccine regimens which more potently induce the activation of this signature.”
The results, published this week in Nature Immunology, also contain hints on a contributing factor explaining why a recent HIV vaccine study conducted in South Africa (HVTN702) did not show a protective effect. HVTN702 was designed as a follow-up to RV144, but multiple parameters were different between the Thai and South African vaccine studies, such as the demographics of the participants, the adjuvant used, and the levels and varieties of HIV circulating.
“Our findings highlight one potential mechanism which may have contributed to the muted efficacy of HVTN702,” says Sekaly, professor of pathology and laboratory medicine at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.
This mechanism involves the choice of adjuvant, a vaccine additive that enhances immune responses. While RV144 used the adjuvant alum (aluminum hydroxide), HVTN702 used the oil-based adjuvant MF59, also found in some influenza vaccines, to stimulate higher antibody production.
“There are multiple ways that a vaccine can promote protection and some of these do not involve antibodies,” Sekaly says. “Since MF59 failed to potently induce the gene signature we found to be associated with protection, this signature could guide us to mechanisms distinct from antibodies which could trigger protection from HIV-1.”
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.
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.
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.”.
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.
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.”
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.
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 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.”
In the race to halt the COVID-19 pandemic, researchers at Yerkes National Primate Research Center of Emory University share two important findings from their latest peer-reviewed, published study in Cell.
Rhesus monkeys are a valid animal model for COVID-19 studies because the way they experience and respond to the virus has comparable similarities to the way the virus affects humans, the researchers say. And baricitinib, an anti-inflammatory medication that is FDA-approved for rheumatoid arthritis, is remarkably effective in reducing the lung inflammation COVID-19 causes when the medication is started early after infection.
The study results have immediate and important implications for treating patients with COVID-19. Baricitinib will be compared against the steroid dexamethasone in a NIAID-sponsored clinical trial called ACTT-4 (Adaptive COVID-19 Treatment Trial), which started in November.
Mirko Paiardini, PhD, a researcher in Yerkes’ Microbiology and Immunology division, and his team selected rhesus macaques as the animal model because they expected the monkeys would mimic the disease course in humans, including the virus traveling to the upper and lower airways, and causing high levels of inflammation in the lungs. The team randomized eight rhesus macaques into two groups – a control and a treatment group; the animals in the treatment group received baricitinib.
“Our results showed the medication reduced inflammation, decreased inflammatory cells in the lungs and, ultimately, limited the virus’ internal path of destruction,” Paiardini says. “Remarkably, the animals we treated with baricitinib rapidly suppressed the processes responsible for inducing lung inflammation, thus elevating baricitinib for consideration as a frontline treatment for COVID-19 and providing insights on the way the drug works and its effectiveness.”
The FDA recently granted baricitinib emergency use authorization in combination with remdesivir based on the results of the ACTT-2 findings. “Our study was under way concurrently and, now, solidifies the importance of baricitinib in treating COVID-19,” Paiardini adds.
Co-senior author Raymond Schinazi, PhD, DSc, inventor of the most commonly used HIV/AIDS drugs to prevent progression of the disease and death, says: “Our study shows the mechanisms of action are consistent across studies with monkeys and clinical trials with humans. This means the nonhuman primate model can provide enough therapeutic insights to properly test anti-inflammatory and other COVID-19 therapies for safety and effectiveness.”
Schinazi is the Frances Winship Walters Professor of Pediatrics at Emory University School of Medicine and is affiliated with Yerkes.
“Ray and his group have been investigating the potential of anti-inflammatory drugs, such as baricitinib, for years in the context of another infection, HIV, in which inflammation is a key cause of sickness and death,” Paiardini says. “Our laboratories have collaborated for years to test therapeutics in the nonhuman primate model of HIV infection, thus placing us in a unique position when COVID-19 hit the U.S. to focus our combined expertise and efforts to halt the virus. It took only a phone call between the two of us to switch gears, begin work to create a reliable and robust monkey model of COVID-19 at Yerkes and test the potential of drugs to block inflammation.”
Tim Hoang, first author and Emory doctoral student in the Immunology and Molecular Pathogenesis Program, says: “It was exciting to be at the forefront of the response to COVID-19 and to be part of this research team that involved collaboration from Yerkes and Emory infectious disease experts, geneticists, chemists, pathologists and veterinarians.”
Co-first author and Emory postdoctoral fellow Maria Pino, PhD, emphasizes: “We knew Yerkes was uniquely suited to conduct this study because of the research and veterinary expertise, specialized facilities and animal colony, and our team’s commitment to providing better treatment options for people who have COVID-19.”
The research team plans to conduct further studies to better understand the inflammation the virus causes and to develop more targeted approached to mitigate the damage COVID-19 leaves behind.
Steven Bosinger, PhD, co-senior author, and his research team conducted the genomic analyses that helped unravel the process by which baricitinib reduces inflammation. “One of the most exciting aspects of this project was the speed genomics brought to the collaborative research,” says Bosinger. “Eight months ago, we began using genomics to accelerate the drug screening process in order to identify treatable, molecular signatures of disease between humans and model organisms, such as the monkeys in this study, In addition to determining the effectiveness of baricitinib, this study highlights Emory researchers’ commitment to improving human health and, in this case, saving human lives.”
Bosinger is assistant professor, Department of Pathology & Laboratory Medicine, Emory School of Medicine (SOM) and Emory Vaccine Center (EVC); director, Yerkes Nonhuman Primate Genomics Core and a researcher in Yerkes’ Division of Microbiology and Immunology.
Some of the others on the Emory research team include: Arun Boddapati (co-first author), Elise Viox, Thomas Vanderford, PhD, Rebecca Levit, MD, Rafick Sékaly, PhD, Susan Ribeiro, PhD, Guido Silvestri, MD, Anne Piantadosi, MD, PhD, Sanjeev Gumber, BVSc, MVSc, PhD, DACVP, Sherrie Jean, DVM, DACLAM, and Jenny Wood, DVM, DACLAM. Jacob Estes, PhD, at Oregon Health & Science University also collaborated.
Paiardini says, “So many colleagues had a key role in this study. First authors Tim and Maria as well as Yerkes veterinary and animal care personnel who worked non-stop for months on this project. This truly has been a collaborative effort at Emory University to help improve lives worldwide.”
This study was funded by the National Institutes of Health, Emory University’s COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant, Yerkes’ base grant, which included support for the center’s Coronavirus Pilot Research Project grants, and Fast Grants.
Grant amounts (direct + indirect) are:
NIH R37AI141258, $836,452/yr (2018-23)
NIH R01AI116379, $783,714/yr (2015-20 + 2021 NCE)
NIH P51 OD011132, $10,540,602/yr (2016-20)
U24 AI120134 $681,214/yr (2020-2025)
S10OD026799 $985,030/yr (2019-2020)
Emory University COVID-19 Molecules and Pathogens to Populations and Pandemics Initiative Seed Grant, $150,000/1 yr
Fast Grants #2144, $100,000/1 yr
Note: Only a portion of the NIH grant funding was applied to the study reported in this news release.
Researchers from the Yerkes National Primate Research Center have shown Zika virus infection soon after birth leads to long-term brain and behavior problems, including persistent socioemotional, cognitive and motor deficits, as well as abnormalities in brain structure and function. This study is one of the first to shed light on potential long-term effects of Zika infection after birth.
“Researchers have shown the devastating damage Zika virus causes to a fetus, but we had questions about what happens to the developing brain of a young child who gets infected by Zika,” says lead researcher Ann Chahroudi, MD, PhD, an affiliate scientist in the Division of Microbiology and Immunology at Yerkes, director of the Center for Childhood Infections and Vaccines (CCIV), Children’s Healthcare of Atlanta (CHOA) and Emory University, and an associate professor of pediatrics in the Division of Pediatric Infectious Diseases at Emory University School of Medicine.
“Our pilot study in nonhuman primates provides clues that Zika virus infection during the early postnatal period can have long-lasting impact on how the brain develops and works, and how this scenario has the potential to impact child behavior,” Chahroudi continues.
The study, published online in Nature Communications, followed four infant rhesus monkeys for one year after Zika virus infection at one month of age. Studying a rhesus monkey until the age of 1 translates to the equivalent of 4 to 5 years in human age. Researchers found postnatal Zika virus infections led to Impairments in memory function, significant changes in behavior, including reduced social interactions and increased emotional reactions, and some gross motor deficits. These changes corresponded with structural and functional brain changes the researchers found on MRI scans – findings that indicate long-term neurologic complications.
“Our findings demonstrate neurodevelopmental changes detected at 3 and 6 months of age are persistent,” says first author Jessica Raper, PhD, research assistant professor at Yerkes. (See Science Translational Medicine for an earlier study by members of the current research team.) “This is significant because it gives healthcare providers a better understanding of possible complications of Zika beyond infection during pregnancy and into the first years of life,” she adds. Read more
Stimulating immune cells with two cancer immunotherapies together can shrink the size of the viral “reservoir” in SIV (simian immunodeficiency virus)-infected nonhuman primates treated with antiviral drugs, Emory researchers and their colleagues have concluded. The reservoir includes immune cells that harbor virus despite potent antiviral drug treatment.
The findings, reported in Nature Medicine, have important implications for the quest to cure HIV because reservoir shrinkage has not been achieved consistently before. However, the combination treatment does not prevent or delay viral rebound once antiviral drugs are stopped. Finding an HIV cure is important because, although antiretroviral therapy can reduce the amount of circulating virus to undetectable levels, problematic issues remain such as social stigma in addition to the long-term toxicity and cost of antiretroviral drugs.
“It’s a glass-half-full situation,” says senior author Mirko Paiardini, PhD. “We concluded immune checkpoint blockade, even a very effective combination, is unlikely to achieve viral remission as a standalone treatment during antiretroviral therapy.”
He adds the approach may have greater potential if combined with other immune-stimulating agents. Or it could be deployed at a different point — when the immune system is engaged in fighting the virus, creating a target-rich environment. Other HIV/AIDS researchers have started to test those tactics, he says.
Paiardini is an associate professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center. The study performed in nonhuman primates, considered the best animal model for HIV studies, was carried out in collaboration with co-authors Shari Gordon and David Favre at the University of North Carolina at Chapel Hill and GlaxoSmithKline; Katharine Bar at the University of Pennsylvania; and Jake Estes at Oregon Health & Science University. Read more
But consider whether someone who was exposed to TB in childhood might still have it in their lungs somewhere. It’s difficult to know if treatments get rid of the bacteria completely.
“The antibiotic treatment we used for this study is a new, shorter regimen the CDC recommends for treating humans with latent tuberculosis, but we did not have direct evidence for whether it completely clears latent infection,” says Yerkes/Emory Vaccine Center researcher Jyothi Rengarajan, who was co-principal investigator along with Deepak Kaushal of Tulane. “Our experimental study in macaques showing almost complete sterilization of bacteria after treatment suggests this three-month regimen sterilizes humans as well.”
In an editorial in the same journal, CDC and Johns Hopkins experts call the results “dramatic” and say application of the drug regimen “could presage a major step forward in TB prevention and control.” Read more