Poop substitute effective vs C. diff

Everyone is intimately familiar with the material necessary for FMT, but its microbial components vary with the individual donor, diet and Read more

Report on first Omicron case detected in GA

The first Omicron case detected in Georgia probably became infected during a visit to Cape Town, South Read more

vaccines

Booster COVID-19 vaccine vs Omicron: thrice is nice

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

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

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

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

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

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

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

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Signature of success for an HIV vaccine?

Efforts to produce a vaccine against HIV/AIDS have been sustained for more than a decade by a single, modest success: the RV144 clinical trial in Thailand, whose results were reported in 2009.

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.”

Rafick-Pierre Sekaly, PhD

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.”

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Multiple myeloma patients display weakened antibody responses to mRNA COVID vaccines

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

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

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

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

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

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

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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.”

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The blind is off: Moderna COVID-19 vaccine study update

Amidst the tumult in the nation’s capital, a quieter reckoning was taking place this week for the Moderna COVID-19 vaccine clinical trial. Lab Land has been hearing from Emory-affiliated study participants that they’re finding out whether they received active vaccine or placebo.

For example, Emory and Grady physician Kimberly Manning, who had written about her participation in the Moderna study in a Lancet essay, posted on Twitter Tuesday. She discovered she had received placebo, and then was offered active vaccine.

After Moderna reported strong efficacy and an Emergency Use Authorization came from the FDA, this was going to happen at some point – the question was when and how. At the advisory panel hearing in December, there was some tension over whether to remove the blind immediately, as this STAT article describes:

“Companies have said that they feel an ethical obligation to deliver vaccine to placebo recipients; the FDA and experts at its advisory panel have debated whether this obligation even exists. Instead, they argue, offering vaccine to volunteers receiving placebo limits the quality of the data about the vaccine’s long-term efficacy and side effects.”

A plan to keep participants in the study under a blinded crossover design was floated, but not implemented. Some participants have said they sensed from the start, based on temporary unpleasant side effects, whether they had received active vaccine or placebo.

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Georgia survey on COVID-19 testing/vaccination shows group differences

Public health experts stress that adequate representation of Black and Latinx people in COVID-19 vaccine studies is a priority. Given how COVID-19 is impacting vulnerable communities, acceptance of a future vaccine – whenever it may become available – is important. A recent article in the Atlanta Journal Constitution highlights how this issue is playing out in Georgia, given the legacy of lack of trust in biomedical research.

“The issue of minority participation in clinical trials is not just in vaccines, it really is in every clinical trial and the point is that the population that is most impacted and most affected needs to be represented in trials,” Emory’s Carlos del Rio said at a media briefing last week.

In a Sunday Op-Ed in the AJC, emergency physician Monique Smith called attention to the disparities in COVID-19 testing and follow-up. In the communities she serves, it is not just a challenge to get a test but to also understand what the results mean, or what to do while waiting for the results, she says.

Lab Land can add some data to that – a survey conducted by neurologist William Hu and colleagues in early August on attitudes toward COVID-19 testing and vaccination among Georgia residents. Non-Hispanic white respondents were more likely than Black/African-American respondents to recommend their loved ones to participate in a COVID-19 clinical trial or be vaccinated after FDA approval.

Green = Black/African-Americans, Clear = non-Hispanic white

From August survey data

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Immunologists identify T cell homing beacons for lungs

Scientists have identified a pair of molecules critical for T cells, part of the immune system, to travel to and populate the lungs. A potential application could be strengthening vaccines against respiratory pathogens such as influenza.

The findings were published online Thursday, September 26 in Journal of Experimental Medicine.

T cells in the lungs, courtesy of Alex Wein. Blue represents respiratory epithelium (EpCAM), while various T cells stain red, yellow or green.

Much research on immunity to influenza virus focuses on antibodies, infection- or vaccine-induced proteins in the blood that can smother viruses. But CD8 T cells, which survey other cells for signs of viral infection and kill infected cells, are an important arm of our defenses too. The epitopes – or bits of viral protein – they recognize generally do not change from year to year.

Researchers led by Jacob Kohlmeier, PhD, at Emory University School of Medicine wanted to learn more about what’s needed to get CD8 T cells into the lungs, since the lungs will often contain the first cells incoming virus will have a chance to infect. However, T cells don’t stick around in the lungs for extended amounts of time.

“The airways are a unique environment in the body,” says Alex Wein, a MD/PhD student who trained in Kohlmeier’s lab. “They’re high in oxygen but low in nutrients. Unlike other tissues, when T cells enter the airways, it’s a one-way trip and they have a half-life of a few weeks, so they must be continually repopulated.”

Wein, his fellow MD/PhD Sean McMaster, now at Boston Consulting Group, and Shiki Takamura at Kindai University are co-first authors of the paper. Kohlmeier is assistant professor of microbiology and immunology and part of the Emory-UGA Center of Excellence for Influenza Research and Surveillance.

The researchers showed that two molecules, called CXCR6 and CXCL16, are needed for CD8 T cells to reach the airways in mice. CXCR6 is found on T cells and CXCL16 is produced by the epithelial cells lining the airways of the lungs. Read more

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Threading the RSV needle: live attenuated vaccine effective in animals

Crafting a vaccine against RSV (respiratory syncytial virus) has been a minefield for 50 years, but scientists believe they have found the right balance.

A 3-D rendering of a live-attenuated respiratory syncytial virus (RSV) particle, captured in a near-to-native state by cryo-electron tomography. Surface glycoproteins (yellow) are anchored on the viral membrane (cyan), with ribonucleoprotein complexes inside (red). Image courtesy of Zunlong Ke and Elizabeth Wright.

Researchers at Emory University School of Medicine and Children’s Healthcare of Atlanta have engineered a version of RSV that is highly attenuated – weakened in its ability to cause disease – yet potent in its ability to induce protective antibodies.

The researchers examined the engineered virus using cryo-electron microscopy and cryo-electron tomography techniques, and showed that it is structurally very similar to wild type virus. When used as a vaccine, it can protect mice and cotton rats from RSV infection.

The results were published this morning in Nature Communications.

“Our paper shows that it’s possible to attenuate RSV without losing any immunogenicity,” says senior author Martin Moore, PhD, associate professor of pediatrics at Emory University School of Medicine and a Children’s Healthcare of Atlanta Research Scholar. “This is a promising live-attenuated vaccine candidate that merits further investigation clinically.”

The next steps for this vaccine are to produce a clinical grade lot and conduct a phase 1 study of safety and immunogenicity in infants, Moore says. Read more

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SIV remission follow-up

The surprising finding that an antibody treatment can push SIV-infected monkeys into prolonged remission, even after antiviral drugs are stopped, continues to rumble across the internet.

siv-a4b7-teaser-copy

Blue circles show how viral levels stayed low even after antiretroviral drugs were stopped.

The Science paper was featured on NIH director Francis Collins’ blog this week. NIAID director Anthony Fauci has been giving presentations on the research, which emerged from a collaboration from his lab and Tab Ansari’s at Emory. Fauci’s talk at the recent HIV prevention meeting in Chicago is viewable here.

At Lab Land, we were pleased to see that the watchdogs at Treatment Action Group had this to say:

“Media coverage of the paper has generally been accurate, but has had to wrestle with the uncertainty that exists among scientists regarding how ART-free control of viral load should be described.”

HIV pioneer Robert Gallo noted in an article accompanying the Science paper that the anti-integrin antibody treatment represents an emerging alternative to the vaunted “shock and kill” strategy, which he termed “soothe and snooze.” Note to reporters: the upcoming “Strategies for an HIV cure” conference at NIH in mid-November might be a good chance to compare the different strategies and put them in perspective.

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Malaria vaccine development: chimeric protein, no myth

Third in a series on malaria immunology from graduate student Taryn McLaughlin. Sorry for the delay last week, caused by technical blog glitches.

It’s easy for me to find reasons to brag when it comes to research here at Emory. However, even an unbiased person should be excited about the malaria vaccine platform being developed by Alberto Moreno at the Emory Vaccine Center.

His vaccine is based on a chimeric protein (a protein that is a combination of bits and pieces of multiple proteins, a la the creature from Greek mythology) that should get your immune system to target multiple stages of the Plasmodium vivax life cycle. Part of it targets the infectious sporozoite, part of it targets the blood stage merozoite, and part of it will even target the transmitted gamete in future versions. This seems like a no brainer. Of course we should be targeting multiple stages! 
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