Tag Archives: HIV & AIDS

Microbiology

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

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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.

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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).

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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

Novel gene-editing strategy harnesses an unusual protective ability to eliminate HIV-1 infection

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Reviewed by Danielle Ellis, B.Sc.May 19 2023

Genetic alterations that give rise to a rare, fatal disorder known as MOGS-CDG paradoxically also protect cells against infection by viruses. Now, scientists at the Lewis Katz School of Medicine at Temple University have harnessed this unusual protective ability in a novel gene-editing strategy aimed at eliminating HIV-1 infection with no adverse effects on cell mortality.

The new approach, described online April 28 in the journal Molecular Therapy – Nucleic Acids, is based on a combination of two gene-editing constructs, one that targets HIV-1 DNA and one that targets a gene called MOGS – defects in which cause MOGS-CDG. In cells from persons infected with HIV-1, the Temple researchers show that disrupting the virus’s DNA while also deliberately altering MOGS blocks the production of infectious HIV-1 particles. The discovery opens up new avenues in the development of a cure for HIV/AIDS.

Proper MOGS function is essential for glycosylation, a process by which some cellular proteins synthesized in the body are modified to make them stable and functional. Glycosylation, however, is leveraged by certain kinds of infectious viruses. In particular, viruses like HIV, influenza, SARS-CoV-2, and hepatitis C, which are surrounded by a viral envelope, rely on glycosylated proteins to enter host cells.

In the new study, lead investigators Kamel Khalili, PhD, Laura H. Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine, and Rafal Kaminski, PhD, Assistant Professor at the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine designed a genetic approach to exclusively turn on CRISPR to impede MOGS gene expression through DNA editing within immune cells that harbor replication competent, HIV-1. Their novel approach is expected to avoid any impact on the health of uninfected cells that retain normal MOGS gene function. Stimulation of the apparatus in HIV-1 infected cells disrupted the glycan structure of the HIV-1 envelope protein, culminating in the production of non-infectious virus particles.

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“This approach is conceptually very interesting,” said Dr. Khalili, who is also senior investigator on the new study. “By mitigating the ability of the virus to enter cells, which requires glycosylation, MOGS may offer another target, in addition to the integrated viral DNA for developing the next generation of CRISPR gene-editing technology for HIV elimination.”

Dr. Kaminski, Dr. Khalili, and Tricia H. Burdo, PhD, Professor and Vice Chair in the Department of Microbiology, Immunology, and Inflammation and the Center for Neurovirology and Gene Editing at Temple and an expert in the use of non-human primate models for HIV-1, have been working together to further assess the efficacy and safety of CRISPR-MOGS strategy in preclinical studies. In previous work, the team demonstrated that CRISPR-based technology can successfully remove viral DNA from the cells of infected non-human primates.

Other researchers who contributed to the study include Hong Liu, Chen Chen, Shuren Liao, and Shohreh Amini, Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University; Danielle K. Sohaii, Conrad R.Y. Cruz, and Catherine M. Bollard, Center for Cancer and Immunology Research, Children’s National Health System, The George Washington University; Thomas J. Cradick and Jennifer Gordon, Excision Biotherapeutics, San Francisco, CA; Anand Mehta, Stephane Grauzam, and James Dressman, Department of Cell and Molecular Pharmacology, Medical University of South Carolina; and Carlos Barrero and Magda Florez, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University.

The research was supported in part by grants from the National Institutes of Health and the W.W. Smith Charitable Trust.

Source:

Temple University Health System

Journal reference:

Liu, H., et al. (2023) Strategic Self-Limiting Production of Infectious HIV Particles by CRISPR in Permissive Cells. Molecular Therapy — Nucleic Acids. doi.org/10.1016/j.omtn.2023.04.027.

Microbiology

Challenging the FDA’s authority isn’t new – the agency’s history shows what’s at stake when drug regulation is in limbo

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Political pressure is nothing new for the U.S. Food and Drug Administration. The agency has frequently come under fire for its drug approval decisions, but attacks on its decision-making process and science itself have increased during the COVID-19 pandemic.

Recent challenges to the FDA’s authority have emerged in the context of reproductive rights.

On Nov. 18, 2022, a group of anti-abortion doctors and medical groups filed a lawsuit against the FDA, challenging its approval from more than 20 years ago of mifepristone, a drug taken in combination with another medication, misoprostol, to treat miscarriages and used to induce more than 50% of abortions in early-stage pregnancies in the U.S.

It is widely believed that the plaintiffs filed the lawsuit in the Northern District of Texas so District Judge Matthew J. Kacsmaryk, a well-known abortion opponent, could oversee the litigation. While Kacsmaryk did issue a preliminary injunction ruling that the FDA lacked the authority to approve mifepristone, an appeal partially reversed the decision and the Supreme Court stayed Kacsmaryk’s order. The case now sits at the 5th U.S. Circuit Court of Appeals and will likely return to the Supreme Court.

The FDA is the government’s oldest consumer protection agency. The effects of this lawsuit could reach far beyond mifepristone – undermining the agency’s authority could threaten its entire drug approval process and change access to commonly used drugs, ranging from amoxycillin and Ambien to prednisone and Paxlovid.

I am a legal scholar whose research focuses in part on the law and ethics of the FDA’s drug approval process. Examining the FDA’s history reveals the unprecedented nature of the current challenges to the agency’s authority.

In its early years, the FDA focused primarily on balancing the competing goals of consumer safety with access to experimental treatments. The priority was strengthening consumer protection to prevent tragedy from recurring.

For instance, at the turn of the 20th century, Congress passed the Biologics Control Act of 1902, providing the federal government the authority to regulate vaccines. This law was introduced after 13 children died from inadvertently contaminated diphtheria antitoxin, which was made from the blood of a horse infected with tetanus.

A few years later, after investigative journalists publicized the unsanitary conditions and food-handling practices in meatpacking plants, Congress passed the Pure Food and Drug Act of 1906, which prohibited the marketing and sale of misbranded and contaminated foods, drinks and drugs.

Similarly, in 1937, approximately 71 adults and 34 children died from ingesting S.E. Massengill’s antibacterial elixir, which contained a poisonous raspberry flavoring added to sweeten the taste. In response, Congress passed the Federal Food, Drug and Cosmetic Act of 1938, requiring manufacturers to show that drugs are safe before they go on the market. This act marked the beginning of modern drug regulations and the birth of the FDA as a regulatory agency.

Then, in 1962, Dr. Frances Oldham Kelsey, a pharmacologist, physician and medical officer working at the FDA, refused to approve thalidomide, a drug marketed in Europe, Canada, Japan and other countries to alleviate morning sickness in pregnant women but later found to cause severe birth defects. Shocking revelations of children born without limbs or suffering from other debilitating conditions motivated Congress to pass the Kefauver-Harris Drug Amendments of 1962, which ushered in a more cautious approach to the drug approval process.

During the 1970s, questions about the limits of safety versus an individual’s right to access arose when cancer patients who wanted access to an unapproved drug derived from apricots, Laetrile, sued the FDA. The agency had blocked the drug’s shipment and sale because it was not approved for use in the U.S. At that time, the Supreme Court upheld the FDA’s protective authority, holding that an unproven therapy is unsafe for all patients, including the terminally ill.

The 1980s, however, marks the FDA’s shift toward increasing access following reports of an emerging disease – AIDS – which primarily affected gay men. In the first nine years of the AIDS epidemic, over 100,000 Americans died. AIDS patients and their advocates became vocal critics of the FDA, arguing that the agency was too paternalistic and restrictive following events like the thalidomide scare.

After massive protests, Dr. Anthony Fauci, then director of the National Institute of Allergy and Infectious Diseases, proposed a parallel track program allowing eligible patients access to unapproved experimental treatments. This, along with other existing FDA mechanisms, helped lay the path for other alternative approval pathways, such as Emergency Use Authorization, which played a large role in permitting use of vaccines and medications pending full FDA approval during the COVID-19 pandemic.

Despite the FDA’s shift toward increased access, the political right has in recent years argued that the agency remains too bureaucratic and paternalistic and should be deregulated – an argument seemingly contrary to the reasoning underlying Kacsmaryk’s recent order that the FDA did not sufficiently evaluate the safety of mifepristone in its approval.

Mifepristone, which has overwhelming data supporting its safety, could remain available to some people in some states regardless of the outcome of this lawsuit. While the FDA approves drugs for consumer use, it does not regulate the general practice of medicine. Doctors can prescribe FDA-approved drugs off-label, meaning they could prescribe a drug with a different dose, in a different way or for a different use than what the FDA has approved it for.

The mifepristone case has broad implications for the FDA’s future and could have devastating effects on health in the U.S. Due in part to FDA involvement, public health interventions have led to a 62% increase in life expectancy in the 20th century. These include vaccines and medications for childhood illnesses and infectious diseases such as HIV, increased regulation of tobacco, and over-the-counter Narcan to combat the opioid crisis, among others.

The FDA needs to be able to use its scientific expertise to make data-driven decisions that balance safety and access, without the ability of a single judge to potentially gut the system. The agency’s history is an important reminder of the need for strong administrative agencies and ongoing vigilance to protect everyone’s health.


Christine Coughlin

The Conversation

Microbiology

Experimental HIV vaccine regimen safe but ineffective, NIH study finds

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An investigational HIV vaccine regimen tested among men who have sex with men (MSM) and transgender people was safe but did not provide protection against HIV acquisition, an independent data and safety monitoring board (DSMB) has determined. The HPX3002/HVTN 706, or “Mosaico,” Phase 3 clinical trial began in 2019 and involved 3,900 volunteers ages 18 to 60 years in Europe, North America and South America. Based on the DSMB’s recommendation, the study will be discontinued. Participants are being notified of the findings, and further analyses of the study data are planned.

Janssen Vaccines & Prevention B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, sponsored the Mosaico study with funding support from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The trial was conducted by the NIAID-funded HIV Vaccine Clinical Trials Network, based at the Fred Hutchinson Cancer Research Center in Seattle.

The experimental vaccine regimen was developed by Janssen. It was based on “mosaic” immunogens—vaccine components featuring elements of multiple HIV subtypes—with the goal of inducing immune responses against a wide variety of global HIV strains. The investigational vaccine regimen consisted of four injections over a year of Ad26.Mos4.HIV. This vaccine candidate uses a common-cold virus (adenovirus serotype 26, or Ad26) to deliver the mosaic immunogens. The final two vaccinations were accompanied by a bivalent (two-component) HIV envelope protein formulation, combining clade C gp140 and mosaic gp140 envelope proteins, adjuvanted by aluminum phosphate to boost immune responses. All study vaccinations were completed in October 2022.

In its scheduled data review, the DSMB determined there were no with the experimental vaccine regimen. However, the number of HIV infections were equivalent between the vaccine and placebo arms of the study. During the clinical trial, all participants were offered comprehensive HIV prevention tools, including pre-exposure prophylaxis, or PrEP. Study staff ensured that participants who acquired HIV during the trial were promptly referred for medical care and treatment.

The Mosaico findings track with developments in the Phase 2b “Imbokodo” (HPX2008/HVTN 705) clinical trial, which was testing a similar HIV vaccine regimen in young women in sub-Saharan Africa. A DSMB determined in 2021 that the experimental regimen in that study was also safe but ineffective in protecting against HIV acquisition.

NIH/National Institute of Allergy and Infectious Diseases

Science X Network

Microbiology

Mpox, AIDS and COVID-19 show the challenges of targeting public health messaging to specific groups without causing stigma

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During infectious disease outbreaks, clinicians and public health officials are tasked with providing accurate guidance for the public on how to stay safe and protect themselves and their loved ones. However, sensationalized media coverage can distort how the public perceives new emerging infections, including where they come from and how they spread. This can foster fear and stigma, especially toward communities that are already mistrustful of the health care system.

The racial and sexual stigma surrounding monkeypox is what spurred the World Health Organization to rename the disease to mpox in November 2022. While this is a step in the right direction, I believe more work needs to be done to reduce the stigma surrounding infectious diseases like mpox.

I am an infectious disease researcher who studies HIV, COVID-19 and mpox. During the COVID-19 pandemic, I was the lead investigator at the University of Pittsburgh for a national survey looking at how COVID-19 has affected different communities. Effective public health communication isn’t easy when conflicting messages may come from many sources, including family and friends, other community members or the internet. But there are ways that public health officials can make their own messaging more inclusive while mitigating stigma.

Inclusive public health messaging can motivate the public to make better decisions regarding their personal health and the health of others. This effort often involves engaging the communities most affected by an outbreak. Unfortunately, because these communities are heavily affected by the infection and tend to experience some form of inequity, they are often blamed by society for spreading the disease.

COVID-19 drove an increase in hate crimes related to the pandemic against Chinese and other Asian communities in the United States. A 2022 UCLA survey found that 8% of Asian American and Pacific Islander adults in California experienced a COVID-19 related hate incident.

Effective public health messaging can focus on the fact that while infections may first affect certain groups of people, they often spread to other groups and eventually encompass entire communities. Infections are caused by bacteria, viruses and fungi. They don’t discriminate by race, gender or sexual orientation. Messages that focus on the pathogens, rather than the communities, may reduce stigma.

Visually inclusive messages are also likely to engage a greater portion of the community. Examples include making sure that the people represented in posters and flyers, images on TV and websites, and other informational material are from diverse backgrounds. This sends a more unified message that what affects an individual also affects the larger community.

Many media outlets, especially on social media, use fear-based messaging to report on infectious diseases. While this may reinforce certain protective behaviors, such as using condoms during sex, it may also increase stress and anxiety. Fear-based messages also worsen stigma, leading to increased discrimination against communities that are already vulnerable and mistrustful of health care. Ultimately, this leads people to avoid seeking health care and can worsen health outcomes.

Public health officials have often used fear-based messaging in response to sexually transmitted infections, or STIs, like HIV, chlamydia and gonorrhea. Sex itself is highly stigmatized by society. I have found that some of my patients would prefer to avoid getting tested and treated for an STI rather than deal with the shame of having an STI.

Making sexual health and STI testing routine and integral parts of overall wellness and health is an important step to reduce the stigma around them. Similarly, messaging that normalizes the challenges faced by people at risk for certain infections could help avoid causing shame.

Infections affect different people differently. COVID-19 might be a mildly stuffy nose for one person, and it could be months in an intensive care unit hooked up to a ventilator for another. Messages that focus on the successes of medical and public health interventions that resonate with communities are most likely to be successful.

Different groups have different exposure risks as well. Mpox heavily affected gay and bisexual men in 2022. One reason why was related to how the virus is transmitted. Prior research suggested that mpox was largely transmitted by close skin-to-skin contact, but emerging studies raised the question of whether the 2022 outbreaks were being driven more by sexual transmission.

There was controversy as to whether public health messaging should highlight sexual encounters as a potential transmission route. This can risk further stigmatizing gay and bisexual men versus potentially overlooking these key at-risk populations. Some advocates argued that promoting the message that mpox was primarily transmitted by close contact would prevent resources and interventions from reaching the groups of people most affected by the disease.

One size does not always fit all when it comes to public health messaging. Multiple messages may be necessary for different groups of people based on their risk of infection or severe disease. An August 2022 Centers for Disease Control and Infection survey found that 50% of gay and bisexual men reduced their sexual encounters in response to the mpox outbreak. Since late summer, mpox rates have been dropping rapidly, and many experts think that both behavior change and vaccination may have contributed to the falling rates. Studies like these further support the importance of directly engaging with communities to encourage healthy behavior change.

Mistrust is also a barrier to effective messaging. Some communities may be mistrustful of medical and health care systems because of prior histories of exploitation, such as the Tuskegee study, where researchers prevented Black participants from receiving syphilis treatment for decades in the mid-20th century, and ongoing fear of mistreatment.

Identifying trusted community champions and health care providers – especially ones who belong to that community – to deliver a public health message may increase its acceptance. One 2019 study, for example, found that Black men were more likely to accept vaccines, medical advice and engage in health care services if they had a Black health care provider.

Effectively delivering public health messaging is a complicated and challenging process. But talking to and listening to the communities most affected by an outbreak can make a difference.


Ken Ho

The Conversation

Microbiology

Enveloped viruses show greater cross-species transmission, according to new research

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Nidhi Saha, BDSBy Nidhi Saha, BDSDec 9 2022Reviewed by Aimee Molineux

A study published in PNAS Microbiology found that enveloped viruses harbor greater cross-species transmissibility and are more likely to cause zoonotic infections than nonenveloped viruses. The research suggested that viral envelopes aid these pathogens in evading host immunity.

Study: Enveloped viruses show increased propensity to cross-species transmission and zoonosis. Image Credit: Kateryna Kon/Shutterstock
Study: Enveloped viruses show increased propensity to cross-species transmission and zoonosis. Image Credit: Kateryna Kon/Shutterstock

Background

Zoonosis refers to the spread of infectious diseases between animals and humans (or between humans and animals). In the past few decades, the cross-species transmission of viruses from wild or domestic animals to humans (zoonoses) has led to major epidemics. Still, our understanding of this complex process remains limited.

Several well-known zoonoses include human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), Zika, Ebola, influenza, COVID, and mpox. Therefore, understanding and predicting virus emergence has become a scientific priority. Several zoonotic risk factors exist, including biodiversity elimination and species invasions, viral host variability, interaction frequency, life cycle characteristics of reservoir hosts, wildlife trade, and host closeness to humans.

Nevertheless, prior studies have revealed that three factors have been identified as contributing to the risk of zoonotic disease spread – viral genetic material – ribonucleic acid (RNA) viruses may be more susceptible than DNA viruses; replication site – viruses that replicate in the host cytoplasm rather than the nucleus may have an advantage; and genome size – smaller genomes may be more zoonotic.

The enveloped nature of viruses is a characteristic feature that distinguishes them from other organisms. Most zoonotic viruses that have caused human disease in the past were enveloped, such as – smallpox, mpox, coronaviruses, rabies, measles, and influenza.

A virus’s genome can provide information regarding host tropism and zoonotic propensity by evaluating characteristics like codon or dinucleotide usage biases and the degree to which these biases reflect those observed in the host-gene transcripts. The fundamental features of viruses remain unknown despite these advancements in understanding cross-species transmission and zoonosis.

The study

Using a database of over 12,000 mammalian virus–host interactions, the current work explored key virological properties that influence cross-species transmissibility and zoonotic propensity to understand better which viral characteristics predominantly determine zoonosis.

Here, the researchers examined a large VIRION database containing 5,149 viruses identified through metagenomic studies. This exploratory analysis utilized the Global Virome in One Network (VIRION) database. Overall, 5,149 viruses belonging to 36 families and 1,599 host species were analyzed from 20 orders, revealing 12,888 virus-host associations. 

Following this, the fundamental characteristics of the viruses were defined based on –their genetic material; single or double-stranded; segmented or non-segmented, replicating in the cytoplasm or nucleus, enveloped or nonenveloped, and the genome size. 

For each virus, the number of natural host species was identified and recorded, excluding humans, to reduce the possibility of bias. The mammalian viruses were then examined for their potential pathogenicity, i.e., their ability for zoonosis.

The findings

The results showed that the number of host species increased more rapidly for enveloped viruses than for non-enveloped viruses, being approximately twice as high for the former type. This difference was also discernible when the envelope factor was combined with the other viral characteristics. 

All other viral characteristics examined were either not significant or marginally significant. Enveloped viruses were more likely to undergo cross-species transmission than nonenveloped viruses. 

It was noted that enveloped viruses tend to have a higher proportion of zoonotic spread than non-enveloped viruses. Using binary logistic regression with N ≥5 sequence records, zoonotic propensity was estimated to increase 2.5-fold for enveloped viruses compared to non-enveloped viruses. Thus, enveloped viruses showed a higher propensity for zoonotic spillover than non-enveloped viruses.

Meanwhile, viruses replicating in the cytoplasm were found to be more likely (1.9 times) to be zoonotic than those replicating in the nucleus. Segmented viruses heightened the chances for zoonosis slightly more than non-segmented viruses. Further, viruses with smaller genomes had a greater probability of precipitating zoonotic infection. 

The lack of significant effects of these two features on cross-species transmission meant that their impact on zoonotic propensity could either be due to human-specific factors or, more likely, to biases within the human-infectious virus datasets.

This study also provided insights into how enveloped viruses might infect hosts. It was likely that envelope proteins were structurally less constraining than capsid proteins, allowing enveloped viruses to bind cellular receptors from different host species with greater flexibility, bind to a larger number of alternative receptors, or accommodate host-switch mutations without compromising other functions. 

Another possible mechanism is an apoptotic mimicry, in which viral particles are engulfed by host cells disguised as apoptotic bodies with defined membrane lipid conformations and get introduced into the host cells. 

Conclusion

The results revealed that enveloped viruses infect more host species and are more likely to be zoonotic than non-enveloped viruses. In contrast, other viral characteristics, such as genome composition, structure, size, and the viral replication compartment, are less significant. 

According to this study, viral envelopes did not significantly impact or even reduce the zoonotic risk contrary to the prior belief, and this may help in prioritizing outbreak prevention efforts. A viral envelope may facilitate cross-species transmission by facilitating structural flexibility of the receptor-binding proteins and allowing for overcoming the viral entry barriers.

Journal reference:
Microbiology

Multi-stage HIV vaccine regimen shows promising results in Phase 1 clinical trial

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Reviewed by Emily Henderson, B.Sc.Dec 8 2022

The George Washington University Vaccine Research Unit in partnership with Scripps Research, IAVI, Fred Hutchinson Cancer Center (FHCC) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases Vaccine Research Center published the results of their Phase 1 Clinical Trial in Science. The results show critical new insights into their novel vaccine strategy, which involves a stepwise approach to producing antibodies capable of targeting a wide range of HIV variants.

The trial, known as IAVI G001, tested the first stage in a multi-stage HIV vaccine regimen the researchers are developing. The trial results show that the vaccine had a favorable safety profile and induced the targeted response in 97% of people who were vaccinated. Importantly, the study also provides a detailed immunological analysis of the vaccine responses.

HIV has continued to be a difficult virus to create a vaccine for given its ability to mutate and quickly evade the immune system. The findings from this trial bring new hope to stopping HIV and may help find vaccines for other difficult infectious diseases as well.”

David Diemert, Professor of Medicine, GWU School of Medicine and Health Sciences

The novel vaccine strategy that was tested in this trial is focused on producing broadly neutralizing antibodies (“bnAbs”), which are a rare type of antibody that can fight and protect against many different variants of a virus, including HIV.

The researchers in the study are using a procedure known as ‘germline targeting’ to eventually produce bnAbs that can protect against HIV. The first step of germline targeting involves stimulating the rare immune cells-;known as bnAb-precursor B cells-;that can evolve into the cells that produce the bnAbs needed to block the virus. To accomplish this, the researchers designed a customized molecule-;known as an immunogen-;that would “prime” the immune system and elicit responses from these rare bnAb-precursor cells.

For this clinical trial, a novel method of sampling lymph nodes was developed by the clinical and biorepository teams at GW, FHCC and IAVI, which included ultrasound-guided fine needle aspiration of lymph nodes near the injection site. “This is the first time such a technique has been used routinely in a vaccine clinical trial,” Jeffrey Bethony, professor of microbiology, immunology and tropical medicine at GW SMHS said. “It enabled us to acquire a cell population critical to germline stimulation that do not circulate but remains sequestered in lymph node tissue.”

The GW VRU has partnered with IAVI on two other HIV vaccine-related Phase I clinical trials over the past five years, serving as a lead site, central biorepository and support unit. In addition, the unit has conducted a number of other clinical vaccine trials to date, including a Phase III trial to test the now FDA-authorized COVID-19 vaccine from biotechnology company Moderna; a Phase II clinical trial for a COVID-19 vaccine booster from the biopharmaceutical company Sanofi; and a Phase I trial of a vaccine to prevent Lassa fever, an acute, animal-borne viral disease endemic to parts of West Africa.

Source:

George Washington University

Microbiology

Miracles Start in the Lab: the quest to find a vaccine to cure AIDS

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Danielle Ellis, B.Sc.Interview conducted by Danielle Ellis, B.Sc.Nov 30 2022
Thought LeadersDr. Larry CoreyProfessor and President and Director EmeritusFred Hutch Cancer Center

To commemorate World AIDS Day, News Medical spoke to Dr. Larry Corey, an internationally renowned expert in virology, immunology, and vaccine development, and the former president and director of Fred Hutch, about his work within the field of HIV/AIDS research and vaccine development. 

Please can you introduce yourself and tell us about your background in virology, immunology, and vaccine development?  

I’m Dr. Larry Corey. I am a Professor at the University of Washington and Fred Hutchinson Cancer Center. I am a virologist by training. I have worked in the field of HIV since the inception of the recognition of the virus. Initially, I was the leader of the US government’s AIDS Clinical Trials Group, which was devoted to antiviral chemotherapy. I was lucky early in my career to be involved in developing the first effective antiviral drug called Acyclovir, which was for herpes virus infections, especially genital herpes.

I switched my interests in the late 1990s from therapy to try and develop an HIV vaccine and founded the HIV Vaccine Trials Network with my friend and colleague Tony Fauci. We’ve worked together to develop an HIV vaccine and set up a network within the US of investigators to tackle the immunology of HIV, which has been very formidable. The network has been where probably 80 or 90% of the HIV vaccine clinical trials have been conducted worldwide over the last 20 years.

How have you seen the field of HIV/AIDS research change in this time? How have patient outcomes changed?

HIV is still a pandemic illness. We still have 1.4 million new infections each year. We have a growing number of people living with AIDS, and it is still a perfect storm. You acquire it subclinically, transmit it subclinically, and get it from people you don’t suspect have it. We still need better prevention methods.

Antiretrovirals have saved more lives than any other medical procedure or medical group of therapies in the last 50 or 60 years. We went from a disease that killed everybody to now a disease that, if you take the pills, you can live a normal lifespan essentially. That’s an amazing feat that occurred in the decade from the virus’s isolation.

Image Credit: PENpics Studio/Shutterstock.com

Image Credit: PENpics Studio/Shutterstock.com

HIV research has markedly changed and become markedly more sophisticated. We’re cloning B-cells in the germ lines. We’re doing things you couldn’t conceive 40 years ago. Certainly, a vaccine will be needed to end AIDS and have my granddaughters grow up like I grew up, not worrying about AIDS.

Patient outcomes for treatment have markedly changed. You can live normal lives. But we haven’t made as many inroads in prevention. The reason is that we don’t have a vaccine. When you look at how to prevent disease acquisition on a population basis, it’s only been with a vaccine. So, as hard as it is, the vaccine effort must continue.

In your lab, you study genetically modified T cells to treat HIV-1. How have recent advancements in cancer treatment influenced the treating HIV/AIDS? How can immunological approaches treat chronic viral infections?

In oncology, using the cell as an anti-tumor drug in CAR T-cell therapy is the biggest advance. The lab is trying to take those approaches used in cancer and employ them against HIV through these adopted transfer experiments. We think we’ve had some successes, so that’s our area of interest at the moment.

You are also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network. How has the COVID-19 pandemic impacted HIV/AIDS research?

People working in HIV and the infrastructure from HIV helped the effort against COVID-19. RNA, used in the COVID-19 mRNA vaccines, can allow experiments to be conducted more quickly because it’s synthetic, and you can make a vaccine and get it into humans by doing an early clinical trial. From the idea to putting a jab in your arm, that’s still not happening as quickly with HIV as it did for COVID-19. Still, it is quicker, and we’re optimistic that this RNA technology will help us develop an HIV vaccine quicker.

The HVTN’s goal is to develop a safe, effective vaccine to prevent HIV globally. How close are we to actualizing this goal? From a global perspective, what would it mean to have an effective vaccine?

We make these vaccines that elicit broadly neutralizing antibodies. If we do, we’ll get there because we’ve already proven that broadly neutralizing antibodies can prevent HIV acquisition. Now the issue is how do we get to that target now that we know what the target is? You need to be optimistic. Miracles start in the lab.

The theme of this year’s World AIDS Day is “Equalize.” What does this theme mean to you personally? What needs to be done to address inequalities and help end AIDS?

Everybody wants to be healthy. I think equalize is a great word for World AIDS Day. I think HIV has always been a disease of the underdog.

Image Credit: fizkes/Shutterstock.com

Image Credit: fizkes/Shutterstock.com

But words have meaning and should be actionable. I think the word equalize is just another call to how we actualize the tools and maximize the use of the tools we have. COVID-19 has taught us that even if research invents a remarkably good vaccine, the process of implementing this on a population basis is complicated and needs to be equalized between the haves and the have-nots. The sociology and economics of health need to be equalized globally.

What is next for yourself and your research?

I’ve got my hands full trying to make an HIV vaccine.

Where can readers find more information?

About Dr. Larry Corey

Dr. Larry Corey is an internationally renowned expert in virology, immunology and vaccine development, and the former president and director of the Fred Hutchinson Cancer Research Center. His research focuses on herpes viruses, HIV, the novel coronavirus and other viral infections, including those associated with cancer. He is principal investigator of the HIV Vaccine Trials Network (HVTN), which conducts studies of HIV vaccines at over 80 clinical trials sites in 16 countries on five continents. Under his leadership, the HVTN has become the model for global, collaborative research. Dr. Corey is also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network (CoVPN) and co-leads the Network’s COVID-19 vaccine testing pipeline. The CoVPN is carrying out the large Operation Warp Speed portfolio of COVID-19 vaccines and monoclonal antibodies intended to protect people from COVID-19. 

Dr. Corey is a member of the US National Academy of Medicine and the American Academy of Arts and Sciences, and was the recipient of the Parran Award for his work in HSV-2, the American Society of Microbiology Cubist Award for his work on antivirals, and the University of Michigan Medical School Distinguished Alumnus Award. He is one of the most highly cited biomedical researchers in the last 20 years and is the author, coauthor or editor of over 1000 scientific publications. 

Microbiology

Duke receives federal funding for HIV vaccine research

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Reviewed by Emily Henderson, B.Sc.Oct 11 2022

The Duke Human Vaccine Institute (DHVI) and the Department of Surgery at Duke University School of Medicine received a grant from the National Institute of Allergy and Infectious Diseases for HIV vaccine research that could total $25.9 million with full funding over five years.

The funding supports a multi-institutional effort called The Consortium for Innovative HIV/AIDS Vaccine and Cure Research that is built around two areas of scientific focus: identification of the components and the mechanisms of protection of preventive vaccines; and the use of the newly identified preventive vaccines along with other immune therapies in advancing potential treatments and/or cures.

The grant’s principal investigators are Guido Ferrari, M.D., a professor in the Department of Surgery and research professor in the Department of Genetics and Microbiology, and Wilton Williams, Ph.D., an associate professor in the departments of Surgery and Medicine, and assistant professor in the Department of Immunology at Duke University School of Medicine.

The researchers will lead work that builds upon ongoing HIV vaccine development research at DHVI and expands investigations of vaccine strategies, including innovative mRNA approaches that induce protective immune responses in non-human primate models.

This grant is synergistic with everything going on at Duke, notably the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) initiative to design an HIV vaccine. We are excited about the wonderful science that will be done in the context of this grant. It expands the capacity at Duke, UNC and others who are collaborating on this effort to move forward with both vaccines and potential cures.”

Barton Haynes, Director of the DHVI

Combining vaccine approaches with cure efforts is designed to stimulate innovative collaborations toward both. Studies in nonhuman primates will investigate how effective HIV/AIDS vaccines protect from initial infection and systemic infection.

Vaccines and other immune interventions will also be used as cure strategies with the goal of eliminating all the infection in the cells. While advances have been made in boosting cellular and antibody immunity, it remains unclear whether the boosted immune response can prevent reinfection after antiretroviral treatments are stopped. With the newly funded grant, the researchers hope to answer that and other questions.

“This grant enables us to do something current vaccine research is not funded to do – explore vaccines with a mission to cure,” Williams said. “Right now, it’s either prevention or cure, and we want to achieve a combination of those things.”

Ferrari said vaccine research has advanced far enough that researchers can now begin applying potential components of vaccines, as well as new technologies such as mRNA vaccine design, to explore ways of eradicating the HIV from infected cells.

“The beauty of mRNA is its ability to be adapted quickly and we can produce it in a timely manner to address new variants, which is important for HIV,” Ferrari said. “We will now focus on how we can capitalize on the current science to eradicate infection.”

“The science underpinning this program has broad applicability, spanning from the immediate goals of eliminating HIV disease, to a more generalizable harnessing of the immune system to prevent emerging infectious diseases, control cancer, and accelerate our understanding of autoimmunity and transplant biology,” said Allan D. Kirk, M.D., Ph.D., chair of the Department of Surgery.

“Our department sees the promise of basic investments like these for transformational approaches to care that do not traditionally fall within a surgical department,” Kirk said. “Drs. Williams and Ferrari are vital members of our translational science community.”

In addition to Williams and Ferrari, collaborators at Duke are Priyamvada Acharya, Mihai Azoitei, Derek Cain, Thomas Denny, Robert J. Edwards, Barton Haynes, David Montefiori, Justin Pollara, Keith Reeves, Wes Rountree, Kevin Saunders, Shaunna Shen, Rachel Spreng, Georgia Tomaras, Kevin Wiehe, Kelly Cuttle and Cynthia Nagle.

Study partners include Katharine Barr, Michael Betts, Beatrice Hahn, George Shaw, Drew Weissman at the University of Pennsylvania; Richard Dunham and David Margolis at the University of North Carolina at Chapel Hill; Sampa Santra at Harvard University; Andrew McMichael, Persephone Borrow and Geraldine Gillespie at Oxford University; Bette Korber and Kshitij Wagh at Los Alamos National Laboratory; and Mark Lewis at BIOQUAL.

Source:

Duke University School of Medicine