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n patients with severe COVID-19 infection, a phenomenon called a cytokine storm is often the underlying reason for complications such as pneumonia and lung failure. Cytokine storms occur when a person’s body releases too many cytokines — a broad group of small proteins integral to the immune system — too quickly. The result is a hyperinflammatory response that may injure tissues in many parts of the body. As reports of the syndrome emerged at the beginning of the pandemic, drugmakers began combing through their drug portfolios, looking for possible treatments.

Physicians are treating hospitalized patients with COVID-19 with dexamethasone, a powerful steroid that quells inflammation, and remdesivir (the Gilead drug sold under the brand name Veklury). However, there’s a need for more effective treatment that could result in fewer patients needing mechanical ventilation and improve outcomes of severe cases of COVID-19. NRx Pharmaceuticals, which is based in Wilmington, Delaware, has an application pending for an EUA of its treatment that targets the cytokine IL-6. In July, the company shared more promising data about the treatment, Zyesami (aviptadil), that suggest it may prevent cytokine storm in patients with COVID-19.

Throughout the phase 2b/3 trial, patients receiving Zyesami did not have a large rise in cytokine level, whereas patients receiving placebo experienced a significant increase. The data showed the treatment yielded a survival benefit for patients, with a sizable drop in 60-day mortality from COVID-19.

Humanigen is a biotech company in Burlingame, California, that is focused on cytokine storm treatment. The company was dealt a setback in September when the FDA rejected its application for an emergency use authorization (EUA) for its leading product, lenzilumab. In a prepared statement, Cameron Durant, M.D., the company’s CEO, said it was committed to the drug. Before the FDA rejection, some analysts were projecting $1 billion in annual sales for lenzilumab.

Humanigen had shared data suggesting that the drug may be especially effective in Black patients, a group with a threefold increased risk of hospitalization and twofold increased risk of death from COVID-19. The company said that results from the phase 3 LIVE-AIR study showed that lenzilumab resulted in a ninefold increase of survival, without the need for ventilation, among Black patients with C-reactive protein levels less than 150 milligrams per/L. C-reactive protein is found in blood plasma and increases in response to inflammation. Across all patients in the study, lenzilumab yielded a more than twofold increased chance of survival without the need for ventilation, which was the basis for the company’s application for an EUA.

Meanwhile, researchers at I-Mab Biopharma, a biotech company based in China, announced positive results for plonmarlimab, which targets the same cytokines as lenzilumab. Results from a phase 2/3 study showed that plonmarlimab reduced the number of patients needing mechanical ventilation compared with placebo and also lowered death rates (4.9% versus 13.3%). 

Jaime Rosenberg is a freelance writer based in Jersey City, New Jersey.

Articles

The FDA rejected Humanigen’s application for an emergency use authorization, but the race is on to develop an effective therapy for the cytokine storms that affect patients with COVID-19.

Drugmakers Look to Quell COVID-19 Cytokine Storms 

When the COVID-19 pandemic hit the United States in 2020, the healthcare community anticipated that people with HIV and other conditions that affected the immune system might be particularly vulnerable to the new respiratory illness.

So far, it looks like their worries were justified when it comes to people with HIV, at least with respect to the risk of experiencing a severe case of COVID-19,

“Although initial case studies and small cohorts found similar rates of infection and severity in PWH (people with HIV), the growing literature in diverse settings throughout the course of the pandemic now suggests that PWH are at greater risk for severe disease, even with well-controlled HIV,” Lauren K. Barbera, of the University of Colorado School of Medicine, and her colleagues said in a review article recently published in 

In one study of over 3 million South African patients included in their analysis, the researchers found that having HIV was associated with a two-fold risk of COVID-19 death, regardless of CD4 count or HIV viral load. Other studies included in the analysis reported similar findings.

The review by Barbera and her colleagues included 212 articles published between March 2020 through July of this year.


The jury is still out, though, on whether people living with HIV are more likely to contract SARS-CoV-2, the virus that cause COVID-19, according to this sweeping review of the HIV-COVID-19 studies. People living with HIV, who account for 0.7% of the world’s adult population, account for approximately 0.5% to 1.5% of COVID-19 cases, they noted.

Here are some other findings about the interplay of HIV and COVID-19 revealed by the review:

The most common symptoms of COVID-19 are fever, shortness of breath and cough. Other symptoms include muscle aches, headaches and loss of smell or taste. The authors said study of 286 people with HIV found the presenting symptoms to the be the same and that other studies corroborated those findings.

The review identified large studies as well as case reports suggest that people with HIV who become ill with COVID-19 are more likely to be admitted to the ICU than those without HIV. The mortality rate is also higher, multiple studies suggest. They cited a study in the United Kingdom that found a higher risk of death from COVID-10 among those with HIV, although the absolute number of deaths was relatively small.

Mental health consequences might be more severe. 

Barbara and her colleagues noted that social distancing and quarantining have left many people feeling isolated and experiencing loneliness.
They said the effects may be “especially impactful” on people with HIV, pointing to results of a study showing that people with HIV have had increased worry about physical health, mental health, finances and accommodations during the pandemic. The researchers note that the uptake of telemedicine has aided in preventing restricted access to care amid the pandemic by offering flexibility and privacy benefits; however, the method of care also comes with barriers for people living with HIV, including low socioeconomic status, reimbursement issues, and digital literacy.

A review of more than 200 studies found no greater risk of contracting COVID-19 among those with HIV but a greater chance of experiencing a severe case.

How Has the COVID-19 Pandemic Affected People With HIV?

Recent years have seen deeper scrutiny and research into gut health and its implications across a variety of diseases, including diabetes and psoriasis. Other research has been focused on how viruses are affected by gut and the

, the trillions of microbes that live symbiotically in the human body, most of them in the gut.

 for the genes of those microbes as opposed to the organisms themselves. More commonly, though, microbiome is used to refer to the organisms themselves.)

, Markus Neurath of the Friedrich-Alexander University Erlangen-Nürnberg in Germany, and his colleagues outlined the latest insights into how the gut microbiome harbors viruses like HIV and COVID-19, and what that means for HIV treatment and repeat COVID-19 infection.

“Recent studies have started to explore the composition and function of the gut virome, which provides a rich reservoir for bacteriophages and viruses,” wrote Neurath and his co-authors. “These studies have highlighted the concept that bacteriophages and viruses play a seminal role in shaping the bacterial microbiome and are important in controlling gut homeostasis.”

The researchers explain that a significant number of HIV-infected cells reside within the gut, even in patients being treated for HIVwith antiretroviral therapy.

Research findings have pointed to the mucosa — the innermost layer of the gastrointestinal tract — as being a reservoir for HIV-infected cells, accounting for an estimated 83% to 95% of all HIV-infected cells in the body. Previous reports have documented significantly higher rates of HIV-infected cells in the mucosa, ranging from five to twelve times as high as levels in the blood.

“The intestine has been identified as a crucial reservoir for HIV-infected immune cells that may reach the bloodstream via immune cell trafficking, thereby potentially impairing the efficacy of ART (antiretroviral therapy) in affected patients,” explained the researchers. “Furthermore, more recent studies of patients with COVID-19 on SARS-CoV-2 infection uncovered a potentially important role of persistent infection of intestinal epithelial cells for prolonged memory immune responses and prevention of reinfection.”

According to the researchers, several studies have indicated that SARS-CoV-2, the virus that causes COVID-19, was persistent in the epithelial cells, which line the surfaces of the body, including in the gut, in about one-third for several weeks or months after they were diagnosed with COVID-19. The findings suggest that the virus antigen remains in the gut even after recovering from COVID-19.

Because intestinal epithelial cells frequently turnover, the persistence of the virus in the gut suggest the virus continues to replicate.

Notably, the researchers underscore that the findings offer insight into a “rapid and effective adaptive immune response” to SARS-CoV-2 if exposed again and how this immune response can offer immunity against COVID-19 reinfection.

In a recent paper, researchers outlined the current understanding  how the gut microbiome includes viruses such as HIV and COVID-19, and what it means for HIV treatment and repeat COVID-19 infection. 

Researchers Outline How Gut Serves as Harbor for HIV, COVID-19

Longer term data from an intervention focused on promoting antiretroviral treatment (ART) and medication for opioid use disorders (MOUD) among people who inject drugs (PWID) living with HIV are highlighting the complexity of targeting vulnerable populations at higher risk of contracting HIV and having uncontrolled infection.

 from the HIV Prevention Trials Network (HPTN) 704 study, which assessed the impact of a flexible integrated intervention among more than 500 PWID living with HIV. In addition to facilitating engagement with and adherence to ART and MOUD, the intervention also included psychosocial counseling and check ins with system navigators.

After a year of follow up, the researchers found that compared with patients receiving standard of care, those receiving the intervention were significantly more likely to report ART use and MOUD. They were also significantly more likely to be virally suppressed, meaning that the amount of HIV in their body was so low that it was undetectable.

However, in their most recent findings, the researchers reported that after another year of the intervention, these improvements started to regress. Among the 111 patients who enrolled in the 1-year extension, viral suppression rates dropped from 41% to 29%. This coincided with declining ART and MOUD use. The researchers suggest that additional support may be needed to ensure continuous and potentially increased use of ART and MOUD and subsequent viral suppression.

“PWID face numerous barriers to HIV care and substance treatment at multiple levels, and barriers may change over time,” they wrote. “Delayed supplemental systems navigation boosters may help address newly developed barriers to HIV care and substance use treatment. Likewise, psychosocial counseling boosters may be warranted to leverage motivational interviewing, problem solving, skills building, and goal setting for maintaining ART and MOUD long-term.”

The researchers note that the anticipated emergence of long-acting injectables may also play a hand in increasing adherence to ART by removing the burden and stigma of daily pills. In January, the FDA approved ViiV Healthcare’s Cabenuva, the first monthly injectable treatment for HIV. Just recently, Gilead 

 for their semiannual treatment lenacapavir in heavily pretreated patients who have stopped responding to other treatments.

While the study highlighted the need for additional supportive interventions to sustain improvements in treatment use and outcomes, it also suggested that the intervention can be reproduced and lead to improved outcomes among PWID based on findings from patients who originally received standard of care but then received the intervention in the extension portion of the study.

There were 94 patients receiving standard of care who enrolled in the extension part of the study and began receiving the intervention. These patients had increases in ART (55% to 69%) and MOUD (16% to 25%) use and rates of viral suppression (40% to 49%).

The researchers suggest that additional support may be needed to ensure continuous and potentially increased use of antiretroviral treatment and medication for opioid use disorders and subsequent viral suppression.

Extended Study Follow-up Highlights Need for Improved Support for Engaging Those Who Inject Drugs Living With HIV in Treatment

As one company announced that its HIV vaccine candidate fell short of its goal in a mid-stage trial, another is set to begin recruiting for the first mRNA trial for 2 experimental vaccines for the virus, a historic mark in the fight against HIV.

 that its experimental HIV vaccine that uses the same technology as its COVID-19 vaccine was not effective at preventing infection in women. The phase 2b Imbokodo study, which included more than 2,000 women in southern Africa, assessed whether the HIV vaccine could reduce the risk of infection by half, finding that the vaccine was able to lower infection rates by 25.2%.

The announcement is the latest blow to the development of a vaccine that can effectively prevent HIV infection, which has evaded researchers since the start of the HIV/AIDS pandemic four decades ago.

However, amid the failure of the Imbokodo trial also comes the anticipation of a new approach to HIV vaccines using mRNA technology, which researchers hope can turn the tide on the promise of a vaccine for these patients.

 for Moderna’s two vaccines, mRNA-1644 and mRNA-1644-v2-Core, which are built on the same mRNA platform used for the company’s COVID-19 vaccine. With mRNA vaccines, the injected RNA carries the code for the antigen, which is produced in abundance and provokes the immune system to produce antibodies. Once primed to recognize the antigen, the immune can more effectively fight off infection when it encounters the virus.


Moderna is aiming to enroll just over 50 patients between the ages of 18 and 50 years in this phase 1 trial. The study is estimated to be completed in the spring of 2023. Sponsors and collaborators of the study also include the International AIDS Vaccine Initiative, The University of Texas at San Antonio, Fred Hutchinson Cancer Research Center, George Washington University, and Emory University.

Moderna’s vaccine approach aims to overcome what has proven to be the biggest barrier to developing an effective HIV vaccine over the course of the pandemic: producing enough neutralizing antibodies — antibodies that defend cells from pathogens such as the HIV virus.

To date, all other HIV vaccine trials, including the Imbokodo trial, have assessed the potential of adenovirus vaccines — vaccines that inject an altered form of a virus to trigger an immune response and produce antibodies against the virus.

Although J&J announced that the Imbokodo study will not continue based on the recently announced results, its second trial called Mosaico will continue. This phase 3 trial is using a similar vaccine but among nearly 4,000 transgender people and men who have sex with men. Both trials use mosaic vaccines, which combines pieces of different strains of the HIV virus. The trial is expected to be completed in 2024.

The least four decades have seen multiple HIV vaccine trials fail to prevent infection across different populations, including the HVTN 702 trial, which was cut short in 2020 after 

 showed the vaccine was not effective across the 5400 participants. Notably, in 2007, Merck’s vaccine candidate was actually shown to increase the risk of participants being infected with HIV.

Glimmers of hope came about in 2009 based on 

 from the Thailand-based RV-144 trial (also known as the phase 3 Thai trial),which looked at how well the experimental vaccine could prevent HIV and reduce the amount of HIV viral load in patients who contracted the virus after enrolling in the trial. More than 10,000 people were enrolled in the study, and results were just shy of being statistically significant, protecting against HIV in 31% of patients over 3.5 years.

Subsequent analyses of the trial have shown that the protective efficacy was actually 60% in the first year, prompting future trials to try and build on the results and create more lasting responses.

Johnson & Johnson’s experimental HIV vaccine, which uses the same technology as its COVID-19 vaccine, was found to not be effective at preventing infection.

One HIV Vaccine Fails While a First-of-its-Kind mRNA Vaccine Trial is Set to Begin

The first trial for an mRNA vaccine against HIV vaccine will soon be underway as Moderna is set to begin recruiting trial of two experimental vaccines.

The vaccines — mRNA-1644 and mRNA-1644-v2-Core— are built on the same mRNA platform used for Moderna’s COVID-19 vaccineas well and Pfizer and BioNTech’s COVID-19 vaccine. With mRNA vaccines, patients are not exposed to the virus. Instead, the vaccines consist of engineered messenger RNA that results in the production of an antigen — in the case of COVID-19, the virus’ spike protein — that provokes an immune response.


Moderna is aiming to enroll just over 50 patients between the ages of 18 and 50 years in its phase 1 trial. In this early stage of development, the company will first test the safety of the vaccines among healthy patients and how their immune systems respond before initiating trials that test the efficacy of the candidates. The trial will split the patients into four group. Some of the study volunteers will receive just one of the vaccines and others, both. 

The study is scheduled to be completed in sometime in the spring of 2023. Sponsors and collaborators of the study also include the International AIDS Vaccine Initiative, The University of Texas at San Antonio, Fred Hutchinson Cancer Research Center, George Washington University, and Emory University.

Researchers are hopeful that this new approach to HIV vaccines, which use mRNA technology, can turn the revive hopes of developing an HIV vaccine. In stark contrast to the speed at which COVID-19 vaccines were developed, researchers have been unsuccessfully in develop an HIV vaccine. The HIV/AIDs pandemic began in the early 1980s.

Moderna’s vaccines aim to overcome what has proven to be the biggest barrier to developing an effective HIV vaccine: producing enough neutralizing antibodies that fend off pathogens like the HIV virus. WHIV directly attacks the immune system which allows the virus to affect the body before the immune system can react and protect itself.

To date, all other HIV vaccine trials have assessed the potential of adenovirus vaccines—vaccines that inject an altered form of a virus to trigger an immune response and produce antibodies against the virus.

One trial of an experimental HIV vaccine to date has shown promise. The trial, 

 (also known as the phase 3 Thai trial), was conducted in Thailand. More than 10,000 people were enrolled in the study, and results were just shy of being statistically significant, protecting against HIV in 31% of patients over 3.5 years.

Moderna's phase 1 trial of mRNA vaccine against HIV is deigned to enroll 40 patients.