HIV vaccine candidate induces immune response in early clinical trial

 An experimental HIV vaccine has been found to induce broadly neutralizing antibody precursors among a small group of volunteers in a Phase 1 study. The findings suggest that a two-dose regimen of the vaccine, given eight weeks apart, can elicit immune responses against the human immunodeficiency virus.

The clinical trial results, published Thursday on World AIDS Day in the journal Science, establish “clinical proof of concept” in support of developing boosting regimens to induce immune responses against HIV infection, for which there is no cure and which can cause acquired immunodeficiency syndrome, known as AIDS.

The vaccine, called eOD-GT8 60mer, had a “favorable safety profile” and induced broadly neutralizing antibody precursors in 97%, or all but one, of the 36 recipients, according to the researchers from Scripps Research, the Fred Hutchinson Cancer Center, the National Institutes of Health and other institutions in the United States and Sweden.

Antibodies are proteins made by the immune system to help fight infections, and broadly neutralizing antibodies are known to neutralize many genetic variants of HIV, but they have been difficult to elicit by vaccination.

“Learning how to induce broadly neutralizing antibodies against pathogens with high antigenic diversity, such as HIV, influenza, hepatitis C virus, or the family of betacoronaviruses, represents a grand challenge for rational vaccine design,” the researchers wrote. “Germline-targeting vaccine design offers one potential strategy to meet this challenge.”

The eOD-GT8 60mer vaccine candidate is germline-targeting, meaning it was designed to induce the production of broadly neutralizing antibodies by targeting and stimulating the right antibody-producing cells.

Inducing ‘super antibodies’

The International AIDS Vaccine Initiative announced the start of this Phase 1 clinical trial in 2018, to evaluate the safety of eOD-GT8 60mer and the immune responses it is able to induce.

The trial included a total of 48 healthy adults, ages 18 to 50, who were enrolled at two sites: George Washington University in Washington and Fred Hutchinson Cancer Center in Seattle.

Among the participants, 18 received a 20-microgram dose of the vaccine and, eight weeks later, a same-size dose of the vaccine with an adjuvant; 18 received a 100-microgram dose of the vaccine and, eight weeks later, a same-size dose of the vaccine with an adjuvant; and 12 received two doses of a saline placebo, eight weeks apart. The adjuvant is called AS01B, developed by the pharmaceutical company GSK. The vaccines and placebo were given into the arm muscle.

The researchers collected and analyzed immune cells from the blood and lymph nodes of participants during the study. They specifically examined how B cells, a type of white blood cell that makes antibodies in the immune system, responded to the vaccine.

The researchers found no serious adverse events reported among the study participants, and no participants acquired HIV infection during the study. About 97% – or all but one – of the 48 study participants reported local or systemic adverse events that were generally mild or moderate, such as pain at the injection site, malaise and headache. In most cases, these events were resolved within a day or two.

After the first immunization, all vaccine recipients but no placebo recipients were found to produce antibodies elicited by the eOD-GT8 60mer vaccine. Those vaccine-induced responses increased after the second vaccination, the researchers wrote.

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Another Phase 1 study on this vaccine candidate is underway, said Dr. Julie McElrath, senior vice president and director of the vaccine and infectious disease division at Fred Hutchinson Cancer Center, who was an author of the study.

What is unique about this HIV vaccine candidate is that it was engineered to directly target the production of broadly neutralizing antibodies, said Dr. Timothy Schacker, vice dean for research and program director in HIV medicine at the University of Minnesota Medical School, who was not involved in the research.

“In HIV, when we’ve designed and tested vaccines in the past, they didn’t for whatever reason induce these broadly neutralizing antibodies,” he said. “Call them super antibodies, if you want. The broadly neutralizing antibodies work more efficiently. They’re better at controlling things.”

By showing that broadly neutralizing antibodies can be induced by a vaccine, this new study could help inform the development of other types of immunizations, not just HIV vaccines, Schacker said.

“The hope is that if you can induce this kind of immunity in people, you can protect them from some of these viruses that we’ve had a very hard time designing vaccines for that are effective,” he said. “So this is an important step forward.”

Although this is “exciting science,” much more work needs to be done before this vaccine may be considered for use in the public, said Dr. Carlos del Rio, co-director of the Center for AIDS Research at Emory University and executive associate dean for Emory School of Medicine at Grady Health System, who was not involved in the new study.

“We know that broadly neutralizing antibodies are a potentially effective strategy to prevent HIV,” del Rio said. “We’re far from using this as a vaccine, but this is very exciting science. … Investing in this kind of research is critically important in not only developing a vaccine for HIV, but if this strategy works, it can be used for other vaccines.”

A ‘key question’

An HIV vaccine will probably need to elicit these broadly neutralizing antibodies, or bnAbs, “which are able to recognize globally diverse HIV strains and can prevent HIV infection. However, triggering bnAbs by vaccination has proven impossible so far. A key challenge is that bnAbs rarely develop, even during infection,” Penny Moore, of the University of the Witwatersrand and the National Institute for Communicable Diseases in South Africa, wrote in an editorial published alongside the new study.

A “key question” that still needs to be answered is how long the elicited antibodies from the first immunization can last.

Also, if the booster shot is too different from the previous vaccine, “antibodies that have been triggered by the first vaccination may not recognize the booster and will not mature further,” Moore wrote. “However, the incorporation of many different shots into an HIV vaccine regimen is unappealing. Getting the balance right between the need for antibody maturation toward bnAbs and feasibility in the real world will be essential.”

Last year, more than 38 million people were living with HIV or AIDS around the globe. More than 20 HIV vaccine clinical trials are ongoing around the world, according to the International AIDS Vaccine Initiative.

Many people in the United States have turned to daily HIV-prevention pills or frequent injections, known as PrEP, to reduce their risk of infection.

“It’s a daily pill or it’s a painful shot. It’s a shot that is uncomfortable at best that you have to get several times a year,” Schacker said of PrEP.

But having an HIV vaccine available would make protection against the virus more accessible, he said. “If you can give a vaccine, you’re going to reach more people and provide, if you have an effective vaccine, more and better coverage to reduce the probability of transmission if you’re exposed.”

https://www.cnn.com/2022/12/01/health/hiv-vaccine-phase-1-study/index.html

CDC’s remote-work policy 'may hinder efforts for agencywide reform'

 Earlier this year, top leadership at the Centers for Disease Control and Prevention began a monumental task: turning the sprawling, labyrinthine organization known for its highly specialized, academically focused scientific research into a sleek, flexible public health response agency primed to serve the American public. It’s an attempt to keep the CDC from repeating the mistakes it made while responding to covid-19.

But agency veterans, outside public health officials, and workplace organization experts said the current workplace structure could be a major barrier to that goal. Like directors before her, agency head Dr. Rochelle Walensky spends a considerable amount of time away from the CDC’s headquarters in Atlanta. The agency has also embraced a workplace flexibility program that has allowed most of its scientists to stay remote.

As of October, 10,020 of the CDC’s 12,892 full-time employees — 78% of the full-time workforce — were allowed to work remotely all or part of the time, according to data that KHN obtained via a Freedom of Information Act request.

Experts said the lack of face-to-face work will likely be a substantial obstacle to the top leadership’s effort to overhaul the agency after its failures during the pandemic — a botched testing rollout, confusing safety guidance, the slow release of scientific research, and a loss of public trust.

They also wondered whether Walensky, who frequently works remotely while traveling, can bring about that change from afar and whether a virtual workforce might experience more challenges battling infectious diseases than one working together in person.

“One of the things that a really strong new leader would do is they’d be visible, they’d be walking the halls, they’d have the open door,” said Pamela Hinds, a professor of management science and engineering at Stanford University. “That’s much harder to accomplish when nobody’s there.”

Key to the effort to reform the CDC is changing its institutional culture, which the agency says is at the core of all its work — from how it interacts with other agencies to how it shares its research. Walensky has said the CDC needs to be faster and nimbler in the face of emergencies and more communicative, both internally and with the public.

A flexible, responsive, and collaborative culture thrived not too long ago — during the Obama administration, when the agency handled crises such as the H1N1 flu pandemic and the Zika virus outbreak, said Dr. Stephen Cochi, who worked at the CDC for four decades before retiring this year. “I would like to see every effort made to try to restore that culture to the extent possible, because CDC will potentially lose some of its excellence if it can’t,” he said.

Changes, such as the transition to a largely remote workforce and a ballooning bureaucracy, he said, made it “almost impossible to get anything done” in his later years at the agency.

Chris Collins, a professor at Cornell University’s School of Industrial and Labor Relations, said that institutional culture includes “the unwritten rules of how work gets done” and that those are hard to learn in a remote work environment.

A largely remote workplace, Collins said, can lead to weaker social connections among staffers, which can ultimately result in less understanding of and investment in the institution’s values. A loss of personal interaction can also suppress innovation. “If you believe great new ideas come from people bumping ideas up against each other, you want to try and create an environment where that happens as often as possible,” he said.

A document that outlines the CDC’s policy and that was last updated in April says remote work can help recruit and retain staffers, keep workers happy, and reduce the cost of leased office space. It followed updated guidance from the U.S. Office of Personnel Management encouraging agencies across the federal government to consider remote work options for staff, considering their utility during the covid-19 pandemic.

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As of early 2020, much of the workforce of the FDA and the National Institutes of Health was working remotely. Today, the NIH is mostly back in the office, but the FDA said many of its employees continue to work remotely when possible. And while the White House COVID-19 Task Force huddled in the early days of the pandemic and held in-person news conferences, its briefings became largely remote events.

Still, Walensky has recently faced pointed skepticism about the workforce flexibility policy from lawmakers, who questioned her ability to remake the CDC with a dispersed staff.

During a congressional hearing in September, U.S. Sen. Bill Cassidy (R-La.) quoted remarks that a former acting CDC director had made to The New York Times: “‘I don’t know how you motivate and inspire culture change when people aren’t together.’”

“People at the CDC are working well, they’re working hard, and they don’t necessarily need to be on-site in Atlanta,” Walensky responded. “In fact, oftentimes, they’re more productive off-site.”

Walensky added that agency staff deployments are common and that many lab staffers, who can’t work from home, are reporting to CDC offices.

Leading the agency also isn’t a traditional office job.

“The role of CDC director has historically involved a significant amount of official travel around the globe; requiring the director to be mobile and able to work from anywhere,” Jason McDonald, a CDC spokesperson, said in a statement. “Dr. Walensky splits her time between CDC domestic sites around the country, Washington, D.C., state health departments, and internationally where CDC has a presence in 60 countries.”

KHN spoke with multiple CDC employees working remotely. They declined to speak on the record because of concerns about job security.

They said the remote work policy had no impact on their work but acknowledged that reduced opportunities for in-person interaction could make some CDC staff members feel less connected to their managers and peers — and to the agency’s mission.

That lack of personal connection can lead to a lack of trust, which can keep important conversations from happening, said Hinds, the Stanford professor. “We’re much more willing to be open, ask difficult questions, bring up problems when we have actually sat down with somebody face-to-face and gotten to know them a little bit better,” she said.

A remote work environment also makes it harder for an incoming leader who has no experience inside an organization to truly understand its quirks, Hinds said. Walensky was an external hire and worked at Massachusetts General Hospital before her appointment as CDC director. And booking time for a video or phone call with a new boss to help them learn about an institution is “a big hurdle,” Hinds said, compared with bumping into them in the hallway or at the coffee cart.

In her early days working at the CDC, Dr. Anne Schuchat said, she relished informal interactions with co-workers and called such unscheduled time creative and productive. “I think you lose some things when you don’t have the informal mentoring and the visibility, perhaps the greater sensitivity to who’s struggling, who needs help,” Schuchat said.

She spent more than three decades at the agency, including two stints as acting director, before retiring in summer 2021. Her departure came on the heels of that of another high-level CDC official, Dr. Nancy Messonnier.

Schuchat said that working remotely part time was encouraged at the CDC before the pandemic because of a lack of office space. She said she imagined that many staffers were indeed more productive while working remotely, despite the possible costs to the agency’s culture.

Many people have fled the U.S. public health workforce in recent years, burned out from the covid-19 response. Public health experts said that keeping talent requires offering benefits such as remote work — especially when it’s hard to offer competitive salaries — and getting staffers to believe in an agency’s mission.

But, the experts said, in-person interactions can lead to strong allegiances and investment in an organization, which can translate to better retention.

“They generally want to feel like their work is important and that they’re valued,” said Dr. Manisha Juthani, who has led the Connecticut Department of Public Health since July 2021. “And the workplace allows for that a little bit more so than just sitting in front of the computer.”

Walensky has said that transforming the CDC’s culture from one that’s methodical and academic to one that’s focused on quick action won’t be easy. Other experts agree on the need for the pivot.

“They tend to be an agency that studies things and then, in their own sweet time, responds, versus being an emergency response agency,” said Dr. Georges Benjamin, executive director of the American Public Health Association.

Overhauling that culture will be a big challenge, with high stakes, for the agency tasked with protecting the public health of all Americans. Benjamin said the CDC would likely have made its pandemic stumbles even if staffers hadn’t been working remotely. But coming to terms with those mistakes — and rebuilding the agency to keep them from happening in the future — could be easier and more sustainable if more people were working together in person, he said.

“How do you become part of a culture, how do you become part of a holistic organization, if you’re not together?” he said. “While I’m not disturbed that they’re not back, my advice is to get there as quickly as they can.”

https://www.cnn.com/2022/12/02/health/cdc-remote-work-khn-partner

Buzzy Lancet long COVID paper under investigation for ‘data errors’

 An early and influential paper on long COVID that appeared in The Lancet has been flagged with an expression of concern while the journal investigates “data errors” brought to light by a reader. 

An editorial that accompanied the paper when it was published in January of last year described it as “the first large cohort study with 6-months’ follow-up” of people hospitalized with COVID-19. The article has received plenty of attention since then. 

Titled “6-month consequences of COVID-19 in patients discharged from hospital: a cohort study,” the paper has been cited nearly 1,600 times, according to Clarivate’s Web of Science. Altmetric finds references to it in multiple documents from the World Health Organization.  

According to the expression of concern, dated November 24, a reader found inconsistencies between the data in the article and a later paper describing the same cohort of patients after a year of follow-up. That discovery sparked an investigation that is still ongoing: 

On Jan 8, 2021, The Lancet published an Article, 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study, by Chaolin Huang and colleagues.1 On Aug 28, 2021, The Lancet published an Article, 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study, by Lixue Huang and colleagues.2 We received an inquiry from a researcher on data inconsistencies between these two Articles, and we sought an explanation from the corresponding author of the two papers. On Nov 7, 2022, Lancet editors were informed that inconsistencies between the 6-month and the 1-year data were due to “some variables in the dataset used for the 6-month paper were mistakenly disrupted in order”. In view of the extent of these data errors, we now issue an Expression of Concern about the 6-month paper1 while we investigate further, including further statistical and clinical review of the corrected data. We will update this notice as soon as we have further information.

The corresponding author of both papers, Bin Cao of China’s National Center for Respiratory Medicine and the China-Japan Friendship Hospital in Beijing, has not responded to our request for comment. 

A profile of Cao published in Lancet Infectious Diseases last March described him as “a leading researcher in pneumonia and influenza” who “has been instrumental in increasing knowledge about COVID-19.” In addition to the follow-up study of hospitalized COVID patients: 

Cao’s seminal papers during the COVID-19 pandemic include the first report of the clinical characteristics of COVID-19 patients in Wuhan, the description of the risk factors for mortality for adult inpatients, and the results of trials testing the use of antiviral drugs, including lopinavir-ritonavir, to treat COVID-19 in China. 

We reached out to The Lancet’s press office and Richard Horton, the journal’s editor-in-chief, and received this statement: 

The Lancet Group treats all communications between editors and authors or readers as confidential. Investigations are continuing, and the Expression of Concern will be updated as soon as we have further information to share. More information about our policies is available here: https://www.thelancet.com/publishing-excellence

This year, The Lancet overtook the New England Journal of Medicine as the medical journal with the highest impact factor, in large part due to the papers it published about COVID-19. 

We’ve counted retractions for three of those papers, most notably a paper about the use of the drug hydroxychloroquine that claimed to use medical data from a company called Surgisphere. As Retraction Watch readers may remember, the article was retracted after sleuths questioned if the data were real, and the company would not produce it for review.

https://retractionwatch.com/2022/12/01/buzzy-lancet-long-covid-paper-under-investigation-for-data-errors/