Some Covid patients developing sudden onset diabetes

 Among all the manifestations and complications of COVID-19, yet another puzzling question is emerging — is the virus triggering cases of diabetes?

Like many doctors around the world, Dr. Mihail Zilbermint began noticing something strange midway in the pandemic.

More and more people seemed to be suddenly developing diabetes.

“My team usually manage about 16 to 17, or 18 patients with diabetes per day,” Zilbermint told CTV News. “And our numbers increased up to 30 per day.”

Zilbermint is an endocrinologist and an associate professor with John Hopkins School of Medicine in Maryland. The sudden change was surprising, he said, and worrying.

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A diagnosis of diabetes was also a shock to John Kunkel, who lives in Arkansas, and had just recovered from a serious case of COVID-19 when he discovered his pancreas had stopped making enough insulin, forcing him into daily blood sugar testing, and metformin to manage his diabetes.

Kunkel tested positive for COVID-19 at the end of June 2020.

He texted his doctor immediately after realizing that he had lost his sense of taste. By the time he arrived at the doctor’s office, he already had a fever of 101 degrees.

“By 7:30 that night I was in the emergency room with 103.5 fever,” he said. “So I went from really losing my taste at 11 o'clock, being in the hospital at night with a very high fever.”

His fever was worryingly high for almost two weeks straight. He was in the emergency room five times.

In July, things took a turn for the worse during his recovery.

“I'll never forget the day,” he said. “It was July 30 when I had bloodwork done.”

When his results came back, it was clear there was a problem with his blood sugar.

“So it's like, “hey, you've got diabetes, we've got to start treating it immediately,” because it was so high,” Kunkel said.

“A lot of it was, you know — why? I didn't have it before. And it was the big question that all the doctors would give is, they really don't know.”

Doctors around the world are now sharing similar case reports of sudden onset diabetes after COVID-19 infection, finding that the link is strongest among patients who were hospitalized with the virus.

“We clearly see people without previous diabetes developing diabetes,” Dr. Remi Rabasa-Lhoret, with the Montreal Clinical Research Institute, told CTV News. “It is highly probable that COVID-19 is triggering the disease.”

Studies suggest that up to 14 per cent of COVID-19 patients may develop sudden onset diabetes.

“We've seen this with influenza and other infections […] but the magnitude of what we see with COVID-19 is above what we're used to,” Rabasa-Lhoret said.

People with diabetes are already more at risk of experiencing severe outcomes if they contract COVID-19, and now the virus may be putting people more at risk of developing diabetes — a connection that an article in the New England Journal of Medicine described as “a bidirectional relationship.”

So why is this happening? Doctors and researchers are investigating, but a specific reason hasn’t been pinpointed yet.

Among the theories is that this could be a side effect of a steroid used to treat COVID-19.

Zilbermint said that patients who experience complications due to COVID-19 frequently receive a steroid medication called Dexamethasone.

“[It’s] our standard therapy for those who have low oxygen levels, and the side effect of this medication is high sugar levels, or diabetes,” he said. “So it's possible that the medications they use to treat COVID may also contribute to increased risk of developing diabetes.”

Kunkel said he was on a round of steroids for an entire month, and now he’s unsure if this contributed to his diagnosis.

“I had three rounds, so that could have elevated and caused it,” he said.” So there's all of these really unknowns.”

There are also signs that the novel coronavirus itself could affect the body in ways that would cause them to develop diabetes.

“There are some suggestions that COVID-19 could go directly in the cells which produce insulin, in the pancreas, and damage them,” Rabasa-Lhoret said.

Zilbermint added that the virus may be able to change the way that cells metabolize glucose itself.

Acute onset of diabetes was also reported more among patients with SARS a decade ago, he said, “compared to those without the SARS pneumonia, […] which I think is important to mention.”

Another thought is that perhaps it’s that the infection tips people who are at risk of developing diabetes into a diagnosis sooner.

“It's possible that [a] patient lives with pre-diabetes for many years and didn't know that,” Zilbermint said. “Now they have COVID-19 infection, and the infection is pushing them towards developing diabetes.”

That’s something Kunkel has considered.

“It could be that, OK, I was on the verge of getting diabetes, and COVID-19 actually pushed it over the edge,” he said.

Some doctors wonder if it’s a new form of diabetes altogether.

In Type 1 diabetes, patients’ immune system destroys beta cells that produce insulin.

However, COVID-19 patients who develop diabetes can also exhibit insulin resistance which is found in Type 2 diabetes. (Insulin resistance is when cells are “resistant” to the hormone insulin, and as a result can’t use glucose. The pancreas produces more insulin and blood sugar spikes.)

Some doctors believe the sudden-onset diabetes after a COVID-19 infection may be a novel condition which features both Type 1 and Type 2 diabetes.

“The main question is, is this going to be transient, or is this going to be permanent?” Rabasa-Lhoret said. “And on the short term, we don't know.”

It’s the questions that haunt patients like Kunkel, as well as the doctors who treat these patients.

But work is being done to figure out what is going on, and how best to treat patients.

“A number of endocrinology specialists and diabetes experts around the world are looking into this,” Zilbermint said.

“For example, my colleagues at the King's College in London and U.K. already established a robust database where all the researchers, clinicians, doctors can submit the information about their patients into a global registry.

This new global database will try to collect all the cases in a bid to understand whether the coronavirus infection truly has yet another nasty side effect.

“I'm sure we'll see more research studies coming out of this registry in the coming months,” Zilbermint said.  

https://www.ctvnews.ca/health/coronavirus/a-new-covid-19-side-effect-some-patients-are-developing-sudden-onset-diabetes-1.5346561

Immune cell implicated in development of lung disease following viral infection

 Scientists at Washington University School of Medicine in St. Louis have implicated a type of immune cell in the development of chronic lung disease that sometimes is triggered following a respiratory viral infection. The evidence suggests that activation of this immune cell -- a type of guardian cell called a dendritic cell -- serves as an early switch that, when activated, sets in motion a chain of events that drives progressive lung diseases, including asthma and chronic obstructive pulmonary disease (COPD).

The new study, published in The Journal of Immunology, opens the door to potential preventive or therapeutic strategies for chronic lung disease. More immediately, measuring the levels of these dendritic cells in clinical samples from patients hospitalized with a viral infection, such as influenza or COVID-19, could help doctors identify which patients are at high risk of respiratory failure and death.

Studying mice with a respiratory viral infection that makes the animals prone to developing chronic lung disease, the researchers showed that these dendritic cells communicate with the lining of the airway in ways that cause the airway-lining cells to ramp up their growth and inflammatory signals. The inflammation causes airway-lining cells to grow beyond their normal boundaries and turn into cells that overproduce mucus and cause inflammation, which in turn causes cough and difficulty breathing.

"We're trying to understand how a viral infection that seems to be cleared by the body can nevertheless trigger chronic, progressive lung disease," said senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine. "Not everyone experiences this progression. We believe there's some switch that gets flipped, triggering the bad response. We're identifying that switch and ways to control it. This work tells us that this type of dendritic cell is sitting right at that switch point."

Holtzman's past work had implicated the lining of the airway -- where the viral infection takes hold -- as the likely trigger for this process.

"But this study suggests that the cascade starts even further upstream," said Holtzman, also director of the Division of Pulmonary and Critical Care Medicine. "Dendritic cells are telling the cells lining the airway what to do. There's more work to be done, but this data tells us that the dendritic cells play an important role in getting the airway-lining cells onto the wrong path."

Holtzman calls this dendritic cell a type of sentinel because its job is to detect an invading virus and trigger the body's initial immune response against the infection. The problem comes when the cell doesn't shut down properly after the threat has passed.

"Many people never develop chronic lung disease after a viral infection," Holtzman said. "But others have a genetic susceptibility to this type of disease. People who are susceptible to virus-triggered disease include patients with asthma, COPD, and viral infections such as COVID-19. It's really critical to look for ways to fix this disease response and prevent the problems that might occur after the virus has gone."

In the meantime, Holtzman said, high levels of these dendritic cells and their products in the lungs of hospitalized patients could serve as a warning to doctors that such patients are likely to develop severe disease and should be provided with respiratory interventions and other supportive therapies that are precisely tailored to their disease process.

"Similarly, if this process is not underway, the patient might be more likely to avoid these types of long-term problems," Holtzman said. "We're pursuing this line of research to help improve prediction of severe lung disease after infection and to provide companion therapies that could prevent this switch from being flipped or flip it back to reverse the disease."

This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID), grant number R01 AI130591 and the National Heart, Lung, and Blood Institute (NHLBI), grant number R35 HL145242, both of the National Institutes of Health (NIH); the Cystic Fibrosis Foundation; and the Hardy Trust and Schaeffer Funds.

Journal Reference:

1. Xinyu Wang, Kangyun Wu, Shamus P. Keeler, Dailing Mao, Eugene V. Agapov, Yong Zhang, Michael J. Holtzman. TLR3-Activated Monocyte-Derived Dendritic Cells Trigger Progression from Acute Viral Infection to Chronic Disease in the Lung. The Journal of Immunology, 2021; 206 (6): 1297 DOI: 10.4049/jimmunol.2000965

https://www.sciencedaily.com/releases/2021/03/210309153825.htm

China Eases Visa Rules for Foreigners Who Get Chinese Vaccines

 The China-made vaccine is becoming the ticket to enter the mainland.

China said it will ease visa application requirements for foreigners seeking to enter the mainland from Hong Kong if they have been inoculated with Covid-19 vaccines made in China.

The new rule will take effect on Monday to resume “people-to-people exchanges between China and other countries in an orderly manner,” according to a government announcement Friday.

Foreigners visiting the mainland for work will face less paperwork in visa applications if they are able to show they have received vaccines produced in China. With the vaccine certificates, these travelers will also be able to skip the requirement for a Covid-19 test or fill out a travel declaration form.

The rule also expands the scope of applicants eligible for a visa due to humanitarian needs, such as taking care of family or attending funerals, if they have received Chinese vaccines. Other applicants should still follow the earlier visa procedure, according to the statement.

The change comes as China has been promoting its home-grown shots globally amid competition from western vaccines. It recently entered a deal with the International Olympic Committee to provide shots made in China for athletes attending the Tokyo Olympics in July and Winter Olympics in Beijing next year.

Most countries in the West have not yet approved vaccines developed by Chinese pharmaceutic companies, which have been reticent in sharing details of their vaccine trials crucial for building public trust around the world. China is having more success introducing its vaccines in Africa and Latin America, where countries including Zimbabwe and Equatorial Guinea have received vaccine aid from Beijing.

https://www.bloomberg.com/news/articles/2021-03-13/china-eases-visa-rules-for-foreigners-who-get-chinese-vaccines

Pneumococcal Vaccination May Decrease COVID-19 Cases

 The Journal of Infectious Diseases recently published a study focused on whether there are interactions that occur between the SARS-CoV-2 coronavirus and Streptococcus pneumoniae.

This research published on March 9, 2021, found after adjusting for risk factors and other exposures, seniors (65+ years) who had received a 13-valent pneumococcal conjugate vaccine (PCV13) experienced a lower incidence of COVID-19 diagnosis, hospitalization, and death.

Based on data from the Kaiser Permanente Southern California healthcare system during the second quarter of 2020, the vast majority (83.4%) of the study participants have received a PCV13 vaccination.

Among the 531,033 seniors who had received the PCV13 vaccine, there were 3,677 COVID-19 cases in the study cohort that led to 1,075 hospitalizations (0.2%) and 334 related fatalities (0.06%).

However, this study found no relationship between COVID-19 risk and receipt of the 23-valent pneumococcal polysaccharide vaccine. The 23-valent pneumococcal polysaccharide vaccine, also recommended for seniors to prevent pneumococcal disease, has not been found to confer strong protection against mucosal endpoints as pneumococcal carriage and non-bacteremic pneumonia, said these researchers.

In summary, these researchers stated 'the reduced risk of COVID-19 among PCV13 recipients, transiently attenuated by antibiotic exposure, suggests pneumococci may interact with SARS-CoV-2.'

Recently, a study published by Mayo Clinic researchers also reported a strong association between pneumococcal vaccination and protection against COVID-19. 

Published in the journal Nature on February 26, 2021, this exploratory study analyzed immunization records from 137,037 individuals who received SARS-CoV-2 PCR tests. 

This study found that polio, Haemophilus influenzae type-B, measles-mumps-rubella, Varicella, PCV13, geriatric Flu vaccine, and hepatitis A/hepatitis B vaccines administered in the past 1, 2, and five years were associated with decreased SARS-CoV-2 infection rates.

Furthermore, age, race/ethnicity, and blood group stratified analyses reveal significantly lower SARS-CoV-2 infection rate among black individuals who have taken the PCV13 vaccine, with a relative risk of 0.45 at the five year time horizon (n: 653, 95% CI (0.32, 0.64), p-value: 6.9e−05).

‘There are prior studies highlighting mechanisms of activation of broad immune signaling pathways by vaccines, which might also be providing protection against SARS-CoV-2. This nonspecific innate response conferring protection to other infections is termed as ‘trained immunity,’ concluded this study.

The Mayo Clinic trained immunity finding may help explain why children are seldom admitted to hospitals for COVID-19.

According to the U.S. Centers for Disease Control and Prevention (CDC), the childhood vaccination rate against pneumococci, which protects against Streptococcus pneumoniae bacteria, ranges between 74% to 92%.

Although the CDC recommends that all adults 18-64 in high-risk groups for COVID-19 and all adults over the age of 65 get a pneumococcal vaccination, about 23% of high-risk adults and 64% of those over the age of 65 have been vaccinated.

In contrast to these studies, as of February 12, 2021, Harvard University’s website’s vaccine information, says ‘vaccines against pneumonia, such as pneumococcal vaccine and Hemophilus influenza type B vaccine, only help protect people from these specific bacterial infections. They do not protect against any coronavirus pneumonia, including pneumonia that may be part of COVID-19.’

Overall, the CDC recommends pneumococcal vaccination for adults 65 years or older. These seniors should receive one dose of PPSV23.

Also, the CDC says clinicians should consider PCV13 vaccinations for seniors who do not have an immunocompromising condition, cochlear implant, cerebrospinal fluid leak, and who have never received PCV13 before.

Viruses, bacteria, and fungi can all cause pneumonia, which is an infection of the lungs that can cause mild to severe illness in people of all ages. Common signs of pneumonia can include cough, fever, and trouble breathing says the CDC.

In the USA, common causes of viral pneumonia are influenza, respiratory syncytial virus, and SARS-CoV-2, the virus that causes COVID-19. 

A common cause of bacterial pneumonia is Streptococcus pneumoniae (pneumococcus). However, clinicians are not always able to find out which germ caused someone to get sick with pneumonia, concludes the CDC.

The Kaiser study was funded by Pfizer, Inc., a producer of PVC13, PPSV23, and COVID-19 vaccines. Study correspondence to Joseph Lewnard, 2121 Berkeley Way, Berkeley, California 94720, United States, jlewnard@berkeley.edu. 

https://www.precisionvaccinations.com/pneumococcal-vaccination-may-decrease-covid-19-cases

State, local governments delay access to public records during pandemic

 As states prepared to reopen their economies following coronavirus shutdowns last spring, The Associated Press asked governors across the U.S. for records that could shed light on how businesses and health officials influenced their decisions.

Nine months later, after several more COVID-19 surges and shutdowns, the AP still has not received records from about 20 states. Some outright denied the requests or sought payments the AP declined to make. Others have not responded, or said they still need more time.

Public records have become harder to get since the world was upended by the pandemic a year ago. Governors, legislatures and local officials have suspended or ignored laws setting deadlines to respond to records requests. They cited obstacles for staffers who are working at home or are overwhelmed with crisis management.

The result is that information that once took a few days or weeks to obtain now often takes months — depriving the public of timely facts about decisions their leaders are making.

“The pandemic rages on, but investigative journalism doesn’t halt. The public’s right to know doesn’t cease to exist,” said Gunita Singh, a legal fellow at the Reporters Committee for Freedom of the Press, which has tracked nationwide delays in responding to public records requests.

“Having these unnecessary measures in place that hinder open government sets a terrible precedent,” Singh said.

U.S. states and local governments are far from alone in their deferrals and delays. Dozens of countries suspended or altered their right-to-information policies last year while citing the pandemic, according to a joint tracking effort by the Centre for Law and Democracy and Access Info Europe.

Open-government advocates have started to worry about potential long-lasting effects.

The pandemic could “give cover for emergency measures to come into force that could then over time become permanent,” said Joe Powell, deputy CEO of the Open Government Partnership, a Washington, D.C.-based nonprofit that works with governments in 78 countries, including the U.S., to promote transparency and public participation.

Even before the pandemic, some government agencies routinely blew past their own deadlines for responding to public records requests. But the number of such cases has grown over the past year, according to AP interviews with government watchdog groups.

New data indicates there has been both a higher demand for government information during the pandemic and longer waits to obtain it.

State, county and city governments experienced a sixfold increase in their time spent on public records requests last year, rising from an average of 346 hours in the first quarter to 2,121 hours by the last quarter, according to an analysis by GovQA, a company that provides cloud-based software to manage public records requests.

That surge was driven by both the volume and complexity of requests. After shutdowns led to a dip in records requests accepted by government agencies from April to June, the number of such requests shot up by 23% over the rest of the year, according to the GovQA data.

Processing delays were exacerbated by remote work, outdated public-records laws, underfunded budgets and increased oversight from top administrators wanting to review potentially sensitive data before it was released, said GovQA spokesperson Jen Snyder.

The AP last May sought copies of communications about the coronavirus between governors’ offices, state health directors and groups representing businesses, health care providers and local governments. By August, the AP had received records from about one-third of the states, revealing that some governors had allowed businesses to help write the reopening rules affecting their own industries.

The AP still has requests pending in Hawaii, Idaho, Iowa, Kansas, Maine, New York and Texas. Illinois this past week finally provided 74 pages of documents, heavily redacted.

After months of repeated AP inquiries, Ohio Gov. Mike DeWine’s office on March 3 released just two documents from last spring — one from a hospital association proposing criteria for resuming elective procedures, the other from a mayor’s group about guidelines for opening swimming pools and camps. A spokesperson for the Republican governor apologized for the delay, citing “human error” for a breakdown of staff communication.

Delaware Gov. John Carney was one of several chief executives who initially suspended the state’s response deadline for public records requests during the coronavirus emergency. With no end to the pandemic in sight, the Democratic governor reversed course and lifted the suspension in September.

But Carney’s administration did not fulfill the AP’s request until Feb. 10, when it provided 109 pages of documents and a note that more could come later. Though most were merely press clippings, the records included emails from representatives of car dealers, home builders and other industries seeking to keep operating during a shutdown.

More than a half-dozen states — Connecticut, Hawaii, Indiana, Mississippi, New Hampshire, Rhode Island and Washington — continue to suspend some open-records requirements through gubernatorial orders, according to an AP review of public-records policies.

Hawaii Gov. David Ige, a Democrat, took the most sweeping action when he suspended the state’s entire open-records law in March 2020. Ige eased the suspension under pressure from open-government advocates. But his most recent order, issued in February, still allows deadlines to be suspended if hard copies of documents are inaccessible, staff are backlogged with other requests or a response would pull agency employees away from other COVID-19 work.

Some state legislatures also relaxed response deadlines for records requests during the pandemic.

The Missouri House in February overwhelmingly passed legislation that would suspend response requirements whenever governmental bodies are closed for extended periods. That bill is now in the Senate.

By contrast, Pennsylvania lawmakers pushed for quicker responses. After the state’s open-records office advised that days when public offices are closed don’t count toward response deadlines, the Republican-led Legislature passed a law prohibiting Democratic Gov. Tom Wolf’s administration from ignoring or suspending records requests during disaster emergencies.

Some local governments also have rolled back records law suspensions.

Last April, Virginia’s Albemarle County, which surrounds Charlottesville, extended indefinitely the deadlines to respond to records requests. The county board later softened that stance before finally repealing the extension in November — a move that came shortly after state Attorney General Mark Herring, a Democrat, said state law does not allow local governments to modify such deadlines.

Albemarle County spokesperson Emily Kilroy said the timing of the repeal was merely coincidental.

“The ordinance was not intended to get out of the responsibilities that we have under the Freedom of Information Act,” she said. “It was really in response to the pandemic.”

The Dallas Independent School District suspended all records requests for seven months while its employees were working from home with laptop computers. Staff likely could have processed some requests for electronic records. But because the legal team was unable to access other records stored in offices, it chose not to process any requests “in order for everyone to be on the same playing field,” district spokesperson Robyn Harris said.

When staff returned to in-person work on Oct. 7, the school district had a backlog of 424 records requests, she said.

Among those was a July 7 request from Keri Mitchell, executive director of the Dallas Free Press, seeking information about internet hot spots provided for students’ families during the previous school year. By the time she finally received the information, Mitchell had moved on to other news stories.

“If we can’t get timely responses to open-records requests, we can’t get people actual answers,” she said. “It just creates another barrier to the information people need to literally survive.”

https://apnews.com/article/business-legislature-health-coronavirus-pandemic-laws-9afc47c83c7678cc3dffcebde84fc94a

Retinal Imaging Study Diagnoses in COVID-19

 José M. Ortiz-Egea; Jorge Ruiz-Medrano; José M. Ruiz-Moreno

Abstract

Background: Hyperreflective lesions at the level of ganglion cell (GCL) and inner plexiform retinal layers (IPL) by optical coherence tomography (OCT) and cotton wool spots in the examination of the eye fundus have recently been described as findings in patients with COVID-19 infection.

Case Report: We report the case of a 42-year-old healthy Caucasian male anesthetist who had treated COVID-19 patients during the previous 5 weeks and suddenly presented with a temporal relative scotoma in his left eye. Best-corrected visual acuity was 20/20 for the left eye, and no discromatopsy or afferent pupillary defect was present. Visual field test was performed, with no significant findings associated with the focal loss of sensitivity described by the patient. The anterior segment was unremarkable on slit lamp examination in both eyes. Fundus examination of the left eye showed no significant findings. A placoid, hyperreflective band at the level of the GCL and IPL was visible in OCT which spared the outer retina, at the time of diagnosis and 1 month later. An oropharyngeal swab test was performed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA), immunoglobulin G (IgG) and immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) determination. Real-time reverse-transcriptase polymerase chain reaction (RT-PCR) was negative. ELISA testing and a third rapid antibody detection test performed 7 days after the onset of symptoms were positive.

Conclusions: Ocular signs and symptoms in COVID-19 cases are rarely reported, but may be underestimated, especially those that affect the retina and occur in asymptomatic or paucisymptomatic cases. We present a case of COVID-19 diagnosis based on retinal ophthalmic examination. ...

https://www.medscape.com/viewarticle/945327

Viral Vector Vaccines Don't Alter DNA

 Adenoviral vector vaccines have been in development for decades, but very few have been approved for use in humans. What does the history of adenoviral vector vaccine development tell us about their safety and their potential to alter DNA?

How Do Adenoviral Vector Vaccines Work?

Essentially, these types of vaccines act like delivery shuttles. They use an adenovirus -- which has been engineered to be incapable of replicating and causing disease -- to deliver the genes for making the antigen; in this case, that's the SARS-CoV-2 spike protein. That in turn elicits an immune response and provides protection against the coronavirus.

Adenoviruses are basically common cold viruses that can cause illnesses ranging from cold-like symptoms to bronchitis, gastroenteritis, and conjunctivitis.

"I think people are unfortunately familiar with adenoviruses ... [A]t far too many points, you know, you've had the sniffle. You've had the cough. You felt crummy. If it's a cold it's often adenovirus," Daniel Griffin, MD, PhD, said on a recent episode of MedPage Today's "Track the Vax" podcast. Griffin is chief of infectious disease at ProHEALTH Care, an Optum unit.

Humans are infected with multiple different types of adenoviruses throughout their lifetimes. Most serotypes cause mild illness, although adenovirus serotype 7 has been associated with more severe illness. Older adults and people who are immunocompromised or have pre-existing respiratory or cardiac disease may have worse illness.

Precisely because adenoviruses are so common, one problem with using them in vaccines is that people may already have antibodies to them, overwhelming them before they can do their assigned work. Researchers get around that issue by using adenoviruses that humans are unlikely to have encountered before.

Currently, five adenovirus vector vaccines for COVID-19 are in use worldwide.

Each works on the same basic principle, although delivery platforms differ. The AstraZeneca/Oxford vaccine uses the ChAdOx1 platform, which is based on a modified version of a chimpanzee adenovirus.

The Johnson & Johnson vaccine uses a proprietary AdVac platform, made up of a recombinant human adenovirus (adv26). It's the same platform used in the company's Ebola virus vaccine (which is approved in Europe) and its investigational Zika, RSV, and HIV vaccines.

Russia's Sputnik V uses recombinant human adenoviruses Ad26 and Ad5 for the first and second doses, respectively. Finally, China's CanSino vaccine uses the recombinant human adenovirus Ad5.

Adenoviral Vector Vaccines: 50 Years in Development

Research into adenoviral vector vaccines goes back decades. In the 1990s, scientists started studying adenoviruses for use in gene transfer therapy to treat diseases like cystic fibrosis. In 1993, researchers at the University of Iowa published the first results of cystic fibrosis gene therapy using an adenovirus vector in three patients. The results seemed promising, and suggested that gene transfer using this approach may compensate for the genetic defect in cystic fibrosis. Unfortunately, later studies have failed to confirm these findings, showing only partial, transient correction.

One reason this approach fizzled is that adenoviruses induce strong T and B cell immune responses, quickly causing viral clearance and limiting their purpose in gene therapy. But the very fact that adenoviral vectors induce a robust immune response made them prime candidates for developing vaccines against infectious diseases, according to Lynda Coughlan, PhD, an adenovirus vaccine researcher at the University of Maryland.

Since then, scientists have worked on adenoviral vector vaccines against a range of viruses, including Zika, RSV, HIV, influenza, tuberculosis, dengue, and MERS. During the Ebola outbreaks in West Africa and the Democratic Republic of the Congo, two adenoviral vector vaccines were quickly developed and deployed. Adenoviruses can also be genetically modified to target and kill cancer cells.

Earlier experience with adenovirus vector vaccines proved advantageous when the COVID-19 pandemic struck. Because these types of vaccines had been in development for so long, all scientists had to do was adapt them to COVID-19. For example, the platform used in the AstraZeneca/Oxford vaccine had been in clinical trials in humans for over 10 years for various other diseases. Going forward, that adaptability may also prove useful when updating vaccines to protect against new variants of COVID-19, according to Coughlan.

"What's attractive about adenoviruses is that you can use them almost like a plug-and-play system. The platform doesn't have to be changed but you can switch out the gene of interest for your disease," she told MedPage Today.

Another advantage: earlier work provided data on dosage and safety of adenoviral vector vaccines in humans.

"We already had quite a lot of information about how adenoviral vector vaccines work in other diseases, and roughly what dose we should give humans," said Coughlan. "Safety data from numerous clinical trials in humans showed that they are safe and induce good immune responses."

So far, phase III trials of adenoviral vector COVID-19 vaccines in humans bear this out. Both AstraZeneca/Oxford and Johnson & Johnson have reported that their vaccines were well tolerated with no serious safety concerns. While serious adverse events were similar between vaccine and control arms of the AstraZeneca/Oxford vaccine phase III trial, three cases of transverse myelitis occurred (one in the control group, two in the vaccine group), prompting a study pause. Upon independent review, two cases were thought unrelated to the vaccine while the third was deemed possibly related to the vaccine.

Nonetheless, adenoviral vector vaccines generally have similar side effects as other types of vaccines like flu shots, said Coughlan, such as pain at the injection site, headache, or mild fever.

"Adenovirus vector vaccines have what I would consider to be normal reactogenicity. I don't see anything that would alarm me in terms of causing concern about receiving an adenoviral based vaccine," Coughlan said. "There might be individuals who may have higher grade reactions than others, but that would be the case with any vaccine or any therapy."

Potential to Change DNA?

Adenoviruses deliver DNA that can enter the cell nucleus, which brings up the question of whether they can alter DNA. That's an easy one -- no.

Adenoviruses -- even as they occur in nature -- just do not have the capacity to alter DNA. Unlike retroviruses such as HIV or lentiviruses, wild-type adenoviruses do not carry the enzymatic machinery necessary for integration into the host cell's DNA. That's exactly what makes them good vaccine platforms for infectious diseases, according to Coughlan.

And, engineered adenoviruses used in vaccines have been further crippled by deleting chunks of their genome so that they cannot replicate, further increasing their safety.

"The cell lines that are used for adenovirus vaccines are highly and well characterized cell lines. They are classified by the FDA as nonintegrating, meaning there has never been any evidence in humans and multiple animal models of vector-borne DNA integrating into a host," said Gregory Poland, MD, of the vaccine research group at the Mayo Clinic in Rochester, Minnesota.

Given this history, Coughlan says she has no personal worries about the current crop of vector-based COVID vaccines.

"I would be very happy to get an adenovirus vaccine," she said. "I think they're great vaccines, and I consider them safe. There's nothing I can really tell you that I would be concerned about administering nonreplicating adenoviral vectors in humans."

https://www.medpagetoday.com/special-reports/exclusives/91604