With a sniff or a swallow, new vaccines aim to put the brakes on Covid-19 spread

 By Brenda Goodman, CNN

Updated 1426 GMT (2226 HKT) July 22, 2022

https://edition.cnn.com/2022/07/18/health/mucosal-immunity-covid-19/index.html?

(CNN)Injected vaccines against the coronavirus that causes Covid-19 have been hugely successful, saving nearly 20 million lives globally in their first year of use and slashing the pandemic's death toll by an estimated 63%, according to a recent study. Yet good as these shots are, they have not stopped the virus from spreading from person to person.

As the SARS-CoV-2 virus spreads, it changes. That's helped it get past our firewalls, the immunity created by vaccines or left behind after we recover from an infection. Which is why, well into the third year of the pandemic, we're in the midst of another wave of Covid-19 caused by the most immune-evasive variant yet, BA.5. And more variants are coming.

Even as vaccine manufacturers race to update the first-generation shots in the hopes of patching up our protection for the fall, other scientists are taking a different approach, making vaccines delivered via nasal sprays or tablets that would deploy more immune defenders to the body's front lines: the lining of the mouth, nose and throat.

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"The hope is to shore up the defenses right there in the nose so that the virus can't even replicate in the nose," said Dr. Ellen Foxman, an immunobiologist at the Yale School of Medicine. "And then someone who has a really effective mucosal vaccination can't even really support viral replication or make viruses that can infect other people.

"That would be like the holy grail," said Foxman, who helped plan the International Congress of Mucosal Immunology meeting this week in Seattle, which is sponsored by pharmaceutical companies Pfizer, Janssen and Merck.

If it works, there's hope that mucosal immunity could slow the development of new coronavirus variants and finally bring the Covid-19 pandemic under control.

There's a long way to go before that happens, however, and many scientists say the approach needs an injection of funding to accelerate the pace of development, much in the same way the billions of dollars doled out by Operation Warp Speed delivered the first generation of Covid-19 vaccines in record time.

An old approach meets new technology

The idea behind vaccinating the mucosa -- the lining of "the tube" (as mucosal immunologists refer to it) that runs from our nose and mouths to our lungs and guts -- isn't new. There are nine existing vaccines that work this way, including oral drops that protect against polio, cholera, salmonella and rotavirus, and a nasal spray, FluMist, that inoculates against the flu.

The quest for longer-lasting Covid-19 vaccines

Most are based on the oldest types of vaccine technologies, using killed or weakened versions of a virus or bacteria to teach the body how to recognize it and fight it off when a real infection gets underway.

Because of those actual pathogens, some people can't use these kind of vaccines. It's risky to expose certain groups -- including pregnant women and those with weakened immune systems -- to even weakened viruses.

None has achieved the goal of blocking the transmission of an infection, but that may be because they haven't gotten the same kind of investment as injectable vaccines, says Ed Lavelle, an immunologist at Trinity College in Dublin.

"What hasn't really happened with mucosal vaccines is kind of huge advances in technology that have happened with injectable vaccines, even before Covid," Lavelle said.

That may be about to change, however.

Can nasal spray vaccines put the brakes on new variants?

More than a dozen nasal spray vaccines against Covid-19 are being tested around the world. Many use new kinds of technologies, like delivering instructions for making the spike protein of the coronavirus through harmless Trojan horse viruses. Others aim to deploy the mRNA technology that was so successful in the injectable vaccines in the form of a nasal spray.

One company, Vaxart, has even made a tablet that delivers instructions for making parts of the new coronavirus to the gut, which then builds immunity in "the tube."

In animal tests, hamsters vaccinated in the nose or mouth have been less likely to spread a SARS-CoV-2 infection to uninfected animals that are in separate cages but share the same air.

"What we found is that if you did an oral immunization, you inhibited the ability for that breakthrough to infect other animals," said Sean Tucker, chief scientific officer for Vaxart.

The Vaxart tablet, which is about the size and shape of an aspirin, uses an adenovirus -- the same delivery system utilized by the Johnson & Johnson and AstraZeneca Covid vaccines -- to ferry instructions for making parts of the SARS-CoV-2 spike protein into cells in the gut, which stimulates the release of antibodies in the nose and mouth.

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In an early trial that included 35 participants, 46% had an increase of antibodies in their nose after taking the tablet vaccine. Those who did seemed to create a broad spectrum of immunity to a number of types of coronaviruses, and they appeared to hold on to that protection for about a year. That may be a bit longer than injectable vaccines, though more research is needed to confirm those results.

Tucker is presenting these early results Monday at the Seattle conference. He says they'll also be published as a preprint study in the coming days.

A phase 2 trial of a tablet with a slightly different formulation, involving almost 900 participants, is also underway, Tucker says. It is scheduled to be completed next summer.

Most of the mucosal vaccines under development are designed to be delivered as a squirt of liquid or mist up the nose, and many are intended to be used as boosters in people who've had a complete primary series of Covid-19 vaccines.

"I don't think of them as nasal vaccines. I think of them as nasal boosts," said Jennifer Gommerman, an immunologist at the University of Toronto who specializes in tissue-specific immunity.

That's important, Gommerman says, because nasal vaccines -- like FluMist -- haven't really worked all that well.

The next generation of inoculations will be something different, she says. They will build on the body-wide immunity that was created by shots; they'll just redeploy it to the nose and throat where it is needed most, she says.

Here's a look at how the different coronavirus vaccines work

"But here, we're actually talking about something else, where we're talking about building on the systemic immunity that was induced by a vaccine to a three shots of mRNA and then training that systemic immunity to go to the upper respiratory tract by boosting through the nose," Gommerman says.

One such approach was recently tested by Akiko Iwasaki, an immunobiologist at Yale University. According to their preprint study, Iwasaki and her team inoculated mice with a low dose of Pfizer's Comirnaty mRNA vaccine and followed up two weeks later with a boost of mRNA vaccine delivered via a nasal spray. The low dose of the injected vaccine was meant to simulate waning immunity. Other groups of mice got only an injection or only a dose of vaccine in the nose.

Only the group that got the injection followed by the nasal spray developed robust immunity against the Covid-19 virus.

"That approach we have shown in the mouse model to be 100% protective against lethal dose of SARS-CoV-2 infection, and it dramatically reduces the viral load in the nose and in the lung," Iwasaki said.

Going for IgA antibodies

Mucosal vaccines also target a slightly different part of the immune system than shots.

Injections trigger the body to make antibodies against the virus that causes Covid-19. Most of these are Y-shaped proteins called IgG antibodies that are programmed to recognized and block specific parts of the SARS-CoV-2 virus along its spikes, the parts of the virus that latch onto and infect our cells.

A much smaller portion of these are IgA antibodies, and they look like two Ys joined together at their tails and turned sideways so it looks more like a dog bone, Gommerman says.

Like bouncers at a bar, IgA antibodies are the primary immune molecules on guard in the mucosa.

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These molecules are beefier than IgG antibodies. They have four arms instead of two, and they're special because they're less picky about what they grab onto than IgG antibodies.

"They might be a little more promiscuous in the way they recognize different variants. And that's obviously a plus," Gommerman said.

Shots increase IgA antibodies in the nose for a short time, but the hope is that mucosal vaccines will really ramp up the population of these sentries and help them stay active for longer.

"Whether they'll be able to confer complete sterilizing immunity, that's a very tall order," Gommerman said. "But we should be now working on ways to slow down person-to-person transmission, because this virus continues to mutate and then fools our immune system and gets past that mucosal layer.

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"This is now a very contagious virus," she said.

Iwasaki says she would love to move her vaccine out of animal studies and into clinical trials in people.

"We're still at the stage where we're kind of struggling to raise money, even make the vaccine for human use, because it takes millions of dollars, and we are not sitting on that kind of money for research lab," she said, "so not yet."

https://edition.cnn.com/2022/07/18/health/mucosal-immunity-covid-19/index.html?

This doctor reversed heart disease. Now he wants to do it for Alzheimer's

By Sandee LaMotte, CNN

Updated 0704 GMT (1504 HKT) July 30, 2022

 https://edition.cnn.com/2022/07/30/health/dean-ornish-lifestyle-study-alzheimers-wellness/index.html

Dr. Dean Ornish says intense lifestyle changes may be able to slow or reverse cognitive decline.

(CNN)In 1990, internal medicine specialist Dr. Dean Ornish did what no other doctor had been able to do: He published results of a randomized clinical trial that used advanced imagery scans to show coronary artery disease could be reversed with nothing more than diet, exercise, stress reduction and social support.

Long life comes from eating right, studies say. Here's how to begin

"I think our unique contribution has been to use these very high-tech, expensive, state-of-the-art scientific measures to prove how powerful these very low-tech and low-cost interventions can be," said Ornish, a professor of medicine at the University of California, San Francisco.

Today, Ornish is trying to do for the brain what he did for the heart. At his nonprofit Preventive Medicine Research Institute in California, he's using the same four lifestyle interventions to see if early-stage Alzheimer's can be "slowed, stopped or even reversed" without the use of drugs, devices or surgeries.

"What's good for your heart is good for your brain and vice versa," Ornish said. "Prior studies have shown moderate changes in lifestyle can slow the rate of progression of dementia and Alzheimer's. So, my hypothesis is that more intense lifestyle changes could stop or even reverse the decline."

Aggressive lifestyle changes

The original study on heart disease was small -- 28 people were in the experimental group Ornish then followed for five years. Some skeptics criticized the program for its small sample size and said there was no way people could remain on the program's stringent plant-based diet without supervision.

In the Ornish meal plan, no more than 10% of one's daily calories can come from fat. To accomplish that, all animal products besides egg whites and one cup of nonfat milk or yogurt each day are banned. Whole grains, fruits, vegetables and legumes are the basis of the diet, along with a few nuts and seeds. Refined carbohydrates, oils and excessive caffeine are avoided, but up to two cups a day of green tea are allowed.

"It's low-fat, but that's just a small part of the overall diet," Ornish said. "It's essentially a vegan diet, low in fat and sugar, eating foods as close as possible to nature."

Ornish's program includes walking or other aerobic exercise.

The program also includes an hour a day of yoga-based stress management using stretching, breathing, meditation and relaxation techniques. Strength training and walking or other aerobic exercise are required for 30 minutes a day or an hour three times a week. Smoking is not allowed.

"There are also support groups," Ornish told CNN, "not just helping people stay on the diet but creating a safe environment where people can let down their emotional defenses and talk openly and authentically about what's really going on in their lives, warts and all.

"That was the part that surprised me the most -- these support groups are really intimate," he added. "Sharing things like 'I may look like the perfect father, but my kids are on heroin,' or whatever. Even by Zoom, they're getting to the same level of intimacy within one or two sessions because there's such a hunger for that."

Ornish calls that part of his program "Love More." He answers skeptics who wonder why intimacy is such an integral part of a plan to reverse disease by pointing to studies on people who are lonely, depressed or isolated.

Those people are "three to 10 times more likely to get sick and die prematurely from pretty much everything" when compared with people who say they have a sense of love, connection and community, Ornish maintained.

"Why? In part because you're more likely to smoke, overeat, stop exercising and other unhealthy things when you're feeling lonely and depressed," Ornish said.

Impact on other chronic diseases

By 1993, insurance giant Mutual of Omaha began reimbursing policyholders for the cost of Ornish's program, making it the first alternative therapy besides chiropractic to win insurance reimbursement. Medicare began covering lifestyle interventions for heart disease in 2006.

Changing your diet could add up to 13 years to your life, study says

"And in October 2021 Medicare agreed to cover my reversing heart disease program when it's done via Zoom, which is really a game changer," Ornish said. "Now we can reach people at home, in rural areas and food deserts wherever they live, which will help reduce health inequities and health disparities."

In the last two decades, Ornish's research has shown the same four-part program can lower blood sugars and heart disease risk for patients with diabetes, reduce prostate cancer cell growth, improve depression within 12 weeks, reduce "bad cholesterol" by an average of 40%, and more.

"With all this interest in personalized medicine, just how is it that these same lifestyle changes stop, and often reverse, the progression of such a wide spectrum of the most common and costly chronic diseases?" Ornish asked.

"Because they all share the same underlying biological mechanisms: chronic inflammation, oxidative stress, changes in the microbiome, changes in gene expression, overstimulation of the sympathetic nervous system, changes in immune function and so on," he said.

"And in turn, each one of these is directly influenced by what we eat, how we respond to stress, how much exercise we get and how much love and support we have," Ornish said.

Those lifestyle improvements likely change the body at a cellular level, he said. A 2008 study found the Ornish program affected some 500 genes in the body via epigenetics, chemical reactions that can activate or dismantle how a gene is expressed.

"After just three months on the Ornish lifestyle program, the research found a number of genes that regulate or prevent disease are turned on, and genes that cause many of the mechanisms that cause all these different conditions are turned off," Ornish said.

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"You're not technically changing your genes, but you're changing the expression of those genes with chemical switches, turning them on or off," he said. "So, that means it's no longer all in our genes, making us victims of our genetic fate. We're not victims. There's a lot we can do."

Ornish lifestyle interventions have also been shown to lengthen telomeres, the tips of chromosomes that control longevity and shorten as we age. Ornish did a 2013 pilot study with UC San Francisco biochemist Elizabeth Blackburn, who won the 2009 Nobel Prize in physiology or medicine for her work on telomeres.

"We found that telomerase, the enzyme that repairs and lengthens telomeres, increased by 30% after just three months on the program," Ornish said. "Then we found that people who had been on the program for five years had telomeres that were about 10% longer, a sign that aging is being reversed on the cellular level."

Will these same lifestyle interventions be enough to slow or even reverse cognitive decline in Alzheimer's and other dementias? Time will tell. Ornish's study is still underway, and while preliminary results appear promising, all the data must be gathered, analyzed and peer-reviewed before an outcome can be reported.

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"But I believe that it's not one diet and lifestyle intervention for heart disease, another for diabetes or prostate cancer, and yet a different one for Alzheimer's. It's really the same for all these different conditions," Ornish told CNN.

"To reverse the disease, you need to follow the interventions nearly 100%. If you're just trying to prevent disease, then the more you change, the more you improve. But what matters most is your overall way of eating, living and loving so that we can all die young as old as possible."

https://edition.cnn.com/2022/07/30/health/dean-ornish-lifestyle-study-alzheimers-wellness/index.html

Coronavirus can be contagious during a Paxlovid rebound, researchers warn, even if people don't have symptoms

 

By Brenda Goodman, CNN

Updated 2003 GMT (0403 HKT) July 30, 2022

This story originally published on May 31, 2022.https://edition.cnn.com/2022/07/30/health/paxlovid-rebound-contagious-study-wellness/index.html

(CNN)People who have a Covid-19 rebound after treatment with the antiviral drug Paxlovid can be contagious and may not know it because they might not have symptoms, researchers warn.

"People who experience rebound are at risk of transmitting to other people, even though they're outside what people accept as the usual window for being able to transmit," said Dr. Michael Charness of the Veterans Administration Medical Center in Boston.

Covid-19 cases that return after antiviral treatment puzzle doctors

Charness and his colleagues recently collaborated with a team of researchers at Columbia University to look into cases of Covid-19 that return after Paxlovid treatment. He said they've found at least two instances in which people have transmitted to others when their infection recurs.

In one case, a 67-year-old man infected a 6-month-old after a half-hour near the child.

The man was 12 days past his first positive Covid-19 test. He had taken a five-day course of Paxlovid and was feeling better. He didn't have any symptoms when he saw the baby, who was his grandson, but about eight hours later, he started to feel ill again.

The baby tested positive about three days later, as did both of his parents. Neither the baby nor its parents had any other close contacts before they got sick.

"It indicates that you can transmit during rebound even before you develop symptoms," Charness said. "And you know, we studied a small number of people. It's certainly conceivable that there are other people out there who don't have symptoms and still have a viral rebound."

In another instance, a 63-year-old man infected two family members during three days of relapse after Paxlovid.

Take precautions after Paxlovid

Based on this research, the US Centers for Disease Control and Prevention issued new guidance last week for people experiencing Covid-19 rebound after Paxlovid.

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The CDC said people who test positive again and whose symptoms come back after finishing their antiviral pills should restart their isolation period and isolate for five full days. The agency says people can end their isolation period after those five additional days as long as their fever has been gone for 24 hours without fever-reducing medication and they're feeling better. The agency also recommends that people wear a mask for 10 days after their symptoms come back.

The findings and guidance come as Paxlovid use has increased in the United States. According the White House, over the past two months, filled prescriptions for Paxlovid have climbed from about 27,000 a week to 182,000 a week.

The administration credits the increase to its test-to-treat program, which created one-stop hubs in grocery and drug stores where people could take a Covid-19 test and immediately receive and fill a prescription for antiviral medications. The antiviral drugs should be taken within the first few days of symptoms.

The drug works well. In clinical trials, Paxlovid reduced the odds that a person at risk of severe Covid-19 would need to be hospitalized by almost 90% compared with a placebo.

Opinion: Rebound after taking Paxlovid is the latest twist in the Covid-19 puzzle

For that reason, the CDC says, early treatment with this medication is still recommended.

As helpful as it is, though, researchers say people should be aware the drug may not completely extinguish the infection.

Charness and his co-authors have now collected at least 10 such cases of Covid-19 recurrence after Paxlovid. Half of them have come from just two families, leading the researchers to conclude that such cases are not all that rare.

The research is shared as a preprint. It has not been scrutinized by outside researchers or published in a medical journal.

Genetic testing suggests that when people get a second round of Covid-19 after Paxlovid, it's not because they've been infected by a different strain of the virus. There's also no sign that the virus has changed or mutated to develop some kind of resistance to the drug.

So far, rebound cases have been mild. There haven't been any reports of severe disease during a Covid-19 relapse. Because of this, the CDC says, there's no reason to think that more treatment is needed.

Cause still not known

Why this might be happening is still a mystery.

In his studies, Charness said, the researchers watched the amount of virus in a person's body -- called their viral load -- go down on Paxlovid treatment.

"People take Paxlovid, and what we know it does very well is, it blocks viral replication," he said. And so the levels of virus go down. But then in some people -- no one knows how many, because not enough people have been studied -- levels of the virus begin to climb again nine to 12 days after they first test positive, Charness said.

It's not entirely clear that that rebound is linked to Paxlovid. In studies of more than 2,200 Covid-19 patients, Pfizer, the company that makes the drug, said there were a few patients who had their Covid-19 come bouncing back after a negative test, but they were in the group that took Paxlovid as well as in those who got the placebo, suggesting that Covid just reappears in some people, even without treatment.

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Charness' team has done its own comparison study, however, and found something different. When researchers looked at 1,000 cases of Covid-19 diagnosed between December and March in players and support staff of the National Basketball Association who had not taken the drug, they didn't find any cases of Covid-19 returning. This study is still unpublished.

They say more research is needed to understand whether there could be any connection to the drug.

Charness said the fact that the infection can come back this way after treatment presents some questions. For one, would rebound be as common in people who started the drug later, maybe on day four or five after their first symptoms, after their immune systems have had longer to initially see the virus? Would a longer course of treatment -- maybe taking the drug for six or seven days, rather than five -- lower the risk that the virus would come back?

"No one knows," he said. "Somebody should be studying this."

https://edition.cnn.com/2022/07/30/health/paxlovid-rebound-contagious-study-wellness/index.html