new research vaccine

Two years after Covid vaccines rolled out, researchers are calling for newer, better options

Two years after the first Covid shots went into arms, a growing chorus of researchers is calling for a new generation of vaccines that provide broader and more long-term protection against the disease.

The U.S. is currently recording around 430 Covid deaths per day, on average, according to NBC News’ tally . That includes many people who received at least two Covid shots: Six in 10 adults who died of Covid in August were vaccinated or boosted, according to a report by KFF , a nonprofit health think tank. And for the most part, vaccinated people don’t avoid infections or reinfections anymore.

“Coming up with a vaccine that’s going to last longer and cover a wider range of the Covid family of viruses is a life and death problem,” said Dr. Tom Frieden, who directed the Centers for Disease Control and Prevention until 2017 and is now president of the public health organization Resolve to Save Lives.

Many people thought the solution to that problem had arrived two years ago, on December 14, 2020, when Sandra Lindsay became the first person in the U.S. to get a Covid vaccine outside of a clinical trial.

“My whole life just changed tremendously in that one moment in time,” said Lindsay, who is now the vice president of public health advocacy at Northwell Health.

“What was going through my mind is, ‘I cannot wait for this needle to pierce my arm,’” she said.

Millions of people shared her impatience, for good reason: Adults who are up to date on their shots are 15 times less likely to die from Covid than those who are unvaccinated. Covid vaccines prevented more than 3.2 million deaths and 18.5 million hospitalizations in the U.S. from December 2020 through November 2022, according to an analysis published Tuesday by the Commonwealth Fund and Yale School of Public Health.

But at first, the shots were perceived to be even more powerful than that — a shield against mild symptoms and a ticket back to pre-pandemic life. The reality proved more complicated and, in certain ways, disappointing.

Many experts maintain that we can — and must — do better.

In particular, researchers think sprays or drops given through the nose or mouth could do a better job of stopping transmission. They also hope that vaccines that target multiple parts of the virus or several variants at once could reduce the need for continuous boosters.

“It’s sometimes easy to forget what a tremendous achievement it was to get a brand new vaccine against a brand new class of viruses. … It was pragmatic, and it was tremendously successful. But it’s certainly not the panacea,” said Matthew Miller, scientific director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University. “We can certainly improve on what we know now.”

The promises and shortcomings of mRNA

Vaccine researchers generally agree that mRNA technology was suited to the needs of this pandemic, since it allowed scientists to develop a vaccine quickly at a time when each day meant more lives lost. Scientists then updated the shots relatively easily to target new variants.

“If it wasn’t mRNA, it wouldn’t have gotten done so fast,” said Dr. Barney Graham, former deputy director of the National Institutes of Health’s Vaccine Research Center, now a senior adviser for global health equity at Morehouse School of Medicine. 

To date, he added, the Covid vaccine is “one of our simplest, safest vaccines that we’ve ever made.”

When Lindsay got her vaccine in 2020, she was dealing with severely ill Covid patients every day as director of nursing critical care at Long Island Jewish Medical Center.

“It felt like you were just walking into a burning building, but it’s your job,” she said. “It’s what I love doing: taking care of people. So I was going in there no matter what, and just praying every day that I don’t fall ill.”

Despite the odds, Lindsay still hasn’t gotten Covid, as far as she knows. But the majority of Americans have, according to CDC estimates — a situation most of the public did not anticipate when clinical trial results showed 95% efficacy against symptomatic disease.

“It may be that the vaccines were their own worst enemies in some ways, because they were so good initially that people had an expectation that went beyond reason,” Graham said.

Experts agree now, though, that protection from Covid shots fades too fast. Plus, a lack of access to vaccines in many countries allowed the virus to spread rampantly and mutate over time, which has undermined vaccines and treatments.

“If we had immunized the whole world in six months, we may not be having all the problems with the variants because we would have constrained [the] virus’ spread earlier,” Graham said.

The future of Covid vaccines: No needles

When Lindsay volunteered to get her vaccine on day one, she wasn’t aware that she was the country’s very first recipient — despite the cameras.

Now, she said, she still gets recognized.

“I was in TJ Maxx the other day and this man who I didn’t expect was basically bowing down at my feet, [saying] that through my one action, I saved his life, his family’s lives, and so many more,” Lindsay said. “Those are the stories that just solidify for me that what I did on that day made a big difference.”

But others see Lindsay as the face of a promise that fell short. 

“You get this on social media, when you post anything: ‘Well, how do you feel now that this thing was all a lie? People are not supposed to get Covid and you got the shots and it’s a big letdown,’” she said.

Researchers still hope that in the future, nasal spray vaccines could inspire more confidence by offering more protection against illness, reducing side effects and removing needles from the equation. 

Because Covid seems to infect most people through the nasal passages first, administering a vaccine in the nose could vanquish the virus before it has a chance to spread, the thinking goes.

“It’s sort of akin to having guards placed outside the door in the mucus layer, versus waiting for the invaders to come in,” said Dr. Akiko Iwasaki, an immunobiology professor at Yale University who is developing an intranasal Covid vaccine.

Globally, 117 intranasal Covid vaccines are in development or have been rolled out, according to an analysis provided to NBC News by Airfinity , a health analytics company. Five have been approved in at least one country — two in China and one each in India, Iran and Russia — and 20 more have entered clinical trials. The majority rely on traditional vaccine platforms, not mRNA.

“There’s probably a number of advantages to the intranasal route that will be realized once that route is fully exploited. People can administer it themselves. You can use it in a developing world setting. You can use lower doses,” said Dr. David Curiel, a professor of radiation oncology at Washington University School of Medicine in St. Louis. “There may even be a safety gain, and you get sterilizing immunity and possibly block transmission.”

Curiel developed the technology for the nasal vaccine approved in India. But the vaccine hasn’t entered trials in the U.S., and trial results from India haven’t been published in a peer-reviewed journal.

Other researchers are betting on inhaled vaccines, which come in the form of aerosolized mists administered through a nebulizer into the lungs, where the virus tends to wreak the most havoc.

In September, China approved an inhaled version of a previously authorized Covid shot, called Convidecia. A small trial showed that the inhaled booster dose produced a stronger antibody response than a booster of the intramuscular shot.

Miller and his McMaster colleagues are testing two inhaled vaccines in phase 1 human trials. The more effective candidate will likely advance to phase 2, he said.

Those vaccines might offer an additional advantage, according to Miller: They target three parts of the coronavirus, whereas the current shots target just the spike protein, which mutates faster than the virus’ other components.

Still, some researchers worry that protection from nasal or inhaled vaccines could also wane quickly.

“If we can give a vaccine at the site where infection typically occurs, we would always love to do it that way. The challenge, of course, is that sometimes it doesn’t generate the same type of bloodstream immunity that we really want,” said Dr. Buddy Creech, director of the Vanderbilt Vaccine Research Program.

Creech said future versions of mRNA shots could potentially be tweaked to target three or more coronavirus strains. (The new bivalent boosters target two.)

“It will not be surprising if at some point we need something like a trivalent vaccine or some other permutation of what we have now,” he said. “It could very well mirror what we do with influenza.”

Then there’s the idea of targeting several different coronaviruses at once. The National Institute of Allergy and Infectious Diseases has allocated more than $62 million for research and development of pan-coronavirus vaccines. 

In July, researchers at the California Institute of Technology showed that their candidate protected mice and monkeys from the viruses that cause both Covid and SARS. In October, researchers at Duke University School of Medicine similarly showed that their pan-coronavirus vaccine protected animals from multiple SARS-related viruses.

But unlike in 2020, the federal government’s motivation to fund Covid-related innovations is drying up. Whatever Covid vaccine comes next is likely three to five years off, Miller estimated — or perhaps longer, according to other experts. 

“The mRNA technology is remarkably successful — these vaccines work better than we had the right to expect,” Frieden said. “But the virus is adapting. And as the virus adapts, we need to adapt.”

Aria Bendix is the breaking health reporter for NBC News Digital.

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Science News

Early mrna research that led to covid-19 vaccines wins 2023 medicine nobel prize.

Biochemists Katalin Karikó and Drew Weissman overcame hurdles that enabled vaccine development

Researchers Katalin Karikó and Drew Weissman discovered how to deliver mRNA into cells inside the body by enveloping the molecule inside lipid bubbles (illustrated). Technology that was essential for developing some COVID-19 vaccines earned the pair the 2023 Nobel Prize in physiology or medicine. 

JUAN GAERTNER/SCIENCE PHOTO LIBRARY/GETTY IMAGES

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By Tina Hesman Saey , Meghan Rosen and Erin Garcia de Jesús

October 2, 2023 at 9:29 am

Updated October 2, 2023 at 1:30 pm

Two scientists who laid the groundwork for what would become among the most influential vaccines of all time have been awarded the 2023 Nobel Prize in medicine or physiology. 

Biochemist Katalin Karikó, now at the University of Szeged in Hungary, and Drew Weissman of the University of Pennsylvania were honored for their research on modifications of mRNA that made the first vaccines against COVID-19 possible ( SN: 12/15/21 ). 

“Everybody has experienced the COVID-19 pandemic that affects our life, economy and public health. It was a traumatic event,” said Qiang Pan-Hammarström, a member of the Nobel Assembly at the Karolinska Institute in Stockholm, which awards the medicine or physiology prize. Her remarks came on October 2 after a news briefing to announce the winners. “You probably don’t need to emphasize more that the basic discovery made by the laureates has made a huge impact on our society.”

As of September 2023, more than 13.5 billion COVID-19 vaccine doses — including mRNA vaccines as well as other kinds of shots — had been administered since they first became available in December 2020, according to the World Health Organization. In the year after their introduction, the shots are estimated to have saved nearly 20 million lives globally. In the United States, where mRNA COVID-19 shots made by Moderna and Pfizer/BioNTech accounted for the vast majority of vaccinations, the vaccines are estimated to have prevented 1.1 million additional deaths and 10.3 million hospitalizations.

A different kind of vaccine

RNA is DNA’s lesser-known chemical cousin. Cells make RNA copies of genetic instructions contained in DNA. Some of those RNA copies, known as messenger RNA, or mRNA, are used to build proteins. Messenger RNA “literally tells your cells what proteins to make,” says Kizzmekia Corbett-Helaire, a viral immunologist at the Harvard T. H. Chan School of Public Health in Boston. Proteins do much of the important work that keeps cells, and the organisms they’re a part of, alive and well.

The mRNA vaccines work a bit differently than traditional immunizations. Most traditional vaccines use viruses or bacteria — either weakened or killed — or proteins from those pathogens to provoke the immune system into making protective antibodies and other defenses against future infections. 

The COVID-19 vaccines made by Pfizer/BioNTech and Moderna instead contain mRNA that carries instructions for making one of the coronavirus’s proteins ( SN: 2/21/20 ). When a person gets an mRNA shot, the genetic material gets into their cells and triggers the cells to produce the viral protein for a short amount of time. When the immune system sees the viral protein, it builds defenses to prevent serious illness if the person later gets infected with the coronavirus. 

Vaccines using mRNA were a good choice to combat the pandemic, Corbett-Helaire says. The technology allows scientists to “skip that step of making large amounts of proteins in the laboratory and instead … tell the body to do things that the body already does, except now we make an extra protein,” she says. 

In addition to protecting people from the coronavirus, mRNA vaccines may also work against other infectious diseases and cancer . Scientists might also use the technology to help people with certain rare genetic diseases make enzymes or other proteins they lack. Clinical trials are under way for many of these uses, but it could take years before scientists know the results ( SN: 12/17/21 ).

A long time coming

The first mRNA vaccine for COVID-19 became available just under a year into the pandemic, but the technology behind it has been decades in the making.

In 1997, Karikó and Weissman met at the copy machine, Karikó said during a news conference October 2 at the University of Pennsylvania. She told him about her work with RNA, and he shared his interest in vaccines. Although housed in separate buildings, the researchers worked together to solve one fundamental problem that could have derailed mRNA vaccines and therapies: Pumping regular mRNA into the body gets the immune system riled up in bad ways, producing a flood of immune chemicals called cytokines. Those chemicals can trigger damaging inflammation. And this unmodified mRNA produces very little protein in the body.  

The researchers found that swapping the RNA building block uridine for modified versions, first pseudouridine and then N1-methylpseudouridine, could dampen the bad immune reaction. That nifty chemistry, first reported in 2005 , allowed researchers to rein in the immune response and safely deliver the mRNA to cells.

“The messenger RNA has to hide and it has to go unnoticed by our bodies, which are very brilliant at destroying things that are foreign,” Corbett-Helaire says. “The modifications that [Karikó and Weissman] worked on for a number of years really were fundamental to allowing the mRNA therapeutics to hide while also being very helpful to the body.”

In addition, the modified mRNA produced lots of protein that could spark an immune response , the team showed in 2008 and 2010. It was this work on modifying mRNA building blocks that the prize honors.

For years, “we couldn’t get people to notice RNA as something interesting,” Weissman said at the Penn news conference. Vaccines using the technology failed clinical trials in the early 1990s, and most researchers gave up. But Karikó “lit the match,” and they spent the next 20 years figuring out how to get it to work, Weissman said. “We would sit together in 1997 and afterwards and talk about all the things that we thought RNA could do, all of the vaccines and therapeutics and gene therapies, and just realizing how important it had the potential to be. That’s why we never gave up.”

In 2006, Karikó and Weissman started a company called RNARx to develop mRNA-based treatments and vaccines. After Karikó joined the German company BioNTech in 2013, she and Weissman continued to collaborate. They and colleagues reported in 2015 that encasing mRNA in bubbles of lipids could help the fragile RNA get into cells without getting broken down in the body. The researchers were developing a Zika vaccine when the pandemic hit, and quickly applied what they had learned toward containing the coronavirus.

The duo’s work was not always so celebrated. Thomas Perlmann, Secretary General of the Nobel Assembly at the Karolinska Institute, asked the newly minted laureates whether they were surprised to have won. He said that Karikó was overwhelmed, noting that just 10 years ago she was terminated from her job and had to move to Germany without her family to get another position. She never won a grant from the U.S. National Institutes of Health to support her work. 

“She struggled and didn’t get recognition for the importance of her vision,” Perlmann said, but she had a passion for using mRNA therapeutically. “She resisted the temptation to sort of go away from that path and do something maybe easier.” Karikó is the 61st woman to win a Nobel Prize since 1901, and the 13th to be awarded a prize in physiology and medicine. 

Though it often takes decades before the Nobel committees recognize a discovery, sometimes recognition comes relatively swiftly. For instance, Emmanuelle Charpentier and Jennifer Doudna won the Nobel Prize for chemistry in 2020 a mere eight years after the researchers published a description of the genetic scissors CRISPR/Cas 9 ( SN: 10/7/20 ).

“I never expected in my entire life to get the Nobel Prize,” Weissman said, especially not a mere three years after the vaccines demonstrated their medical importance. Perlmann told him the Nobel committee was seeking to be “more current” with its awards, he said.

The timely Nobel highlights that “there are just a million other possibilities for messenger RNA therapeutics … beyond the vaccines,” Corbett-Helaire says.

The researchers said at the Penn news conference that they weren’t sure the early morning phone call from Perlmann was real. On the advice of Weissman’s daughter, they waited for the Nobel announcement. “We sat in bed. [I was] looking at my wife, and my cat is begging for food,” he said. “We wait, and the press conference starts, and it was real. So that’s when we really became excited.”

Karikó and Weissman will share the prize of 11 million Swedish kronor, or roughly $1 million.

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The Updated COVID Vaccines Are Here: 9 Things to Know

BY KATHY KATELLA April 19, 2024

[Originally published: Oct. 2, 2023. Updated: April 19, 2024.]

Note: Information in this article was accurate at the time of original publication. Because information about COVID-19 changes rapidly, we encourage you to visit the websites of the Centers for Disease Control & Prevention (CDC), World Health Organization (WHO), and your state and local government for the latest information.

There has been better protection against severe disease, hospitalization, and death from COVID-19 since newly updated (2023–2024 formula) mRNA COVID vaccines became available last fall. Shots are available to protect everyone 6 months and older from serious illness, hospitalization, and death from the disease.

The Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) approved the updated vaccines by Pfizer-BioNTech and Moderna for everyone 6 months and older, and authorized an updated Novavax vaccine for those 12 and older in the fall of 2023. In February of this year, the CDC recommended an additional dose for adults ages 65 and older.

The vaccines target XBB.1.5, a subvariant of Omicron that dominated the United States—and the world—from November 2021 until last year. The CDC says the updated vaccines should also work against currently circulating variants of the SARS-CoV-2 virus—many of which descended from, or are related to, the XBB strain. The vaccine is also expected to protect against JN.1, the current dominant strain in the U.S.

While COVID has been causing mostly mild illness recently, Yale Medicine infectious diseases specialist Onyema Ogbuagu, MBBCh , reminds people that the disease can still lead to hospitalization and death. “Infections can have long-term consequences,” Dr. Ogbuagu says, adding that even healthy people can develop Long COVID —a condition in which new, continuing, or recurring (and sometimes debilitating) symptoms are present four or more weeks after an initial coronavirus infection.

Below, Yale experts tell you what you need to know about the updated COVID vaccine.

1. Why would another COVID vaccination help?

The updated vaccines are not expected to prevent all cases of COVID, including those causing mild illness; rather, their aim is to reduce severe illness, hospitalization, and death from infection. According to the CDC, COVID is still a major cause of serious respiratory illness. While hospitalizations and deaths from COVID have been declining, 7,318 people were hospitalized with the disease during the first week of April 2024 alone (that number rose as high as 35,000 during one week in January, a month when respiratory diseases tend to peak).

Older people (especially those ages 50 and older) are more likely than younger people to get very sick from COVID. Immunocompromised people and those with chronic medical conditions, such as diabetes or heart disease, are at the highest risk of severe disease and death, but some young, healthy people have also gotten very ill and died from COVID. In addition, the CDC recommends the vaccine for pregnant women to protect both mother and baby.

An analysis by the CDC in September 2023 suggested that making its vaccine recommendation universal could prevent 400,000 hospitalizations and 40,000 deaths in the U.S. over the next two years.

2. How is the updated COVID vaccine different from the previous one?

The bivalent booster, which is no longer available, was introduced in the fall of 2022. It targeted the BA.4 and BA.5 Omicron subvariants and the original SARS-CoV-2 virus. The updated vaccine is monovalent, designed to prevent severe disease from the Omicron XBB.1.5 subvariant. By September 2023, the long-running XBB.1.5 accounted for only about 3% of cases in the U.S., but most of the strains circulating now are descended from (or closely related to) it.

That’s a good example of how the virus has evolved—and it’s still evolving—so rapidly that it may be impossible to match each new vaccine update to the variants circulating at the time it is released, explains Scott Roberts, MD , a Yale Medicine infectious diseases specialist. “But we know from experience that the vaccines hold up very well, even against multiple variants, unless there is a significant shift like we saw with Delta to Omicron in the winter of 2021,” he says. “Basically, if you have some immunity to a variant and are exposed to a new offshoot of it, you’ll have some protection.”

3. Why isn’t the new COVID vaccine considered a booster?

The FDA is calling the newest shots “updated vaccines” in anticipation of needing to provide updated formulas annually, similar to the flu shot, which changes each year.

A booster shot gives a “boost” to the recipient's existing immunity from a previous vaccination. Updated vaccines are different in that they are expected to provide protection against currently circulating variants, helping the body build a new response to those variants. “Barring the emergence of a markedly more virulent variant, the FDA anticipates that the composition of COVID vaccines may need to be updated annually, as is done for the seasonal influenza vaccine,” the FDA noted in its approval and authorization of the new vaccine.

“I think we're going to fall into a pattern very similar to the flu, where every year the virus is going to mutate slightly, and the vaccine formulation for the fall will be an educated guess,” says Dr. Roberts. “We will make a vaccine targeted against whatever we predict or whatever is currently circulating and hope our vaccines are a good match, because we will be developing them before we know what variants will be circulating in the fall."

4. How safe is the updated COVID vaccine?

COVID vaccines are safe and effective, according to the CDC . The safety of COVID vaccines has been rigorously monitored and evaluated since their emergency use authorization (EUA) in December 2020. According to the CDC, the updated mRNA COVID vaccines for 2023-2024 are manufactured using a similar process to the previous vaccines.

The benefits of the COVID vaccine continue to outweigh any potential risks, and serious reactions after COVID vaccination are rare, according to the CDC. The agency cited a study showing the risk of cardiac complications, including myocarditis (an inflammation of the heart muscle) was significantly higher after a COVID infection for both males and females in all age groups.

5. Are there any special COVID vaccine recommendations for children?

The FDA approved the updated mRNA vaccines for adolescents and teenagers ages 12 and older and authorized them for emergency use in children ages 6 months through 11 years.

Children are less likely to get seriously ill with COVID, but some still do, says Magna Dias, MD , a Yale Medicine pediatric hospitalist. She tells parents who are still not sure whether they should get the vaccine for their children to talk to their pediatrician, especially if their child is immunocompromised. “In that case, I think it’s a no-brainer to protect them,” she says.

6. Is there an updated COVID vaccine from Novavax?

The FDA authorized an updated version of a vaccine Novavax developed to target the XBB.1.5 strain. Individuals 12 and older previously vaccinated with a COVID vaccine (and who have not already been vaccinated with a recently updated mRNA COVID vaccine) are eligible to receive one dose; unvaccinated individuals can receive two doses.

According to the FDA , the updated vaccine addresses currently circulating variants to provide better protection against serious consequences of COVID, including hospitalization and death.

The Pfizer-BioNTech and Moderna vaccines use messenger RNA (mRNA) technology, which instructs the body’s cells to make proteins that trigger an immune response against COVID. The Novavax protein-based vaccine uses an older, more traditional technology and a different mechanism—it directly injects the spike protein (formulated in a laboratory) and another ingredient into the body, leading to the production of virus-fighting antibodies and T cells. The Novavax vaccine is the only non-mRNA COVID vaccine available in the U.S.

7. When should I get the updated COVID vaccine?

People 5 years and older may get one dose of the updated vaccine at least two months after the last dose of any previous COVID vaccine. Babies and young children usually need more doses than older children and teens. Anyone who recently had COVID may consider delaying their vaccine by 3 months.

People who are 65 or older should receive their second dose of the updated vaccine at least four months after the first dose. Those in that age group who are immunocompromised should get the additional dose earlier—at least 2 months after the first one.

8. Should I get the updated COVID vaccine and other seasonal shots at the same time?

The CDC considers it safe to get the COVID shot and annual flu vaccine simultaneously. There is even research in progress to explore the effects of administering both vaccines in a single shot.

But the respiratory syncytial virus (RSV) vaccines for older adults and pregnant women (who can pass the antibodies along to their newborns) were brand new in fall 2023, and there isn’t data to say for sure whether giving those at the same time as the other two shots is the best strategy.

9. Where can I get the updated COVID vaccine?

As with previous COVID vaccines, this one will be available at participating pharmacies and provider offices. To find a location near you that carries the vaccine and to schedule an appointment, go to Vaccines.gov . You can also call 1-800-232-0233 (TTY 1-888-720-7489). Be aware that current distribution and insurance issues may delay availability of the vaccines temporarily in some places.

According to the CDC, the vaccines are covered by insurance, including private insurance, Medicare plans, and Medicaid plans. Uninsured children and uninsured adults also have access through the Vaccine for Children Program and Bridge Access Program , respectively.

Information provided in Yale Medicine articles is for general informational purposes only. No content in the articles should ever be used as a substitute for medical advice from your doctor or other qualified clinician. Always seek the individual advice of your health care provider with any questions you have regarding a medical condition.

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Scientists create vaccine with potential to protect against future coronaviruses

Researchers say experimental shot is step towards goal of creating vaccines before a pandemic has started

Scientists have created a vaccine that has the potential to protect against a broad range of coronaviruses, including varieties that are not yet even known about.

The experimental shot, which has been tested in mice, marks a change in strategy towards “proactive vaccinology”, where vaccines are designed and readied for manufacture before a potentially pandemic virus emerges.

The vaccine is made by attaching harmless proteins from different coronaviruses to minuscule nanoparticles that are then injected to prime the body’s defences to fight the viruses should they ever invade.

Because the vaccine trains the immune system to target proteins that are shared across many different types of coronavirus, the protection it induces is extremely broad, making it effective against known and unknown viruses in the same family.

“We’ve shown that a relatively simple vaccine can still provide a scattershot response across a range of different viruses,” said Rory Hills, a graduate researcher at the University of Cambridge and first author of the report. “It takes us one step forward towards our goal of creating vaccines before a pandemic has even started.”

Tests in mice showed that the vaccine induced a broad immune response to coronaviruses, including Sars-Cov-1, the pathogen that caused the 2003 Sars outbreak, even though proteins from that virus were not added to the vaccine nanoparticles. Details of the work, a collaboration between the universities of Cambridge and Oxford and the California Institute of Technology, are published in Nature Nanotechnology.

The universal coronavirus vaccine can be made in existing facilities for microbial fermentation, Hills said, adding that the researchers were working with industrial partners on ways to scale up the process. The nanoparticles and viral proteins can be made at different times in different places and mixed together to produce the vaccine.

Medical regulators do not have procedures for proactive vaccinology and the researchers say these would have to be worked out with the relevant bodies. If the vaccine were found to be safe and effective in humans, one option would be to use it as a Covid booster with the added benefit of it protecting against other coronaviruses.

More likely is that countries would hold stocks of the vaccine, and others designed to target separate pathogens, once they have been manufactured and approved. “In the event that a coronavirus or other pathogen crosses over you could have pre-existing vaccine stocks ready and a clear plan to quickly scale up production if needed,” Hills said.

Prof Mark Howarth, a senior author of the study, said: “Scientists did a great job in quickly producing an extremely effective Covid vaccine during the last pandemic, but the world still had a massive crisis with a huge number of deaths. We need to work out how we can do even better than that in the future, and a powerful component of that is starting to build the vaccines in advance.”

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Vaccine Research & Development

How can covid-19 vaccine development be done quickly and safely, typical vaccine development timeline.

• Each clinical trial phase follows completion of the prior phase
• Can take a long time to accumulate cases to assess vaccine efficacy outside pandemic
• Manufacturing capacity is scaled-up after phase III trial and regulatory approval

Accelerated timeline in a pandemic

• Some clinical trial phases are combined
• Cases accumulate rapidly to assess vaccine efficacy because of the pandemic
• Manufacturing capacity is scaled up during the clinical trials but at financial risk

Typical Timeline

A typical vaccine development timeline takes 5 to 10 years, and sometimes longer, to assess whether the vaccine is safe and efficacious in clinical trials, complete the regulatory approval processes, and manufacture sufficient quantity of vaccine doses for widespread distribution.

to the Accelerated Timeline

Preclinical Trials

Preclinical testing of vaccine candidates typically starts in animal models, first in small mammals such as mice or rats and then non-human primates such as monkeys. Preclinical studies are important for eliminating potential vaccines that are either toxic or do not induce protective immune responses. But many vaccines that appear to be safe and induce protective immune responses in animals fail in human studies. Only vaccine candidates that are very promising in preclinical testing move forward into phase I clinical trials.

Phase I Clinical Trials to Assess Safety, Dosing, and Immune Responses

Phase I clinical trials are the first step in assessing vaccines in people. Typically involving one to several dozen healthy volunteers, phase I trials assess short-term safety (e.g., soreness at the site of injection, fever, muscle aches) and immune responses, often with different vaccine dosages. Only if a vaccine candidate is shown to be safe in phase I trials will it move to larger phase II trials.

Phase 1 trials can be completed in two to three months, allowing for two doses of a vaccine three to four weeks apart

Phase II Clinical Trials to Assess Safety and Immune Responses

Phase II clinical trials continue to assess safety and immune responses but in a larger number and more diverse group of volunteers, typically one to several hundred people. Phase II trials may include target populations of a specific age or sex, or those with underlying medical conditions. Vaccines for children start with adult volunteers and move to progressively younger groups of children. Different types of immune responses are often measured, including antibodies and cell-mediated immunity, but phase II trials do not assess how well a vaccine actually works. Only in phase III trials is vaccine efficacy assessed.

Phase 2 trials can be completed in three to four months, allowing for longer follow-up to better assess safety and immunogenicity. This timeline is shortened when phase 1 and phase 2 trials are combined.

Phase III Clinical Trials to Assess Safety and Efficacy

Phase III clinical trials are critical to understanding whether vaccines are safe and effective. Phase III trials often include tens of thousands of volunteers. Participants are chosen at random to receive the vaccine or a placebo. In Phase III, participants and most of the study investigators do not know who has received the vaccine and who received the placebo. Participants are then followed to see how many in each group get the disease. Assessing short- and long-term safety is also a major goal of phase 3 trials.

Phase 3 trials may take six to nine months to allow early assessment of safety and efficacy, particularly if conducted in areas with a high risk of infection, but with follow-up continuing for two years or more to assess long-term safety and efficacy.

Regulatory Approval Process

Each country has a regulatory approval process for vaccines. In the United States, the Food and Drug Administration (FDA) is responsible for regulating vaccines. In situations when there is good scientific reason to believe that a vaccine is safe and is likely to prevent disease, the FDA may authorize its use through an Emergency Use Authorization (EAU) even if definitive proof of the efficacy of the vaccine is not known, especially for diseases that cause high mortality.

Scaling Up Vaccine Manufacturing

Scaling up vaccine manufacturing is typically done near the end of the regulatory process because of the huge financial investment needed. In the United States, the FDA will inspect the manufacturing facilities. The cost of developing a new vaccine can be several billion U.S. dollars prior to the scale up of manufacturing facilities.

Post-Licensure Vaccine Safety Monitoring

After a vaccine is approved and in widespread use, it is critically important to continue to monitor vaccine safety. Some very rare side effects may only be detectable when large numbers of people have been vaccinated. Safety concerns that are discovered at this late stage could lead a licensed vaccine to be withdrawn from use, although this is very rare.

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New vaccine could protect against coronaviruses that haven't even emerged yet

by Rory Hills, The Conversation

The rapid development of vaccines that protect against COVID was a remarkable scientific achievement that saved millions of lives . The vaccines have demonstrated substantial success in reducing death and serious illness after COVID infection.

Despite this success, the effects of the pandemic have been devastating, and it is critical to consider how to protect against future pandemic threats. As well as SARS-CoV-2 (the virus that causes COVID), previously unknown coronaviruses have been responsible for the deadly outbreaks of SARS (2003) and MERS (2012 outbreak with ongoing cases). Meanwhile, several circulating bat coronaviruses have been identified as having the potential to infect humans—which could cause future outbreaks.

My colleagues and I have recently shown , in mice, that a single, relatively simple vaccine can protect against a range of coronaviruses—even ones that are yet to be identified. This is a step towards our goal of what is known as "proactive vaccinology," where vaccines are developed against pandemic threats before they can infect humans. Our work is published in the journal Nature Nanotechnology .

Conventional vaccines use a single antigen (part of a virus that triggers an immune response) that typically protects against that virus and that virus alone. They tend not to protect against diverse known viruses, or viruses that have not yet been discovered.

In previous research , we have shown the success of "mosaic nanoparticles" at raising immune responses to different coronaviruses. These mosaic nanoparticles use a type of protein superglue technology that irreversibly links two different proteins together.

This "superglue" is used to decorate a single nanoparticle with multiple receptor-binding domains— a key part of a virus located on the spike protein—that come from different viruses. The vaccine is focused on a sub-group of coronaviruses called sarbecoviruses that includes the viruses that cause COVID, SARS and several bat viruses that have the potential to infect humans.

As a virus evolves, some parts of it change while other parts remain the same. Our vaccine incorporates evolutionarily related receptor-binding domains (RBDs), so a single vaccine trains the immune system to respond to the parts of the virus that remain unchanged. This protects against the viruses that are represented in the vaccine and, critically, also protects against related viruses that are not included in the vaccine.

Despite this success with mosaic nanoparticles, the vaccine was complex, making it difficult to produce on a large scale.

Simpler vaccine

In a collaboration between the universities of Oxford, Cambridge and Caltech, we have now developed a simpler vaccine that still provides this broad protection. We achieved this by genetically fusing RBDs from four different sarbecoviruses to form a single protein that we call a "quartet." We then use a type of protein glue to attach these quartets to a " protein nanocage" to make the vaccine.

When mice were immunized with these nanocage vaccines, they produced antibodies that neutralized a range of sarbecoviruses, including sarbecoviruses not present in the vaccine. This show the potential to protect against related viruses that may not have been discovered at the time that the vaccine was produced.

Along with this streamlined production and assembly process, our new vaccine elicited immune responses in mice that at least matched, and in many cases exceeded, those raised by our original mosaic nanoparticles vaccine.

Given the large fraction of the world vaccinated or previously infected with SARS-CoV-2, there was a worry that an existing response to SARS-CoV-2 would limit the potential to protect against other coronaviruses. However, we have shown that our vaccine is able to raise a broad anti-sarbecovirus immune response even in mice that had previously been immunized against SARS-CoV-2.

Our next step is to test this vaccine in humans. We are also applying this technology to protect against other groups of viruses that can infect humans. All of this brings us closer to our vision of developing a library of vaccines against viruses with pandemic potential before they have had the opportunity to cross over into humans.

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COVID-19 Vaccination Public Education Campaign Saved Thousands of Lives, Billions of Dollars

Study found vaccine campaign saved $90 for every $1 spent 

The U.S. Department of Health and Human Services’ (HHS) COVID-19 Vaccination Public Education Campaign, We Can Do This, resulted in an estimated$731.9 billion in societal benefits due to averted illness and related costs, resulting in a nearly $90 return in societal benefits for every $1 spent, according to research published today in the American Journal of Preventive Medicine .

“At the height of the pandemic, we launched one of the largest public health education campaigns in U.S. history to encourage and educate Americans on the steps they could take to get and stay healthy. We now have research to confirm the COVID-19 Public Education Campaign, We Can Do This, was an indispensable part of efforts to vaccinate people and protect them from COVID-19, saving thousands of lives and billions of dollars in the process,” said HHS Secretary Xavier Becerra. “HHS is responsible for protecting the health and well-being of all Americans. As stewards of the public’s money, we wanted to deliver impact for the American people in the most efficient and effective ways. This confirms we did exactly that. We will no doubt use what we learned in this campaign to further improve our public health efforts in the future.”

The study showed the Campaign encouraged 22.3 million people to complete their primary COVID-19 vaccination series between April 2021 and March 2022, preventing nearly 2.6 million SARS-CoV-2 infections, the virus that causes COVID-19, including nearly 244,000 hospitalizations, during the time period that the highly contagious Delta and Omicron virus variants were spreading.

Preventing these outcomes resulted in societal benefits to the U.S. of $740.2 billion, accounting for such factors as medical expenses, wages, and other costs that people and institutions would have incurred in the absence of the Campaign. In comparison, the Campaign cost $377 million, with an additional $7.9 billion spent to vaccinate 22.3 million people in that time period.

According to the study, from April 2021 to March 2022, the net benefit of the Campaign—how much money these efforts saved minus how much they cost—came to $731.9 billion, translating to a return on investment of $89.54 for every $1 spent.

In April 2021, HHS launched the We Can Do This Public Education Campaign to increase COVID-19 vaccine confidence and uptake in the U.S. The Campaign, one of the largest public health education efforts in U.S. history, promoted COVID-19 vaccine uptake using integrated, multichannel, research-based strategies. It aimed to reach 90% of adults in the United States at least once per quarter, with even more intense outreach to high-risk communities. The Campaign featured more than 7,000 ads in 14 languages, with many culturally tailored and geographically targeted to specific minority, racial, and ethnic audiences. A multimedia approach bolstered widespread engagement with trusted messengers, partner organizations, and influencers who delivered persuasive, accurate, and culturally relevant information to vaccine-hesitant populations.

The benefit-cost study of We Can Do This is the only research study to date that looked at the contributions of a media campaign to encourage people to get COVID-19 vaccines during the pandemic emergency period. The newly published study is unique in that it demonstrates that the nationwide media Campaign was an indispensable component of the nation’s efforts to vaccinate people and protect them from COVID-19. It also adds to the body of evidence that shows the Campaign’s impact on behavior change.

“This research confirms the benefits of public health campaigns as part of a multi-layered response to a public health crisis and to the effort to provide accurate information to the American public,” said May Malik, Senior Advisor for Public Education Campaigns at HHS.

To evaluate the benefits and costs of the national Campaign, researchers used real-world data from multiple sources, such as data on COVID-19 outcomes, uptake of COVID-19 vaccines, and vaccine effectiveness, from the U.S. Centers for Disease Control and Prevention (CDC), along with survey data collected to measure the Campaign’s effects on vaccination behaviors over time.

The findings can help inform the Federal response to future public health threats. As part of a multipronged approach to addressing public health crises, this study demonstrates the return on investment possible from public education campaigns given their effectiveness in building vaccine confidence and supporting healthy behavior change.

The study, Benefit-Cost Analysis of the HHS COVID-19 Campaign: April 2021–March 2022 , was conducted by researchers from HHS Office of the Assistant Secretary for Public Affairs and Fors Marsh in Arlington, Virginia.

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Covid Vaccine Side Effects: 4 Takeaways From Our Investigation

Thousands of Americans believe they experienced rare but serious side effects. But confirming a link is a difficult task.

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By Apoorva Mandavilli

Apoorva Mandavilli spent more than a year talking to dozens of experts in vaccine science, policymakers and people who said they had experienced serious side effects after receiving a Covid-19 vaccine.

Soon after their arrival in late December 2020, the Covid-19 vaccines turned the pandemic around and opened a path back to normalcy. They prevented about 14.4 million deaths worldwide, according to one estimate .

In a small percentage of people, they also produced side effects.

Over the course of more than a year, The New York Times talked to 30 people who said they had been harmed by Covid vaccines. Their symptoms may turn out to be unrelated to the shots. But they — along with more than a dozen experts — felt federal officials are not doing enough to investigate their complaints.

All vaccines carry some risk of side effects. More than 270 million Americans received about 677 million doses of the Covid vaccines, and even rare side effects — occurring, say, in just 0.001 percent of patients — might mean thousands of recipients were affected.

Indeed, more than 13,000 have submitted claims to a government fund that compensates people for Covid vaccine injuries. So far, however, only a dozen people have been compensated, nearly all of them for a heart problem caused by the vaccines.

Here are four takeaways from our investigation.

For most people, the benefits of Covid vaccines outweigh any risks.

Even the best vaccines and drugs have some side effects. That does not negate their benefits, nor does it suggest that people should stop taking them.

The rotavirus vaccine, for example, is an unmitigated success, but it can lead to intussusception — a life-threatening condition in which the intestine folds in on itself — in about 0.02 percent of children who are vaccinated.

Some side effects caused by the Covid vaccines may be equally rare. Researchers in Hong Kong analyzed that country’s health records and found that about seven of every million doses of Pfizer-BioNTech vaccine triggered a bout of shingles serious enough to require hospitalization.

Other side effects are slightly more common. The Covid vaccines may lead to myocarditis, or inflammation of the heart, in one of every 10,000 adolescent males. (Myocarditis is one of the four serious side effects acknowledged by federal health officials.)

Deaths from the vaccines are vanishingly rare , despite claims from some conspiracy theorists that vaccines have led to a spike in mortality rates.

More intensive analysis may indicate that in some groups, like young men, the benefit of Covid shots may no longer outweigh the risks. But for the majority of Americans, the vaccines continue to be far safer than contracting Covid itself.

Federal surveillance has found some side effects but may miss others.

To detect problems with vaccines, federal agencies rely on multiple databases. The largest, the Vaccine Adverse Event Reporting System, is useful for generating hypotheses, but contains unverified accounts of harms. Other databases combine electronic health records and insurance claims.

These systems spotted blood-clotting problems associated with the Johnson & Johnson vaccine and a potential risk of stroke after mRNA immunizations, which is still under investigation. But federal researchers trailed Israeli scientists in picking up myocarditis as a problem among young men.

The American health care system is fragmented, with medical records stored by multiple companies that do not collaborate. Electronic health records do not all describe symptoms the same way, making comparisons difficult. Insurance claims databases may have no record of shots administered at mass vaccination sites.

Federal systems may also miss symptoms that defy easy description or diagnosis.

Proving vaccination led to an illness is complicated.

Among the hundreds of millions of Americans who were immunized against Covid, there were deaths, heart attacks, strokes, miscarriages and autoimmune illnesses. How to distinguish illnesses caused by the vaccine from those that would have happened anyway?

The rarer the condition, the harder it is to answer this question.

Merely judging by the timing — the appearance of a particular problem after vaccination — can be misleading. Most famously, childhood vaccines were mistakenly linked to autism because the first noticeable features often coincided with the immunization schedule.

Serious side effects may first turn up in animal studies of vaccines. But few such studies were possible given the nation’s desperate timeline in 2020. Clinical trials of the vaccines were intended to test their effectiveness, but they were far from big enough to detect side effects that may occur only in a few people per million doses.

Most independent studies of side effects have not been large enough to detect rare events, nor to exclude their possibility; others have looked only for a preset list of symptoms and might have missed the rare outliers.

An expert panel convened by the National Academies concluded in April that for most side effects, there was not enough data to accept or reject a link to Covid vaccination.

Understanding the full range of side effects may take years.

Federal health officials acknowledge four major side effects of Covid vaccines — not including the temporary injection site pain, fever and malaise that may accompany the shots.

But in federal databases, thousands of Americans have reported that Covid vaccines caused ringing in the ears, dizziness, brain fog, sharp fluctuations in blood pressure and heart rate, new or relapsed autoimmune conditions , hives , vision problems , kidney disorders, tingling , numbness and a loss of motor skills.

Some studies have examined reports of side effects and largely concluded that there was no link . Closer scrutiny may reveal that many, perhaps most, of the other reported side effects are unrelated to immunization. Most of them are also associated with Covid , and may be the result of undiagnosed infections. But without in-depth studies, it is impossible to be sure, experts said.

Apoorva Mandavilli is a reporter focused on science and global health. She was a part of the team that won the 2021 Pulitzer Prize for Public Service for coverage of the pandemic. More about Apoorva Mandavilli

New Strategy Could Lead to Universal, Long-Lasting Flu Shot

Experimental vaccine targets portions of the flu virus that don’t change

Duke researchers have opened a new avenue in the attack against influenza viruses by creating a vaccine that encourages the immune system to target a portion of the virus surface that is less variable.

Their approach worked well in experiments with mice and ferrets and may lead to more broadly-protective influenza vaccines and less reliance on an annual shot tailored to that year’s versions of the virus. Even with vaccines, influenza kills about a half-million people each year around the world.

This new vaccine approach, described May 1 in the journal Science Translational Medicine, is part of a 5-year-old effort to develop a longer-lasting universal flu vaccine that would be able to foil all versions of the virus.

Influenza strains are referred to by a shorthand code, H5N1 for example, that describes which flavors of two particular surface proteins it carries. The H (sometimes HA), is hemagglutinin, a lollipop-shaped protein that binds to a receptor on a human cell, the first step toward getting the virus inside the cell. The N is neuraminidase, a second protein that enables a newly made virus to escape the host cell and go on to infect other cells.

“On the virus particle, there's five to 10 times more hemagglutinin than neuraminidase,” said Nicholas Heaton, PhD, an associate professor of molecular genetics and microbiology at Duke who led the research. “If we took your blood to see if are you likely to be protected from a strain of flu, we'd be measuring what your antibodies do to hemagglutinin as the best metric of what's likely to happen to you. The strongest correlates of protection have to do with hemagglutinin-directed immunity.”

Vaccines teach the immune system to react to pieces of the virus that have been specifically tailored to the versions of influenza that are expected to be the most threatening in the coming flu season. The reason we need a new flu shot every fall isn’t because the vaccine wears out; it’s because the influenza virus is constantly changing the surface proteins that vaccines target.

Flu shots -- and immune systems -- tend to target the bulb-like “head” of hemagglutinin rather than the stalk. But the details of that head region also change constantly, creating an arms race between vaccine design and viruses. The stalk, by comparison, changes much less.

“A number of groups have gone through and experimentally mutagenized the whole hemagglutinin and asked ‘which areas can change and still allow the hemagglutinin to function?’” Heaton explained. “And the answer is, you can't really change the stalk and expect it to continue to function.”

So the Duke team sought to design proteins that elicit an immune response more focused on the stalk rather than the head. “The virus has evolved to have the immune system recognize these (features on the head region). But these are the shapes the virus can change. That is an insidious strategy,” Heaton said.

Using gene-editing, they created more than 80,000 variations of the hemagglutinin protein with changes in one portion right on the top of the head domain and then tested a vaccine filled with a mixture of these variations on mice and ferrets.

Because of the broad variety of head conformations being presented to the immune system and the relative consistency of the stalks, these vaccines produced more antibodies to the stalk portion of hemagglutinin in response. “The opportunity for the immune system to see that (head portion) over and over and over, like it needs to, is compromised because there's diversity there,” Heaton said.

In lab tests and animals, the experimental vaccine caused the immune system to respond more strongly to stalk regions because they stayed consistent. This boosted the immune response to the vaccine overall, and in some cases, even improved antibody responses to the head region of the protein as well.

“Antibodies against the stalk work differently,” Heaton said. “Their mechanism of protection is not necessarily to block the first step of infection. So then our idea was, ‘What if we can come up with a vaccine that gives us both? What if we can get good head antibodies and at the same time also get stalk antibodies in case the vaccine selection was wrong, or if there's a pandemic?’”

“Essentially, the paper says, Yes, we can accomplish that,” Heaton said.

After a shot of the highly variant vaccine was administered in some experiments, 100 percent of the mice avoided illness or death from what should have been a lethal dose of flu viruses.

The next steps of the research will attempt to understand whether the same level of immunity can be achieved by presenting fewer than 80,000 hemagglutinin variants.

This research was funded in part with a contract from the NIH/National Institute of Allergy and Infectious Diseases (75N93019C00050). It also involved the use of the Duke Regional Biocontainment Laboratory, which received partial support for construction from the NIH/NIAID (UC6 AI058607)

Zhaochen Luo and Nicholas Heaton have a patent on the methods used to create large antigen libraries for this study.

CITATION: “Vaccination with Antigenically Complex Hemagglutinin Mixtures Confers Broad Protection From Influenza Disease,” Zhaochen Luo , Hector A. Miranda, Kaitlyn N. Burke, M. Ariel Spurrier, Madison Berry, Erica L. Stover, Rachel L. Spreng , Greg Waitt, Erik J. Soderblom, Andrew N. Macintyre, Kevin Wiehe, Nicholas S. Heaton. Science Translational Medicine, May 1, 2024. DOI: 10.1126/scitranslmed.adj4685

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