The World Health Organization (WHO) estimates that immunization efforts have helped save 154 million people over the past 50 years. This information highlights the helpfulness of vaccines.
However, certain immunizations, such as the flu vaccine, are not always as effective as wed like them to be due to various factors.
A recent mouse study examined how healthy dietary interventions prior to vaccination could influence metabolic health and increase flu vaccine effectiveness. The findings show that improved metabolic health led to better immune function, which increased the vaccine response.
Future research could explore how these findings, recently published in Nature Microbiology, could apply to humans.
The researchers note that obesity is associated with a higher risk of severe infectious diseases, including the flu.
While this heightened risk makes it more critical for this group to get vaccinated, researchers note that obesity can also decrease the effectiveness of flu vaccines.
For the study, they tested a few different scenarios to see if dietary changes helped prior to and after vaccination.
They took two groups of mice and fed one group a lean diet and the other a high fat diet. The mice then received a flu vaccine. After vaccination, some mice that were on the high fat diet were switched to the control diet. Mice then received a lethal dose of the flu virus, homotypic H1N1, after either 4 weeks or 12 weeks on the control diet.
Researchers found that switching to a healthy diet post-vaccination did not improve survival despite the weight loss that the previously obese mice experienced.
The previously obese mice had only a 24% survival rate after 4 weeks on the control diet and a 28% survival rate after 12 weeks on the control diet. However, the results suggested that dietary changes to lose weight after vaccination may help control viral spread.
The results were much different when the dietary changes were made pre-vaccination. To test this, researchers had certain obese mice switch to the lean control diet 4 weeks before vaccination. This switch allowed for several systemic measurements of metabolic dysfunction to return to normal and for weight loss to occur.
Researchers observed an improved immune response in these mice, particularly among their T cells, and decreased morbidity and mortality.
After exposure to the flu virus, the formerly obese mice had a 100% survival rate. The results suggest that specific dietary changes and weight loss may help improve the flu vaccines effectiveness.
The research also adds to what we know about how obesity may impact immune response, which will be an area for continued research.
We have known since the 2009 H1N1 flu epidemic that people with obesity are at increased risk of severe flu and death, and we have seen similar findings with COVID-19. It is not entirely clear why, however it could be decreased lung function and/or other factors, non-study author Marci Drees, MD, chief infection prevention officer and hospital epidemiologist for ChristianaCare, told Medical News Today.
Its important to remember that this study was conducted in mice, and of course, mice are not humans so it is certainly not definitive in terms of proving that people with obesity dont respond as well to flu vaccines, Drees said.
The studys main limitation is that it was conducted in mice, meaning further investigation is needed before these findings could be applied to humans.
Researchers also note they were limited in their ability to determine certain factors, as they had a low sample size of mice on the high fat diet who survived exposure to the flu. They acknowledge the need for a more in-depth investigation of how nutrition affects immune cell function during vaccination and infection.
There have been some small studies in the past that showed that people with obesity were more likely to get the flu, even if vaccinated, compared to vaccinated people who were not obese and despite having good levels of antibodies against the flu strains in the vaccines that year, Drees said.
There is a lot more that needs to be studied in this area to better understand the interactions between obesity, the flu virus, and the flu vaccine.
Non-study author Dr. Linda Yancey, director of infection prevention at the Memorial Hermann Health System in Houston, noted the following to MNT:
First off, this is a mouse study. It goes without saying that mice are not people. This looks like a nice foundational study to base future human trials on. Studies like these are more important than many people give them credit for because they prove something that everyone generally agrees upon a healthy diet and weight loss are good for you. While we all believe this to be true, it is nice to see solid scientific data backing this up.
The findings demonstrate that a healthy diet could affect vaccine effectiveness, but this doesnt mean that people with obesity should avoid vaccination.
As the Centers for Disease Control and Prevention (CDC) notes, people with a body mass index (BMI) of 40 or higher can be at an increased risk for flu complications. Thus, vaccination might be even more important in this demographic.
People can talk with their doctors about personal risk factors that may increase complications if they get sick with the flu. They can also discuss any potential risks from the vaccine itself and how effective the vaccine may be for them.
While the study wont lead to immediate change in clinical practice or recommendations, weight loss among individuals who are obese is generally encouraged by healthcare professionals.
[The study] will need to be followed up by a human trial to see if the observation holds up, Yancey noted.
If so, then we could potentially recommend a healthy diet and weight loss in the weeks leading up to vaccination. However, this is a general recommendation for everyone already. So, there wouldnt be any big changes in overall health advice.
Dress said she wouldnt change any current recommendations based on this one study in mice, noting the following:
There are many health benefits to losing weight, and [a] better response to vaccines might be one of them. But that is really just a theory right now. I definitely would still highly promote influenza vaccine regardless of your weight and I would probably recommend it even more highly in persons with obesity because we know their risk of severe flu is higher.
So, I wouldnt want someone to not get vaccinated because they think the flu vaccine wont work for them there is also good evidence that even if you get the flu after being vaccinated, your risk of severe disease and death is lower. Persons living with obesity should discuss with their doctor what their options are for weight loss, but should still definitely get their annual flu shot.
FORT LAUDERDALE, Fla. (NewsNation) In a first-ever human clinical trial, researchers at the University of Florida developed an mRNA vaccine that reprograms the immune system to fight the most aggressive and lethal brain tumor.
Glioblastoma has a median survival rate of around 15 months, according to the University of Florida Health, with treatment including surgery, radiation, and some combination of chemotherapy.
Researchers used mRNA technology and lipid nanoparticles, similar to COVID-19 vaccines during the pandemic, to fight notoriously treatment-resistant cancers.
However, there were two differences researchers used patients tumor cells to create a personalized vaccine and a newly engineered complex delivery mechanism within the vaccine, the University of Florida said in a news release.
Scientists and researchers at the University of Florida reported their findings Friday in the journal Cell, a culmination of more than seven years of studies.
The team started their research with pre-clinical mouse models that then turned into a clinical trial of 10 pet dog patients with terminal brain tumors. They lived a median of 139 days, compared to a median survival of 30 to 60 days for dogs with the condition, researchers said.
Following promising results with the dogs, the team advanced the research to a small U.S. Food and Drug Administration-approved clinical trial that involved four human patients.
Researchers said patients lived longer than expected.
We extended survival in these patients to nine months, eight months, 10 months they all eventually succumbed. But I have to mention when we started this trial, we started at very low dosing, Dr. Elias Sayour, an associate professor of neurosurgery and pediatrics at the University of Florida, told NewsNation. We only gave a few vaccines two patients got two vaccines; the other two patients got four vaccines. So, we still have a lot left to learn.
Scientists and researchers said their next step is to test a Phase 1 clinical trial for brain cancer, including up to 24 adults and pediatric patients, to validate their findings.
Researchers said once an optimal and safe dose is confirmed, an estimated 25 children would participate in Phase 2.
This is a breakthrough for two important reasons we talk about the mRNA vaccine technology which has been in the making for 30-plus years; this is not new stuff, said NewsNation medical contributor Dr. Dave Montgomery. The second part of this, which is really fascinating and very different from COVID, is that they used the tumor biology of each of these patients to make the vaccine more specific to that particular tumor.
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.
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.
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 immunised with these nanocage vaccines, they produced antibodies that neutralised 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 immunised 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.
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 publics 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 Campaignhow much money these efforts saved minus how much they costcame 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 nations efforts to vaccinate people and protect them from COVID-19. It also adds to the body of evidence that shows the Campaigns 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 Campaigns 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 2021March 2022, was conducted by researchers from HHS Office of the Assistant Secretary for Public Affairs and Fors Marsh in Arlington, Virginia.
Yanna Marie Orcel accesses a recording available at the Beneath Our Skin exhibit at the Clemmons Family Farm in Charlotte on Thursday, May 2, 2024. Photo by Glenn Russell/VTDigger
CHARLOTTE Samirah Evans hates needles. So she wasnt thrilled when she saw on TV the first folks receiving the Covid-19 vaccine in December 2020.
That needle looks long and it made me nervous, she outlines in an audio account that is now a part of a storytelling project by Clemmons Family Farm capturing the range of reactions of Black and African American Vermonters during the early rollout of the vaccine.
Funded by the Vermont Department of Health, the exhibit includes original stories, songs, poems and visual art by 30 Black Vermont residents and three white health providers who administered the vaccine in its early days.
As the pandemic wreaked havoc in the early months of 2020, Evans, a Black musician in Vermont, recalls her horror at the passing of a colleague, followed by the father of an acquaintance, followed by musicians in New Orleans, both Black and white.
Until her cousin got rushed to the hospital critically ill from the virus, most of her family members had refused to take the vaccine. Because for decades African Americans have been used for experiments that led to death. And many of us are marginalized in various ways when it comes to having access to proper health care and nutrition, she said.
Evans understood the lack of trust in the government and health care system, but she also saw the pandemic did not discriminate that people of all races were dying alone and so fast that timely burials were difficult.
So how did I feel about taking the vaccine? Absolutely 100% ready, in line to take one for the sake of humanity, she continues in her account. And yes, it helps that a female African American scientist Kizzy Corbett was on the front lines of developing the Moderna vaccine.
Evans is among the artists participating in the Beneath Our Skin exhibit, which opened last month and is now on display at the Clemmons Family Farm in Charlotte, the South Burlington Public Library, the Root Social Justice Center in Brattleboro, the University of Vermonts College of Nursing and Health Sciences and online.
Her contribution is a song titled The proof is in the pudding:
But when we hit the million mark
So many were still in the dark
More lives lost than World War II
Yet there is something that we can doIts time to let go of the fears
Stop watching those around us disappear
Find the courage to protect yourself
Save anothers life Dont let one more life perish
Consider the lives that you cherish
This is a shared responsibility
The proof is in the pudding.
The global pandemic threw into light the disparate health treatments and outcomes of marginalized communities nationwide. In an effort to counteract that, the Vermont Professionals of Color Network helped to create the Vermont Health Equity Initiative in the spring of 2021, to promote Covid vaccine clinics for Black people, Indigenous people and people of color, giving them a chance to get to the head of the line.
The BIPOC community is growing in the nations second-whitest state, but Black people make up a mere 1.4% (about 8,000 people) of Vermonts population, up from 1% in 2010, according to the 2020 census.
According to the health departments Covid data, white Vermonters ages 5 and above recorded the highest updated booster rate at 34%, while Black Vermonters have lagged at 17%.
All but two of the Black Vermonters who participated in the Beneath our Skin project were vaccinated (booster shots were not available at the time); 12 were from the U.S., nine were from East Africa and one was from the Pacific Islands, according to a report compiled by the Clemmons Family Farm in March.
The key lessons from the project include the need to develop restorative interventions to address mistrust in government and public health systems, which, the report notes, is more prevalent among U.S.-born Black people, and improve communication about the virus and the vaccine, according to the report. Black Vermonters who participated expressed a strong desire for bodily autonomy, and the project found that family members experience strongly influenced vaccine decisions. It also noted that transportation and weather posed barriers to accessing the vaccine.
The storytelling project, conducted at the height of the pandemic, is an effort to highlight and learn from the Black experience and help build a shared understanding of needs and perceptions related to improving Covid-19 vaccination access and uptake, states a release from the Clemmons Family Farm, one of Vermonts few historic African American-owned farms.
It is also an effort by the health department to generate qualitative data about vaccine acceptance and hesitancy, and about health provider care-giving attitudes and practices that may improve future vaccine behaviors of Black Vermonters.
The nonprofit collected stories of Black Vermonters who were fully, partially or not at all vaccinated against Covid-19 between October 2021 and December 2022. Curated by Yanna Marie Orcel, a wellness arts adviser at the farm, the exhibit includes three collections:
13 stories from Black Vermonters and three anonymous white vaccine providers who gave the vaccine to Black clients around Chittenden County
7 Black residents sharing their stories anonymously over the phone with a trained facilitator
10 stories from members of the Vermont African-American/African Diaspora Artists Network beyond Chittenden County.
Last Thursday, Orcel walked through the Charlotte exhibit housed in what was once a blacksmiths shop on the farm.
She pointed out quotes displayed on one wall to show the gamut of reactions from fear and mistrust to relief and gratitude. They are printed in red on cards modeled after the vaccination cards issued during the pandemic. Many of them refer to the infamous syphilis experiment on Black men in Tuskegee, Alabama, in which human subjects were offered free food and checkups, but never told that they were part of a study in which medical treatment would be withheld.
The idea of the Vermont project was to get people to not only remember what happened but also to get them to think differently, explained Orcel, who has a background in art therapy. Since the arts are known to support public health and mental health and well being, its a perfect integration, she said.
Robin Anthony Kouyate, a member of the farms board and a senior adviser on the larger How Are We Doing? project of which this exhibit is a part, said the exhibit is intended to really bring to light some of the attitudes and the perspectives of Black and white Vermonters.
A public health-trained social and behavioral scientist, Anthony Kouyate said the stories definitely spark some uncomfortable conversations but her favorite aspect is that art was used as a way of collecting data.
Recalling her own experience, Orcel said she was terrified being in Massachusetts when the pandemic began in 2020. Curating the exhibit brought back the fear of crowds, the inability to go out without a mask, the hoarding of toilet paper things people have already begun to forget about, she said.
Light blue face masks, ubiquitous during the height of the pandemic, were pinned around the room.
One of the displays the outline of a pink human head filled with colorful words and a black spiky virus superimposed in the middle represents a word cloud generated from the audio transcripts of all the stories, Orcel said. Freedom, Tuskegee, white folks and choice loom in large letters, representing the words that came up the most.
The project shows that Black Vermonters are a complex group that didnt feel one way about the vaccine, said Orcel.
Orcel hopes the display will help inform Vermonts public of how Black Vermonters actually felt and to contextualize it so that the general public can understand more about why Black Vermonters were hesitant.
I would like this exhibit to also serve as a way for Black Vermonters to feel seen, represented, heard and understood and for their voices to be amplified in the realm of public health, which they usually are not, Orcel said.
Actor Shreyas Talpade, who was shooting for his upcoming filmWelcome 3- Welcome To The Jungle, suffered a heart attack and was rushed to Mumbais Bellevue Hospital. This was earlier this year in January. And recently, the news that went viral on social media was that Covid-19 vaccinations led to multiple heart attacks.
Speaking about the same with Lehren Retro, the actor said, I dont smoke. Im not really a regular drinker, I drink perhaps once a month. No tobacco, yes, my cholesterol was a little high, which I was told is normal these days. I was taking medication for that, and it had come down reasonably. So, if all the factorsno diabetes, no blood pressure, nothing, then what could be the reason?
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Talpade added, I would not negate the theory. It was only after the Covid-19 vaccination is when I started experiencing some fatigue and tiredness. There has to be some amount of truth, and we cannot negate the theory. Maybe it is Covid or the vaccine, but there is something associated post thatIt is very unfortunate because we genuinely dont know what we have taken inside our bodies.
He is now doing fine and while speaking to Times Of India, gave a detailed account of what happened to his health during the shoot.
He revealed, Suddenly, after the last shot, I felt breathless, and my left hand started paining. I could barely walk to my vanity van and change my clothes. I thought it was a muscle pull since we were shooting action sequences. You dont think of the worst-case scenario, right? I had never experienced this kind of fatigue.
The actor added, As soon as I got into the car, I felt I should head straight to the hospital, but thought I should go home first. My wife, Deepti, saw me in that state and within 10 minutes, we were on our way to the hospital. We were almost there and could see the hospital gate, but the entry was barricaded, and we had to take a U-turn. The very next moment my face went numb, and I passed out.
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To state the obvious, vaccination is a divisive subject right now. In 2021, the year after the COVID-19 pandemic first took hold, research suggested that around 18 percent of Americans would not agree to be vaccinated. But what about if the vaccine was not in a needle, but in your salad? Stay with us.
In Tennessee, right now, people are worried about vaccines turning up in their lunch. In fact, theyre so concerned, the state has actually now passed a bill that would require any food that contains a vaccine to be labeled as a drug.
Lets get one thing clear: the lettuce in your local grocery store does not contain a vaccine. For better or worse, the new Tennessee bill is future-proofing the states food system rather than reacting to an immediate situation. However, while the idea of munching on a vaccine sounds ridiculous, it actually isnt that far-fetched.
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At the University of California, researchers are currently looking into whether a pathogen-targeting mRNA could be implanted into the cells of edible plants. Ideally, a single plant would produce enough mRNA to vaccinate a single person, Juan Pablo Giraldo, an associate professor in UC Riversides Department of Botany and Plant Sciences, said in a statement in 2021.
We are testing this approach with spinach and lettuce and have long-term goals of people growing it in their own gardens, he added. Farmers could also eventually grow entire fields of it.
The long-term goal of the research is to make vaccines more accessible. Right now, vaccines developed with mRNA technology have to be kept cold at all times, but when implanted in food, they might be able to be stored at room temperature. Making vaccines easier to transport, store, and administer could potentially be life-saving for millions of people.
According to the World Health Organization (WHO), vaccination is one of the most impactful and cost-effective public health interventions available. And yet, across Africa, only one in five children receive the vaccines that they need.
The University of California is not alone in its research into edible vaccines. At the University of Tokyo, researchers have been experimenting with creating a cholera vaccine with edible rice. Cholera infects up to four million people every year and causes up to 143,000 deaths. Vaccines are available for the disease, and four of them are needle-free, but again, they require cold storage.
Research into edible vaccines is promising, but it is still ongoing. The Tennessee bill, which is awaiting signature into law, is not a sign that there are now vaccines in the food system. It simply states that if vaccines were added to food, that food would have to feature clear medical labeling, as you would see on medication.
Republican State Rep. Scott Cepicky has expressed concern that vaccinated lettuces would be available in grocery stores in the future.
When you go into a grocery store, you should know as a consumer that this head of lettuce is a head of lettuce, the head of lettuce right next to it could contain a vaccine in it, he said during a House Health Committee session earlier this year. All were saying is, if it does have the vaccine in it, have it listed as a pharmaceutical so that people can get the proper dosage.
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Its important to note that there has been no indication from any researchers on this topic that, if studies were successful, any food containing mRNA would be widely available on grocery store shelves in the future.
The ability to reproduce mRNA vaccines in plants is a technology that has not been successfully demonstrated, either at lab or commercial scale, a spokesperson for the University of California told Newsweek in February 2024. Its feasibility is still being tested and the technology does not yet exist.
Tennessees Vaccine Lettuce Bill, known formally as HB 1894, was passed in a 23 to six Senate vote in March. It now awaits Governor Bill Lees signature into law.
Charlotte is a writer and editor based in sunny Southsea on England's southern coast.
The US Department of Health and Human Services' (HHS's) COVID-19 vaccination campaign saved $732 billion by averting illness and related costs during the Delta and Omicron variant waves, with a return of nearly $90 for every dollar spent, estimates astudy by HHS and the research firm Fors Marsh.
The study was published yesterday in the American Journal of Preventive Medicine.
In April 2021, HHS launched its"We Can Do This"public education campaign to boost US COVID-19 vaccine uptake, especially among high-risk populations and those reluctant to receive the vaccine. The push, one of the largest of its kind in US history, aimed to reach 90% of adults at least once per quarter, with more than 7,000 television, digital, print, and radio ads in 14 languages.
The study authors used weekly media market data, information from the Centers for Disease Control and Prevention (CDC), and survey data on the drive's effects on vaccination from launch up to March 2022.
The researchers estimated that the campaign encouraged 22.3 million Americans to complete their primary COVID-19 vaccine series, preventing nearly 2.6 million infections, including nearly 244,000 hospitalizations.
Findings underscore the utility of public health education campaigns in promoting behavior change and in corresponding health and fiscal benefits.
"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," the authors wrote. "In comparison, the Campaign cost $377 million, with an additional $7.9 billion spent to vaccinate 22.3 million people in that time period," for an estimated return on investment of $89.54 on every dollar spent.
"Findings underscore the utility of public health education campaigns in promoting behavior change and in corresponding health and fiscal benefits," the researchers wrote. "Furthermore, findings may guide the implementation of public health education campaigns to combat future public health crises."
In an HHSpress release, May Malik, MA, HHS senior advisor for public education campaigns, said, "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."
Sunday, 5 May 2024, 23:20
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AstraZeneca's was perhaps one of the biggest controversies following the launch of the global Covid-19 vaccination campaign. Three vaccines developed by Pfizer, Moderna and AstraZeneca were the first to bring hope to a population engulfed in a pandemic that kept them confined at home for months and took the lives of millions of people. AstraZeneca's (later renamed Vaxzevria) was the third to arrive in Spain on 6 February 2021, having been authorised by the European Commission on 29 January 2021.
But this vaccine, developed by the University of Oxford, was soon linked to cases of "blood clots, often in unusual locations (for example, in the brain, intestines, liver or spleen), along with low blood platelets, in some cases accompanied by haemorrhaging", as admitted by the European Medicines Agency (EMA) itself. This became so prevalent that, in 2021, the EMA decided to include in the package leaflet for this vaccine a mention of the side-effects related to coagulation disorders, namely thrombosis syndrome with thrombocytopenia (TTS - blood-clotting with low blood platelets), thrombosis of the veins and cerebral venous sinus thrombosis (CVST), venous thromboembolism (VTE - blood clots in a vein) and thrombocytopenia. However, the EMA has always maintained that these are "very rare" adverse reactions and that "the benefits of the drug far outweigh any potential risks."
To date AstraZeneca has not commented on the matter. However, as part of a High Court case in which 51 cases of victims and their families claiming up to 100 million in damages from the pharmaceutical company for adverse side-effects with its vaccine, the company has admitted for the first time that its Covid-19 formula can cause side-effects such as thrombosis in "very rare cases". It made this statement in a legal document filed in the UK High Court in February, as reported in The Telegraph.
AstraZeneca continues to deny the plaintiffs' claims, but accepts that the vaccine doses "may, in very rare cases, cause thrombosis". Indeed, the plaintiffs' lawyers argue that the vaccine "has had a devastating effect on a small number of families."
The British newspaper reports that one of the first cases to go to court was that of Jamie Scott, who has been left with a permanent brain injury after suffering a blood clot and haemorrhage in his brain that prevented him from working after receiving AstraZeneca's vaccine in April 2021. In May 2023 AstraZeneca, also by court response, replied that it did not accept the assertion that Scott's medical condition was caused by its vaccine.
As the Spanish government specifies in its Covid-19 vaccination strategy, after changing the recommendations for the use of Vaxzevria (as the AstraZeneca vaccine is currently known) on several occasions, as new data on its effectiveness in the elderly and its possible relationship with certain types of thrombosis became available, the Ministry of Health restarted the roll-out of this vaccine on 24 March 2021.
However, it did so with certain limitations. Its use was recommended only for people aged 60-plus. In fact, for people under 60 years of age who had already received the first dose of Vaxzevria, it was advised to complete vaccine top-ups with either Pfizer or Moderna (Comirnaty) vaccines unless, after signing an informed consent form, the patient agreed to receive a second dose of the AstraZeneca vaccine.
So why is it only given to people over 60 years of age? Because most of the instances of thromboses occurred in under-60s, mainly women, and very rarely did they occur in older people.
Vaccine formulation alters the durability of LN expansion
First, we identified a vaccine formulation eliciting robust and durable LN expansion. Mesoporous silica (MPS) rod-based vaccines, previously found to elicit strong cellular and humoral responses against diverse antigen targets compared with a traditional bolus (liquid) vaccine, were explored18,19,20,21. These high-aspect ratio, silica-based nanoparticles can adsorb vaccine antigens and adjuvants for sustained release, and form a three-dimensional scaffold promoting antigen-presenting cell (APC) recruitment in mouse models. MPS vaccines previously induced potent and long-lived germinal centre responses dependent on sustained antigen release from the vaccine site22,23. Here, MPS rods used in vaccine formulation had an average length of 85.9m and released vaccine components cytosine-guanosine oligodeoxynucleotide (CpG) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in a sustained manner (Extended Data Fig. 1ae). Draining (dLN; ipsilateral to vaccine site) and non-draining (ndLN; contralateral) inguinal LNs of mice immunized with MPS or bolus vaccines were imaged for 100days post-vaccination using HFUS.
Although PBS injection did not affect LN volume, both vaccine formulations induced LN expansion, but with markedly different durability (Fig. 1a,b and Supplementary Fig. 1ac). At the early stage of expansion (within days), both MPS and bolus-vaccinated mouse LNs expanded to a similar extent (Fig. 1c). However, while the bolus vaccine LNs peaked at this time, resulting in a two-fold transient increase in LN volume, the MPS vaccine induced a significantly more substantial (~7) LN expansion over 1week which was maintained for ~3weeks (Fig. 1b,c). Although LN volume in the MPS-vaccinated mice began to decrease ~20days after immunization, it remained elevated out to 100days (Supplementary Fig. 1d). NdLNs did not change in volume with either vaccine, and normalizing the dLN to ndLN volume within each mouse indicated a similar pattern of dynamic LN expansion and contraction (Fig. 1d and Supplementary Fig. 1e). The removal of either CpG or GM-CSF from the vaccine formulation diminished the magnitude of dLN expansion (Extended Data Fig. 2a). An MPS vaccine with log-fold lower doses of ovalbumin (OVA) and CpG also induced long-term LN expansion (Extended Data Fig. 2b). While other published depot-based vaccine formulations including alum, MF59 emulsion and cryogel-based scaffolds also induced LN expansion, expansion was notably lower than with the MPS vaccine (Extended Data Fig. 2c). The MPS vaccine formulation was thus selected as a model of strong vaccination resulting in persistent LN expansion for subsequent investigation.
Mice were immunized with MPS or bolus vaccines delivering GM-CSF, CpG and OVA protein, and compared to PBS-injected controls. Vaccine-draining and non-draining LNs were longitudinally imaged using HFUS. a, Representative HFUS images of vaccine-draining LNs (defined by yellow dashed area) out to 100days after vaccination. Scale bar, 2 mm. b, Quantification of vaccine-draining LN volume over time. Statistical analysis was performed using a two-way analysis of variance (ANOVA) with repeated measures. Significance relative to the PBS group is depicted at each timepoint (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). Exact P values between MPS and PBS are P=0.04, day 3; P=0.0008, day 5; P=0.006, day 7; P=0.01, day 9; P=0.001, day 11; P=0.004, day 13; P=0.004, day 15; P=0.03, day 17; P=0.01, day 37; P=0.001, day 44; P=0.01, day 62. Exact P values between bolus and PBS are P=0.009, day 1; P=0.02, day 5; P=0.03, day 9; P=0.008, day 11; P=0.04, day 44. c, Plots of LN volume among groups on days 3 (left) and 19 (right). Statistical analysis was performed using ANOVA with Tukeys post hoc test. d, Representative HFUS images of MPS or bolus vaccine-draining or non-draining LNs 15days after vaccination (left) and quantification of dLN/ndLN volume ratio (right). Statistical analysis was performed using ANOVA with Tukeys post hoc test. For ad, n=7 (MPS and bolus) or 8 (PBS) biologically independent animals per group, imaged longitudinally in two cohorts; meanss.d.
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To assess tissue-scale alterations involved in durable LN expansion, LN mechanical properties and extracellular matrix (ECM) distribution were next characterized. Here, MPS-vaccinated mouse dLNs were collected 7days after immunization, beyond the initial expansion phase (when MPS outpaced bolus vaccine LN expansion). At this time, LN collagen architecture was largely maintained, as expected (Fig. 2a)6. Hyaluronic acid (HA) localization was increased in the periphery/follicle, most visibly 7days after immunization, although still notable up to 3weeks later, demonstrating persistent alterations (Fig. 2a,b and Supplementary Fig. 2a). In contrast, the cellular F-actin signal was greater towards the centre of both control and MPS dLNs, with greater polarization between the centre and periphery in the MPS condition (Fig. 2c and Supplementary Fig. 2bd). These changes suggest that LN expansion may be accompanied by changes in tissue mechanical properties, as both HA and F-actin are involved in cellular mechanotransduction and signalling pathways. Through nanoindentation of thick (~500m) LN slices (Fig. 2d), we found that LNs with enduring expansion had reduced stiffness (G) and loss modulus (G) compared with control LNs (Fig. 2e,f). Viscoelasticity, measured by G/G (tan()), was significantly increased in MPS dLNs compared with LNs from control mice, suggesting decreased matrix crosslinking (Fig. 2g).
Mice were treated with MPS vaccines (delivering GM-CSF, CpG, OVA) or PBS, and LNs were collected after 7 and 20days. a, Representative immunohistochemistry (IHC) images depicting LN ECM on day 7. b, Representative IHC image depicting LN ECM on day 20. c, Representative IHC images of LNs stained for F-actin on day 7. For ac, n=3 biologically independent animals per group. d, Schematic depicting nanoindentation of a thick LN slice (above) and experimental timeline (below). eg, Mean G (e), G (f) and tan() (g) across LNs. Statistical analysis was performed using MannWhitney test (e) or two-tailed t-test (f,g). h, Heat maps depicting G across individual LNs. Scale bar, 1mm. i, Mean G of sample points across each LN, separated into those collected at the centre or periphery. n=11 (control, centre), 10 (MPS, centre), 16 (control, periphery) and 15 (MPS, periphery) biologically independent animals per group; results are means.d., combined from three independent experiments. Statistical analysis was performed using MannWhitney test. j, Plot of LN mass versus mean G. For eg, i and j, each data point represents a unique LN per mouse; n=10 (MPS) or 11 (PBS) biologically independent animals per group; means.d., combined from two independent experiments. k, Representative IHC images depicting Hoechst stain within LNs on day 7. Scale bar, 100m. l, Quantification of Hoechst signal across LNs; n=3 (MPS) or 4 (PBS) biologically independent animals per group; means.d.
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Spatial variations in mechanics across LNs were next investigated using nanoindentation (Fig. 2h and Supplementary Fig. 3). Both control and MPS-vaccinated mouse LNs were softer and more viscoelastic in the centre than in the periphery, and this finding was confirmed through intentional sampling at the centre or periphery of nave LNs (Supplementary Fig. 4ae). The LN periphery (~12kPa) was approximately twice as stiff as the centre (~6kPa). Interestingly, after vaccination, LN G and G were only significantly altered at the periphery, while tan() increased only in the LN centre (Fig. 2i and Supplementary Fig. 5ae). LN peripheral stiffness correlated negatively with LN mass, suggesting that the degree of tissue softening relates to the extent of LN enlargement induced by vaccination (Fig. 2j). LN cellular distribution and tissue density remained unaltered, despite expansion (Fig. 2k,l and Supplementary Fig. 6ad). Taken together, these results suggest that LN tissue encompasses a range of mechanical properties, dependent on location within the node, and these parameters change as LNs expand.
Considering that tissue-level changes may impact or reflect cellular responses, changes in LN cellularity during expansion were next characterized, ranging from early-stage (day 4) to long-term (day 51) changes (Supplementary Figs. 7 and 8a). Cellular expansion was greater and more sustained in MPS-vaccinated mice than in the bolus-vaccinated mice or PBS-injected control; notably, the total cell counts within a LN correlated with its volume (Fig. 3a,b). As early as day 4, monocytes, neutrophils and macrophages were expanded in MPS dLNs, while conventional dendritic cells (DCs), plasmacytoid DCs and T cells peaked at day 7 before declining over time (Fig. 3c,d and Supplementary Fig. 8bi). Monocytes in particular expanded ~80-fold in MPS dLNs compared with PBS controls 4 days after vaccination, relative to ~25 expansion in the bolus group, but this increase was maintained for several weeks in the MPS condition only (Supplementary Fig. 8n). B cells also significantly expanded by day 7 and remained elevated until day 17 (Fig. 3e). A variety of stromal cells expanded following MPS vaccination, typically peaking later (days 1117) than the immune cells, except for natural killer (NK) cells, which also tended to expand later (days 711) (Fig. 3f and Supplementary Fig. 8jm). By comparison, changes in the bolus vaccine group were more modest beyond 4days, and PBS-treated control dLNs and ndLNs from all groups demonstrated minimal changes in cell populations. These results indicate that vaccine-induced LN expansion engages the temporal dynamics of a pathogen-induced immune response, with innate immune cells rapidly responding followed by lymphocytes at later times.
Mice were immunized with MPS or bolus vaccines containing GM-CSF, CpG and OVA protein, euthanized on days 4, 7, 11, 17 and 51 for LN collection and analysis through flow cytometry and compared to PBS-injected controls. a, Total LN cell counts over time. b, Linear regression of LN cell count on a given day versus volume (measured through HFUS). cf, Numbers of dendritic cells (c), T cells (d), B cells (e) and follicular dendritic cells (FDCs; CD45 CD31 CD21/35+) (f) over time. For af, n=4 (MPS dLN days 4, 11 and MPS ndLN day 7) or 5 (all other timepoints and groups) biologically independent animals per group per timepoint; means.d. For a and ce, statistical analysis was performed using ANOVA with Tukeys post hoc test; differences present between one group and all other groups are shown. For f, statistical analysis was performed using KruskalWallis test with Dunns post hoc test; the statistical difference between the MPS and PBS dLN groups is shown. For gj, mice were injected with MPS or bolus vaccines (GM-CSF, CpG, OVA) and dLNs were collected at a late timepoint (days 2021). Nave mice were included as controls. n=5 biologically independent animals per group, barcoded and pooled for sequencing. g, Schematic of processing pipeline for single-cell sequencing. LNs were digested and FACS-sorted to enrich live, CD45+ CD3 CD19 cells for sequencing. h, UMAP of 20,858 cells across conditions coloured by cluster membership. i, UMAP as in h, here coloured by cell density. Red indicates high cell density, blue low density. j, Heat map of relative average expression of marker genes in each cluster from h. Colour bar indicates relative gene expression as z-score. a.u., arbitrary units. k, Frequency of individual cell clusters within each sample. Statistical analysis was performed using ANOVA with Tukeys post hoc test. pDCs, plasmacytoid DCs; Mig., migratory; Infl., inflammatory.
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Because LN expansion is known to be mediated by myeloid interactions with LN stromal cells, we next performed single-cell RNA sequencing (scRNA-seq) on the LN myeloid compartment after vaccination (Fig. 3g and Supplementary Fig. 9a)2. LNs were examined at a late timepoint (days 2021) to consider mediators of durable expansion. After removal of lymphocytes and stromal cells, we identified nine clusters from the remaining 20,858 cells analysed (Fig. 3hj). Clusters were annotated as type-2 conventional DCs (cDC2s; c0, Sirpa, H2-Ab1), plasmacytoid DCs (c1, Siglech, Bst2), migratory DCs (c2, Ccr7, Clu), type-1 conventional DCs (c3, Xcr1, Clec9a), Langerhans cells (c4, Cd207), plasma cells (c5, Ighg2b, Ighg1), inflammatory monocytes (c6, Csf1r, Ly6c2), neutrophils (c7, S100a8, S100a9) and proliferating cDC2s (c8, Top2a, Mki67) (Fig. 3j and Supplementary Fig. 9b). Consistent with the flow cytometry analysis, scRNA-seq identified broad changes in LN cell populations after immunization, with notable differences based on vaccine strength (Fig. 3i,k). Compared with the PBS condition, both bolus and MPS vaccines increased DC2 proportions and decreased frequencies of migratory DCs and DC1s. Maintenance of LN expansion was associated with increased frequencies of inflammatory monocytes and plasma cells and decreased Langerhans cells (Fig. 3k).
Given the importance of sustained antigen presentation in maintenance of LN immune responses24,25, we hypothesized that vaccine antigen availability and APC populations may affect LN expansion. Compared with LNs of mice given the full MPS vaccine, LNs of mice given an MPS vaccine without antigen became prominently less enlarged and contracted sooner (Fig. 4a,b and Extended Data Fig. 3a). This indicates that long-term antigen presentation at the vaccine site is important for sustained LN expansion. Indeed, injecting the antigen separately as a bolus (that is, not delivered from the MPS scaffold) similarly reduced the degree and duration of expansion, indicating a critical role of sustained antigen presentation (Extended Data Fig. 3b).
a,b, Mice were immunized on day 0 with a full MPS vaccine (containing GM-CSF, CpG and OVA protein) or an MPS vaccine without antigen (GM-CSF and CpG only). LN volume was tracked using HFUS imaging. n=5 biologically independent animals per group. a, Representative HFUS images of vaccine-draining LNs. Scale bar, 2 mm. b, Quantification of LN volume over time. Statistical analysis was performed using two-tailed t-tests. For a and b, n=5 biologically independent animals per group. cj, Mice were injected with MPS or bolus vaccines (GM-CSF, CpG, OVA) and dLNs were collected at a late timepoint (days 20 and 21). Nave mice were included as controls. n=5 biologically independent animals per group, barcoded and pooled for sequencing. c, Numbers of differentially expressed protein coding genes by cell type between the MPS and bolus conditions. P value calculated using DESeq2. d, Volcano plot displaying differentially expressed cDC2 genes between the MPS and bolus conditions. e, Ltb (lymphotoxin ) expression among DC subtypes in the different conditions. f, Proportion of inflammatory monocytes (cluster 6 from Fig. 3h) in LNs. g, UMAP of 1,468 inflammatory monocytes coloured by cluster membership. h, UMAP as in g, here coloured by cell density. Red indicates high cell density, blue low density. i, Proportion of cluster c0 among inflammatory monocytes. j, Pathway analysis for inflammatory monocyte cluster c0. For c and d, statistical analysis was performed with DESeq2. For f and i, statistical analysis was performed using ANOVA with Tukeys post hoc test.
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To identify potential mediators of this differential response, we next focused the analysis of our scRNA-seq dataset on LN APC populations. Broadly, we identified varying numbers of differentially expressed genes within immune cell clusters between the MPS and bolus vaccine conditions (Fig. 4c). The most dramatic transcriptional changes were in the LN-resident cDC2 and cDC1 compartments, more so than in migratory DCs and Langerhans cells. The cDC2s showed the greatest number of differentially expressed protein coding genes between the two vaccine strengths (Fig. 4c,d), and consensus non-negative matrix factorization (cNMF) analysis26 identified a cDC2-specific programme (CNMF_X14) enriched with MPS vaccination (Supplementary Fig. 10ad). This programme included genes involved in inflammation (Il1r2m, Cd86), immune regulation (Clec4a2, Sirpa, Lst1), cell migration machinery (Rasgef1b, Elmo1) and smooth muscle contraction (Ppp1r14a) (Supplementary Fig. 10d). Furthermore, the gene encoding lymphotoxin beta (Ltb), another member of CNMF_X14, was strongly upregulated in cDC2s with MPS vaccination relative to the bolus condition (Fig. 4d,e and Supplementary Fig. 10d,e). The involvement of mechanosensing genes and Ltb, involved in lymphoid organogenesis, suggests that cDC2s may both respond and contribute to the changing LN microenvironment during expansion. Despite robust LN expansion and immune activation, Cd274 (PD-L1) was not notably upregulated on myeloid cell subsets 20days after immunization (Supplementary Fig. 11a,b). MPS immunization also increased the frequency of CD19 plasma cells and directed gene expression towards more mature immunoglobulin (Ighg1 versus Ighm) expression (Supplementary Fig. 12ad).
Inflammatory monocytes demonstrated significant transcriptional changes between the MPS and bolus vaccine groups (Fig. 4c), and the greatest expansion by both total number and relative proportion following MPS vaccination (Fig. 4f and Supplementary Fig. 8n). Therefore, we were interested in how MPS vaccination affected their gene expression profile. Monocytes, similar to DCs, can present antigen to T cells in LNs27, and particular attention was paid to potential T cell interactions. Monocyte-specific clustering identified three subpopulations of inflammatory monocytes (Fig. 4g,h). Of these, c0 formed the predominant monocyte phenotype in LNs with sustained expansion (MPS condition) relative to nave or bolus-vaccinated mice (Fig. 4h,i). Gene set enrichment analysis identified pathways associated with antigen processing and presentation, IFN response and inflammatory signalling that differentiated monocytes in the strong and weak vaccine LNs (Fig. 4j). These gene alterations position inflammatory monocytes as a potential stimulatory, APC type involved in sustained LN expansion.
To confirm the impact of vaccine strength on antigen-presenting, inflammatory monocytes, LNs of mice vaccinated with the MPS vaccine (with or without antigen) were collected and further compared to LNs of mice given bolus or PBS controls (Fig. 5a). Consistent with the scRNA-seq analysis, Ly6Chi inflammatory monocytes27,28 comprised the majority (~6070%) of LN monocytes in the MPS group over time, significantly higher than the PBS and bolus groups (~4050%) by day 20 (Supplementary Fig. 13a,b). Inflammatory monocytes were also significantly expanded in terms of number and proportion in the LNs of MPS-vaccinated mice at day 20 compared with the PBS and bolus, and were visualized in LNs through CCR2 expression (Fig. 5b and Supplementary Fig. 13c,d)29. Inflammatory monocyte responses were abrogated at later timepoints when the MPS vaccine was delivered without antigen, equivalent to the PBS or bolus controls by day 20, suggesting a relationship between long-lived antigen presentation, LN expansion and monocyte responses (Fig. 5b). Consistent with scRNA-seq data and previous investigation on the MPS vaccine system, MPS immunization elicited robust and persistent germinal centre B cell responses, also dependent on the presence of antigen in the vaccine (Extended Data Fig. 4ac).
Mice were treated with MPS or bolus vaccines (containing GM-CSF, CpG, OVA), MPS vaccine without antigen (GM-CSF, CpG only) or PBS, and LNs were collected on days 7, 14 and 20 for cellular analysis. n=5 biologically independent animals per group per timepoint. a, Experimental timeline and conditions. b, Inflammatory monocyte number in LNs over time. Statistical analysis was performed using ANOVA with Tukeys post hoc test. c, Representative flow cytometry histograms depicting MHCII expression on Ly6hi inflammatory monocytes. Median percentage MHCII expression in each group is listed on the right. d, MHCII expression on Ly6hi inflammatory monocytes in the LN at day 20. Statistical analysis was performed using ANOVA with Tukeys post hoc test. For b and d, meanss.d. eh, Mice were administered MPS vaccines (containing GM-CSF, CpG, OVA) or PBS. One group of MPS-vaccinated mice was treated with MC-21 CCR2-depleting mAb daily from days 15 (MC-21 expansion) and one group was treated daily from days 1014 (MC-21 maintenance). Peripheral blood was collected on days 6, 8, 14 and 20 for cellular analysis. n=5 biologically independent animals per group. e, Experimental timeline and conditions. f, Inflammatory monocyte proportion in blood over time. Differences between groups are statistically significant (day 6 MPS versus MPS/MC-21 expansion, P=0.005; day 6 MPS versus PBS, P=0.03; day 8 MPS versus PBS, P=0.001; day 14 MPS versus MPS/MC-21 maintenance, P<0.0001; day 14 MPS versus PBS, P=0.002). Significant differences between the MPS group and other groups are indicated on the figure (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). g, Proportion of effector CD8+ T cells (CD44+ CD62L) in blood over time. h, Proportion of OVA-tetramer+ of CD8+ T cells in peripheral blood 20days after vaccination. Statistical analysis was performed using ANOVA with Tukeys post hoc test. For fh, meanss.d. For f and g, statistical analysis was performed using KruskalWallis test with Dunns post hoc test (day 6 timepoint) or ANOVA with Tukeys post hoc test (days 8, 14, 20). For b, f and h, only differences between one group and all other groups are shown (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001).
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Unlike LNs, spleens did not demonstrate superior cellular expansion after MPS vaccination compared with other vaccine groups (Extended Data Fig. 5a). Although total numbers of splenic immune cells including B cells and DCs were largely unaffected by vaccination, transient increases in T cells and macrophages were detected (Extended Data Fig. 5be). Notably, significantly higher numbers and proportions of inflammatory monocytes were found in MPS-vaccinated mouse spleens compared with all other conditions on day 20 (Extended Data Fig. 5f,g). These cells also remained elevated in circulation at the latest timepoint (Extended Data Fig. 5h).
Inflammatory monocytes in the MPS group displayed characteristics of antigen presentation; MHCII expression significantly increased in the MPS vaccine group compared with all others several weeks after vaccination (Fig. 5c,d). Numbers of monocyte-derived DCs (CD11c and MHCII-expressing Ly6Chi monocytes) were also significantly increased in the MPS-vaccinated dLN at this time compared with PBS-treated mice, or any condition in the spleen (Extended Data Fig. 6a). In the spleen, MHCII expression on inflammatory monocytes was unaltered with vaccination (Extended Data Fig. 6b). These results indicate that Ly6Chi monocytes induced by MPS vaccination may engage in antigen presentation, specifically within the LN compartment.
To further discern the impact of inflammatory monocytes on lymph-node expansion and vaccine response, specific depleting reagents were next employed. MPS-vaccinated mice were treated with the CCR2-targeting MC-21 monocolonal antibody (mAb)30,31,32 either early (days 15, LN expansion phase) or later (days 1014, LN maintenance phase) after immunization (Fig. 5e). MC-21 mAb effectively depleted Ly6Chi monocytes in the blood, LN and MPS scaffold during the treatment course, although numbers in the blood rebounded within days (Fig. 5f and Supplementary Fig. 14ac). Early depletion of Ly6Chi monocytes delayed the effector CD8+ T cell response to vaccination, which peaked later, after monocytes had been restored, relative to the MPS vaccine group (Fig. 5g). Furthermore, only the MPS-vaccinated group treated early with MC-21 antibody had significantly elevated tetramer-specific CD8+ T cells by day 20, after the monocyte rebound, compared with the PBS controls (Fig. 5h). Administration of MC-21 mAb in the later phase of the LN response (days 1014) had no discernible impact on the T cell response. These results further suggest a role of inflammatory monocytes in effector CD8+ T cell responses to MPS vaccination, potentially through direct antigen presentation or inflammatory stimulation.
LN expansion kinetics in the absence of inflammatory monocytes or other immune cell subsets were next assessed. MC-21 mAb and/or clodronate liposomes were used to deplete Ly6Chi monocytes and macrophages, respectively (Extended Data Fig. 7a). Lymphocyte (anti-CD4, CD8 and B220) and neutrophil (anti-Ly6G) antibodies were also tested. No differences were observed in the magnitude or kinetics of LN expansion with depletion of any immune cell subset alone (Extended Data Fig. 7bg). However, depleting both inflammatory monocytes and macrophages together restrained the maintenance of LN expansion (Extended Data Fig. 7h). Taken together, these data indicate a stimulatory and antigen-presenting role of inflammatory monocytes, and that these cells in association with macrophages may be required for sustained LN expansion.
Finally, we considered whether durable LN expansion could indicate functional outcomes of vaccination. In a therapeutic model of mouse melanoma, LN expansion after vaccination against a tumour-expressed antigen was not affected by tumour presence (Supplementary Fig. 15ac). The MPS vaccine generated stronger adaptive immune responses than the bolus vaccine, leading to therapeutic benefit (Fig. 6ac and Supplementary Figs. 15dg and 16ac). Importantly, LN expansion associated positively with antibody titres, CD8+ T cell responses and antitumour efficacy of cancer vaccine formulations (Fig. 6df and Supplementary Fig. 17ac). The degree of LN expansion also correlated strongly with effector CD8+ T cell proportions following vaccination across experiments (Supplementary Fig. 17d). In a tumour-free setting, MPS vaccination also enhanced long-term antibody production (day 90) and splenic CD8+ T cell (day 103) responses as compared with the bolus vaccine, and responses associated with earlier degree of LN expansion (Extended Data Fig. 8af). Sustained inflammatory cytokine expression in splenic CD8+ T cells suggested a long-lived adaptive immune response in multiple lymphoid organs.
Mice were inoculated with B16-OVA melanoma tumours and 3days later treated with MPS or bolus vaccines containing GM-CSF, CpG and OVA protein, and compared to PBS-injected controls. A fourth group of tumour-free mice was treated with MPS vaccines (called MPS, no tumour). Inguinal dLNs were imaged using HFUS at multiple timepoints, and blood was collected 8 and 21days after vaccination to assess T cell responses and serum antibody titres, respectively. n=6 (MPS, B16-OVA) or 5 (all other groups) biologically independent animals per group. a, Serum anti-OVA IgG2a antibody titre 21days after immunization. Statistical analysis was performed using KruskalWallis test with Dunns post hoc test. b,c, T cell analysis in the peripheral blood 8days after immunization. b, Representative flow cytometry plots of OVA-tetramer binding to CD8+ T cells. c, Proportion OVA-tetramer+ of CD8+ T cells in blood. Statistical analysis was performed using ANOVA with Tukeys post hoc test. For a and c, meanss.d. d, LN fold expansion 7days after vaccination versus blood IFN+ CD8+ T cell response to SIINFEKL restimulation 8days after vaccination. e, LN fold expansion 7days after vaccination versus anti-OVA IgG1 titres 21days after vaccination. f, LN fold expansion 7days after vaccination versus tumour area at the latest timepoint with all mice surviving (day 21).
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We next assessed potential indicators of toxicity or T cell dysfunction that could result from sustained LN expansion. In MPS-vaccinated mice, serum HMGB-1 levels, indicative of inflammatory cytokine responses and/or cellular death33,34, were comparable to PBS controls (Extended Data Fig. 8g). Long-term (day 103) PD-1 expression on splenic T cells was also not different between the MPS vaccine group and PBS controls (Extended Data Fig. 8h,i). Mice monitored for 485days after MPS vaccination did not display changes in weight, LN or spleen cell counts, or proportions of immune cell subsets in blood or secondary lymphoid organs, although elevated OVA-specific CD8+ T cells remained detectable in all immune compartments investigated (Extended Data Fig. 9ai). Furthermore, MPS vaccine-generated T cells retained functional, antigen-specific antitumour response when challenged 50 days after immunization (Extended Data Fig. 10ac). Altogether, these results suggest that enduring LN expansion is associated with immune memory and antitumour efficacy, without indications of T cell dysfunction.
To explore whether LN expansion could directly improve vaccine efficacy, the MPS vaccine without antigen (Fig. 4a,b) was employed to jump-start LN expansion before administration of a full, antigen-containing bolus vaccine (Fig. 7a). LNs of mice given the antigen-free MPS jump-start expanded over the first week and continued to increase in size after administration of the bolus vaccine, becoming significantly enlarged compared with all other groups (Fig. 7b). The jump-start plus bolus vaccine broadly improved vaccine responses compared with the traditional bolus vaccine. The proportion of OVA-tetramer+ CD8+ T cells in blood was significantly increased in this condition (Fig. 7c,d). Blood CD8+ T cells restimulated ex vivo with SIINFEKL peptide had superior cytokine production (IFN and TNF) with the jump-start (Supplementary Fig. 18ac), and the jump-start also increased the proportion of effector CD8+ T cells and decreased the blood CD4/CD8 T cell ratio relative to mice given the bolus vaccine alone (Supplementary Fig. 18d,e). The combination treatment improved short- and long-term IgG2a antibody titres, with 10/10 (versus 6/10 with the bolus only) detectable IgG2a titres after 100 days (Fig. 7e and Supplementary Fig. 18f). In these experiments, the jump-start was dosed 7days before the bolus vaccine to match the peak of LN enlargement (Supplementary Fig. 19a). Spacing the jump-start closer to bolus vaccination (4days) tended to increase antigen-specific cytokine expression (IFN and TNF) and OVA-tetramer binding; however, increasing the dose separation (11days) increased granzyme B and reduced PD-1 expression, suggesting that the timing of jump-start and bolus vaccination can alter functional T cell outcomes, and the day 7 timepoint balances both sets of outcomes (Supplementary Fig. 19bh). All additional experiments were conducted with a 7-day spacing. In treating B16-OVA tumour-bearing mice, the jump-start strategy (Supplementary Fig. 20a,b) elicited prolonged tumour regressions compared with the bolus vaccine, which induced only transient tumour regressions, with all mice in this condition eventually succumbing to tumour burden within 50days. In the jump-start plus bolus group, 25% of mice survived at 200days, a significant improvement over all other groups (Fig. 7f,g). In summary, jump-starting LN expansion before vaccine administration improved T cell responses and antitumour efficacy in a model antigen tumour model.
a, Experimental timeline for be; mice were injected with PBS or a bolus vaccine on day 0, or injected with an MPS no-antigen jump-start on day 7 followed by PBS or a bolus vaccine (GM-CSF, CpG and OVA protein) on day 0. Mice were bled after 8 and 21days for T cell analysis and serum antibody titres, respectively. b, LN expansion measured by HFUS imaging. Values are normalized to the baseline volume for each individual LN. n=5 biologically independent animals per group; only differences between one group and all other groups are shown. c, Representative flow cytometry plots depicting CD8+ T cell OVA-tetramer binding in cells derived from blood on day 8. d, OVA-tetramer+ proportion of CD8+ T cells. e, Anti-OVA IgG2a titre on day 21. Statistical analysis was performed using KruskalWallis test with Dunns post hoc test. f,g, Mice bearing B16-OVA tumours (inoculated on day 8) were treated starting at day 7 as per studies in ae with an MPS jump-start (MPS material, GM-CSF and CpG without antigen) or left untreated, and then injected with a bolus vaccine (GM-CSF, CpG and OVA) or left untreated at day 0. Tumour growth and survival were tracked. f, Tumour growth curves. n=10 biologically independent animals per group. g, KaplanMeier curves depicting survival. n indicates naive/non-vaccinated (n+bolus, naive + bolus vaccine; jump-start+n, jump-start + naive; n+n, naive + non-vaccinated). Statistical analysis was performed using log-rank (MantelCox) test, correcting for multiple comparisons. n=17 (n/n) or 16 (all other groups) biologically independent animals per group; results are combined from two independent experiments, the second performed in a blinded manner. For b and d, statistical analysis was performed using ANOVA with Tukeys post hoc test. For ce, n=9 (PBS) or 15 (all other groups) biologically independent animals per group; results are combined from two independent experiments. For b, d and e, meanss.d.
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Finally, we assessed the impact of a booster vaccine format on LN expansion kinetics and adaptive immune responses. Following the MPS prime vaccine, dLN volume increased over the following 12weeks and declined by day 42 (Supplementary Fig. 21a,b). On day 43, a booster MPS vaccine was delivered, and this led to more immediate LN expansion, reaching peak volumes within 4days, compared with day 7 with the initial vaccine. Seven days after the booster vaccine, peripheral blood was collected and compared to mice that had received only prime vaccination at the same timepoint as the boost in the prime-boost group. No differences in the IFN+ proportion of CD8+ T cells after OVA peptide restimulation were detected; however, the IFN+ proportion of CD4+ T cells was significantly increased relative to both nave control mice and mice that had received only prime vaccination (Supplementary Fig. 21c,d). The proportion of effector-phenotype (CD44+ CD62L) CD8+ T cells was elevated with the MPS prime and further increased after the booster (Supplementary Fig. 21e). Both IgG1 and IgG2a titres against OVA were increased after the booster dose compared with either the same mice on day 21 (pre-boost) or the prime-only mice at the same timepoint (Supplementary Fig. 21f,g). These results indicate that a booster vaccine may elicit more rapid LN expansion along with a stronger adaptive immune response.
