Analysis | Robert F. Kennedy Jr.’s running mate and the vaccine wars – The Washington Post

Pharmaceutical medicine has its place, but no single safety study can assess the cumulative impact of one prescription on top of another prescription, and one shot on top of another shot on top of another shot, throughout the course of childhood. We just dont do that study right now and we ought to. We can and we will. Conditions like autism used to be one in 10,000. Now here in the state of California it is one in 22.

Independent vice-presidential candidate Nicole Shanahan, remarks in Oakland, March 26

Shanahan, a technology lawyer tapped by Robert F. Kennedy Jr. to be his running mate in his independent bid for president, has a child who she says was diagnosed with autism. She has said the discovery prompted her to delve deep into research on autism. In her first news conference as a candidate, she devoted a lengthy passage to describing what she had learned, including suggesting that vaccines play a role.

Autism spectrum disorder (ASD) is an umbrella diagnosis covering a range of neurological and developmental disorders that include autism and Aspergers syndrome. Symptoms and severity vary dramatically from one person to another, but they typically impair a persons ability to communicate and interact with others or result in restricted, repetitive behaviors.

We checked with five autism experts about her full comments, repeated below, and they said much of what she claimed is misguided, wrong or lacks context. Kennedy himself is a longtime purveyor of falsehoods about vaccines, spreading misinformation. He has repeatedly claimed that vaccines cause autism, despite study after study showing there is no link. (Our colleagues at FactCheck.org last year published a three-part series that closely examined his vaccine claims.)

In recent interviews, Shanahan has expressed skepticism about vaccines but said she and Kennedy are not anti-vaxxers. In an interview with Newsweek after being named his running mate, she said Kennedy is not an anti-vaxxer; hes just someone who takes vaccine injuries seriously. In February, she told the New York Times I do wonder about vaccine injuries, adding, I think there needs to be a space to have these conversations.

The Kennedy-Shanahan campaign did not respond to a request for comment.

Here are Shanahans full comments about autism from her news conference:

Because it has been so personal for me and my daughter, I got deep into the research and consulted some of the best scientists and doctors. Let me tell you what I found. There are three main causes.

One, is the toxic substances in our environment, like endocrine disrupting chemicals in our food, water, and soil, like the pesticide residues, the industrial pollutants, the microplastics, the PFAs, the food additives, and the forever chemicals that have contaminated nearly every human cell. Yes, and it makes you angry to hear this. It makes me angry to say it because we shouldnt be here right now.

Second is electromagnetic pollution. You dont hear politicians talking much about that either, but it is something we need to look at. As Bobby says, we need to investigate every possible cause of the chronic disease epidemic that is devouring our nation from the inside.

Third, Im sorry to say, is our own medications. Pharmaceutical medicine has its place, but no single safety study can assess the cumulative impact of one prescription on top of another prescription, and one shot on top of another shot on top of another shot, throughout the course of childhood. We just dont do that study right now and we ought to. We can and we will. Conditions like autism used to be one in 10,000. Now here in the state of California it is one in 22. One in 22 children affected.

Lets address these claims in order.

Toxic substances and electromagnetic pollution

This is speculative and so far without evidence. First of all, genetic factors are estimated to contribute a significant portion of risk from ASD, with more than 100 genes identified.

Paul A. Offit, director of the Vaccine Education Center, an attending physician at Childrens Hospital of Philadelphia and author of the 2008 book Autisms False Prophets, said in a telephone interview that there is no evidence that post-birth events, like the environment, result in a diagnosis of ASD, whereas there is increasing evidence of pre-birth factors.

For instance, a significant increase in risk has been found depending on the age of a father, especially if he is in his 40s or older. Moreover, Valproate, a drug used to treat epilepsy and other neuropsychological disorders, has been found to significantly increase the risk if used during pregnancy.

Every piece of legitimate evidence we have suggests that the causes of autism are present in utero, said David Mandell, director of the Penn Center for Mental Health at the University of Pennsylvania, in an email. To the extent that environmental factors are causative, they likely interact with genetic risk factors in the womb.

Abnormalities in brain function and organization are likely present during fetal development, even though the behavioral ramifications may not be seen for years in some children, Catherine Lord of the Center for Autism Research and Treatment at the University of California-Los Angeles said in an email.

Of course, even if a link to air pollution is not yet proved, that does not mean it can be ruled out. Its hard to disagree with the opinion that exposure to neurotoxins and air pollution is bad for our health and that we should be doing more to protect our environment and prevent these exposures, Maureen Durkin, chair of the Department of Population Health Sciences at the University of Wisconsin-Madison, said in an email. Credible research into the causal links of these exposures to autism specifically is difficult to do but should be done and critically evaluated to inform environmental policies.

Shanahan told Newsweek that she wholeheartedly attributes her daughters autism to environmental toxins.

Our own medications

Pharmaceutical medicine sounds like code for vaccines, given that she links it in the same sentence with one shot on top of another shot on top of another shot during childhood and its hard to imagine what that might refer to other than multiple vaccines, a mainstay of childhood medicine. But a link to autism has been debunked in study after study.

Fears about a link between autism and vaccines started in 1998 after the publication of a genuine hoax the Wakefield study, in the journal Lancet. Based on a supposedly random sample of 12 children, now-discredited anti-vaccine activist and former physician Andrew Wakefield suggested that the measles, mumps and rubella (MMR) vaccine led to gastrointestinal symptoms, which in turn put harmful proteins in the bloodstream that resulted in autism.

Dozens of studies followed, including one that studied 1.8 million children over 14 years, all of which showed there was no link. Eventually, it was revealed that Wakefield had received secret payments from a lawyer seeking to sue MMR manufacturers and who supplied some of the patients, had filed a patent application for his own measles vaccine, and had misrepresented or altered medical histories of the 12 patients. In 2010, the article was retracted and Wakefield lost his medical license.

But the damage has never been erased, as fears about a link between vaccines and autism persist among parents. There are dozens of studies looking at autism and vaccines, and they dont show a link, said Alison Singer, president of the Autism Science Foundation, which has posted dozens of studies on its website. It is not even a case of needing to do more research.

No single safety study can assess the cumulative impact

This is a false construct, asking for a study that experts say would be unethical as a randomized study would require a group that took no vaccines, exposing them to potentially dangerous risks and would not be informative. It is an untestable hypothesis, Offit said.

In 2002, Offit co-wrote a report for the American Academy of Pediatrics that reviewed existing studies and concluded that children respond to multiple vaccines given at the same time in a manner similar to individual vaccines. Current studies do not support the hypothesis that multiple vaccines overwhelm, weaken, or use up the immune system, the study said. On the contrary, young infants have an enormous capacity to respond to multiple vaccines, as well as to the many other challenges present in the environment.

No single study can assess the cumulative effects of everything (all medicines and vaccines) on autism risk over the life course, Durkin said in her email. Neither a randomized controlled trial nor an observational study design would be feasible for this. Most pharmaceutical safety studies focus on one or a few medications or vaccines at a time and invariably find some adverse effects, but if the benefits dont outweigh the adverse effects, the medication should not be approved.

Offit and Mandell said the call for a study is an example of Kennedy and other vaccine skeptics often changing the goal posts.

This is fearmongering, Mandell said, noting that Wakefield first said autism was the result of the MMR vaccine and no link was found. Then RFK Jr. said that the thimerosal in vaccines caused autism. Then thimerosal was removed from vaccines, with no change in increasing rates of diagnosis. Then they said that it was the number of vaccines or the timing of the vaccines.

Autism used to be one in 10,000. Now it is one in 22 [in California].

These numbers are in the ballpark but lack context. The percentage of people diagnosed with ASD has gone up mainly because of expanded definitions and better detection. There is no blood test for autism, so a diagnosis is based on observations of a persons behavior.

Much of the rise in autism prevalence in recent years is likely due to expansion of the concept of autism from a narrowly defined condition to a spectrum, and to more screening, better tools and training for diagnostic assessments, and more access to therapies and services, Durkin said. Mandell agreed, adding that there may be effects of increased parental age and our increased ability to keep compromised infants alive.

Infantile autism was first coined in 1943, But not until 1980 did autism receive its own diagnosis in the Diagnostic and Statistical Manual of Mental Disorders; the category was broadened in 1987 and then again in 1994. Finally, in 2013, for the DSM-5, autism, Asperger syndrome and pervasive developmental disorder-not otherwise specified (PDD-NOS) were folded into a single diagnosis.

Thats why the earliest studies of autism in the 1960s and 1970s estimated that autism was in 2 to 4 people per 10,000, which led to the impression that autism was a rare childhood disorder, according to a 2015 book published by the the National Academies of Sciences, Engineering, and Medicine. The 1 in 22 estimate for California is based on a survey by the Centers for Disease Control and Prevention in one county in the state. Nationally, the 2023 CDC estimate of autism prevalence at age 8 years is 1 in 36 children, compared with 1 in 150 children in 2000, when CDC began monitoring the prevalence of autism in the United States.

Indeed, while diagnosis of autism has increased, those of intellectual disability have decreased, indicating that previously children may have been misdiagnosed with other conditions.

Shanahan does not quite say that vaccines cause autism, but she implies it, demanding a study that is not feasible because it would be unethical. She cites numbers that claim that autism has spiked, without acknowledging the main reason is because the definition of autism has been greatly expanded. This is textbook anti-vaccine rhetoric. The overall effect is to cast doubt on the safety of vaccines. She earns Four Pinocchios.

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Early one morning this January, a school nurse in Suffolk County received an email with a distressing subject line: STATEWIDE ALERT False Immunization Records Baldwin Midwifery. New Yorks Department of Health was notifying schools across the state that a Long Island midwife named Jeanette Breen had falsified 12,499 records related to 1,452 students at 300 schools. Rather than administer shots to protect kids against hepatitis B, chicken pox, and other diseases, Breen had given nearly all of her patients homeopathic pellets.

Follow-up emails alerted the Suffolk nurse that a student at her school was among those who had seen Breen. I called the mom and I said, Do you have any other health records from any other doctors other than Breen? the nurse said. Her answer was no and, once she got an inkling where this was going, she decided to pull her child out of school that day. She hasnt been back. They decided to homeschool her.

From a public-health standpoint, the nurse (who asked that I not use her name) wasnt concerned. Her school had more than 500 students, and just one was unlikely to start an outbreak. Still, she was irked. First of all, what Breen did is just wrong and illegal, she said. Beyond the lying and deceit, I was worried about the one or two students here who cant be vaccinated because they have cancer and are going through chemo. I was shocked she wasnt arrested.

Rather than bring criminal charges, in November, the state reached a settlement with Breen. The midwife agreed to pay a $300,000 fine and admitted to fraud in a detailed stipulation. Still, questions lingered. Had Breen, who is 77, tricked parents who thought their kids were getting genuine inoculations? Or had anti-vaxxers sought her out? Was Breen motivated by money or ideology?

Recently, I went to visit Breen at her office in Baldwin, a hamlet in Long Islands South Shore. Her midwifery is one in a quaint row of storefronts, next to a travel agency and two doors down from a pediatrician. Her assistant said she was too busy to speak with me, and later Breen sent me a text: The NYS is watching me like a hawk and I am sure they would have a field day with anything you would report. So sorry to say no comment .

Public records, news reports, and interviews fill in some of the story. Over decades, Breen built a dedicated following among her obstetrics and gynecological patients, though she often sparred with hospitals and the medical Establishment. Then, in the middle of 2019, her practice changed conspicuously.

That year saw the largest measles outbreak in New York State in 27 years, with more than 1,000 cases, largely in Orthodox communities. Lawmakers responded by tightening vaccination requirements, doing away with exemptions for those with religious, philosophical, and personal reasons. The shift meant that going into the 201920 school year, some 26,000 students across the state whod used those exemptions to skip vaccinations would need to show proof theyd gotten their shots or intended to. Three months after the vote, in September 2019, Breen started seeing adolescents.

The Department of Health hasnt said what the parents and guardians of Breens pediatric patients knew about the midwifes history or what kind of care they expected their children to receive. But while some of her clientele along the South Shore could have conceivably chosen her thinking she would provide care similar to a standard pediatric provider, others were enrolled in schools as far away as Erie County. Those parents would need a powerful incentive to make a seven-hour drive for medical care.

My understanding is people sought her out. They knew what they were doing, says Kathleen Shortis, an obstetrics patient of Breens. Although Shortis took her kids to a pediatrician for health care, she says she has empathy for anyone who may have used Breen to skirt the law. People dont want to feel pressured about something theyre putting into their childrens bodies. That scares people. And it became very politicized.

Shortis insists that Breen, like her patients, does not easily fit into a political or ideological stereotype. I think people probably have the idea that she is one thing and she is not flat-earthy. Shes also not a Birkenstock hippie. COVID made strange bedfellows on this issue.

Whether they knew it or not, the parents who went to Breen enlisted a health-care provider who seemed to have a deep-seated distrust of traditional medicine and its practitioners. At least some of her animus was personal. My three boys were all born in hospitals, she told Newsday in 1978, while attending a conference on alternative childbirth. I had three different obstetricians, none of whom Id recommend to anyone. And I would never have another hospital birth. (I also saw some evidence suggesting that the father of Breens children, who is now deceased, was a hospital executive.)

Breen became a certified midwife in New York in 1984. In March 1988, she was granted privileges to practice at Winthrop-University Hospital in Nassau County. A year later, Breen clashed with a doctor there over a newborn shed delivered in a home birth. Dr. Bernard Leonard was concerned about the results of a jaundice test and wanted a follow-up done immediately; Breen advised the parents it could wait until the next morning. Leonard filed a complaint with Breens sponsor at the hospital saying she had interposed her limited knowledge and her considerable rapport with the patient and undercut the fragile patient-doctor relationship. The hospital immediately revoked Breens privileges. Breen filed a lawsuit against the hospital and a defamation suit against Leonard, both of which were unsuccessful. (The baby turned out fine.)

Breens practice thrived, and according to court records, she delivered hundreds of babies in the early 1990s, including dozens of home births every year. One significant dispute came in 2002, when a new mother and father sued Breen for medical malpractice, claiming, among other things, that shed failed to recognize a medical/surgical emergency and should have contacted a hospital. Breen settled with the parents for $315,000.

In 2005, Breens privileges at another hospital, the Nassau University Medical Center, were suspended for disregarding infection-control protocol: Shed walked out of the hospital with a placenta in Tupperware. Its a common belief among midwives, and those who enlist midwives, that the organs shouldnt be discarded as medical waste. In this case, a new mother told Breen she didnt have a place to bury her own placenta, and Breen offered to inter it for her. At the time, Breen indicated she had 50 to 60 placentas buried in her garden. I have two or three in my freezer right now, ready to go, she told the New York Post. Again, Breen sued the hospital to have her privileges restored. She forced the hospital, and eventually the state, to consider more deeply the rules and regulations of medical-waste disposal, but her lawsuit was unsuccessful.

Breen continued to run afoul of common medical practices. In 2014, the board for midwifery suspended her from practicing in New York for two years after she failed to document informed consent for vaginal births in patients who have had prior Cesarean sections, self-reporting of blood sugar levels, and some of her actual patient care for three patients. The suspension was stayed while she adhered to a two-year probationary period.

Soon after that period ended, Breen wrote a flu-vaccine exemption letter for a pregnant woman who worked at NYU Winthrop Hospital, which mandated all employees receive the shot. When the hospital refused to accept Breens exemption letter, Breens patient sued under the Pregnancy Discrimination Act. In a deposition for the case, Breen said she believed the Centers for Disease Control was a political organization not necessarily representing factual information. When asked why she thought the American College of Obstetricians and Gynecologists wasnt a reputable organization, she responded, Well, a doctor doesnt always know best. (Her patient lost the case.)

Over the years, Breen had taken courses in homeopathy the pseudoscientific theory that people can ward off disease by administering very small doses of substances that trigger immune responses. (According to the National Institutes of Health, theres little evidence that homeopathy is effective at treating any known condition.) After the 2019 change in vaccine regulation, Breen treated her patients with something called the Real Immunity Homeoprophylaxis Program, a series of oral pellets advertised as a safe, effective, non-toxic approach to disease prevention. Also known as nosodes, homeoprophylaxis has long been marketed to people experiencing vaccine hesitancy. Study after study shows nosodes are no substitute for vaccination.

The Real Immunity program was developed, marketed, and sold by Dr. Cilla Whatcott, who held a Ph.D. in homeopathy from Kingdom College of Natural Medicine. (As to whether that school is accredited, its website says, Yes, but not nationally or regionally accredited, which means that KCNH is not listed with the U.S. Department of Education, nor does it wish to be.) Earlier this year, Whatcott took to Instagram to warn customers that the pellets could be deactivated by the 5G network. A subsequent post on her Instagram account said that Whatcott died in February from cancer.

In April 2020, Breen began logging records into a database, the New York State Immunization Information System, that made it look as if her pediatric patients had been immunized. This was, of course, the same time that COVID-19 was spreading rapidly worldwide and expectations were building of a vaccine that might become required for billions. Conspiracy theories about microchips and sinister plots by pharmaceutical companies proliferated, and more people began to talk about refusing vaccines of all kinds as a political statement, rather than as a personal or public-health decision.

In January 2021, the Department of Health established a Vaccination Complaint Investigation Team tasked with looking into complaints of COVID-vaccine fraud. In 2022, the team helped police take down Julie DeVuono, a Long Island nurse practitioner who turned a $1.5 million profit by falsifying vaccine cards. DeVuono eventually pleaded guilty to forgery and money laundering. According to Joseph Giovannetti, the departments director of investigations, the team began looking into frauds involving all sorts of vaccines, not just for COVID, and at the end of 2022, a tip came in about Breen. After a six-month inquiry, the Department of Health confronted her and eventually reached a settlement.

Giovannetti says his department has a number of open investigations, but he doesnt think the state will be engaged in a never-ending war on vaccine fraud. This isnt an intractable situation. Its not something thats just going to be cat-and-mouse or anything like that, he says. Were going to be able to nip it in the bud.

Still, real dangers are posed by vaccine resistance. The percentage of kindergarteners vaccinated against measles, which the CDC declared eliminated in 2020, has dipped nationwide since 2019, from 95 to 93 percent. A recent Pew survey found that only 57 percent of Republicans believed measles, mumps, and rubella vaccines should be required for children to attend public schools down from 79 percent before the pandemic.

When Breens fraud made headlines in January, it stoked furor from both people concerned about anti-vaxx vigilantes and those who heralded the midwife as a kind of civil-rights hero. By then, Breen had reportedly paid half of her $300,000 fine. Shortis created a fundraiser on GiveSendGo, a Christian crowdfunding platform popular among right-wing causes, to help pay the rest. Coffee & Covid, a conservative newsletter written by a Florida attorney, which claims to have more than 138,000 subscribers, promoted the fundraiser, and within days the effort raised more than $172,000. Bravo for those like Jeanette who put principle above propaganda and personal safety! wrote one donor. Another wrote, Thank you for saving all those children from the poison of Dr Fauci and Bill Gates eugenics shots! [sic]

Meanwhile, the school nurses tasked with keeping track of Breens unvaccinated patients are upset. Its an insult to the nursing profession, said Sylvia Kallich, president of the Nassau County Association of School Nurses. Over the past few months, the Department of Health has been circulating a tip sheet to schools about identifying vaccine fraud. Red flags include records from health-care practitioners who are not located within a reasonable distance from the student or school and records from an office that doesnt typically administer childhood immunizations including homeopathic practices and midwiferies.

An inverse vaccine developed by Nykode Therapeutics to boost immune system tolerance to a specific protein target was able to prevent the development of multiple sclerosis (MS) in a mouse model of the disease.

The vaccine, known as a Vaccibody, is designed to teach the immune system to recognize certain proteins as self without impacting other immune cell functions, as is often seen with current MS therapies.

The data, which were presented in a poster at the 2024 Antigen-Specific Immune Tolerance Drug Development Summit, provide additional motivation for us to pursue a completely new approach to treating autoimmune diseases, Agnete Fredriksen, chief business officer and co-founder of Nykode, said in a company press release.

The immune system usually protects the body against potential threats by attacking what it doesnt recognize as self. In autoimmune diseases, however, the ability to distinguish what is self from what isnt becomes impaired, and the immune system starts to attack the bodys own tissues, driving a lasting inflammatory response.

In MS, for example, the immune system attacks the myelin sheath, a fatty coating that wraps around nerve fibers to help them send electrical signals faster, and the resulting damage causes a range of symptoms.

The idea behind an inverse vaccine is to induce immune tolerance. In contrast with a regular vaccine, which teaches the immune system how to fight a threat, it instead tells the immune system that certain targets (antigens) should not be seen as a threat and should be left unharmed.

Nykodes inverse vaccine technology is designed to deliver small circular DNA molecules to muscle cells that provide the instructions for making the Vaccibody proteins. These proteins are then secreted by the cells and, once in circulation, they target antigen-presenting cells (APCs).

APCs are immune cells capable of processing and presenting certain targets to immune T-cells, promoting an immune response against those targets. However, Vaccibody vaccines are instead developed to recruit APCs that present targets to regulatory T-cells, which limit the activity of other immune cells.

The company has now presented data from a Vaccibody called TV004, which was designed to induce tolerance against myelin oligodendrocyte glycoprotein (MOG), a myelin protein.

In a mouse model of experimental autoimmune encephalitis, which is commonly used to mimic MS in mice, TV004 infections before MS induction effectively protected the animals from disease, with very mild or no symptoms at all over 28 days.

The treatment also showed a dose-dependent reduction in the amount of pro-inflammatory molecules found at the peak of disease symptoms.

The effect was specifically related to immune tolerance to the MOG protein, as treatment with a Vaccibody designed to induce tolerance against ovalbumin (the major protein found in egg white) resulted in symptoms as severe as those on a placebo.

In addition to stopping the disease development, the data show that the disease protection is antigen-specific, Fredriksen said.

This supports our technologys potential to offer future treatments that precisely target specific autoimmune disorders without negatively affecting a fully functional immune system, a common side effect associated with todays available treatments, Fredriksen added.

The researchers have plans to carry out an in-depth analysis aimed at further dissecting the immunological and molecular mechanisms behind the disease control mediated by Vaccibody vaccine, they wrote.

Key takeaways:

Participants at HJF Medical Research International in Abuja, Nigeria, have been vaccinated in the first Phase 2 clinical trial of a Lassa fever virus (LASV) vaccine candidate to date, according to IAVI, a nonprofit scientific research organization and the trial sponsor. The study (IAVI C105/PREVAIL15) is funded by CEPI, an innovative global partnership working to accelerate the development of vaccines against epidemic and pandemic threats.

The trial in Nigeria has been designed in consultation with in-country partners, including the Nigeria Centre for Disease Control and Prevention and the Nigeria Lassa Vaccine Taskforce. HJF Medical Research International, Ltd/Gte (HJFMRI) has been conducting infectious diseases research in collaboration with HJF and the Walter Reed Army Institute of Research in Nigeria since 2014. In addition to Nigeria, and pending regulatory approval, IAVI expects to enroll additional participants at the Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences, University of Ghana, and the Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL)[1].

Nigerian clinicians, scientists andcommunity membersare key leaders in this international collaboration, which will ensure that vaccine development incorporates local context, experience and perspectives while fostering sustainable in-country research capacity and partnerships, said Dr. Abdulwasiu Bolaji Tiamiyu, clinical research center director, HJFMRI, and principal investigator of IAVI C105 in Nigeria.

No approved vaccine currently exists for LASV, which causes an acute viral hemorrhagic illness called Lassa fever. Given its potential to cause a public health emergency of international concern, LASV is included in the World Health Organization R&D Blueprint of priority pathogens for which there is an urgent need for accelerated research and development (R&D) and countermeasures[2]. IAVI and members of the global Viral Hemorrhagic Fever Consortium have been collaborating since 2018 to accelerate clinical development of IAVIs single-dose LASV vaccine candidate in studies supported and funded by CEPI and the European & Developing Countries Clinical Trials Partnership (EDCTP). Read more.

An estimated 5,000 people die each year from LASV, and about 300,000 people fall ill across West Africa annually though the true disease burden is thought to be much higher. Nigeria, Liberia, Sierra Leone, and Guinea are most affected, but increasingly, neighboring countries are experiencing their own emerging outbreaks, with travelers occasionally carrying infections to other regions. Although most people who develop LASV have mild or no symptoms, approximately 20% will develop more serious symptoms including widespread bleeding and major organ failure. Approximately a third of those infected with LASV experience associated deafness, sometimes resulting in lifelong disability. Children under 10 years old, pregnant people, and health care workers are especially vulnerable to LASV infection.

Continued outbreaks of Lassa fever and the emergence of Ebola Sudan in Uganda both underscore the need to have vaccines for known disease threats available for evaluation and use during outbreak situations the overarching goal of IAVIs emerging infectious disease program. said Swati Gupta, DrPH, MPH, vice president and head of emerging infectious diseases and epidemiology, IAVI. IAVI C105 is an important step toward attaining eventual licensure of a Lassa fever vaccine, should IAVIs vaccine candidate prove to have an acceptable safety profile and be efficacious. We are grateful to our funders, our clinical partners, and our consortium collaborators for their continued support of IAVI and commitment to a more secure world.

Lassa fever has long been a threat to much of West Africa, and factors like climate change and population growth could exacerbate its transmission in coming decades, explainsDr. Richard Hatchett, CEO of CEPI. The world urgently needs a Lassa vaccine for routine immunization. The initiation of IAVIs new Phase 2 trial the most advanced Lassa vaccine trial to date is an important milestone in public health and signals that better tools to manage and prevent outbreaks are coming. We look forward to continuing to collaborate with IAVI and regional partners to advance this promising vaccine as quickly as possible.

IAVIs LASV vaccine candidate was well-tolerated and immunogenic among participants in both the U.S. and Liberian cohorts of IAVIs Phase I LASV vaccine trial (IAVI C102). Robust immune responses appear to be sustained for up to one year after vaccination[3]. In the Phase 2 study, researchers will evaluate the vaccine candidates safety, tolerability, and immunogenicity at two different dosage levels in adults, including people living with HIV, as well as in adolescents and in children two years of age and older. Approximately 612 participants will be enrolled and followed for six months after vaccination to monitor their safety and immune responses. A subset of participants will be followed for an additional two years for extended safety and immunogenicity.

CEPI and IAVI are united in their commitment to global equitable access. Should the candidate be found to be safe and efficacious in clinical testing, IAVI is committed to making its Lassa vaccine affordable and accessible to all populations in need.

Harnessing a proven platform technology for global preparedness

IAVIs LASV vaccine candidate uses the same recombinant vesicular stomatitis virus (rVSV) vector platform as ERVEBO, Mercks single-dose Zaire ebolavirus (ZEBOV) vaccine, which is licensed in North America, Europe, and 10 African countries. The rVSV platform has been used extensively in adults and children[4].

IAVIs goal is to develop and test rVSV-based vaccines against emerging infectious disease pathogens that pose epidemic threats as part of an overall preventive strategy which includes routine immunization as appropriate as well as stockpiles which can be rapidly deployed for larger outbreaks as needed. IAVIs EID portfolio includes a Sudan ebolavirus vaccine candidate supported by BARDA; a Lassa fever vaccine candidate supported by CEPI and EDCTP; a Marburg virus vaccine candidate supported by BARDA and the Defense Threat Reduction Agency (DTRA) of the U.S. Department of Defense (DOD); and an intranasal SARS-CoV-2 vaccine candidate supported by DOD DTRA and the Japan Ministry of Finance.

Much of the R&D on IAVIs rVSV platform is performed at the IAVIVaccine Design and Development Lab(DDL) in Brooklyn, New York. The DDL is one of the worlds leading viral vector vaccine R&D labs, known for innovation and generation of novel vaccine design concepts. Scientists with IAVIsHuman Immunology Laboratory(HIL) in London, U.K., are involved in processing participant samples and developing the analytical assays needed to evaluate IAVI C105 participants immune responses. They are also facilitating technology transfer of the assays to West African partner institutions.

IAVIs LASV vaccine candidate was manufactured byBatavia Biosciencesin Leiden, The Netherlands, a contract-development and manufacturing organization focused on delivering sustainable, low-cost manufacturing solutions in the field of infectious disease and cancer. Through itspartnershipwith Batavia, IAVI intends to develop an end-to-end platform for flexible, low-cost production of epidemic preparedness vaccines.

Results from IAVI C105 are expected in 2025 and will be made available through open-access publications and via scientific meetings to ensure all can benefit from the research.

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IAVI Media Contact Rose Catlos Rcatlos@iavi.org 212-847-1049

CEPI Media Contact press@cepi.net +44 7387 055214

HJFMRI Media Contact Lisa Reilly lreilly@Global-ID.org 301-339-3566

About IAVI

IAVI is a nonprofit scientific research organization dedicated to addressing urgent, unmet global health challenges including HIV, tuberculosis, and emerging infectious diseases. Its mission is to translate scientific discoveries into affordable, globally accessible public health solutions. Read more atiavi.org.

Follow IAVI on Facebook, LinkedIn, Instagram, and YouTube, and subscribe to our news updates.

About CEPI

CEPI was launched in 2017 as an innovative partnership between public, private, philanthropic and civil organisations. Its mission is to accelerate the development of vaccines and other biologic countermeasures against epidemic and pandemic threats so they can be accessible to all people in need. CEPI has supported the development of more than 50 vaccine candidates or platform technologies against multiple known high-risk pathogens or a future Disease X. Central to CEPIs pandemic-beating five-year plan for 2022-2026 is the 100 Days Mission to compress the time taken to develop safe, effective, globally accessible vaccines against new threats to just 100 days.

About IAVIs rVSV vaccine candidates

IAVI holds a nonexclusive license to the rVSV vaccine candidates from the Public Health Agency of Canada (PHAC). The vector was developed by scientists at PHACs National Microbiology Laboratory.

IAVI initially developed its rVSV vector for HIV vaccine candidates and has since expanded its use to the development of vaccines addressing emerging infectious diseases (Lassa Fever, Marburg, Sudan ebolavirus, and COVID-19).

Funders who have made the development of IAVIs rVSV-vectored vaccine candidates possible include the Bill & Melinda Gates Foundation; the Government of Canada; the Danish Ministry of Foreign Affairs; the Government of Japan; the Irish Department of Foreign Affairs and Trade; the Netherlands Ministry of Foreign Affairs; the Norwegian Agency for Development Cooperation; the U.K. Foreign, Commonwealth & Development Office; the U.S. National Institutes of Health; and through the generous support of the American people from the United States Agency for International Development. This project is funded in whole or in part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority under contract number 75A50121C00077.

[1] PREVAIL is aLiberia-U.S. clinical research collaboration established in 2014 by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and the Ministry of Health in Liberia. In 2015, PREVAIL participated in a clinical trial (PREVAIL 1) of Mercks now-licensed Ebola Zaire vaccine ERVEBO, which uses the same recombinant vesicular stomatitis virus (rVSV) vector backbone as the candidates in IAVIsemerging infectious diseases(EIDs) vaccine development portfolio, including the IAVI LASV vaccine candidate being evaluated ina Phase I clinical trial.

[2] Blueprint (who.int)

[3] https://www.iavi.org/wp-content/uploads/2023/11/C102_ASTMH_Poster_Chicago2023.pdf

[4] https://cdn.who.int/media/docs/default-source/blue-print/who-vaccine-prioritization-report-uganda-ebola-trial-nov-16-2022.pdf

After press reports flagged the possibility of an inactivated polio vaccine (IPV) shortage in India, Sanofi says it's ready to supply the nation with a newly approved shot.

Thursday, after the company gained an approval for a new polio vaccine, IMOVAX-Polio, Sanofi issued an assurance that it will be able to keep providing sufficient supplies. The developments come quickly on the heels of an Economic Times report alleging that a shortage crisis was looming following Sanofis decision to shut down certain vaccine manufacturing operations in the country.

Last September, Sanofi revealed plans todiscontinue its previous polio shot in India.

Still, to hear Sanofi tell it, India shouldnt be concerned.

The companys local branch remains dedicated to supporting Indias public health program for polio, a Sanofi India spokesperson told Fierce Pharma on Thursday. To ensure that there is no interruption to the availability of IPV vaccines, we have already obtained approvals for our product IMOVAX-Polio, she added.

Regarding the companys decision to discontinue its previous polio shot, Sanofi Indias spokesperson pointed to the rapidly shifting healthcare environment in the country following the COVID-19 pandemic.

Amid rising demand for production capacity in India, Sanofi last year opted to discontinue its older polio shot. The company's spokesperson noted that the shot was only filled and packaged at the companys factory in Hyderabad, while the antigens themselves were manufactured in France.

Sanofi and its Indian affiliate Shantha Biotechnics pledged to supply polio vaccines for Indias universal immunization program through UNICEF back in 2015.

Sanofi got its hands on Shantha in 2009 when the French drugmakers vaccine division agreed to pay 550 million euros ($784 million) for the Merieux Alliances controlling stake in the Indian shot maker.

Elsewhere in India, Sanofi last week called on local drugmakers Cipla and Dr. Reddys Laboratories to help sell its central nervous system (CNS) drugs and vaccines in country.

Cipla is slated to market six Sanofi CNS medicines, including the leading epilepsy therapy Frisium, which Sanofi will continue to own, import and manufacture.

Dr. Reddys, for its part, is on deck to sell five Sanofi vaccines in the country.

As a recent study in Scotland made clear, girls who were vaccinated before age 12 and 13 had zero cervical cancer, Robert Bednarczyk, an epidemiologist at Emory University and member of the HPV Vaccination Roundtable of the Southeast, told the Atlanta Journal-Constitution. The fact that the vaccine prevents six types of cancer that tens of thousands of Americans get each year should be our message.

According to the CDC, the vast majority of cancers caused by HPV are cervical cancer in women, and throat cancer in men. The good news is vaccinations prevent at least 90% of these cancers. The more mixed news is that vaccination rates dipped during the pandemic, and experts in Georgia and California say they are still playing catch up.

We were on such a good trajectory in the U.S. and in California, and then came COVID, Catherine Flores Martin, executive director for the California Immunization Coalition (CIC), told The Atlanta Journal-Constitution. We lost ground, but we are working with parents and providers to build confidence in vaccines again.

Though 63% of children in the U.S. are fully vaccinated against HPV, California and Georgia both are lagging the national average, with about 61% of adolescents ages 13-17 in each state vaccinated.

During the pandemic, HPV vaccination rates in the U.S. slid 13.6%, according to the CDC, compared to a 5.7% fall for measles vaccinations.

While measles vaccination rates in Georgia have returned to pre-pandemic labels, the states HPV vaccination rate remains 18% lower than before the pandemic, CDC data show.

As cervical cancer rates in younger, vaccinated women have fallen, rates have increased among middle-age women who may not have had the chance to be vaccinated. Moreover, about 70% to 90% of head and neck cancers in the U.S. are now linked to HPV. Survival rates are high if the cancer is found early. HPV testing alone detects more abnormalities than Pap tests alone, especially in young women thats why the American Cancer Society recommends co-testing with a Pap test and an HPV test every five years, or a Pap test every three years.

About 37,000 annual cancer cases in the U.S. are attributable to human papillomavirus, 34,400 of which may have been prevented through vaccination. Preventing and treating HPV-associated diseases costs the U.S. at least $9 billion annually, according to the CDC.

Flores Martin says Californias strategy is to normalize vaccine uptake so parents see it as a standard vaccine, like those against measles, tetanus, flu.

Last year, California passed legislation to inform parents that HPV vaccination can prevent cancers, and that the state strongly recommends children be immunized by the 8th grade, or age 13-14. Letters to that effect will be sent out this spring.

It might just seem like a letter, but we see it as another opportunity to get information to parents who might have been unaware or on the fence about it, Flores Martin said.

The approach was seen as a compromise. Although U.S. states like Rhode Island or countries like Portugal were able to achieve HPV vaccination rates of over 80% by requiring it for school matriculation, Flores Martin said the political climate in the U.S. right now made a mandate unlikely, even in California. Moreover, Texas subsequent reversal of its 2011 HPV vaccine mandate has led California to favor an approach that emphasizes parent-doctor cooperation in HPV vaccination planning.

A parental consent process like the one adopted in California has been a success in Australia, said Karen Canfell, a researcher at the The Daffodil Centre, a partnership between the Cancer Council New South Wales and The University of Sydney.

Its a parental-consent process in Australia, Canfell told the AJC. And from the beginning, there has been clear messaging to parents of young girls and boys that this has been a lifesaving vaccine.

Australia adopted a WHO recommendation that one dose of the vaccine in children would provide lasting protection, after initially giving children two doses.

Australia wants to increase coverage rates to meet and exceed 90% coverage, and the one-dose regime will be an enabler of that, she said.

Walter Orenstein, formerly Director of the United States Immunization Program and currently of Emory Vaccine Center, said the U.S. needs to do a better job in explaining to parents the seriousness of HPV. One way to accomplish this, he said, could be to compensate physicians for family vaccine counseling.

Even if physicians do not give the vaccine that day, this will give them an incentive to invest the time in talking to families, Orenstein told the AJC. If nothing else, we should do research to see whether or not this would enhance vaccine uptake.

Efforts to increase outreach should also include adults, who also can benefit from HPV vaccinations until at least age 45, said Joshua ONeal, Director of Sexual Health, Medical and Preventive Services at the Fulton County Board of Health.

And he says Georgia needs to overcome a taboo around talking about HPV.

HPV is the leading cause of throat cancer among men, but we dont talk about it enough, ONeal told the AJC. We talk about cervical cancer, but I hardly ever hear people talk about how they are connected.

Who should get the HPV vaccine? CDC recommends HPV vaccination for:

How do I know if I have HPV?

Most people with HPV do not know they have the infection or have developed cancer. The American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines recommend HPV testing for women aged 30 to 65 years as part of a cervical cancer screening. The HPV test is used in conjunction with a Pap test every 5 years. Some women over 65 might require more frequent testing. The tests may also be beneficial to gay men. HPV tests are not recommended to adolescents, or women under the age of 30 years.

Source: Centers for Disease Control and Prevention and ASCCP

Following on average one additional ancestral mRNA vaccine dose, pediatric solid organ transplant recipients do not exhibit significantly different humoral responses compared to their healthy siblings

Humoral responses were evaluated in pHCs and pSOTRs who received the ancestral monovalent vaccines only (pSOTR M) after approximately 200 days and pSOTR bivalent recipients (pSOTR B) after 300 days post-vaccination, just before the time at which boosting has been recommended for older adults and adult SOTRs due to waning immunity. The pSOTR M group received, on average one additional mRNA vaccine dose compared to pHCs (median three vs. two doses, respectively), while pSOTR B group received on average five mRNA vaccines, including the bivalent dose (Supplementary Table 1). Anti-S immunoglobulin (Ig)-G and anti-S1 receptor binding domain (RBD) IgG titers were not significantly different between pHCs and pSOTR groups (Fig. 1a). Interestingly, despite a previously documented infection in 11 (55%) pSOTR M, four (44%) pSOTR B, and five (50%) pHC participants, we observed no detectable anti-nucleocapsid (N) IgG in most individuals (Fig. 1b). While failure to acquire anti-N IgG following infection in children has not been reported, this is consistent with what has been observed in adults who were infected following vaccination22.

a Anti-S and anti-S1 RBD IgG titers in pHCs (n=10) and pSOTR monovalently vaccinated (M) (n=20) at approximately 6 months (180 days) since last vaccination and pSOTRs who received the bivalent dose (B) (n=8) 300 days post-vaccination. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. KruskalWallis test, ns = not significant. b Anti-nucleocapsid IgG titers. The WHO cutoff of 12.3 units (positivity for natural infection) is depicted by dotted line. Filled circles represent individuals with self-reported or documented SARS-CoV-2 infection. c Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. KruskalWallis tests, *p<0.05. The dotted line represents 25% ACE2 inhibition (limit of detection). d Correlations between anti-S IgG titers and ACE2 binding inhibition of ancestral strain and Omicron BA.5. e Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 for each individual within the groups. Wilcoxon matched-pairs rank test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. f Anti-S and anti-S1 RBD IgG titers in pSOTR (n=8) six months since last vaccination and adult SOTRs (n=38) at peak vaccine responses (day 14). MannWhitney test, *p<0.05. g Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5 in pSOTRs (n=8) and adult SOTRs (n=38). MannWhitney tests, *p<0.05. The dotted line represents 25% ACE2 inhibition (limit of detection). h Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 in pSOTRs (n=8) and adult SOTRs (n=38). Wilcoxon matched-pairs rank test, *p<0.05, ****p<0.0001. In (ac, f, g), boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values).

To assess antibody functionality, we measured percent angiotensin-converting enzyme 2 (ACE2) binding inhibition of the SARS-CoV-2 ancestral strain and Omicron BA.5 as a surrogate of neutralizing antibody function. This assay was previously validated in adult SOTRs23,24 and strongly correlated with live virus-neutralizing antibody titers in transplant recipients. Inhibition of the ancestral strain and BA.5 following monovalent vaccination was not significantly different between pSOTRs and pHCs; however, the pSOTR B group continued to exhibit slightly enhanced inhibition of Omicron BA.5 ten months post-vaccination (Fig. 1c). Although anti-S IgG titers positively correlated with ACE2 inhibition of both ancestral strain and Omicron BA.5 for all groups, there was a significant decrease in BA.5 surrogate neutralization compared to the ancestral strain, especially in monovalently vaccinated pHCs and pSOTRs (Fig. 1d, e).

Next, we compared antibody responses between pSOTR six months post-vaccination to 38 adult SOTRs two weeks post-third mRNA COVID-19 vaccine dose (i.e., peak response). To minimize heterogeneity, this analysis included only pSOTRs and adult SOTRs who were previously uninfected and who received three mRNA ancestral monovalent doses. pSOTRs six months post-vaccination exhibited significantly higher IgG titers (Fig. 1f) and greater neutralization capacity (Fig. 1g) compared to adult SOTRs at peak vaccine responses. Comparing percent inhibition of ancestral and Omicron BA.5 protein binding to ACE2 in the same individuals demonstrates that pSOTR and adult SOTRs had significantly lower BA.5 surrogate neutralization versus ancestral strain (Fig. 1h). Collectively, these data indicate that an additional mRNA vaccine dose in pSOTRs induced comparable IgG titers and neutralization capacity compared to immunocompetent children and that, despite waning, pSOTRs had significantly enhanced antibody responses six months post-vaccination compared to adult SOTRs at peak vaccine responses. Additionally, bivalent doses enhanced neutralization capacity against Omicron BA.5 in pSOTRs.

As anticipated, anti-S IgG antibody levels in pSOTRs significantly increased after the bivalent vaccination (day 14) compared to pre-vaccination (day 0), followed by a decline in responses approximately ten months later (day 300) (Fig. 2a). Given that monovalent vaccination was discontinued, it was not possible to determine if the same effect would be observed if the additional dose were not a bivalent vaccine. Three individuals in the bivalent group had matched pre- and post-bivalent dose samples. Anti-S IgG titers increased for all three, and anti-S1 RBD IgG titers increased for two out of the three individuals at day 14, before decreasing again at six months post-vaccination (Fig. 2b). Bivalently boosted pSOTRs also displayed a high capacity to neutralize both the ancestral strain and Omicron BA.5 at day 14 (Fig. 2c) in the surrogate neutralization assay. The three pSOTRs with matched pre- and post-bivalent dose samples all demonstrated a significant increase in ACE2 inhibition following the bivalent boost, especially for the BA.5 subvariant (Fig. 2d), including the child who did not demonstrate globally increased antibody titers (Fig. 2b, green star). Additionally, at day 14, bivalent recipients exhibited robust ACE2 binding inhibition of other Omicron subvariants, including BA.1, BA.2.75, BA.4.6, BF.7, and the more recently circulating BQ.1.1, BQ.1, and XBB.1, that was not significantly different from that of BA.5 surrogate neutralization (Fig. 2e). Importantly, no individuals had neutralizing capacity below the 25% ACE2 binding inhibition cutoff (previously shown to be specific for the presence of live-virus neutralization in SOTRs), suggesting overall excellent performance against Omicron subvariants. This suggests that not only are pSOTRs capable of effectively neutralizing Omicron BA.5, but also that an additional dose may help to protect this population from newly emerging SARS-CoV-2 variants. Ten months post-bivalent dose, pSOTRs exhibited decreased neutralizing capacity for every Omicron subvariant tested, with approximately half of individuals staying above the 25% cutoff (Fig. 2e). Lastly, while there was a positive correlation between anti-S IgG titers and ACE2 inhibition for both the ancestral strain and Omicron BA.5, decreased BA.5 inhibition was observed compared to the ancestral strain (Fig. 2f, g). Together, these findings provide evidence that either bivalent boosting or an additional mRNA vaccine dose significantly enhances antibody responses in pSOTRs, including increased total anti-SARS-CoV-2 IgG titers and improved surrogate neutralizing capacity against the ancestral strain, Omicron BA.5 and other variants of concern. However, anti-SARS-CoV-2 IgG titers and neutralizing capacities wane by ten months post-vaccination, suggesting that additional boosting might be beneficial in this population.

a Anti-S and anti-S1 RBD IgG titers in the pSOTR bivalent group at days 0 (D0; pre-bivalent) (n=4), 14 (D14; peak responses) (n=9) and 300 (D300; waning responses) (n=8). KruskalWallis test, *p<0.05, **p<0.01. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). b Anti-S and anti-S1 RBD IgG titers at days 0, 14, and 300 since the bivalent vaccination in three individuals with matched plasma samples. c Percent ACE2 binding inhibition of ancestral strain and Omicron BA.5 in bivalent vaccine pSOTR recipients. KruskalWallis tests, *p<0.05, **p<0.01, ***p<0.001. The dotted line represents 25% ACE2 inhibition (limit of detection). Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). d Percent ACE2 binding inhibition of the ancestral strain and Omicron BA.5 at days 0, 14, and 300 since the bivalent vaccination in three individuals with matched plasma samples. e Percent ACE2 binding inhibition of the ancestral strain and Omicron variants of concern (VOC) in bivalent dose recipients at peak (left) and day 300 (right). A single individual was infected between days 14 and 300 (red circles). Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). f Correlations between anti-S IgG titers and ACE2 binding inhibition of ancestral strain and Omicron BA.5 at peak responses (see Fig. 1d for correlations at day 300). g Matched pair percent ACE2 binding inhibition of ancestral strain vs. Omicron BA.5 at days 0 and 14 (see Fig. 1e for day 300). Wilcoxon matched-pairs rank test, **p<0.01.

Although 22% of the U.S. pediatric population has reported a positive COVID-19 test since the beginning of the COVID-19 pandemic, infection seroprevalence could be as high as 96%21,25. In this cohort, approximately 50% of participants in each group reported an infection (Supplementary Table 1). Given the frequency of pediatric infection in the U.S. and that little is known about SARS-CoV-2 vaccine immunity in pSOTRs since the Omicron variant emerged, we stratified antibody responses by COVID-19 infection status (Supplementary Table 1).

One individual in the pSOTR group had COVID-19 twice and one of the infections occurred when Omicron BA.5 was circulating. All other study participants were infected between May 2021 and June 2022 (i.e., before Omicron BA.5 became the dominant variant in the U.S.). There were no significant differences in total IgG titers and ancestral or BA.5 surrogate neutralization between vaccinated uninfected and vaccinated infected individuals within each group (Supplementary Fig. 1a, b). This suggests that the antibody results likely reflect vaccine-induced rather than infection-induced or hybrid immune responses.

To examine S antigen-specific T cells induced by ancestral monovalent vaccination and vaccination plus infection, participant PBMCs were stimulated with overlapping ancestral (W.1) and Omicron BA.4/5 S protein peptides. Subsequently, the production of interferon (IFN)-, tumor necrosis factor (TNF), interleukin (IL)-2, and IL-21 cytokines was assessed by flow cytometry (Fig. 3a, b). As with antibody responses, no significant differences in CD4+ T-cell responses were observed between uninfected vaccinated participants and those vaccinated and previously infected (Supplementary Fig. 2). In contrast to the antibody responses, pSOTRs and pHCs vaccinated with monovalent mRNA vaccines exhibited no significant differences in the frequency of CD4+ T-cell responses recognizing Omicron BA.5 epitopes compared to the ancestral strain (Fig. 3c). Interestingly, despite receiving one fewer vaccine dose on average than the pSOTR M group and more than two fewer doses on average than the pSOTR B group, pHCs demonstrated greater production of IFN- by S-specific CD4+ T cells in response to both ancestral and BA.4/5 peptides (Fig. 3d). This result remained significant after accounting for prior COVID-19 infection, immunosuppression (mycophenolate mofetil use), liver transplant history, age, number of vaccines received, and time between vaccination and sample collection (Supplementary Table 2). Production of other cytokines was not statistically significantly different between pSOTRs and pHCs six months post ancestral vaccination or pSOTRs ten months post bivalent dose. However, compared to three times vaccinated uninfected adult SOTRs at peak vaccine response26, three-times vaccinated and uninfected pSOTRs produced significantly more IFN-, IL-2, and TNF in response to ancestral S protein stimulation, and TNF in response to BA.4/5 S protein stimulation six months post-vaccination (Fig. 3e). In sum, while immunocompetent children produced significantly more IFN- in response to S peptide stimulation, pSOTRs showed comparable production of all other cytokines and greater production of most cytokines assessed six months post-vaccination compared to adult SOTRs at peak responses.

a Representative flow cytometry gating of cytokine-producing S-specific CD4+ T cells. b Representative cytokine production by S-specific CD4+ T cells unstimulated (baseline) or stimulated with ancestral (W.1) or Omicron BA.4/5S protein peptides. c Cytokine production by S-specific CD4+ T cells in responses to ancestral and BA.4/5S peptides in pSOTRs and pHCs vaccinated with monovalent mRNA COVID-19 vaccines. One-way ANOVA with Tukey correction, ns = not significant. d Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptide stimulation. Squares denote individuals with history of COVID-19, circles represent no history of COVID-19. Darker shades of color indicate more vaccines received. Two-way ANOVA with Tukey correction for multiple comparisons, **p<0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). e Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides in pSOTRs (n=8) six months since the last vaccine dose and adult SOTRs (n=19) for which we had PBMC samples at peak vaccine responses (day 14). Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values).

Bivalent boosting in pSOTRs enhanced CD4+ T-cell production of IFN- and TNF following ancestral S peptide stimulation compared to days 0 and 300, and IL-21 compared to day 300 (Fig. 4a). Similarly, bivalent recipients exhibited improved production of IFN- and TNF in response to BA.4/5 peptides compared to days 0 and 300 (Fig. 4a). This suggests that memory CD4+ T cells in pSOTRs can be boosted and successfully recalled following additional mRNA vaccine doses and/or the bivalent dose, but wane over time to pre-bivalent levels. Two out of three matched bivalent recipients exhibited increased CD4+ T-cell responses following bivalent boosting in response to both ancestral and BA.4/5 peptides (Fig. 4b, c). Interestingly, IFN- production increased in one individual in response to ancestral peptide, and two individuals in response to BA.4/5 peptides, however, neither had a reported SARS-CoV-2 infection between days 14 and 300 post-vaccination. There were no differences in the frequency of CD4+ T-cell responses recognizing ancestral and Omicron BA.4/5 epitopes in pSOTRs bivalent recipients at days 0, 14, and 300 (Fig. 4d). Overall, bivalent boosting in pSOTRs led to an enhanced cytokine production by CD4+ T cells at peak with conserved recognition of ancestral strain and BA.4/5 peptides. CD4+ T-cell cytokine production waned over time, which is in contrast with cytokine production observed in immunocompetent children after two to three doses of ancestral monovalent vaccines (Fig. 3).

a Frequencies of cytokine-producing S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides at 0, 14, and 300 days post-bivalent vaccination. Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). b, c Cytokine production by S-specific CD4+ T cells in response to BA.4/5 or ancestral S peptides for three pSOTR individuals with matched PBMC samples at 0, 14, and 300 days post-bivalent vaccination. d Cytokine production by S-specific CD4+ T cells in responses to ancestral and BA.4/5 S peptides at days 0, 14, and 300 post-bivalent vaccination. One-way ANOVA with Tukey correction, ns = not significant.

Live attenuated and viral vector-based vaccines have traditionally elicited strong CD8+ T-cell responses, which may offer additional protection independent of antibody responses27,28,29. Although mRNA vaccine-induced S-specific CD8+ T-cell responses in pSOTRs have not been comprehensively characterized, studies in adult SOTRs have reported limited CD8+ T-cell responses26,30. For both pSOTRs and pHCs, the overall frequency of cytokine producing CD8+ T cells upon stimulation with ancestral or Omicron BA.4/5 peptides remained low, often comparable to background (S peptide unstimulated) levels (Fig. 5ac). Furthermore, at six months post bivalent dose, pSOTRs exhibited limited cytokine production by S-specific CD8+ T cells (Fig. 5c). Bivalent boosting slightly improved CD8+ T-cell production of IFN- and TNF at peak vaccine responses, but not significantly (Fig. 6ad). Overall, cytokine production by CD8+ T cells was limited, demonstrating that mRNA COVID-19 vaccines induce more robust CD4+ than CD8+ T-cell responses in pediatric populations.

a Representative cytokine production by S-specific CD8+ T cells unstimulated (baseline) or stimulated with ancestral (W.1) or Omicron BA.4/5 S protein peptides. b Cytokine production by S-specific CD8+ T cells in response to ancestral and BA.4/5S peptides in monovalently vaccinated pSOTRs and pHCs. One-way ANOVA with Tukey correction, ns = not significant. c Frequencies of cytokine-producing S-specific CD8+ T cells in response to BA.4/5 or ancestral S peptides. Two-way ANOVA with Tukey correction. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values).

a Frequencies of cytokine-producing S-specific CD8+ T cells in response to BA.4/5 or ancestral S peptides in pSOTRs at days 0, 14, and 300 post-bivalent dose. Two-way ANOVA with Tukey correction. An = ancestral strain. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). b, c Cytokine production by S-specific CD8+ T cells in response to BA.5 or ancestral S peptides for three pSOTR individuals with matched PBMC samples at days 0, 14, and 300 post-bivalent dose. d Cytokine production by S-specific CD8+ T cells in response to ancestral and BA.4/5S peptides in pSOTRs bivalent recipients at days 0, 14, and 300 post-bivalent dose. One-way ANOVA with Tukey correction, ns = not significant.

Early studies reported that SARS-CoV-2 infection induces robust CD8+ T-cell responses in adults31,32. Hence, we stratified CD8+ T-cell responses by previous history of COVID-19. Comparable to CD4+ T-cell and antibody results, CD8+ T-cell responses were not significantly different between those with and without a history of SARS-CoV-2 infection (Supplementary Fig. 3). Additionally, as mentioned previously, all cytokines tested were present in very low frequencies preventing trend evaluation in each group. These results further confirm that the responses we observed were induced mainly by vaccination and that S-specific CD8+ T-cell responses were low compared to CD4+ T-cell responses.

Polyfunctionality is defined as the ability of T cells to produce more than one cytokine simultaneously and has been associated with protection in previous studies against other infections33,34. Due to overall low CD8+ T-cell responses (Figs. 5, 6), we evaluated polyfunctionality in CD4+ T cells only. Ancestral and BA.4/5 peptide stimulation induced no significant difference in overall frequencies of S-specific polyfunctional CD4+ T cells within each group (Fig. 7a). However, pHC participants demonstrated increased polyfunctionality in response to ancestral and BA.4/5S peptide stimulation compared to the pSOTR groups (Fig. 7b, c), primarily due to increased simultaneous production of TNF and IFN- (category 6, purple). Additionally, S-specific CD4+ T cells in pHCs produced significantly more IFN- only (category 8, orange), while pSOTR CD4+ T cells produced more TNF only in response to both ancestral and BA.4/5 peptides (category 14, dark pink) (Fig. 7c). Together, these findings suggest that while pSOTRs produce polyfunctional CD4+ T cells in response to mRNA vaccination, they are qualitatively different compared to polyfunctional CD4+ T cells produced by immunocompetent children, and lack robust production of IFN-.

a Ancestral and BA.4/5 peptide stimulation induced no significant differences in frequencies of polyfunctional CD4+ T cells in each group. Pie charts are broken down by the 15 cytokine combination categories. Arcs identify slices of the pie that express each specific cytokine. b Heatmap identifying absolute differences between groups for each category (115). c Frequencies of CD4+ T cells producing cytokine combinations in response to ancestral or BA.4/5 peptides. Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Error bars represent standard error of the mean.

We next assessed S-specific CD4+ T-cell polyfunctionality and whether an additional dose of vaccine could increase IFN- production by pSOTRs (Fig. 8). We did not observe significant differences in ancestral or BA.4/5-induced cytokine production (Fig. 8a), but overall polyfunctionality was significantly improved shortly after post-bivalent vaccination (Fig. 8b, c). Bivalent boosting primarily increased the frequency of CD4+ T cells simultaneously producing IL-2 and TNF (category 10, green) in response to BA.4/5S peptides at peak responses. Additionally, the production of IFN- only (category 8, orange), IL-2 only (category 12, dark blue), and TNF only (category 14, dark pink) significantly increased at peak compared to prior and ten months post-bivalent boosting (Fig. 8b, c). In sum, bivalent boosting enhances IFN- production by CD4+ T cells 14 days post-vaccination, but not long-term, as seen in pHCs. Instead, bivalent doses in pSOTRs enhanced long-term TNF and IL-2 cytokine production (Figs. 7c, 8c).

a Cytokine production by CD4+ T cells in response to ancestral and Omicron BA.4/5 peptides at days 0, 14, and 300 post-bivalent vaccination. Pie charts depict the 15 cytokine combination categories. Arcs identify slices of the pie that express each specific cytokine. b Heatmap identifying absolute differences between groups for each category. c Frequencies of CD4+ T cells producing cytokine combinations in response to ancestral or BA.4/5 peptide stimulation. Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Error bars represent standard error of the mean.

Subsequently, we investigated whether CD4+ T-cell polyfunctionality differs in the nine pSOTR bivalent recipients depending on history of COVID-19 (Supplementary Fig. 4). While infected individuals tended to exhibit slightly increased production of IFN- (category 8) and TNF (category 14), no significant differences in cytokine production or polyfunctionality between individuals with or without previously documented SARS-CoV-2 infection were noted (Supplementary Fig. 4a, b), further indicating that the responses observed in this study are predominantly vaccine-induced.

We then comprehensively evaluated phenotypic and functional markers of S-specific CD4+ T cells induced in response to ancestral and BA.4/5 peptides using high parameter flow cytometry. The panel includes 29 surface and intracellular markers designed to evaluate T-cell subsets, metabolism, activation, and exhaustion phenotypes (Supplementary Table 3). No significant differences in S-specific CD4+ T-cell phenotypes were observed between responses to the ancestral (Supplementary Fig. 5) and BA.4/5 peptides (Fig. 9). Therefore, the subsequent analysis represents the response to BA.4/5 peptide stimulation.

a UMAP dimension reduction plot for each group. b Unsupervised clustering algorithm Xshift identified 8 clusters on the UMAP. c Heatmap of normalized mean fluorescent intensity (MFI) values of markers expressed in each cluster. d Frequency of clusters in each group. Two-way ANOVA with Tukey correction, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Error bars represent standard error of the mean. e MFI plots for significant clusters determined in (d), ungated clusters (gray) and bulk T cells (black).

The uniform manifold approximation and projection (UMAP) revealed significant differences in S-specific CD4+ T-cell phenotypes, especially between the transplant recipient groups and pHCs (Fig. 9a). The unsupervised clustering algorithm that uses k-nearest neighbors density estimation, Xshift35, was then applied, and identified eight distinct S-specific CD4+ T-cell clusters on the UMAP (Fig. 9b). The mean fluorescent intensities (MFIs) of markers expressed in each cluster are depicted in Fig. 9c. The frequencies of three clusters (6, 7, and 8) were statistically significantly different among the groups (Fig. 9d, e). Clusters 6 and 7 were enriched in the pHC group compared to the transplant recipient groups (Fig. 9d). Cells in these two clusters were metabolically active (GLUT1+, PD-1+), and expressed comparatively very high levels of IFN- (Fig. 9e). Cluster 7 cells were more polyfunctional than cluster 6 cells, expressing high frequencies of all four cytokines. Clusters 6 and 7 also expressed CD27 and CD28, consistent with a functional memory T-cell phenotype. Monovalently and bivalently vaccinated pSOTRs had the highest frequency of S-specific CD4+ T cells in cluster 8 (Fig. 9d, e). Cluster 8 cells expressed high levels of cytokines TNF and IL-2, but very little IFN- compared to other clusters (Fig. 9e). This is consistent with our polyfunctionality results in which pSOTR bivalent recipient CD4+ T cells co-expressed TNF and IL-2 (Fig. 8). Similar to clusters 6 and 7, cluster 8 cells expressed CD27, CD28, PD-1 and GLUT1, indicative of activated and functional memory T-cell phenotype.

We then applied the same analytical pipeline to cells from bivalent recipients prior to boosting, at peak and ten months post-vaccination. Again, no significant differences in S-specific CD4+ T-cell phenotypes were observed between responses to the ancestral (Supplementary Fig. 6) and BA.4/5 peptides (Fig. 10). The UMAP revealed slight differences in S-specific CD4+ T-cell phenotypes (Fig. 10a), especially expression of various cell markers on day 14 compared to days 0 and 300, and Xshift then identified seven S-specific CD4+ T-cell clusters on the UMAP (Fig. 10b). MFIs of markers expressed in each cluster are depicted in Fig. 10c. All seven clusters were present in comparable frequencies in each group (Fig. 10d).

a UMAP dimension reduction plot for each group. b Unsupervised clustering algorithm Xshift identified 7 clusters on the UMAP. c Heatmap of normalized mean fluorescent intensity (MFI) values of markers expressed in each cluster. d Frequency of clusters in each group. Two-way ANOVA with Tukey correction, all not significant. Error bars represent standard error of the mean.

Overall, our analysis of S-specific CD4+ T cells induced in response to BA.4/5 peptide stimulation suggests that despite immunosuppression, pSOTR recipients can generate metabolically active S-specific CD4+ T cells that are qualitatively distinct, primarily producing TNF and IL-2, less IL-21 and very little IFN- relative to pHCs. T cells of this phenotype were enhanced following bivalent vaccination, demonstrating that bivalent vaccination did not result in a higher proportion of T cells producing IFN-. This is distinct from CD4+ T cells generated in pHCs that were also metabolically active but mostly produced IFN-. Since monovalent pSOTR recipients produce similar frequencies of IFN--producing CD4+ T cells as bivalent recipients, we hypothesize that immunosuppressive regimens alter the S-specific CD4+ T-cell compartment rather than that IFN- production is associated with fewer vaccine doses.

Finally, we performed T-cell proliferation assay to further assess T-cell responses following vaccination (Fig. 11a). Cell trace violet dye-labeled PBMCs were cultured for five days in the presence of ancestral S peptides to drive the proliferation of S-specific T cells. Individuals who received bivalent vaccination exhibited the highest proliferation 14 days post-vaccination, as expected (Fig. 11b, c). Surprisingly, the pHC and pSOTR groups showed comparable S-specific T-cell proliferation at the time of waning immunity, potentially because children generally require lower doses of immunosuppressive regimes compared to adults. Interestingly, S-specific CD8+ T cells exhibited remarkable proliferation despite limited cytokine production. We then correlated CD4+ T cells proliferation with cytokine production and found a strong correlation between cytokine production and CD4+ T-cell proliferation in healthy children, but this correlation was not observed in pSOTRs (Fig. 11d). This further suggests that cytokine production and proliferation of S-specific CD4+ T cells is dysregulated in pSOTRs.

a Representative gating of cell trace violet-labeled, S-specific, proliferating daughter T cells in response to ancestral SARS-CoV-2 S peptides. b Proliferating S-specific CD4+ and CD8+ T cells (% memory) in pHC, pSOTR M, and pSOTR B groups at the time of waning immunity. No significant relationships. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). c Proliferating CD4+ and CD8+ T cells (% memory) in pSOTR B at days 0, 14, and 300. Kruskal-Wallis test, *p<0.05, ns = not significant. Boxplots were used to summarize data (median, 1st3rd quartiles (IRQ), whiskers represent minimum and maximum values). d Heatmap depicting correlations between proliferation of S-specific CD4+ T cells and cytokine production in pHCs and pSOTRs. The cytokine category combines TNF, IL-21, IL-2, and IFN- production. Pearson correlation coefficients are depicted in each square. Higher coefficient represents greater correlation.

It takes only one case of measles or other vaccine-preventable diseases for an outbreak to begin. In fact, in 2023 measle cases were up 80%, according to a TIME Magazine report, and the Michigan Department of Health and Human Services reported the first case of measles for the state this year in February.

But vaccines can prevent or lessen the severity of the condition in question for everyone, according to Peter Gulick, professor of Osteopathic Medical Specialties at the Michigan State University College of Osteopathic Medicine.

Unfortunately, disinformation and fear cause people to choose not to vaccinate themselves or their children, Gulick said. Its the reduction in immunity over time, and then all you need is one case, and then if it hits other people who dont have immunity, it spreads.

Some of that misinformation has included a paper published linking the mumps/measles/rubella, or MMR, vaccine that protects against measles to autism. That was found to be a totally false article it was retracted, and the publisher said there is no evidence, the data was put together wrong. But people still bring it up, Gulick explained.

Sean Valles, professor and director of the MSU College of Human Medicines Center for Bioethics and Social Justice suggests listening to those who are reluctant to get vaccinated and address their concerns.

Vaccine hesitancy, he said, includes concern about potential side effects, a false belief that a vaccine can cause the disease it is supposed to protect against, unfounded rumors and distrust of medical science fed by Internet conspiracies, and even a fear of needles. Most vaccine skeptics are not completely opposed to vaccination, Valles said.

In the case of measles, it is so contagious, far and away more than almost anything else, Valles said, that we dont have room for error.

The MMR vaccine has been available and highly effective in preventing the deadly disease since the early 1970s, lulling some parents into a false sense of security that measles has been eradicated, although, in fact, it never left. Other parents fall prone to a highly politicized climate of misinformation.

Vaccine hesitancy has sort of always been there, Valles said, but its become much more organized.

There are always going to be those people who are going to be a hard no, he added, no matter what you say.

The key, he said, is to find those who remain at least partially open-minded.

Read more about vaccines and vaccine hesitancy.

MONTGOMERY, Ala. (WIAT) Every year, Alabama students must stay up to date on their vaccinations. One lawmaker said that the government can only do so much when it comes to religious beliefs.

Under current Alabama law, parents must receive written notice from the county health department to exempt their child from a vaccination. State Sen. Arthur Orrs (R-Decatur) bill to change the current vaccine exemption policy was passed by the Senate Education Policy Committee.

The bill mandates written statements from parents as the only documentation needed to get exemptions. Orr said hes heard concerns from many of his constituents.

Ive received complaints from parents saying Well, I went to the county health department. I waited for an hour or two to see the right person, then I had a government bureaucrat start questioning me about why I have certain religious beliefs,' Orr said.

But Dr. Nola Ernest, president of the Alabama Chapter of the American Academy of Pediatrics, said children might get diseases that are preventable as a result of this bill.

For pediatricians, our reaction to increasing religious and philosophical exemptions for vaccines is a little bit one of fear, Ernest said. Many of us have not practiced in a time where vaccine preventable diseases were rampant.

Orr said the bill is about parents right to religious exemptions.

But we need to take the government out of the process as far as determining, or probing, ones religious beliefs, Orr said.

After passing through the committee, the bill now heads to the floor for a vote.

(Precision Vaccinations News)

According to an article written byAdam Tooze, in a world of polycrisis, in which intersecting problems compound each other and there are few easy wins, it is all the more important to recognise those policy choices that are truly obvious.

Funding vaccine development isone such investment.

Published by The Financial Times on April 1, 2024, this opinion article says modest expenditures on public health have saved tens of millions of lives, reduced morbidity, and allowed children around the world to develop into adults capable of living healthy and productive lives.

The complete, unedited article is posted at this link.