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FDA Advisers Bullish on RSV Shots for Kids, Even as Safety Signals Shut Down Moderna Trials

By Brenda Baletti, Ph.D. | The Defender | December 13, 2024

Advisers to the U.S. Food and Drug Administration (FDA) met Thursday to discuss the future of pediatric respiratory syncytial virus (RSV) vaccines after Moderna was forced to abruptly halt clinical trials for its mRNA RSV vaccine in children ages 5-23 months.

Clinical trial data released earlier this week in an FDA briefing document showed that rather than preventing RSV disease in small children, Moderna’s vaccine likely caused higher rates of severe RSV illness in its Phase 1 clinical trial.

Moderna halted the trial in July after it was informed that two babies in the vaccine group had developed severe RSV disease. The company didn’t publicly announce that the trial was discontinued until September.

The data presented Thursday at the Vaccines and Related Biological Products Advisory Committee meeting showed that 12.5% of vaccinated children developed severe RSV disease as compared to just 5% of children in the placebo group.

Among the children who developed symptomatic RSV disease, 26.3% in the vaccinated group progressed to severe disease, while only 8.3% of those in the placebo group did.

These results were concerning given the history of past attempts to develop an RSV vaccine for infants. In the 1960s, an experimental formalininactivated RSV vaccine for children led to two toddler deaths, and 80% of vaccine recipients required hospitalization for severe RSV.

The illnesses were attributed to vaccine-associated enhanced respiratory disease (VAERD) — a phenomenon that occurs when vaccination promotes immune responses that exacerbate the disease caused by subsequent infection with the pathogen the vaccine was meant to protect against.

In light of that history, and because the mechanisms that cause VAERD are still largely unknown, the FDA convened the advisory committee to discuss the implications of Moderna’s trial outcomes for other pediatric RSV vaccines.

The committee did not vote on Thursday or make any formal recommendations. Members watched presentations from consultants, the FDA, and pharmaceutical companies and discussed the risks and benefits of developing RSV vaccines for children.

They also commended Moderna for reporting its results and the existing clinical safeguards for recognizing early safety signals in pediatric RSV trials.

Vaccine makers developing 26 different RSV vaccines or monoclonal antibodies

The briefing document stated that the FDA was halting enrollment for all investigational trials for RSV vaccines for infants and toddlers under age 2 and children ages 2 through 5 who haven’t previously had RSV.

The FDA clarified at the outset of the meeting that the hold does not apply to vaccine candidates that use live attenuated vaccines, because there is no evidence that vaccines developed on this platform cause VAERD.

Advisers seemed to agree, except for Dr. Karen Kotloff who voiced concerns there was not enough information to assume that live attenuated vaccines don’t carry the same potential risk.

Dr. Pedro Piedra, who presented on clinical and non-clinical aspects of RSV vaccine safety shared a slide listing RSV vaccines and monoclonal antibodies currently in trials.

There are five pediatric vaccines other than Moderna’s — which Moderna’s Christine Shaw, Ph.D., definitively stated is no longer moving forward — in the pipeline. Four of them are for live-attenuated vaccines.

Vaccine makers are developing 26 different RSV vaccines or monoclonal antibodies for all age groups, all vying to enter a rapidly expanding market.

PR Newswire projected in 2023 the global RSV vaccine and antibody market would be worth $2.61 billion dollars in 2024 and rise to $13.59 billion by 2030.

Piedra — who began his presentation with the quick disclosure that he has grants for RSV prevention research from GSK, Icosavax and Merck and is a paid consultant in the field for Merck, Moderna, Pfizer and Sanofi — presented an optimistic picture of RSV vaccine development, citing protection offered by recently approved maternal vaccines and monoclonal antibodies.

Moderna’s results did raise some platform-specific concerns, Piedra conceded.

He listed the types of safety concerns that could be associated with different vaccine platforms — febrile seizures with adjuvanted or high-dose vaccines or when RSV vaccines are co-administered with other vaccines, autoimmunity that could be associated with new adjuvants, respiratory issues with intranasal vaccines, and systemic illnesses with vector-based or mRNA vaccines.

‘Unmet need’ as justification to push for more RSV vaxes for small children

Presenters repeatedly stated that there was an “unmet need” for pediatric RSV vaccines, especially for children between 8 months and 2 years old.

RSV usually causes mild cold-like symptoms, but in some cases can lead to hospitalization and death in infants and the elderly. By age 2, 97% of all babies have been infected with RSV, which confers partial immunity, making any subsequent episodes less severe.

The disease burden for infants can be serious. In the U.S., RSV infection is the leading cause of infant hospitalization among those younger than 6 months, although a very small percentage of children with the virus will die.

An FDA representative said the Centers for Disease Control and Prevention (CDC) estimates that 100-200 infants die per year from the disease. However, internist Dr. Meryl Nass told The Defender that even those low numbers may overestimate mortality.

Nass pointed to a CDC study analyzing RSV deaths in infants between 2005 and 2016 and found a total of 314 deaths in children under age 1, or 25 on average per year, Nass reported. Only 17 of those deaths per year listed RSV as the underlying cause of death.

The FDA also said that maternal vaccines and monoclonal antibodies had begun to reduce those numbers, but emphasized there is still an “unmet need” for a vaccine for children going into their second RSV season — even as it presented data showing hospitalizations in that season are lower.

Moderna said this “unmet need” drove them to develop their failed vaccine. A Sanofi representative, who gave an update on their live-attenuated RSV virus, said the company sought to meet that “unmet need” for children in their second RSV season.

Sanofi also sells nirsevimab — brand name Beyfortus — the monoclonal antibody shot the CDC recommends for all newborns to protect them in their first RSV season.

Sanofi and the National Institutes of Health (NIH) are collaborating on the live-attenuated virus vaccine platform. The NIH developed 16 different vaccine candidates that it trialed in children and currently has one SP-125 in Phase 3 clinical trials.

These vaccines have not shown VAERD after one season of surveillance, the Sanofi representative said. The safety trials showed no safety concerns and SP-125 is currently being tested for efficacy in toddlers 6-22 months of age, but it is not yet fully enrolled.

During the “public comments” section of the meeting, three other vaccine makers promoted their vaccines to the committee.

Goal is more RSV shots for kids to provide passive immunity followed by ‘active immunity’ 

FDA asked the committee members to discuss existing evidence on whether infants and toddlers could eventually get sequential administration of RSV monoclonal antibodies followed by RSV vaccines.

That would mean even more shots on the childhood immunization schedule. The monoclonal antibodies or maternal vaccination would provide babies with “passive immunity” — antibodies to fight the virus that weren’t created by their own immune systems.

Then, in this schema, a two- or three-shot course of an RSV vaccine could protect babies from RSV in the second season, giving them “active immunity.”

Most committee members said more data were necessary to evaluate the safety of such a plan, but they generally agreed that it was a good direction to move in.

Watch the meeting here.

This article was originally published by The Defender — Children’s Health Defense’s News & Views Website under Creative Commons license CC BY-NC-ND 4.0. Please consider subscribing to The Defender or donating to Children’s Health Defense.

December 15, 2024 Posted by | Science and Pseudo-Science | , , , | Leave a comment

DISEASE X: A WARNING, OR A THREAT?

The Highwire with Del Bigtree | January 18, 2024

As the WHO and media attempt to keep the public in fear with the threat of an unknown disease, we breakdown what ‘disease X’ really symbolizes. Meanwhile, gain-of-function experiments continue to put humanity in great peril.

A WARNING FOR PREGNANT WOMEN ABOUT THE RSV VACCINE

The Highwire with Del Bigtree | January 18, 2024

Del takes a deep dive on the newly approved RSV vaccine’s side effects on pregnant women. Using data straight from ABRYSVO’s own box insert for data, he highlights the increased risk of preterm birth and buffer ingredients such as polysorbate 80 and residual DNA from host cell proteins from Chinese hamster cell lines. Does this sound safe to you?

January 20, 2024 Posted by | Science and Pseudo-Science, Video | , , | 1 Comment

Low RSV Vaccine Acceptance Among Pregnant Women

By Peter A. McCullough, MD, MPH | Courageous Discourse | January 10, 2024

Vaccination during the third trimester of pregnancy is unprecedented and risky, since a vaccine induced fever could precipitate stillbirth or premature delivery of the baby. The CDC and the Bio-Pharmaceutical Complex has told young mothers they should take the risk for theoretical protection of the newborn.

As of August 30, 2023, the CDC recommends: “Vaccination for pregnant people, 1 dose of maternal RSV vaccine during weeks 32 through 36 of pregnancy, administered immediately before or during RSV season. Abrysvo is the only RSV vaccine recommended during pregnancy.” Now the CDC is reporting that only Asian women in the US have topped 10% on the respiratory syncytial virus RSV vaccination rate while African American mothers remain the most conservative with under 5% rates of acceptance. For any mass vaccination campaign, these data would indicate a program failure. The mothers and families have been burned by genetic COVID-19 vaccines and unprecedented rates of injury, disability, and death. There is little appetite for a new vaccine during pregnancy among obstetricians, midwives, and expecting mothers.

These data on the lagging maternal RSV immunization campaign indicate that “vaccine mania” may be cooling in the United States. As a consulting internist and cardiologist, I do not recommend the new RSV vaccine for pregnant women. There are insufficient data on short and longer term safety. Theoretical protection of infants for an easily treatable illness is simply not compelling enough to risk the pregnancy altogether.

January 12, 2024 Posted by | Science and Pseudo-Science | , , | 1 Comment

Vaccines galore

But is more better?

By Dr Ros Jones | Health Advisory & Recovery Team | July 9, 2023

The picture above may shortly be out of date when the latest monoclonal antibody against respiratory syncytial virus (RSV) is added to the CDC list. The US approach stands in stark contrast to Europe’s.

So another dilemma for parents of young children who have already laboured long and hard over whether to give their children a covid-19 vaccine – will their children need this latest new immunisation?

An RSV vaccine developed in the 1960s got as far as human trials, but had to be hastily withdrawn when it became apparent that subsequent disease was far worse in the vaccinated than the controls. As expected, the babies made a good antibody response and there were no obvious serious side effects. Fast forward a few months to the next autumn’s RSV season and sadly for the drug company and even more sadly for the babies and their families, the vaccinated group developed much more severe disease than the controls (18/20 vaccinated infants hospitalised with 2 deaths versus 0 deaths and 1 hospitalisation in the 21 controls gives placebo efficacy of 100% against death and 95% against hospitalisation – wonderful stuff that normal saline!) Animal studies with the RSV vaccine had already highlighted such problems.

Similar difficulties were seen in candidate vaccines for SARS (SARS-CoV-1). No less than four new coronarvirus vaccines produced after the SARS outbreak in 2003 looked hopeful initially, until the animals were exposed to the SARS virus. Although the vaccinated animals cleared the virus more rapidly, they developed severe eosinophil infiltrates in their lungs, in contrast to the control animals, highly suggestive of an immune overreaction in the presence of the virus (a Th2 helper cell hypersensitisation).

Dengue vaccines have had similar problems, with Dengvaxia withdrawn after the vaccinated group experienced much more severe disease the following season.  In that case, the vaccine had been rolled out widely in the Philippines without awaiting the one-year trial follow-up, in a moment of political hubris which resulted in their Minister of Health facing criminal charges, but far more seriously it also resulted in the deaths of at least 10 healthy children.

What all these disasters had in common was a condition called ADE (Antibody Dependent Enhancement). In the presence of a large immune response, inflammatory markers are activated; this led to acquired respiratory distress in the case of the SARS vaccine, severe wheezing and airway inflammation in the case of the RSV vaccine, and a severe systemic reaction with the Dengue vaccine.

So what of this latest RSV prophylactic? There are two types, firstly monoclonal antibodies which give so-called passive immunisation i.e. the infant is given injections of antibodies to protect them against RSV in the early months of life but these just disappear naturally. There is an existing drug called palivizumab which has been around since 1998, so it is not clear why they need the new one, nirsevimab. The main advantage of the new product is that it is given as a single dose, rather than the monthly injections recommended for palivizumab, which makes it more practical, hence the new version has been authorised for all infants, rather than the high risk groups only for whom the monthly palivizumab injections were recommended. Nirsevimab was approved for use in the EU and the UK last November, following trials involving 3580 treated infants. The report combines various studies – one involving only infants at high risk from RSV such as preterm babies or those with heart or lung disease, for whom there was a reduction in hospitalisation from 4.1% in the placebo group to 0.8% in the nirsevimab group.  A second study then recruited healthy low risk babies and for them the reduction in hospitalisations was only from 1.6% to 0.6%. There was a reduction in overall infections, but it is not clear whether that means these infants will simply get RSV infection the following winter. Having said that, most hospitalisations for this condition are in infancy. But as so often, it seems that no longer-term outcomes are required for approval to be given.

Interestingly, the FDA have yet to approve it, although their advisory committee last month voted 21:0 to recommend it for all infants. A worrying observation in the FDA approval paperwork was an increase in all cause deaths in the nirsevimab arm of the various trials (12/3710 (0.32%) nirsevimab versus 4/1797 (0.22%) controls). I could find no mention of this on the European Medicines Agency or MHRA websites, although the same drug company results were submitted.

Meanwhile in April, the FDA approved a new RSV vaccine from GlaxoSmith Klein(GSK), Arexvy for use in over 60s, followed in May by approval of a similar Pfizer vaccine, Abrysvo. As with Covid-19 vaccines, Pfizer gave results as relative risk reductions, so an encouraging 66.7% efficacy, but much less impressive when looking at the absolute risk reduction of 0.24% (from 0.36% to 0.12%) for symptomatic lower respiratory tract infections. The number of hospitalisations was too small to look at efficacy. More worrying is that looking at the supporting information on the FDA website reveals both vaccines showing an increase in atrial fibrillation compared to the placebo and also neurological adverse events, namely Guillain-Barré syndrome and Acute Disseminated Encephalomyelitis (ADEM) in the vaccinated group, with one fatality and one woman requiring 6-months hospitalisation. In two of the studies, flu vaccine and the new RSV vaccine were given simultaneously making it impossible to know which of the vaccines to blame.

The Pfizer Abrysvo RSV vaccine is expected to be approved by the FDA in August for pregnant women, for whose infants there was a 0.8% reduction in hospital admissions for RSV infection over the following 6 months (from 1.3% to 0.5%). But the independent panel vote was not unanimous, and concerns were raised about an increase in preterm births. Indeed, the GSK RSV vaccine trial for use in pregnancy was already stopped for this reason. Because this is proposed for use in the mothers, it will need a large number to vaccinate to prevent one infant hospitalisation, given most babies don’t go anywhere near hospital for this condition. It is not at all clear whether those infants whose mothers have already been vaccinated, will also be offered the monoclonal antibody in a ‘belt-and-brace’ approach or whether the two different types of preventative are simply to provide a choice. GSK have specifically said that they do not anticipate their vaccine being used in infants: ‘evidence from an animal model strongly suggests that AREXVY would be unsafe in individuals younger than 2 years of age because of an increased risk of enhanced respiratory disease’ (remember the 1967 vaccine, whereas the Pfizer document only says of Abrysvo‘Pediatric studies should be delayed until additional safety or effectiveness data have been collected’.

It is noteworthy that approval for the vaccines has  progressed via the FDA’s Priority Review mechanism – the excuse for Covid-19 vaccines was of course that there was an emergency due to a novel and deadly virus sweeping across the world, with a saviour vaccine the only way out of endless lockdowns.  But what is the possible excuse for a priority vaccine for RSV? This virus was first isolated in 1956 and was presumably around long before that. But of course, if we’d been listening, we would have heard Sir Patrick Vallance in 2014 saying “In the future, medicines will come to market quicker with less data, with more research being conducted in the post-license phase”.  It seems that the future has arrived.

The plethora of new vaccines in the pipeline, in particular mRNA vaccines which will be developed at the new UK government-funded Moderna facility in Oxford, must be subject to the proper scrutiny which has sadly been totally lacking in recent years.

This begs the question: what of the multitude of existing vaccines shown so graphically in the picture at the top of this article? It struck me that as a retired paediatrician in my seventies, now being labelled by the government as a conspiratorial ‘antivaxxer’, I had of course only had 2 vaccines in my infancy, smallpox and diphtheria. At age 7, I received the new polio vaccine and as a 13-year-old BCG against tuberculosis (and that only after a negative skin test showed I wasn’t already naturally immune). And that was it, until I reached medical school where I got the new tetanus vaccine. Yellow fever and Typhoid vaccines followed for a student elective in South Africa and then nothing until Hepatitis B vaccine 20 years later.

The generation below mine had only diphtheria, tetanus and polio in infancy with measles at 13 months. This UK timeline makes interesting reading. But my grandchildren’s generation are apparently offered 15 in their preschool years (many of course are combinations so an 8-week infant is now vaccinated against 8 different diseases simultaneously). But this is still well below the number offered (and indeed mandated for many schools) to American children. Perhaps the JCVI are full of ‘anti vaxxers’, let alone the Danish authorities where infants are only vaccinated against 6 diseases and with a much more spaced out programme at 3, 5 and 12 months.

Can anyone point me to the randomised trials showing that this huge sum total of vaccines is beneficial in terms of overall outcomes? Because I have failed to find it. Instead I have found interesting articles such as that from the Bandim project in Guinea Bissau, where the delayed introduction of childhood vaccinations in the 1970s gave a natural control group. In collaboration with the Statens Institute in Denmark, they found that killed vaccines were associated with an increase in childhood mortality. Or this one comparing the infant mortality of the healthiest 30 countries by number of vaccines given, which certainly showed no support for the idea that more is better.

Figure 1: Mean infant mortality rates and mean number of vaccine doses 2009

Statements from WHO, Gates Foundation etc that vaccination has been the biggest life-saving breakthrough does beg the question: if the same amount of money and effort had been put into ensuring every child had access to clean drinking water and adequate food (the most basic physiological need in Maslow’s hierarchy of needs), then how many more lives would have been saved?

Would ‘Big Plumbers’ now be dominating public health policy?

Dr Ros Jones is a HART member and retired Consultant Paediatrician.

July 10, 2023 Posted by | Economics, Science and Pseudo-Science | , , | 1 Comment