FDA Advisers Bullish on RSV Shots for Kids, Even as Safety Signals Shut Down Moderna Trials
Advisers to the FDA met Thursday to discuss the future of pediatric RSV vaccines after Moderna was forced to abruptly halt clinical trials for its mRNA RSV vaccine in children ages 5-23 months.
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 formalin–inactivated 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:
Like most aspects of human ill-health, RSV would be much less of a problem if everyone had at least the 50 ng/mL circulating 25-hydroxyvitamin D their immune system needs to function properly.
25-hydroxyvitamin D, as measured in "vitamin D" blood tests, is made primarily in the liver, over several days, from ingested or production in ultraviolet-B exposed, ideally white, skin.
There's very little vitamin D3 in food, fortified or not. It can be made by UV-B skin exposure, but this always damages DNA and so raises the risk of skin cancer. Far from the equator, sufficient UV-B light is only available, from high elevation sunlight on cloud-free summer days, without being absorbed by glass, clothing, sunscreen or large amounts of melanin in the skin.
Without proper vitamin D3 supplementation, or lots of UV-B skin exposure, most people attain half or less of the 50 ng/mL 125 nmol/L (1 part in 20,000,000 by mass) level of circulating 25-hydroxyvitamin D the immune system needs to function properly.
Neither vitamin D3 cholecalciferol no 25-hydroxyvitamin D are hormones. The immune system does not use hormonal signaling. Many types of immune cell require a good supply of 25-hydroxyvitamin D, via diffusion from the bloodstream, to supply their 25-hydroxyvitamin D -> calcitriol intracrine signaling system, which operates entirely within the cell, and is crucial to the cell's ability to respond to its changing circumstances.
Please see the research cited and discussed at: https:// vitamindstopscovid.info/00-evi/.
It is easy to find research of specific interest for RSV, with a Google Scholar search for:
RSV "vitamin D"
https://scholar.google.com.au/scholar?hl=en&as_sdt=0%2C5&q=RSV+%22vitamin+D%22&btnG=
For recommendations (from New Jersey based Professor of Medicine Sunil Wimalawansa) on how much vitamin D3 to supplement, as a ratio of body weight - with higher ratios for those suffering from obesity - please see: https:// vitamindstopscovid.info/00-evi/#00-how-much. These recommendations are now in a peer-reviewed journal article he wrote with another professor of medicine and a professor of pediatrics, all of them long-time vitamin D researchers: https:// www.sciencedirect.com/science/article/pii/ S2405844024107220.
These recommendations are intended to safely raise the circulating 25-hydroxyvitamin D level to at least 50 ng/mL, with no need for blood tests or medical monitoring. 70 kg (154 lb) adults need about 1/8th of a milligram of supplemental vitamin D3 a day, on average, in order to attain (over several months) at least the 50 ng/mL circulating 25-hydroxyvitamin D they need for full immune system function.
This is 125 micrograms = 0.125 milligrams and is also known by the frighteningly high number of 5000 IUs ("International Units"). An IU is a cranky old unit from a century ago: 1/40,000,000 th of a gram of vitamin D3.
"5000 IU"s sounds like a lot, but it is a tiny amount. Meanwhile, many doctors recommend only 1000 IU a day (a gram every 110 years) vitamin D3 supplementation, which may raise the 25-hydroxyvitamin D of average weight adults to about half of the 50 ng/mL needed for proper immune system function.
Newborns' 25-hydroxyvitamin D levels depend directly on their moms'. Measurements of vitamin D3 and 25-hydroxyvitamin D levels vary widely, in part due to the difficulties in measuring such low levels: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2023.1229445. One recent study https://www.mdpi.com/2072-6643/13/2/573 found approximately equal amounts of vitamin D3 and 25-hydroxyvitamin D in human breast milk. Since (at least in adults) the liver only coverts about 1/4 of ingested vitamin D3 into circulating 25-hydroxyvitamin D, this means that the bulk of the benefit to the breast-fed child's 25-hydroxyvitamin D comes from the 25-hydroxyvitamin D component of breast milk. This depends on the mother's 25-hydroxyvitamin D level.
All part of the Pfizer master plan, when competitors RSV Jabs "drop out of the market".
https://geoffpain.substack.com/p/pfizer-appoints-chris-boshoff-who