RSV Vaccines for Children: Still Crazy After All These Years

Vaccine-enhanced disease raises its ugly head again. When will they ever learn?

Stories matter; they form the foundations for how we define ourselves and our relationship with the world. Over time, fact-based stories are often transformed into myths. There are stories that define the public perception of vaccinology and the practitioners of this art. The mythic genius and heroics of Edward Jenner, involving clear-skinned milkmaids, cowpox, and the Smallpox vaccine, is the origin myth for modern western vaccinology. The competitive race between Drs. Salk and Sabin to save the world’s children from Polio is another.

But vaccinology also has its dark stories. The approved COVID vaccine narrative that will pass down through time is still either disputed or being negotiated, depending on your point of view, but I suspect history will not be kind to Operation Warp Speed and its gene therapy-based prophylactics that prevented neither infection nor disease from SARS-CoV-2. Unfortunately, these products did cause myocarditis, stroke, a variety of blood clotting disorders, and at this point, God only knows how many other problems, including both sudden and delayed death. Most vaccinologists are still in denial about the facts of this story.

The first licensed rotavirus vaccine was withdrawn in 1999, within a year following FDA authorization and introduction, due to its association with a complication called intussusception in which a vaccinated child’s bowel would sort of fold into itself, a tube within a tube, resulting in life-threatening intestinal blockage. Left untreated, this leads to a horrible, painful death. The subsequently developed vaccine is less frequently associated with intussusception than the first, and remains on the market. The latter was developed in part by Dr. Paul Offit, and is the basis of his claim to vaccine expertise and fame. The Rotavirus vax story embodies the ever-present risks of an unpredicted vaccine-associated disease that provides a dark warning to vaccine developers (and regulatory authorities) worldwide. No wonder vaccine developers insist on legal protection from liability if they are to continue to participate in the business.

Respiratory Syncytial Virus Vaccines for Children and Infants

Historically, the darkest story for vaccinology (prior to the genetic COVID vaccines) involves the Respiratory Syncytial Virus (RSV) candidate that actually enhanced RSV disease risk and killed children during clinical trials. This was an unexpected and unanticipated severe adverse event. Every vaccine developer knows the story, and this cautionary tale hovers like a dark shadow in the minds of all except the most florid vaccine development “true believer” fanatics. During prior pediatric RSV vaccine development, vaccine-associated enhanced respiratory disease (VAERD) was unexpectedly observed, including two toddler deaths, following administration of “old school” formalin-inactivated respiratory syncytial virus (FI-RSV) vaccines to infants in the 1960s (Fulginiti, 1969; Kapikian, 1969; Kim, 1969). This tragic and unexpected finding stalled RSV vaccine development for many years.

Fulginiti VA, Eller JJ, Sieber OF, et al. Respiratory virus immunization. I. A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am J Epidemiol. 1969 Apr;89(4):435–448.

Kapikian AZ, Mitchell RH, Chanock RM, et al. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol. 1969 Apr;89(4):405–421.

A cautionary parable is often shared between all drug and biologics investigators who work with animal models, particularly among vaccine developers. Mice lie, monkeys mislead, and the only animal model that reliably predicts human responses (safety and efficacy) is humans. Fortunately or unfortunately, the world of vaccinology and vaccine development has just been dealt another reminder of this fundamental truth. And as if that is not enough, Moderna and its much-celebrated Nobel Prize-winning mRNA technology has been at the center of this latest debacle that is being spun as a conundrum. Once again, not surprisingly, vaccine-associated enhanced respiratory disease (VAERD) has raised its ugly head.

“This all seems like an incredible conundrum with lots of unanswered questions remaining—lots to still learn,” Henry Bernstein, professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell, told a reporter from Fierce Pharma.

After hearing presentations from Moderna on its trial findings and from the FDA, the advisory committee members generally agreed that RSV shots for infants should be examined on a “vaccine platform-by-vaccine platform basis,” according to Arnold Monto, M.D., an epidemiology professor at the University of Michigan. ….. Monto, for one, said that he believes the safety signal is legitimate and it deserves more study. The answers, he said, will not emerge if companies and regulators “shut down programs.” “Either we go forward very carefully with clinical trials where we may be able to get an answer or we continue to observe natural infection in which over 50 odd years we haven’t really been able to identify anything that would helps us in answering the questions that are currently being raised.”

From a summary published by BioSpace:

Moderna’s mRNA-1345 won the FDA’s approval in May for use in adults aged 60 years and above, and is being marketed under the brand name mRESVIA. The company was also previously developing the shot for use in infants, but dropped this program in September, according to reporting by Endpoints News. According to the biotech’s website, mRNA-1345 continues to move forward in high-risk adults aged 18 to 59 years, and in a pediatric population.

Meanwhile, mRNA-1365 is being developed as a combination vaccine for RSV and the human metapneumovirus. The candidate is currently in a Phase I study in this indication.

In its briefing document, the FDA revealed that in one study, inoculation with mRNA-1365 led to a case of severe or very severe RSV LRTI in the subgroup of participants aged 8 months to less than 24 months. In a younger subpopulation—aged 5 months to less than 8 months—five such side effects were reported after mRNA-1635 administration.

Moderna was made aware that there were at least two positive RSV LRTI tests in the study by July 17, triggering one of the study’s pause criterion. A few days later, Moderna enacted a “study-wide pause,” according to the briefing document, amid its ongoing safety investigation.

These new safety data come as a blow to Moderna, which was already struggling to find its footing in the RSV vaccine space, where it is in third place. GSK became the frontrunner in this field when it won the FDA’s first approval in May 2023 for Arexvy, which has since gone on to corner around two-thirds of all retail RSV vaccinations in the U.S.

Pfizer has fallen to second place with its Abrysvo, though recent approvals in a broader adult population and in immunocompromised adults could help the pharma shore up sales for its shot.

Why the emphasis on vaccinating infants and young children for prevention of RSV-associated disease?

Like SARS-CoV-2, influenza, bacterial pneumonia, mycoplasma and other upper respiratory infections, RSV disease is associated with an increased risk of death in the elderly. In adults and older, healthy children, respiratory syncytial virus (RSV) symptoms are mild and typically mimic the common cold. Self-care measures are usually all that's needed to relieve any discomfort.

RSV can cause severe infection in some people, including babies 12 months and younger (infants), especially premature infants, older adults, people with heart and lung disease, or anyone with a weak immune system (immunocompromised). Severe RSV disease is associated with a range of symptoms, including upper respiratory disease that can progress to lower respiratory tract disease (LRTD), leading to respiratory distress, respiratory failure, and death. The Centers for Disease Control and Prevention (CDC) recommends RSV vaccines for adults aged 75 and older, and those aged 60-74 with risk factors for severe RSV disease, such as chronic heart or lung disease, weakened immune system, diabetes, or living in a nursing home. Vaccinating these high-risk individuals to reduce their chance of dying from or with RSV pneumonia appears to make sense - there is a positive benefit/risk ratio for people in this category. Apparently, because all of these elderly have been previously infected with RSV and therefore have been immunologically “imprinted,” they are not at risk for developing VAERD - or at least that is the hypothesis. That said, there is no evidence to suggest that the adult RSV vaccines prevent transmission of RSV to others. The vaccines are designed to protect the individual who receives them from developing severe illness if they contract RSV, rather than preventing transmission to others. If you are not at risk of severe disease or death from RSV infection, there is no reason for you to take these vaccines. As with any vaccine there is risk, but in the case of RSV vaccines administered to healthy adults and children over two years, no apparent benefit. Frankly, if your physician or pharmacist recommends accepting an RSV vaccine and you are not in the CDC-recommended high-risk groups, you should find another physician or pharmacist, as yours is probably accepting some sort of enticement to make such a recommendation. Financial enticements for physicians and pharmacists to recommend vaccination are common in the industry.

By the age of two years old, virtually all children have been infected with RSV, and develop some degree of natural immunity to subsequent RSV infection. This immunity is not “sterilizing” or perfect. Those that have been infected with RSV are often infected again, but develop a less clinically significant or even clinically “silent” infection. Previously infected healthy normal children and adults can be infected with RSV, and can infect others, but rarely develop clinically significant disease. This fact demonstrates that it is unlikely that a vaccine that prevents infection and spread of RSV can be developed; as with influenza (and coronaviruses including SARS-CoV-2), a vaccine that reduces disease severity may be possible, it is difficult or unlikely that one could develop a vaccine that will be more effective than natural infection, and extremely unlikely that a vaccine to prevent infection or spread can be achieved. As healthy normal children older than 2 years are not at significant risk of RSV disease (due to universal natural immunity at that age) if they receive an RSV vaccine there is only risk of vaccine-associated adverse events- no probability of any significant benefit. Current RSV vaccines do not prevent infection or spread, and it is highly unlikely that a RSV vaccine could be developed to prevent infection or spread since natural immunity does not confer sterilizing protection.

That said, RSV infection and disease notoriously kills premature infants and the very young at a relatively modest frequency (USA: 100- 300 deaths in children under 5 per year, biased to premature and those with underlying risk factors). The immune systems and lungs of very young children, particularly premature infants, are still developing, and by definition they do not have the benefit of having natural immunity from a prior RSV infection.

At the root of this is that the immunology that underlies the development of RSV vaccine VAERD in infants and young children is not well understood. One leading hypothesis for RSV VAERD is that the folding of a key RSV protein found in the original formalin-inactivated vaccine, upon injection, results in formation of antibodies that act to enhance RSV infection in some way. You may recall that the FDA was concerned about this same possibility occurring with the SARS-CoV-2 mRNA vaccines, as it had repeatedly compromised prior coronavirus vaccine development programs. Something about having a natural RSV infection seems to prevent this process - the current hypothesis invokes the vague term “immune imprinting,” which is not the same as actually understanding what is going on.

In the case of the Moderna vaccine candidate, based on the spectrum of adverse events associated with the Moderna and Bio N Tech/Pfizer mRNA vaccines, it is possible that the increased disease signal detected in these recent RSV vaccine studies in children may include additional toxicities associated with the Moderna mRNA platform technology.

Because there is a market (unmet medical need) for RSV vaccines, years of animal model experiments were performed to try to better understand and predict the cause, consequence, and prevention of VAERD associated with RSV vaccines. What has been demonstrated in the intervening years is that if you (or an experimental animal) have previously been “naturally” infected with RSV, then your chances of developing VAERD plummet. There is something that happens, some form of immune imprinting (?), that happens with natural infection that prevents this. But, of course, the important clinical need is to protect premature and newborn infants that have not been infected previously!

So, what is an obstetrician or pediatrician to do?

Many years ago, a spinout corporation with roots in US Army infectious disease research programs called “Medimmune” came up with an answer. A monoclonal antibody directed against RSV, which was FDA authorized and is now widely available and standard of care in premature infants. Since that initial product, another has been developed which may have some useful advantages. But the bottom line seems to be that these products, when used as directed, greatly reduce the risk of developing severe disease if the infant is infected with RSV. According to the FDA briefing document Considerations for Respiratory Syncytial Virus (RSV) Vaccine Safety in Pediatric Populations, “Monoclonal antibodies (mAbs) with activity against RSV are a critical element of a preventive strategy in infants; however, availability and cost may limit global implementation.” Therefore, the justification for developing an RSV vaccine for neonates, the only major unmet medical need, distills down to a problem of “global implementation.” In other words, there could be a market in economically underdeveloped regions (where things like malnutrition and clean water are a much more compelling, clear and present danger to neonates), but in the developed world one can administer monoclonal antibody preparations.

Which leads to suspicions that there is some other commercial agenda here driving Moderna to try to push its RSV product down into children. Such as the indemnification that would be associated with getting the product authorized for the pediatric schedule and the Federal government vaccines for children acquisition program.

The bottom line is that there is not a clear, compelling clinical need for an RSV vaccine for children- who have universal immunity, let alone for neonates. Why should we continue to pursue clinical testing of these products in neonates when every child enrolled in such clinical trials will be at risk of VAERD due to some poorly understood mechanism? This has all the hallmarks of another example of an industry that has become enthralled with its own narrative of the power of its technology to solve all related infectious disease problems, and is willing to pursue every potential indication and market opportunity at the expense of humanity.

If I were the incoming Director of CDC or Commissioner of the FDA, I know what I would do about this. I would just say no.

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For those seeking additional details and information, I strongly recommend the FDA Vaccines and Related Biological Products Advisory Committee Meeting briefing document of December 12, 2024. I have served on many large Federal grant and contract study sections addressing RSV vaccine development, and have read extensively on the subject. I have rarely, if ever, read such a well-written and generally objective summary of the history and state of the art of this domain as the corresponding sections of this document. Whomever at FDA was responsible for preparing this document deserves a hearty “thank you” from all concerned, and their diligence was rewarded by the reasonable and responsible conclusions reached by the VRBPAC in this case.

I only wish similar depth, accuracy and objectivity had characterized the various briefing documents developed and presented in the context of the Pfizer, Moderna, and J&J COVID “vaccine” products. If this had been the case, we might have had a very different outcome.

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