FDA VRBPAC Meeting, May 18, 2023 — Meryl Nass, M.D.

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Hello. today the FDA will review whether giving pregnant women RSV vaccines will prevent severe RSV disease in their infants.

Dr. Atreya broke up a few times for me so I am not certain if I missed another charge to the committee.

This is the first time I recall seeing Dr. Hana El-Sahly, who was the committee chair but absent for all COVID meetings. Dr. Offit is here. Kevin Ault recently left an association with the CDC’s ACIP. Dr. Feikin worked at CDC and WHO and wonder why he is here. McMorrow is another CDC employee in addition t o Amanda Cohen. Saad Omer is a temp member. Why are there 4 temporary members today? Did the usuals have conflicts of interest? And if so, why aren’t the current members thought to have conflicts, especially when at least 4 work for the federal government.

So, all of that talk seems to have been intended to immunize the FDA against charges of conflicts of interest.

3d day to discuss RSV vaccines. They are oh so new, are you dazzled? This is the new head of FDA’s OVRR speaking.

An application has been submitted to license this vaccine. He emphasized “available” evidence in the application, suggesting there is not enough evidence, but FDA is demanding the members don’t ask for me and deal with it!

In other words, he has warned the members to only consider the info they are providing to make a decision whether or not they think it is adequate. Will Offit comply?

I wonder if there are repurposed drugs that might be effective for RSV? HCQ and IVM are not acknowledged to work by FDA. Are there RSV drugs FDA may be hiding?

The vaccine was tested in 7,000 pregnant women in poor countries. And a smaller number of pregnant women were tested in the US and more developed countries. Where do they get the pregnant women and what did the consent form look like?

Meryl Nass:: The FDA will ask the committee if the data are adequate for licensure

And they will ask if the data are adequate for safety.

The issue will not only be severe RSV disease in young infants but also does it prevent milder RSV pneumonia. I did not say above that the Q is whether the data are adequate for efficacy.

Dr. Bernstein surprises by asking how safe the vaccine is for the mothers who get it between 24-36 weeks of gestation. Kaslow jumps in and tries to do a runaround the question.

Clearly FDA does not want the issue of maternal safety to be raised, so we must pay it a lot of attention as the day progresses.

Dr. Thornburg of CDC will try and convince us the studies are of high quality. RSV is a single stranded RNA virus with A and B variants. It ‘s genome is about half as long as covid.

OMG–there are medical countermeasures available for some of the proteins–in other words the US government has given a special designation to products for RSV, rather than a license. Do they have EUAs? Why does RSV have “countermeasures” designated for possible treatment?

These CDC presenters are oh so careful to tell us what they must while saying it so fast most people miss it. This means the medical countermeasures (MCMs) have not ever been regulated like regular drugs and vaccines–they have had much less attention by regulators.

Not sure why we are going through all this discussion of variability in A and B viruses, seems a waste of time.

It is good they know what neutralizing antibodies to look for (likely to be most potent) using various methods to predict this. But the emphasis on this makes me wonder if they are going to try and substitute the claim that a certain product ‘ought to work’ when it turns out the product does not work as well as predicted.

Meryl Nass:CDC is planning genomic surveillance. Shouldn’t they have done it before the vaccines are being discussed for possible licensure?

Meryl Nass:The vaccine today is designed to cover RSV A and RSV B variants.

Because I cannot see what benefit is obtained by all the sequencing of RSV, I wonder if they are doing it to prototype the genomic surveillance that would be required by the new International Health Regulation amendments to be considered by WHO members next week and next year.

Next is Dr. Fleming-Dutra. She is here to convince that the product is desperately needed.

Now she tells us the babies who should be treated prophylactically, but 79% of babies hospitalized for RSV had no predictive factors–in other words all should be treated.

Meryl Nass:currently paluviz–imab is given to 2% of US infants and must be used monthly.

Meryl Nass:: NOTE THAT HER NUMBERS ARE ESTIMATES AND HER RECENT INCREASE IN RSV IS BASED ON UNPUBLISHED CDC DATA

RSV_Net is also unpublished data.

1 in 250 young infants are said to need hospitalization in ICU for RSV.

Meryl Nass:: Minorities are at higher risk. She now shows some sky-high rates in Alaskans and other minorities.

The data on RSV in pregnancy is limited.

But rates of hospitalization in adults is very low.

Pregnancy actually led to lower rates of RSV hospitalization than in nonpregnant population

RSV infections highly season like flu–Dec-Feb are highest.

COVID ‘disrupted’ the circulation of RSV which did not follow the usual pattern.

RSV vaccine dosing needs to be sorted out by timing–CDC WILL EXAMINE THIS. CDC suggests year round dosing–then you get the vaccine into everyone, whether they need it or not.

While prematerity and certain comorbidities increase the risk, every baby is at risk for severe RSV. RSV may be returning to its previous seasonality.

Paul Offit has a question. He just asked why a different antibody (used in the licensed RSV vaccine) was not being used. I think the mfr needs to answer that, not CDC.

RSV immunity is poor–people get it over and over again. Dr. Bernstein asks if vaccinating mothers will reduce transmission. 50% of infections are asymptomatic.

Chu from the BMGF’s own university will discuss natural immunity. Her talk sounds like it will have more substance.

RSV is #1 cause of baby hospitalization. But lack of sterilizing immunity from prior infections, and virtually all babies by age 3 have had it. 13 days is mean duration of illness. Paluvizimab directed against F protein provides efficacy. How much?

Chance of severe RSV is lower after first case.

Only IgG is transferred across the placenta to the fetal circulation.

Antibody half life was 38 days–in other words, the amount of antibody in the blood drops by half at 38 days, and then by half again by 38 days.

Maternal antibody expected to last 3-4 months in infant

According to a nirsevimab study, having given babies antibody did not impair their ability to mount a response to RSV infection. The claim is that in this case, original antigenic sin is not active. Is this sufficient evidence however?

Giving RSV vax and TDap to women led to reduced antibody response to pertussis toxoid. This could be a problem.

Now she says whether the infant response is blunted with material vax will need to be monitored over time.

El-Sahly states that reduced pertussis antibodies only drops by 20-30%, and is this clinically relevant?

Dr. Chu says the study was done in non-pregnant women so we don’t really know if it will hold. Needs repeat with evaluation of antibody levels in cord blood.

Dr. Bernstein asks whether changing the timing of RSV to separate it from TdaP and give earlier would be better? Dr. Chu agrees that an early 3d trimester vaccination would probably be better wrt antibody levels.

Dr. Monto asks about coadministration of flu and RSV vaccines. GSK and Pfizer are doing those studies.

10 min break

Sorry I’m late. Dr. Gruber of Pfizer is back. I have explained before that in December 2016 Congress passed the 21st century cures act. Buried in it was granting a liability waiver for all vaccines CDC recommended in pregnancy.

Gruber says the efficacy is 82% at 3 mos of age and 69% at 6 months.

Dr. Simoes has 16 conflicts of interest in the last 36 months, including CDC and BMGF.

2/3 of ER visits for RSV are in those under 6 months of age

Dr. Munjal will discuss the studies. 2 studies in pregnant participatns; 5,000 women but fewer that were pregnant.

They did phase 1 and 2 in pregnant women it seems. 579 women, most in US. Randomized to 120 or 240 mcg w or without aluminum hydroxide. 120 mcg was the dose selected.

Moms vaxxed at 24-36 weeks and everyone claims the baby antibody levels are higher than in mom.

Meryl Nass:: She is a saleswomen, emphasizing that Pfizer has already had all its standards approved by FDA before the trial started–therefore members, you better be satisfied with the results.

45% of subjects were American. It is rather remarkable that the study began in June 2020 in the middle of lockdowns–how did that work?

There was a lot of moderate fatigue, but I did not see how that got defined. Which makes me concerned about whether other side effects were collected correctly.

I think Pfizer is trying to hide how long after vaccination premature births occurred, based on what hse is emphasizing. I might be wrong.

1 vaxxed mom died and 25% more babies died in the vaxxed group than in the placebo group. 12 infant deaths in placebo group. Were the placebo subjects a higher risk group, since so many more babies died in this group.

Efficacy over time is as expected early–but it seems the vaccine worked too long!

Efficacy should have dropped off more (at least my expectation) with a half life of antibodies of 38 days. But the hospitalization slide does show efficacy down to 33% at one year.

The slides flash by too quickly so some I cannot assess.

Now a Pharmacy PhD is giving the safety talk. Why?

“We are aligned with FDA” that no safety problems were identified. Clearly the claim that Pfizer and FDA are in agreement is the theme for today.

She gave no data, just explained what they will do and look for. Now Bill Gruber is back. Therefore I am still wondering about safety.

Bill also gave no data, but offered to give flu plus RSV shot data in pregnant women, so El-Sahly says she will look at that later in the day.

Dr. Pergam asks if there are differences in breastfeeding between placebo and vaxxed, and if antibodies in breast milk were measured. Were breastfed babies less apt to get RSV?

Amanda Cohn of CDC looks like she is still staying home from the office. Dr. McDonald of Pfizer says what Pfizer is PLANNING to do. Not what data they have so far.

She says “no additional safety risks” in the maternal trial. Additional to WHAT exactly?

The one vaxxed pregnant woman who died had a premature unexpected home birth and bled post partum. The prematurity could have been a vaxxine side effect.

Dr. McDonald says there were very few low birth weights. But there were more in the vaxxed group, and more preemies in the vaxxed group

Total preemies in vaxxed were 23% higher than in unvaxxed

There was also more preeclampsia and more hypertension in the vaxxed group.

Munjal grabs a slide where it appears these other side effects are not higher in the vaxxed. El Sahly says she still wants to Omer question answered: and Munjal will provide it later.

Now Dr. Hong-Nguyen from FDA gives the FDA impression of all the inforation.

Up to 10 K pregnant people were to be studied but only about 7300 were enrolled.

Basically FDA has so far repeated what Pfizer said about efficacy.

Efficacy was much worse in mom vaxxed before 29 weeks

Severe AEs were 50% higher in vaxxed group. Also, moderate fatigue vs all fatigue was not separated out in FDA’s chart, yet this seemed important in the pfizer data.

Stillbirths were not reported as infant AEs

No infant participants were withdrawn due to an AE!!! Well duh, it was there pregnant moms who were treated, not them–they were not due for any doses. This phrase is misleading.

Preterm births twice as high in vaxxed as unvaxxed in South Africa.

Very high congenital anomalies in both vaxxed and placebo

of 17 deaths in infants, only 5 were in the vaxxed, suggesting the placebo group had been selected for higher risk

Twice as many premature birth in vaxxed in the 460 person 1003 study of dosing

Wondering why we are looking at the data from the small study and not the large study for efficacy by month

Dr. Ault says you ought to be aware of how much pertussis occurred in these babies and that would be another measure of vaccine safety since antibodies for pertussis were lowered in the vaxxed

Dr Portnoy asks if there was enhanced disease (VED or AED or other abbreviations) due to vax in babies? This is important . Gruber says no but provides no data.

David Allely gave a knockout performance in which FDA twice tried to not show his slides. He waited till FDA got the slides back up. He pointed out that safety signals were hidden in the data shown to us today.

Jester Jersey wants more shots! Invest more! Equitable vaccine access! Support social media influencers! Build trust!

No wonder he did not provide a real name.

Yet another advocacy organization to educate women to make good decisions for their health. They buy the healthcare products in general, so they are the target audience for selling health.

Sounds like she is reading someone else’s script she is unfamiliar with.

She hopes all women will have access to this critical protection. I guess she does not know it is only intended for pregnant women.

Have you noticed that whenever someone wants to make RSV sound awful, they give worldwide stats, which are of course irrelevant to the US where virtually every very sick kid is hospitalized and deaths are rare.

It has gone silent on me despite refreshing several times!

I got another computer to work. Did FDA shut me off?

Offit asks why GSK abandoned a vaccine that was very similar–why? Can we believe the Pfizer data? Joe Turner is the new acting deputy dir at OVRR who is refusing to talk about the GSK vaccine.

Offit pushed back and the FDA person stutters a bit but is adamant that he will NOT discuss the GSK data but Offit can do so if he wants to.

Pfizer data slide 4 reveals that there were more preterms in the US and South Africa in the vaxxed. Gruber says GSK had more deaths and Pfizer did not have more deaths in the vaxxed. He says though both vaccines used a pre-conformation F protein they are a bit different. But the data still show more low birthweights and more preterm births in the vaxxed group.

Offit points out that severe prematurity led to the GSK deaths so the end points were virtually identical.

Now it turns out syna gis (the monoclonal antibody) was received by 10 in placebo group and 2 in vax group.

The members are not supposed to smoke out the problems in the trials–that is really FDA’s job. And the fact that FDA has been mum is yet another example of how it is simply not doing its job.

El-Sahly says the vaccine did not prevent non-severe respiratory infections. Pfizer says most of the kids on testing had multiple pathogens. But RSV considered the main problem.

Fascinating! Pfizer only found 22% of kids with respiratory infection had RSV, and they blamed this on the pandemic changing patterns of infections.

The efficacy is much better after 28 weeks, but I wonder if the safety improves or worsens if you look at the 3 subgroups by duration of pregnancy when vaxxed. Slide BU-513 from Dr. Gruber.

The non-Pfizer industry rep points out that the confidence interval for the women given vax at 24-28 weeks goes below zero, raising the possibility of negative efficacy in that age group.

FDA’s Dr. Hong just admitted that FDA is also concerned about the preterms by time mothers were vaxxed and FDA has asked Pfizer for more details on that.

I much prefer El-Sahly running the meeting, compared to Monto. She now asks about giving multiple vaxes to pregnant women and whether that will be harmful to mother or child.

FDA’s Turner says it is a great question. FDA solves these problems by disclosing their ignorance on the label. The FDA has so many flunkies that are only good at dodging responsibility. I sure hope he is no MD.

El-Sahly says “These data are concerning.” The window for use, the multiple vaxes, the reduction in antibodies when coadministered with other vaccines are concerning. Good to express the obvious.

No, Joe TOERNER is an MD, MPH. Amanda chirps in and says we have seen concomitant administration has reduced antibody titers before, but we have managed it. She cannot recall which vaccine and thinks it was in the 4-6 age group, a very different situation.

Pfizer’s strategy is to heavy the committee–we will do X as a postmarketing study, basing this on the supposition they get the license. They are not offering to do more research. They want a positive vote today. I think the Pfizer employees are not cognizant of how distrusted their company is now.

Joe Toerner waffles through another question. El-Sahly gives him a hard time. Holly James looks disgusted.

Even Amanda is unhappy about the proposed loose post-marketing surveillance proposed by Pfizer. Wow. The committee seems to be revealing they will vote no. But I have been very wrong before.

Gruber is tap dancing quickly and well. He is not obviously nervous that his plan is falling apart. El-Sahly does not let him off. He has now heard from several people that the quality of post-marketing data will not be adequate to answer the outstanding questions, at least before millions of pregnant women have been vaxxed. And Pfizer admitted they could probably answer the question with a focused study of 10,000 women. Amanda says yes to Feikin, the VSD database is so much better and has about 10,000pregnancies a month. She is actually telling us that the ability of the VSD to solve this is iffy. She says there should be transparency about other data that do exist but have never been presented.

Now FDA wants to show us some new slides. They want this approved today, so will explain to the committee how the data they already have are adequate according ot their processes. Furthermore FDA can demand a postmarketing study of the data that is needed.

Those slides are worthless, simply an attempt to placate the committee.

Omer says if they do a postmarketing plan, do it using subsets by race etc. Which means he plans to vote yes.

10 min break

Okay, it seems like the members will do a CYA by simply asking for a good postmarketing study. Even though some of them said that was not gonna happen.

Dr. Bernstein says he does not want another rotavirus vaccine repeat, in which the signal was known when licensed, but was not statistically significant. The rotavirus vaccine had to be pulled after under a year because of intussusception. This would be a good quote for a tweet

Holly James is a very good epidemiologist and she is doubtful they can tease out the info needed with the usual postmarketing surveillance, which is simply using claims databases.

Paul Offit says yes the efficacy is good. Then you have a trend of safety issues. But the GSK experience with an almost identical vaccine really worries him–it had to be canned.

Saad Omer is longwinded. I think he is monologuing to give shade to his colleagues and provide reasons to go ahead and vote yes.

He championed mandates early on–he is crazy in favor of covid vaccines. Here is his nasty paper: https://www.nejm.org/doi/full/10.1056/NEJMp2020926

Pergam tells us that Bell’s palsy is more common from COVID than from the vaccine. These are the folks who are deciding on what gets licensed.

El-Sahly points out that the premature births were apparent in the Phase 2b study and yet the Phase 3 study did not take this into account and gather adequate evidence to rule it in or out for sure. She points out we don’t need to be in a hurry since this vaccine is not for a pandemic.

I never heard how many american babies die from RSV per yeaer. But I just looked it up and CDC says 300-500/yr. 4 million babies are born yearly in the US. No one has balanced the injuries from preterm deliveries vs the lives saved–and CDC is most likely putting a high estimate on RSV deaths.

I just discovered why no one talked about how many US babies die from RSV. The CDC published a paper with these data in 2021. They collected 12 years of data from death certificates. There were only a total of 300 deaths in children less than one year over the 12 years, or 25 average per year. So, while we don’t know how many died without being diagnosed or having it on their death certificate, the number of injuries caused by vaccinating during pregnancy is almost certainly going to outweigh the loss of 25 babies a year from RSV.

Here is the CDC paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562311/

This is why FDA tries to avoid balancing risk and benefit–because we learn how bad their data are, and that they cannot justify any new vaccines using the available data to perform such an analysis.

No surprise, everyone voted yes that the data were adequate to show efficacy. I expected this. This was the easy question. I expect about 3 will vote no on safety, which comes next

Offit, El-Sahly and James I predict will vote no on safety.

No one breathed a word that the Pfizer data on COVID never lived up to the hype presented to this committee, and why should they think the RSV efficacy data will stand up to inspection and time.

These days are so long…. I am going to beg off as soon as the safety votes are announced. I cannot tolerate hearing them justify their votes for a second time.

I think the info I dredged up from CDC on deaths in babies due to RSV is important. Yes, many babies get hospitalized for this infection, which is sad and costly, but 99% or more get better and have no lasting side effects, though some think perhaps RSV stimulates ongoing asthma. I don’t know about that. The anthrax vaccine data showed that anthrax vaccine was associated with asthma.

Why does FDA take so long to vote? Does any arm-twisting occur?

4 voted no. Bernstein voted no, El-Sahly. James and Offit voted no. I was only wrong on 1 out of 14.

Gotta go, this part is nauseating to me. The vax will be licensed over the next couple of days.