Waning COVID Vax Immunity; FDA Medical Device Oversight

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include predicting COVID mortality, immunity following COVID vaccination, surgery for recurrent ovarian cancer, and FDA oversight of medical devices.

Program notes:

0:34 Waning immunity from COVID after vaccination

1:34 Who developed breakthrough infections?

2:34 Doesn’t address severity of infection

3:37 Some vaccines not directed to the spike protein

3:55 Predictors of COVID death

4:55 Elevated cytokines and tissue injury markers

5:50 Even by day five, vRNA predicts

6:36 Scrutiny of medical devices by FDA

7:36 Approved using 510K

8:36 Device creep

9:26 Recurrent ovarian cancer and second surgeries

10:26 Surgery with platinum-based chemo

11:28 Carefully selected population

12:27 Change in chemotherapy?

13:36 End

Transcript:

Elizabeth Tracey: Is there a benefit to additional surgeries when ovarian cancer recurs?

Rick Lange, MD: Waning COVID vaccination efficacy.

Elizabeth: Can we predict who is going to die from COVID-19 infection?

Rick: And medical device safety.

Elizabeth: That’s what we’re talking about this week on TT HealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, how about if we turn first to the BMJ since everybody is top-of-mind regarding, “Oh, no, we have this new variant that’s emerged,” and that everybody is panic-stricken about. What is the elapsed time since vaccination against COVID and subsequent risk of SARS-CoV-2 infection?

Rick: Elizabeth, you set that up very nicely. How did we do this study? We have a lot of data from Israel, which really was among the first countries to initiate both a large-scale vaccination campaign and they did it very early on. By July of 2021, more than 5.2 million Israelis were fully vaccinated with the same vaccine — they had gotten both doses of the Pfizer mRNA vaccine. Despite that, they noticed that since June of 2021 there has been a resurgence of individuals with COVID infection. So their concerns were whether there would be decreasing levels of immunity as a result of just the time since the vaccines were given.

They looked at those individuals that had developed breakthrough COVID infections. They had been fully vaccinated — this was 3 weeks after the vaccination which was the earliest time point — and they chopped it up from 0 to 90 days, from 90 to 120, 120 to 150, and 150 to 180, to determine if the time since vaccine contributed to a breakthrough COVID case.

What they discovered was that was indeed the case. Those that had their vaccination 90 to 120 days had about a 2 or 2½-fold increased risk of developing a breakthrough infection. That carried off for the next 150 to 180 days and even greater than 180 days. It looks like that there is waning efficacy and it begins not at 6 months, but as early as 3 months after vaccination.

Elizabeth: I am wondering if we’re going to find out that this is the Achilles’ heel of mRNA vaccines eventually.

Rick: The data are pretty clear not only from this study, but from other studies suggesting that there is waning antibody response. Now, what this study doesn’t address is the severity of the infection. But I agree with you that currently this does appear to be the Achilles’ heel and hence the recommendation is to get a booster for everybody over the age of 18. The Pfizer vaccine is now petitioning the FDA to do it to individuals as low as 16 years of age.

Elizabeth: Well, as Omicron — I’m sure we are going to detect it here domestically pretty shortly; that’s my bet — in light of that, everyone who isn’t boosted really needs to get boosted or what I have called in the past, of course, the third dose. I am even wondering about, well, what about even more than that for those who are willing?

Rick: As we get more variants, I think what we may be doing is having different types of boosters, ones that target these variants. I am sure we are going to be telling our listeners more about this in the weeks to come.

Elizabeth: I do think that also, and I am going to recall for you this pan-sarbecovirus notion that we talked about relative to the antibody production. And my question, which I subsequently investigated, is about vaccines that are targeted against those conserved regions of the spike protein. There is that out there, but it’s not as robust as I thought it should be at this point.

Rick: Yeah. But some of these vaccines are not even directed towards the spike protein, so stay tuned.

Elizabeth: Still speaking about SARS-CoV-2, let’s turn then to Science Advances. Let me just ask you. It’s my recollection that this is the first time we have talked about a paper that’s in this journal.

Rick: Right, and we have been doing this for about 18 to 19 years, Elizabeth, and so I’m surprised that Science Advances has escaped our reporting before. But this is an important study.

Elizabeth: This is entitled “Immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.” Clearly, this is something we all want to know clinically. When somebody comes into the hospital and they need to be ventilated, can we determine which of them is most at risk of death?

They did these immunovirological tests on plasma from 279 people. They collected samples at what they call DSO11, so days from symptom onset in a discovery cohort. They performed three different assessments in this: viral RNA that was circulating, low receptor binding domain-specific IGG and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers. So a constellation of those.

They developed this 3-variable model of viral RNA that they actually predefined adjustment by age and sex. By doing this, they were able to very reliably identify patients with fatal outcomes. This model remained really robust in independent validation. They are suggesting that these are the kinds of assessments that can be done so that we can say, “This person is really at high risk for mortality.”

Rick: Elizabeth, a lot of people have tried to identify who is going to be at risk of death with COVID-19 so we could direct therapies. They looked at just viral RNA, how many RNA particles were actually in the blood, 26 different cytokines and tissue markers, and six different types of immunologic responses. What they found out is really all we need to do is measure viral RNA by Day 11. By the way, when they went back and said, “Gosh, can we predict even earlier?” Even by Day 5, the amount of viral RNA predicted who was likely to die. The downside is this is a fairly small study by most of our standards, but it does need to be validated in a larger cohort.

Elizabeth: I thought they were very intellectually honest in taking a look at remdesivir and other things that might interrupt that whole cascade, and kind of speculating we are not really sure if that’s going to make a difference and also that this circulating or this plasma viral RNA does not indicate intact virions or infectability either.

Rick: Right. It could be viral particles that have undergone degradation. But what’s clear is the more viral particles, the more tissue injury you have, the higher the immunological response. Instead of measuring those other things, just the viral particle number alone can provide insight.

Elizabeth: Now, let’s turn to one that I very specifically wanted you to address.

Rick: All right, Elizabeth, our listeners may not be aware, but I chair one of the FDA panels for circulatory devices. I have had the privilege of serving on this panel for, gosh, probably 10 to 12 years now.

This is a particular article calling for reforms to the medical device safety. When a device is considered to be low-risk, Class I or Class II, it’s going to be approved by the FDA with really minimal involvement of committees.

When it may be life-threatening, it’s called a Class III device. If it’s a new device, we have what’s called pre-market approval. They want to look at the device. They want to have randomized control trials showing that it’s both effective and it’s safe. But once you have that device, when you have other devices like it to speed things up, but to try to make it safe, we have what’s called a 510(K) process. If a device looks like another device that’s been effective, then it can be approved. It’s called predicate device.

There was a device that was approved using the 510(K) to suck clots out of people that were having strokes. This device was based upon another device. Then this device went through 12 different iterations over the course of time. By 2019, this device, called the Penumbra, was recalled after about 200 adverse reports and 19 deaths associated with it. What this reform says is, “Gosh, obviously, in this particular case this 510(K) approval device pathway failed.”

Elizabeth: Yeah. Of course, this reveals both of our biases, your bias toward the FDA and the policies that are employed in these device situations and mine against, where I really feel that there is not enough scrutiny. We have other examples of devices — hip implants that have caused a lot of harm and were also approved under that same aegis. The editorialist, of course, says, “Hmm, maybe it’s time for a new paradigm here.”

Rick: I think there are some things within the FDA’s control and some things that are not. There is what’s called device creep. This was a device that was approved years ago and it went through iteration after iteration after iteration. But obviously, over the course of those 12 iterations, the device didn’t look anything like the original device, so we need to have some way of dealing with that.

There are some things the FDA can’t do, post-marketing surveillance. It doesn’t have the teeth to demand that the company do post-marketing studies, and if they don’t, to shut the product down. It just doesn’t have that regulatory authority to do that.

We have a way of reporting device safety issues, but it’s voluntary. There are some regulatory things that need to be done to give the FDA the information they need and the clout — regulatory authority — to enact some of these things. I agree with you, there are glaring holes that can be fixed.

Elizabeth: Well, I’m really glad to hear you make that admission and that’s, of course, in JAMA Internal Medicine. Let’s finally turn to the New England Journal of Medicine, what I served up as, “Is there any benefit to doing second surgeries after women have relapsed and they have already had surgery for ovarian cancer?” We will just remind everybody that ovarian cancer has a dismal prognosis, and that’s largely many people feel because it doesn’t get diagnosed until it’s advanced. A lot of women have what’s called cytoreductive surgery to remove as much of the cancer as possible and traditionally then they are not offered surgery again at recurrence.

This study is an iteration of an ongoing bunch of studies that have been examining this a little bit more closely. They had patients who had recurrent ovarian cancer and had a first relapse after a platinum-free interval. That’s an interval during which no platinum-based chemotherapy is used of 6 months or more to undergo a secondary cytoreductive surgery and then receive platinum-based chemotherapy, or to receive platinum-based chemotherapy alone. Let me just note that some of these women also received some other agents and we can talk about that a little bit later.

They have developed a metric that’s called the AGO score, which is a performance status score of 0 on a 5-point scale, with those higher scores indicating greater disability for entry to the study, ascites of less than 500 ml, and complete resection at the initial surgeries.

They had 407 patients who underwent randomization, about half in each group. Complete resection was achieved in almost 76% of these patients. Those patients who had the second cytoreduction in this carefully selected group of women lived almost 54 months, while those who only got the platinum-based chemotherapy and did not have a second surgery lived for 46 months.

Rick: As you noted, Elizabeth, the prognosis with ovarian cancer is dismal. The key to this particular study is, again, careful selection of women that have recurrent ovarian cancer. Because there was a previous study that’s showing that a second surgery doesn’t really increase survival. Now, by the way, this survival increase is meaningful — it’s 8 months — but it’s obviously not what we would like and that is a cure.

The other thing that I thought was particularly notable about this study is that it not only looked at survival, but it looked at the quality of life. When these women are carefully selected, they have a good outcome. Seventy-six percent had what was thought to be another complete resection; they don’t have perioperative complications, and the quality of their life was no different than those who didn’t have surgery. This is a small, incremental, but nevertheless an advance in the treatment of recurrent ovarian cancer.

Elizabeth: I agree. I wanted to note that, of course, some of these women also received, in addition to the paclitaxel and the carboplatin, they received bevacizumab as part of their second-line therapy. They also, some of them, just very few, received what’s called a PARP inhibitor. I am wondering about either the addition, or even substitution, of those agents in women who have recurrences. I think we don’t know the answers to that.

Rick: Right. There is at least in a subgroup analysis the evidence that the individual that had cytoreductive surgery and received one of those agents actually did worse. These are called post-hoc analyses. That is you look at the whole picture and you try to carve out small little pieces of it to see who drives the best benefit or who may receive harm. In this particular case, the numbers are so small I don’t want to draw any conclusions about what the best type of chemotherapy is. But woman should be offered cytoreductive surgery if they have recurrence and they fall into that selective group of individuals.

Elizabeth: I absolutely agree. Finally, I would applaud the authors for saying that the results of this trial cannot be extrapolated to interval debulking after chemotherapy or to treatment of relapse after later lines of treatment. So they definitely identify the limitations of this particular strategy.

Rick: Right.

Elizabeth: On that note, then, that’s a look at this week’s medical headlines from Texas Tech. I am Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.