ACIP – Pediatric Infection Connection

Meh

Bud WiedermannJune 30, 2024June 30, 2024Leave a comment

I had expected last week's ACIP meeting to include more presentations and discussions about which covid strain to include in our fall vaccine. I viewed only a small portion of the meeting live (darn those pesky patient care issues!), so I probably missed any brief mention of strains; the slides themselves didn't address strain selection, other than to go with the FDA's statement for use of JN.1 lineage with preference for KP.2 if possible. I still found some interesting details about covid and nirsevimab and will share those with you. Perhaps meh is a bit of a harsh judgement, but I love the word.

In the meantime, thankfully still not much going on in the pediatric infectious diseases world this summer.

Love That New Technology

The CRISPR technology has been in the news for a long time. In case you had forgotten, like I did, it stands for Clustered Regularly Interspaced Short Palindromic Repeats and is now reported to have high sensitivity and specificity for detecting antiviral drug resistance and influenza subtype rapidly enough to be used as a point-of-need assay. The study itself requires journal subscription (thank you, GWU faculty status) to read in full. Investigators studied influenza isolates from the 2020-21 season looking primarily at AH1N1 and AH3N2 strains. The report is highly technical, beyond my ability to critique the laboratory methods, but the take-home message is important: if such a method is scalable (e.g. cheap enough) to employ across the world, including in resource-poor communities, it would be a boon to early warnings of resistant and/or new flu strains. I'm keeping my fingers crossed.

I must applaud scientists in this realm for their acronym constructions: in addition to CRISPR and others, they also used DETECTR (DNA endonuclease-targeted CRISPR trans reporter) and SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) assays. Elementary, my dear Watson. (And, that phrase never appeared in any of Arthur Conan Doyle's writings!)

Dengue HAN

Perfect timing after my mention of dengue last week, the CDC issued a Health Alert Network warning about dengue in the US. According to the Pan American Health Organization, early signs are that cases in the Americas this year will exceed last year's numbers, a year that was already much higher than previous years. Here's an example from the report of what's going on in the Caribbean subregion:

Puerto Rico is under a healthcare emergency because of dengue, and we will certainly have cases of autochthonous (acquired in the US without travel to an endemic area) transmission in the mainland US again this year, primarily in Florida and other southern states. The HAN is worth reading.

This would be a good time to review clinical presentations of dengue and be prepared to investigate/obtain consultation for suspected cases.

Pustules and Vesicles in Afebrile Infants <60 Days of Age

Pediatrics had a nice retrospective review of 183 infants from 6 academic hospital-based pediatric dermatology practices. It's open access and has a nice suggested management algorithm.

Note the first branch in the algorithm details key features to decide whether HSV evaluation and treatment is recommended.

ACIP Meeting Highlights

The regular meeting was spread over 3 days last week. Slides are posted, and I picked out a few that contained interesting new information.

First, even with all the problems of supply chain and late administration, nirsevimab appears to have been incredibly effective in preventing RSV hospitalizations and healthcare visits.

Yes, that's about 98% effectiveness in preventing hospitalization, with very narrow confidence intervals. When this slide was shown it elicited a round of applause from the committee members. This is truly remarkable. Similar results were seen using a different RSV surveillance method. Both the above and below slides are from the Payne presentation on June 28.

It appears we'll have better availability of nirsevimab for the next RSV season, so please prepare for that. I find myself fantasizing of some future day when new pediatric trainees won't see hordes of infants hospitalized with RSV bronchiolitis, with worried parents at the bedside.

Second, although I mentioned I didn't see any new data/discussion about strain selection, the covid vaccine discussion had useful updates about epidemiology and risk factors, mainly from the Haver presentation on June 27.

About half of children hospitalized for covid had no underlying risk factors; we already knew that, but here's a more detailed breakdown. Note that these numbers are for the past year, at time when virtually all US children had some prior antibody from infection and/or vaccine.

Here is the vaccination status, including the low numbers who received the 2023-24 version, of the hospitalized children:

One BIG disappointment for me with the presentations: there was no mention of a control group - i.e. what are the rates of underlying medical conditions and 2023-24 vaccine status in the pediatric population as a whole? Adjusting for rates in the general population would provide a better estimate of the relative contributions of risk factors and vaccination to more serious outcomes and give us a better handle on the magnitude of benefit of vaccination, for example. Still, nothing has changed; for the individual child, covid vaccination is better than not being vaccinated, even factoring in the low rates of serious outcomes and adverse vaccine events in children.

The 2023-24 vaccine was highly effective against emergency department and urgent care visits in all age groups, though waning of protection over time was seen. Lack of enough events of hospitalized children precluded reliable estimates of VE against pediatric hospitalizations. (Link-Gelles presentation June 27.)

Bird Flu

Exciting (to me) news that CDC is collaborating with the Michigan health officials to carry out a seroprevalence study for H5N1 infection in Michigan dairy workers. This should produce much better information about asymptomatic and mild infection in humans and possibly lead to more clues about transmission.

Covid Uptick?

Still a question, but positive test percentages are increasing, albeit at a low level and predominantly driven by western states.

Wastewater variant detection is lacking across the country, see all the block dots (no sequencing data) below, but you can magnify your area of the country and find a few sites with enough data to determine predominant covid strain.

For example, in my neck of the woods most of the sites have no sequencing data. Of the 2 that did, one showed a predominance of KP.2 and the other LB.1. Nationally, KP.3 is starting to exceed KP.2. Again, we're still at low numbers.

A Tip of the Hat to "The Simpsons."

I knew that "meh" might have been adopted from a Yiddish term meaning so-so or unimpressive, but it looks like a 1994 episode of the TV series The Simpsons, featuring ultraconservative Sideshow Bob, popularized the term. Lisa Simpson was investigating voter fraud as the reason Sideshow Bob was elected as Springfield's mayor, and the "meh" word was uttered by a Hall of Records bureaucrat when Lisa expressed disbelief that he would give her the entire mayoral voting records that should have been kept secret. (Thie episode is available only with subscription, but I verified the quote at about 15:30 time in the recording.)

Voter fraud 30 years ago?

No Spoilers From Me

Bud WiedermannAugust 6, 2023August 6, 2023Leave a comment

It's my usual Sunday to put the final touches on this week's post though working on it earlier than my usual late morning start since I had to watch the Women's World Cup soccer match. In case you recorded it to watch later, I won't reveal any spoilers.

It's Official for Nirsevimab

On August 3 the ACIP voted to recommend the long-acting monoclonal antibody nirsevimab (brand name Beyfortus) to prevent RSV. It is recommended for use in all infants under 8 months of age, just before or during the RSV season, and also for infants 8-19 months of age with the usual high-risk medical conditions just before their second RSV season. Dr. Mandy Cohen, the new CDC director, formally adopted those recommendations. It will eventually replace the current product, palivizumab (Synagis), which has been administered just to the high-risk groups monthly during RSV season.

I didn't log in to the ACIP meeting but did review the slides and reports (available here). Most of the information had already seen the light of day at the prior FDA meeting that approved the product, but a few items are noteworthy.

First, authorities now refer to this product as a vaccine, although that's not quite true in the scientific sense. This is a strategy to try to have this funded by the Vaccines for Children program. The product will be very expensive (probably around $450 - 500 for a dose), and even standard health insurance companies are notorious in avoiding reimbursement for new products.

For infants born just before or during RSV season, nirsevimab would best be administered by the birthing hospital prior to discharge. I was surprised to learn that only 10% of US birthing hospitals participate in the VFC program. Most provide bundled services for deliveries; hepatitis B vaccine is often covered in this manner, but that cost is only $13-16 per dose. Will bundling work for a much more expensive product? These payment issues could impact ability to administer the new therapy particularly for the upcoming RSV season. There isn't much time to figure out these details.

Presentations from CDC personnel helped show the potential impact of nirsevimab, using a Number Needed to Immunize (again with the vaccine nomenclature). Based on the available 2 randomized controlled trials in mostly healthy infants, where ICU admissions were rare and deaths thankfully absent in the study infants, NNI was favorable particularly for preventing hospitalization but also for prevention of medically-attended illness.

In other words, 128 infants would need to receive nirsevimab to prevent 1 additional child from being hospitalized for RSV. Various cost-effectiveness analyses showed this to be a good use of funds.

Data are not yet available to perform similar analyses for high-risk infants receiving therapy prior to their second RSV season, but antibody levels in those infants following treatment strongly suggest it will be effective.

CDC will provide us with more detailed recommendations soon. They did provide an example of timing for "vaccination" with nirsevimab. As mentioned above, for children born just before or during RSV season (October 1 through March 31 in most parts of the US), nirsevimab would be administered at birth. Otherwise, administration would be timed for the well-child checks in primary care provider offices, perhaps in October and November. The October batch could include infants born the previous April (at their 6-month visit), June (4-month visit), and August (2-month visit). Infants born the previous May (6-month visit), July (4-month visit), and September (2-month visit) would receive their dose in November. A bit complicated, but at the moment I can't think of a better plan to make this run smoothly for office practices.

We also need guidance if FDA approves the maternal RSV vaccine for pregnant people. Providing nirsevimab to infants whose mothers were vaccinated during pregnancy is probably unnecessary. FDA is supposed to decide this month on the maternal RSV vaccine once they receive updated results from the ongoing trials.

Regardless, all pediatric healthcare providers need to stay tuned; this could be a major change in office practice this fall.

Don't Go Home With the Armadillo, etc.

A case report of possble authochthonous leprosy in central Florida reminds us that, Jerry Jeff Walker notwithstanding, one can acquire leprosy in the US without having contact with humans or armadillos with leprosy. The report and other epidemiologic evidence suggests that leprosy may be endemic in southeastern US.

Cold air might aid in croup treatment according to a new randomized controlled trial in an emergency department. In addition to treatment with dexamethasone, children with croup were randomized (not in a blinded fashion, obviously) to outside cold air for 30 minutes, compared to room temperature indoors. The cold air kids seemed to improve faster.

Conflict in My Favorite Medical Feed

I've been reading ProMED posts several times a day for years and have donated funds to them during that time. They were the first to report all 3 coronavirus outbreaks this century. I was a bit disappointed to learn recently that they will start charging a subscription fee but was resigned to the fact that I'd be shelling out a few more bucks. Now I've learned there's a big kerfuffle in the background. The frontline folks who do all the work are protesting new management moves. I hope this is resolved, I can't imagine life without ProMED.

'Demic Doldrums

No big changes this week, CDC numbers are similar to last week and all indicators point to an increase in SARS-CoV-2 activity in the US and elsewhere. Not to rely too much on anecdotal data, but my own primary care provider remarked to me at a visit last week that he has seen an upswing in positive tests in his practice. Let's hope this will be a minor blip and not the start of a large new wave.

Some Good News From Down Under

Again, no soccer spoilers from me. But, maybe flu has peaked in Australia; if so, this season is a bit better than 2022 and might bode well for our own flu season.

Before the Flood

Bud WiedermannOctober 17, 2021October 17, 2021Leave a comment

I'll touch on 2 versions of flooding today, first with regard to the perhaps outdated FDA rules for acting on data in the midst of a pandemic and secondly with respect to the flood of calls and visits we all might experience if a COVID-19 vaccine is authorized for children later this month.

Has the FDA Become Antediluvian?

The term, said to have been used first in the 17th century, literally means "before the flood" (as in Noah, not Curt). I wasn't able to watch the FDA VRBPAC proceedings regarding Moderna boosters on October 14 but did catch almost all of the live presentations for the Janssen (J&J) boosters on October 15. I've perused all the meeting materials for both days. Suffice to say that this included a virtual "flood" of new data, but we should have formal ACIP/CDC recommendations for both sometime this week. Let me mention just 1 key study that leads to my charge of antediluvianism and is already misrepresented in the lay press.

The so-called "Mix and Match" study is an unpublished NIH-funded trial designed to determine whether it is safe to boost with a COVID-19 vaccine product different from that used in the primary series and to characterize the resulting immune response. Note that it was not designed to determine what is the best product to boost a particular primary series, but some pundits have attempted to skew the data to that purpose in spite of comments to the contrary by Dr. Kirsten Lyke who presented the data. While it is true that participants who originally received a dose of J&J vaccine had higher antibody levels when boosted with Moderna or Pfizer vaccines compared to a J&J boost, the study simply wasn't designed to know how that translates clinically. Limitations include the very small numbers of participants (50 in each of the 3 booster groups, or 150 total participants) as well as the short follow up period to date, only 29 days after the boosters. This is particularly important because it is already suspected that an adenoviral-vector vaccine similar to the J&J vaccine has very different antibody kinetics compared to the mRNA products leading to a much slower decline in antibody. With this difference, it could be that levels following a booster dose could continue to rise after 29 days and thus not yet detected in the NIH study. The NIH study is planned to measure these kinetics in the coming months. Also know that the trial enrolled down to age 18 years of age only.

I thought the FDA could have been a bit more flexible in allowing some conclusions regarding mix and match options starting even now, ergo my antediluvian reference. The study's safety data did not reveal any real concerns, and given those results I think it is biologically implausible that serious adverse events such as myocarditis are likely. Allowing mixing would make booster dosing much easier from a public health implementation standpoint. We'll see if some official FDA statement or ACIP recommendation permits mixing. Most importantly, in terms of public health no matter what we do with boosters the emphasis should be on vaccinating the unvaccinated.

Future Flood of Frantic Fonecalls

October 26 is circled and blocked off on my calendar. That's the day FDA/VRBPAC meets to discuss the Pfizer vaccine data for 5-11 year-old children. None of the meeting materials are posted yet, but it is likely that the antibody data in this immunobridging study look good if we believe Pfizer's press releases. What I'm not sure about is how much safety data FDA will require before authorizing use. This was a relatively small study, less than 10 thousand subjects even with an expanded safety cohort enrolled a few months after the start of the original study and thus shorter follow up period. If the vaccine is authorized for this age group, note that you can't use any old Pfizer vaccine stock you might have in your office. The doses are different and will be all new vials; it will take a bit of time to distribute.

Update on Pfizer COVID-19 Vaccine

Bud WiedermannDecember 12, 2020Leave a comment

I wanted to give a quick update and some suggestions about the now-authorized vaccine. Unless you've been carefully avoiding all media notices, you know that the FDA published their Emergency Use Authorization for this vaccine late on December 11. I had attended the Advisory Committee on Immunization Practices (ACIP) meeting earlier that day, and because of the EUA coming through they moved their scheduled Sunday meeting to today (December 12) at 11 AM, which I also attended. The ACIP and CDC did comment about many of the special considerations (e.g. pregnant and breastfeeding women, immunocompromised individuals); ultimately the recommendations passed unanimously.

Many details will be evolving in terms of guidance, etc, but I did want to give front-line providers some useful links to peruse in the meantime.

First, all of the slide presentations for the 2 ACIP meetings are posted. I'd particularly recommend the session on Clinical Considerations from December 12, but recognize much is changing with guidance for certain situations including allergies and pregnancy.

Another extremely important resource is the Vaccination Communication Toolkit. This also is still an evolving resource, but I'd strongly recommend all providers start to become familiar with these tools. Know that educational videos for vaccine storage, administration, etc are in the works, as are fact sheets for the general public in several languages.

Next Steps? At this point, don't worry about your specific role in this entire process, except in helping your patients and families realize that the vaccine was approved after a very transparent and extensive review of data and that they will be notified when they or family members are eligible to receive vaccine based on the pre-established allocation plan. Vaccine is in very limited supply now, so very few individuals will be vaccinated next week.

Some of the public may be concerned about the rapidity with which this vaccine was studied and authorized, not to mention concerns with possible undue political pressures. I am completely satisfied that FDA and ACIP/CDC have been very thoughtful and transparent in all their proceedings. From my point of view there is only 1 difference for this vaccine's approval compared to other vaccines approved under "normal" circumstances, and that is the duration of immunity. We will know the answer to that question relatively soon, but I don't find anything about safety or efficacy that has been short-circuited by the EUA process.

Probably every day the next week we'll see new materials and information made available. Next Thursday the FDA will again meet, this time regarding EUA for the Moderna vaccine. ACIP/CDC has planned the same Friday and Saturday or Sunday discussion schedule if this vaccine moves forward from FDA.

Also, you might be interested in upcoming Clinician Outreach and Communication (COCA) call entitled "What Every Clinician Should Know about COVID Vaccine Safety."

Be Well and Stay Safe!

Vaccine Anticipation

Bud WiedermannOctober 31, 2020Leave a comment

Yesterday, October 30, was a day off for me. To celebrate, I attended the 7-hour online meeting of the Advisory Committee on Immunization Practices (ACIP) of the CDC. The topic was COVID-19 vaccines. This was the last regular meeting of the ACIP until February, although they will convene on an emergency basis before that time if/when a COVID-19 vaccine trial has enough data to merit discussion. Everyone fully expects that to happen within the next few to several weeks.

The day included presentations from 14 speakers representing FDA, CDC, and vaccine manufacturers and covered regulatory, ethical, scientific, and other topics. I found the modeling discussion most enlightening; it was an attempt to display various outcomes for infection rates and deaths based on how effective a potential vaccine might be, what groups are prioritized for vaccine administration in the early stages of vaccine deployment, and what the US epidemic curve is doing at the time immunization is begun. It was definitely not intended to be a predictive model but rather a general methodology to use whenever a vaccine is ready to be released for use. At that time, more specific data regarding vaccine efficacy and current epidemiology can be plugged into the model to help guide early deployment. More about the modeling later. Here are my take-home points for pediatric healthcare providers distilled from those 7 hours.

Worldwide we now have over 200 COVID-19 vaccines in various stages of study. Honing down to the US, we have 5 vaccines in either Phase I or Phase II testing in humans and 4 in Phase III. Let's focus on the Phase III products since 1 or more of those likely will have results to report in the next few weeks to months. Two of them, AZD1222 (AstraZeneca/Oxford, the UK vaccine you've probably heard a lot about) and Ad26CoV2S1 (Janssen) were paused for safety monitoring but now have resumed recruiting volunteers, though the AstraZeneca product is still on hold in the US. mRNA-BMT162 (Pfizer/BioNTech) is recruiting still but is far along, having enrolled around 42,000 subjects of which about 35,000 have received the second dose of the 2-dose series. Finally, mRNA-1273 from Moderna has completed enrollment of around 30,000 people of whom ~25,000 have received the second and final dose of that series. Most likely we will hear trial results on the Moderna product within a few weeks.

An FDA representative (full disclosure, happens to be a longtime colleague and friend of mine) provided an overview of how FDA rules will be applied in this situation. Again, you've probably seen a lot about this, with some back and forth on the application of product release under Emergency Use Authorization (EUA) which can only be applied in national emergency situations like we have now. Understand that in general EUA is a "lower bar" to clear than is full licensure, but the FDA has very clearly laid out their requirements in this situation. It's really a balance of ensuring safety but not delaying consideration for EUA for such a prolonged period of time that we find ourselves in a worse hole with cases and deaths.

Let's get to the modelling discussion. The group at CDC stratified the population into 5 age groups, 0-4 years of age, 5-17, 18-49, 50-64, and 65+. Note that this oldest category consists of 55 million people nationally (including yours truly!). They also stratified by low-risk or high-risk, the latter consisting of at least 1 of the following medical conditions: COPD, heart disease, diabetes, kidney disease, or obesity. Nationally 40% of adults, 100 million people total, fall into the high risk category. Another interesting tidbit is that ~40% of adults 18-64 years of age, or 80 million people, are classified as essential workers; 1/4 of those are healthcare workers. The modelers made various assumptions about vaccine efficacy in different age groups, etc, and the main focus of their presentation was in Phase 1 distribution of 200 million courses of vaccine. This phase has been divided into Phase 1A consisting of healthcare personnel (20 million courses) and Phase 1B for adults 65+, high-risk adults, and essential workers (180 million courses total). The modeling discussion was most interesting in trying to prioritize Phase 1B individuals - which of those 3 groups should go first, second, third. Various modeling assumptions and outcomes (i.e. what strategy prevents the most infections versus what prevents the most deaths) produced slightly different suggestions for vaccine prioritization.

What was most important, however, was that the timing of vaccine in relation to the epidemic surges going on was by far the biggest determinant of how effective a vaccine will be at any of these outcomes. This isn't surprising particularly, it's why we don't target annual flu vaccination to start in the middle of our annual epidemics. However, the modelling numbers were impressive and point to the main take-home message for all of us: it has never been more important than right now to use those SARS-CoV2 mitigation strategies. Failure to do so diminishes the benefit from a COVID-19 vaccine and makes it even more likely that we'll see more preventable deaths and more harm to our economy.

A few other interesting details from the session. Federal officials are working hard to reach out to everyone in our society to provide vaccine information, including providing information sheets in >20 languages. Also, vaccine recipients will be asked to use a smartphone app to provide real-time feedback for safety monitoring and illness after vaccination. CDC officials provided a brief review of the evidence to date regarding possibility of reinfection with SARS-CoV2. So far this is at most an uncommon event in the first 3 months following infection, but possibly could become more common if immunity wanes later after natural infection. Multiple individuals weighed in regarding vaccination during pregnancy. New data from CDC, so far unpublished, indicate that pregnant women are at higher risk for worse outcomes with COVID-19 (earlier published data were a bit more equivocal). We likely won't have a lot of data on vaccine safety in this population very soon, and it seems that pregnancy will be listed as a precaution but not a contraindication for vaccination.

Which brings us to our final group, children. We need to be very careful with the safety of any vaccine being administered to a healthy child, particularly for an infection that has a much lower complication rate than in adults. So far, we have no pediatric data at all about these vaccines. Certainly children will eventually be enrolled in vaccine trials, once we have sufficient longer term safety and efficacy information from the adult studies. We'll have to be a little patient here.

There is so much more I'd love to tell you about this session, but I've probably already used up some of that patience you need to save waiting for the pediatric vaccine trials. Soon more details from this meeting will be available at the ACIP website. Just know this: I am very reassured with the transparency surrounding vaccine development and distribution, and I am confident I'll see enough of the results from these trials that I'll be able to judge independently whether or not to recommend a vaccine for a specific group. Although you won't be providing COVID-19 vaccine for your pediatric patients anytime soon, you undoubtedly will hear a lot of vaccine questions from your patients and families. A primary care provider is probably the most important individual to help families with vaccine decisions, now more than ever. Whenever a vaccine becomes available for use in the US, of course I'll let you know what I think but know that ACIP/CDC will have toolkits available for you to consult and assess as well.

In the meantime, please ensure all your patients receive their seasonal flu vaccine and are practicing safe COVID-19 mitigation strategies.

Tag: ACIP

Meh