monoclonal antibody – Pediatric Infection Connection

Happy Holidays! 2

Bud WiedermannJune 18, 2023June 18, 20232 Comments

I'm putting this post together on Father's Day, and tomorrow is Juneteenth, a holiday increasingly recognized in the US. Today two of my 3 sons are farther away than usual, one in Berlin, Germany, at the Special Olympics World Games and another working in healthcare in Mekele, Ethiopia. The third member of the triumvirate remains in the eastern US time zone.

Can anyone guess which state was the first to make Juneteenth a permanent state holiday?

Influenza Rising in Southern Hemisphere

The most recent World Health Organization update on influenza, published on June 12 with data current as of May 14, not surprisingly shows an uptick in flu activity in sections of the southern hemisphere. The influenza AH1N1 2009 pandemic strain and B Victoria lineages predominate, meaning we are likely in good shape from a vaccine standpoint for next winter in the US.

RSV and covid haven't increased to the same extent as flu in the south, for the most part.

Polio Vaccine for Travelers

'Tis the season for world travel, but I'm thinking many folks aren't aware of newer polio risks around the world. Spurred by the pandemic and various war zones, polio vaccination has waned. Also, as I've noted in the past we're seeing vaccine-derived polio disease via transmission from recipients of the oral live polio vaccine. The CDC continues to update polio vaccine recommendations for travelers. Twenty-nine countries around the world have circulating poliovirus, but in addition to the "usual suspects" the list now includes both Canada and the United Kingdom.

Certainly the risk can vary in settings within these countries, but primary care providers should remember to discuss vacation plans with families, not just out of interest but to make sure they are informed of any risks and where to find resources. Make sure all children are up to date on immunizations, including polio, and some adults may wish to receive a one-time killed polio vaccine booster if traveling to a high risk country.

'Demic Doldrums

Here in the US we continue with our low levels of SARS-CoV-2 circulation in most jurisdictions; now we rely primarily on ED visits and hospitalization rates for any early warning given our lack of other good community monitoring tools. The FDA VRBPAC group met on June 15 to advise on composition of the next covid vaccine, and I was able to attend most of the meeting including the important parts of the discussion sessions. All 3 US vaccine manufacturers (Moderna, Pfizer, and Novavax) presented data.

As most providers know, the XBB sublineages (XBB represents a recombination of omicron strains) now predominate; the ancestral strain has virtually disappeared from circulation in humans, as have all subsequent strains except for the omicron lineage. Without going into perhaps agonizing detail, most authorities agree that covid vaccines for the near future should focus on the XBB sublineage. The vaccine manufacturers have a fair amount of preliminary data on immunogenicity of XBB-containing vaccines. Results suggest good safety signals and good neutralizing antibody activity against currently circulating XBB strains. Less data are available for memory B- and T-cell responses to these vaccines, and nothing substantial so far on XBB vaccination of children. Work continues, and we should see more about pediatric XBB vaccination in the next month or 2.

A very important part of the presentation has to do with cross-reactivity of antibody among the various XBB strains that were tested. Because of this, a monovalent vaccine with any XBB strain is likely to be effective against these closely related sublineages. Since among other reasons all 3 companies had the most experience with the XBB.1.5 vaccine and can readily ramp up vaccine production for this product, the VRBPAC members unanimously voted to go this route and the FDA officially signed off on this recommendation. Next up is a discussion at the ACIP meeting on June 23, but don't expect any vote or final recommendations at this session. That should come a bit later. In particular, we will need guidance on pediatric use, combined use with other vaccines such as for influenza and RSV, and whether to recommend for all or just for certain high-risk populations.

Last week I perhaps dissed the CDC's use of color in their depiction of variants, but now I need to acknowledge I was wrong. The most recent MMWR had some nice graphics. The graph below not only shows the colorful distribution of variants but also the relatively low numbers of cases recently (with the caveat that testing in general is less now than in 2022).

As can be seen, we have been in an omicron world for some time, with XBB now in charge.

Quickly, a few other covid notables from last week:

A new monoclonal antibody product on the horizon
Myocarditis associated with pediatric SARS-CoV-2 infection can be severe (note not a vaccine study)
Metformin might have role in treatment (overweight or obese adults)
Stopping routine admission covid testing associated with increased covid infections in a few UK hospitals

Juneteenth

Perhaps not what you would have guessed, but my home state of Texas was the first to make Juneteenth a permanent state holiday, in 1980, which was decades before most of the rest of the country. I left Texas in 1984 and parts of it now are unrecognizable to me, but it's easy to understand why that state was out in front on Juneteenth. The original event was June 19, 1865, in Galveston, TX, when Union troops arrived and finally enacted the January 1, 1863, Emancipation Proclamation and freed slaves in Texas. In my childhood, unless you kept yourself under a rock, if you lived in Texas you knew about Juneteenth.

Happy Father's Day to all fathers out there, and to everyone please use Juneteenth to reflect on its many lessons that continue to challenge us to do better.

A Few Good Reads This Week

Bud WiedermannNovember 13, 2022November 13, 2022Leave a comment

I love to read. However, I've got a long ways to go to match comedian Mel Brooks's literary appetite. In a recent NY Times interview (sorry, subscription only), his past reading list is prolific. I suppose he could be exaggerating to pull our collective legs, but I doubt it.

Compared to the previous week, it wasn't difficult to find new articles to talk about this week. I'll just pick a few.

A mAb-Less Winter

I stole this phrase from Dr. William Werbel, an adult infectious diseases physician and researcher at Johns Hopkins, speaking at a CDC/IDSA Clinician Call webinar on November 12. It's a great sound bite of how variants are changing our prophylactic and therapeutic landscape for COVID-19 particularly with regard to use of monoclonal antibody products.

It's getting tough to keep track of all the variants going around, but keep in mind we are seeing exclusively omicron subvariants. We haven't had a major change in variant type since omicron appeared almost a year ago. Here's the latest picture from the CDC:

What you can see most recently is the decrease in proportion of BA.5 accompanied mainly by increases in BQ.1, BQ.1.1, and a little of BF.7. It's still a bit early to understand all of the clinical implications of these newer sublineages, but the main concern is that they appear to have specific mutations that limit the effectiveness of current monoclonal antibody preparations we have come to rely upon.

Bebtelovimab is the only monoclonal antibody effective for treatment currently, but laboratory studies strongly suggest that it loses significant potency with mutations in the 444 region; BQ.1 and BQ.1.1 have the K444T mutation. Similarly, Evusheld (combination of tixagevimab and cilgavimab) is an important agent for prophylaxis of SARS-CoV-2 infection, long-acting and widely recommended (though underutilized) for individuals with immune compromise. Evusheld loses potency against viruses with mutations in either the 444 or 346 regions. BQ.1 has the K444T mutation only, BF.7 has the R346T mutation only, and BQ.1.1 has both mutations, Together, these 3 subvariants comprise over half of the circulating viruses in the US and are rising. Thus the concern that this winter will leave us stranded without effective monoclonal antibody products for treatment and prevention. Of course research is ongoing to develop new monoclonal antibody preparations, and we still have antiviral agents like ritonavir-boosted nirmatrelvir (Paxlovid), remdesivir (Veklury), and molnupiravir (Lagevrio) that appear to retain activity against new subvariants.

For the most part, monoclonal antibodies exert their effects by providing neutralizing antibody against the viruses. However, vaccines go a bit further to stimulate not only neutralizing antibody production in the recipient but also to activate other parts of the immune system to lower risks of infection and severe disease. I'll play the broken record again: everyone eligible should be vaccinated and boosted against COVID-19.

Covid and Kids

Two recent reports of covid and young children are helpful. One, from the CDC, was widely publicized. The other, from the UK, was not, at least not in the US that I could appreciate. Whenever I see data drawn from administrative databases I worry about drawing too many conclusions, because clinical details often are lacking or inaccurate. However, we do have some more refined clinical details in both of these studies.

The CDC report focuses on infants under 6 months of age during the time period June 2021 through August 2022 (first half mostly delta variant, second half omicron). What struck me most were the risk factors for hospitalization which did not change during the study period. Overall almost a quarter of all hospitalized infants had at least one risk factor for severe disease, with prematurity being most common. The proportion of infants with risk factors generally increased with age. This is clearly an alarm to promote immunization of pregnant people to protect not only themselves but their infants as well.

The UK study looked at deaths in children and young adults less than 20 years of age; having a national health system makes this data collection much more accurate than we can provide in the US. Over 13 million individuals comprise this UK age group, and the investigators identified almost 3 million covid infections during the study period of March 2020 through December 2021 (almost all pre-omicron). They found 185 deaths within 100 days of a positive SARS-CoV-2 test and then dug deeper with clinical questionnaires. Ultimately they concluded that 81 of the deaths were caused by covid with the remainder attributed to other causes. With this small number it's tough to break this down further, but about half of the non-covid death subjects had no comorbidities compared to about a quarter of the covid deaths. Within the covid death group, severe neurodisability was particularly striking to me at about one-third of that group. Note that during the study time period, covid vaccines were not available to the under 12-year-old population.

School Masking Works

This might be a case of closing the barn door after the horses have escaped, but we now have further evidence that masking works. The study from multiple institutions in Boston looked at covid incidence before and after school masking mandates were lifted and, although this was an observational study rather than a prospective randomized trial, it did confirm that masking can help prevent infection and illness. This should be useful should we encounter a severe upswing in covid cases in the future; masking could mitigate students missing school. Another important feature of this article is that schools with poor ventilation and higher rates of students with language barriers, disabilities, and low-income families are at highest risk of infection. The discussion portion of the article should be required reading for school administrators and policy experts.

My Homework Just Increased

But back to Mel Brooks, one of my all-time favorite entertainers and personalities. In the Times interview, he mentioned over 20 books/authors, plus 9 pieces of music and 4 entertainers, in a wide-ranging commentary on life influences. I think my reading list just doubled. I was totally taken aback when, asked about the best book he ever received as a gift, he mentioned Gogol's "Dead Souls" as a "life-changing gift" that he reads annually. I'll be searching for a copy in my area used bookstores.

Hang In There

Bud WiedermannDecember 26, 2021Leave a comment

No point in sugar-coating, things are likely to get worse before they get better. The news is disappointing, but we can at least hope that omicron and influenza will crest quickly and recede somewhat.

Omicron is Different

Yes, you already knew that. We certainly know it is (much) more highly transmissible but we still don't have enough data to know if severity is different. Full vaccination (primary series plus booster) is likely to be helpful against severe illness though much less so against infection itself.

Our most commonly available monoclonal antibody regimens are unlikely to be effective against omicron; at Children's National we have paused offering both the bamlanivimab/etesevimab and casinivimab/imdevimab monoclonal cocktails given the high rate of omicron in our region. Sotrovimab should be effective against omicron, but currently we don't have this agent on hand and availability is likely to be limited for the next few weeks. Note that use is limited to outpatients 12 years of age and older and weight 40 kg and greater with positive SARS-CoV-2 testing and high risk for hospitalization or death.

We now have emergency use authorization for 2 oral medications, molnupiravir and nirmatrelvir/ritonavir (Paxlovid), for treatment of mild-to-moderate COVID-19 illness. Paxlovid, consisting of 2 viral protease inhibitors, is authorized down to the 12 years of age/40 kg weight category with high risk for disease progression. Note that Paxlovid is a CYP3A inhibitor, so beware of drug interactions. Molnupiravir is less effective but can be used in adults at high risk for progression who cannot access or receive other treatment options. In the coming weeks molnupiravir is likely to be more available than Paxlovid, but note that it should not be given to children - concerns for joint problems in juvenile animals likely will delay pediatric trials. Because it is a mutagenic agent, use in pregnancy is an unknown risk and patients of reproductive age should use methods to prevent pregnancy while taking the medication and for either 4 days after (females) or 3 months after (males) the 5-day treatment course.

Another difference for omicron is that some SARS-CoV-2 tests may show false negative results. It is a little tough to keep track of new information about this, but the FDA has a great resource.

Influenza on the Rise

Influenza has been creeping up nationally and also at Children's National Hospital, though at the hospital it has not yet reached numbers that we associate with the official start of flu season. Now a preprint study suggests that the 2021-22 influenza vaccine has reduced ability to inhibit replication of the H3N2 clade most likely to be circulating this year. That could mean an antigenic mismatch for this flu season, but we won't have an estimate of that for at least a few months. Even if this is true, influenza vaccination is still very important and I would encourage everyone to be immunized - it's not too late.

Whirlwind Week

Bud WiedermannDecember 19, 2021Leave a comment

Somebody pushed the reset button this past week. Although we don't yet have the weekly variant reports from CDC (they are published on Tuesdays) it is very clear from just my small world at Children's National Hospital that omicron has hit with a vengeance. I was speaking in the hallway on Friday with my longtime friend and esteemed colleague Dr. Larry D'Angelo who likened what we are seeing to the early situation in South Africa where omicron increased exponentially even while delta was still very much present. An important caveat, however: it's risky to make too much out of day-to-day data, many factors affect case rates and sometimes we can be misled by "hot off the presses" numbers.

A Triple Whammy Ahead?

Most winters in pre-pandemic times I kept my fingers crossed that we would not have our RSV and influenza seasons occur concurrently; the few years we had a double whammy like that it really strained our resources. This winter could be worse. The good news is that although RSV is still around it seems to be on a downward trend. However, influenza A numbers have been increasing both at Children's National and nationally, suggesting we will hit full-blown flu season soon. The second and third components of the trifecta are delta and omicron. If we see all 3 of these viruses causing infections in large numbers at the same time it will be very tough. One silver lining of the omicron era is that it may stimulate more individuals to seek out primary series and booster vaccinations. Also, with school winter break and perhaps a bit more caution on the part of the public, we might have less viral circulation the next couple of weeks. We'll see.

For now clinicians should remember we have two effective influenza antiviral medications, oseltamivir (Tamiflu) and baloxivir marboxil (Xofluza), available. From a treatment perspective we don't have a lot of choices for outpatient therapy for pediatric SARS-CoV-2 infections, and the monoclonal antibody combination bamlanivimab and etesivimab just authorized for use down to newborn ages but isn't likely to be effective against omicron. (Note that currently Children's National is not using age under 1 year as an independent risk factor for use of this combination.) NIH has a nice web site to check the latest on effects of different therapeutics for SARS-CoV2 variants, much based on in vitro data rather than solid efficacy studies because it's just too soon in the omicron wave for reliable analysis.

Setback and Hope for Pediatric COVID-19 Management

On December 17 we all learned via a press release that the Pfizer vaccine trial failed to reach the pre-established noninferiority margin for children 2 - 4 years of age, although that goal was reached in the 6 - 23 month old age group. As you know I am an investigator in that trial, at the time of this writing still waiting to hear specific plans for modification of the trial presumably to administer third doses to those children.

Also on December 17, CDC released reports of 2 studies of the "Test to Stay" (TTS) strategy for managing school attendance with positive covid cases, one from Los Angeles County, CA, and the other from Lake County, IL. A lot of us have been waiting for high-quality published data on this approach. The basic approach to TTS is described on the CDC web site, suffice to say ready access to testing must be available as well as compliance with masking and other prevention methods. We of course do not have data available for TTS efficacy in the omicron era but at the moment this seems to be a reasonable approach.

Bottom line for all of this, we are entering another worrisome time for COVID-19, no reason to panic but be careful and stay abreast of new developments. Please encourage everyone to get their influenza and COVID-19 vaccinations, including boosters for the latter.

Ebola Redux

Bud WiedermannFebruary 20, 2021Leave a comment

COVID-19 is still going strong, far outstripping my lame intentions to post something weekly. I have been keeping close tabs on all developments, but I feel like I would need to post a few times a week to be useful and I can't seem to make time for that. I do hope to give a COVID-19 summary update at the next Montgomery County Pediatric Society virtual meeting on March 8. In the meantime if you have particular questions please use the Comments section to pose them.

This week the news media finally seemed to start paying attention to disturbing developments in Ebola virus infections in both East and West Africa. It's worth discussion, especially since the world is much better prepared to handle it now than it was during the large outbreak in West Africa a few years ago.

First to East Africa, where we have new cases appearing in the Democratic Republic of Congo. The total number of cases is low, perhaps 6 (it's difficult to be certain of the exact number mostly based on media reports), but what is noteworthy is that the index case may have been infected by semen from an Ebola survivor originally infected in the 2018-20 outbreak in the DRC. Fortunately public health resources are being mobilized rapidly in a locale which like many other countries previously has had significant barriers to public health measures for Ebola control.

In West Africa, Guinea is the epicenter of a new outbreak. This was one of the countries, along with Liberia and Sierra Leone, most affected by the 2014-16 outbreak that spilled over into the US and elsewhere. Here the index case appears to be a nurse who first sought medical attention on January 18, was misdiagnosed for a time, and ultimately died on January 28. She was buried without safety protocols, further exposing others to the virus. As in the DRC, public health interventions are proceeding much more rapidly than in the past. As I write this, the World Health Organization is deploying staff to the area, along with millions of dollars in funding. Importantly, we have 2 main tools today that were not available in past outbreaks.

First, we now have specific treatment for Ebola virus disease in the form of a monoclonal antibody cocktail approved by the FDA a few months ago; results of a large trial were published in the NEJM in December. The trade name is Inmazeb, a bit less of a mouthful than the trio of monoclonal antibodies that make up the pharmaceutical: atoltivimab, maftivimab, and odesivimab-ebgn. It is effective in lessening mortality in infected individuals especially if given early in the disease course. Unfortunately it is administered IV so it is a little more cumbersome especially in resource-poor areas.

Second are Ebola vaccines. The US FDA approved one, called Ervebo, last December. It is a live recombinant vaccine made using a backbone of vesicular stomatitis virus (VSV) with the envelope glycoprotein of the Zaire ebolavirus substituted into the nucleic acid code. (VSV is primarily a disease of cattle, horses, and swine, and outbreaks have occurred in the US. Humans occasionally can be infected, primarily from direct contact with infected animals.) This vaccine is used to immunize contacts of Ebola virus patients in what is termed "ring vaccination;" the technique was highly successful in controlling and eventually eliminating smallpox, for example.

A second vaccine, not reviewed by the FDA, is available for use in other countries. It is actually a combination of 2 vaccines, a first dose Zabdeno which is an adenovirus-vector vaccine and a second dose called Mvabea which contains Vaccinia Ankara Bavarian Nordic virus supplemented with parts of various Ebola and related filoviruses. Because of the requirement for 2 doses, Zabdeno is not that helpful for immediate outbreak control such as with ring vaccination, but it is another tool to help contain the virus in a population.

The WHO announced creation of Ebola vaccine stockpiles just on January 12, 2021, good timing for what we are experiencing now. Immunization programs started in the DRC on February 15; vaccine shipments will arrive in Guinea on February 21 with vaccine campaigns starting on February 22.

Perhaps the US currently is at less risk for imported Ebola because of somewhat limited international travel, but we should not relax. Just as with SARS-CoV-2, any health crisis anywhere in the world affects all of us. Outbreaks in resource-poor populations can be devastating. I'm hopeful all the new advances in Ebola virus disease will prevent a repeat of the tragic 2014-16 West African outbreak.

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