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An interesting week with the FDA VRBPAC meeting and release of a few new studies, but still no word from CDC on relaxing covid testing for asymptomatic individuals. Bottom line though, some more reasons to remain optimistic. Let's dive in.

RESP-NET

Trends continue downward overall as well as individually for covid, flu, and RSV in RESP-NET. This bodes well, although in the pandemic era anything seems possible. Of course still worthwhile to get flu and covid vaccines if eligible.

You might be interested to have a peek at the WHO influenza information, what is pictured below is current as of January 8. It is more or less a typical global flu picture.

As you can see, southern hemisphere activity is low for the most part, with a predominance influenza B and A H1N1pdm09 strains rather than the AH3N2 that predominated earlier. This change in strains is typical at the end of a flu season, both the B and H1N1 strains are well covered by this year's vaccine.

Covid Vaccine Horizon

As planned, the FDA VRBPAC did meet last Thursday. I was able to watch most of the day's proceedings. (It was a long day, you can watch a recording of the whole thing if you want!) Presentations by Pfizer, Moderna, Novavax, FDA, CDC, and others were followed by multiple questions and discussions, all very good. Rather than lull you to sleep with too many details, let me try to summarize key points which were all about simplification. First, the VRBPAC members voted unanimously to recommend harmonization of the covid vaccines going forward. By that I mean that each manufacturer will be providing the same vaccine for both primary series and boosters. So, we won't need to worry about whether a monovalent or bivalent vaccine is needed for a particular individual. If the FDA follows these recommendations and CDC/ACIP agrees, only the bivalent vaccines will be used for primary and booster series - we won't be able to access the monovalent mRNA vaccines. I certainly concur with this - we have had so much lost in translation in implementing covid vaccination in the US, it is too confusing for providers and vaccinees - and data are very reassuring that the bivalent mRNA vaccines have an excellent safety profile and at least equivalent efficacy, if not a little better. More on that later.

Not to be forgotten, we have a third vaccine from Novavax also authorized in the US. It is an adjuvanted vaccine that does not involve mRNA technology, and studies have shown excellent safety and efficacy in adults. Pediatric studies have lagged considerably and the company did not present any substantive new data for young children.

What remains confusing still is how individuals with prior infection but no prior vaccination will be treated. Probably one dose of vaccine would suffice, but how do we verify prior infection for an individual? Also, how do we determine exceptions to what could be a recommendation for annual covid vaccination for most people? Those exceptions include elderly, immunocompromised, and perhaps young children. Will some of them be recommended to receive 2 vaccines per year? Although this is a move towards simplicity, none of this is easy, and the devil will be in the details. I hope the CDC and other agencies are up to the communication task.

Expect more updates on timing and composition of vaccines to be available in late summer/early fall. Churning out an mRNA vaccine targeting newer variants takes about 100 days, maybe a little longer for the Novavax vaccine. It looks like the VRBPAC will be meeting again around May. We should all be very thankful for the efforts of VRBPAC staff and committee members.

Advice for Immunocompromised

Speaking of communication (pun intended), CDC has a nice graphic and somewhat clearer guidance for immunocompromised folks.

This definitely helps, but we all know that not all immunocompromise is equal, so the vaccine nuances (especially whether to administer subsequent doses once or twice a year) will be tough to explain for those with milder underlying conditions.

New Studies of Bivalent Covid Vaccines

Last week saw publication of three updates of results of bivalent covid boosters; all were discussed at the FDA meeting. First, a group at the University of North Carolina reported state data suggesting bivalent vaccine efficacy was pretty good against some of the newer omicron variants. The bivalent boosted individuals (study included ages 12 years and up) had better protection against severe infection than did those who received the monovalent booster. However, numbers were small resulting in wide confidence intervals, and as always protection lessened with longer time after boosting.

CDC reported early estimates of bivalent booster protection against BA.5 and XBB/XBB.1.5 sublineage variants in adults. The study had the same caveat about small numbers and wide confidence intervals, but again a suggestion that the bivalent booster might be performing better than the monovalent booster for these newer omicron variants.

Finally, a study just looking at the Pfizer vaccine showed somewhat better serum neutralization activity against the newer variants in adults who received the bivalent booster compared to those who received just the monovalent booster. This is an important study but less helpful since it is looking at a surrogate marker (neutralization levels) rather than true vaccine efficacy.

More Good News About mRNA Vaccines in Children

A large meta-analysis published last week provides more information about the excellent safety and efficacy of covid mRNA vaccines in children in the 5-11-year-old age group. Benefits far outweigh any risks from these vaccines.

Vaccine Conversations: AAP to the Rescue

The American Academy of Pediatrics published a 49-page report on methods for productive discussions of vaccines with families. If you don't have time to wade through that, AAP will have a 1-hour webinar this Thursday, February 2. I don't think you need to be an AAP member to attend.

Hope

The line "hope springs eternal" is buried somewhere in Alexander Pope's poem An Essay on Man. I also learned that it was the title of a 2018 indie film. I'm not planning to look into either Pope's poem or the movie. However, I can recommend the book I'm reading now, Sea of Tranquility by Emily St. John Mandel, especially if you've read any of her earlier books. It's contains a story of a fictional pandemic, but since I haven't finished it I don't know whether the ending is hopeful or not!

A few interesting items last week. I also enjoyed the CDC COCA call on Saturday - not much new stuff, but a nice summary of issues surrounding covid variants and immune escape among other topics. The recording should be posted soon. It was mostly geared towards adult care.

Tripledemic Receding

I made a great (for me) discovery of RESP-NET - I'm not sure if it is new or if I just wasn't aware of its existence, but it tracks the 3 viruses of interest all on one page. Here is the most recent view:

This is an interactive graph, note on the left side and at the top there are multiple views. The age group 5-17 years is selected here and you can see that downward trends are present for combined respiratory virus-associated hospitalizations as well as for influenza and RSV. Covid doesn't have a consistent downward trend but the recent data (which may be affected by reporting delays) also is heading down. Let's hope so.

Vaccine Coverage

CDC just started reporting covid vaccine rates for children under 5 years of age. It's not pretty and is similar for all ages.

Again, this is an interactive graph, so you can look at rates by sex and age.

A Brief Word on Variants

Here is the latest. Also, I may not have mentioned this before, but if you look at the top right the NOWCAST designation for the past 3 weeks indicates this is a forecast, not based on data collected those specific weeks. The variant data always have a lag time to allow time for sequencing to be performed. For example, the latest actual data we have on this graph is for the week ending December 31, 2022.

Are you starting to get too confused about variant nomenclature? I am. As a quick review, the original omicron variant that appeared in 2021 was BA.1. In January 2022 it was mostly replaced by BA.2. Subsequently we've seen new omicron lineage variants labelled BA.3, BA.4, BA.5, and XE.

The variants taking over in the US now are labelled XBB and BQ.1 and are descended from the BA.5 sublineage. (XBB is a recombinant of BA.2.10.1 and BA.2.75 sublineages, not to confuse you more.) XBB has a high level of immune escape (i.e. immunity from vaccines and prior infection is lessened and current monoclonal antibody therapies are less effective) and also probably enhanced binding to the ACE2 receptor on our cells.

On the other hand, it appears that BF.7 is circulating now in China - this is a sublineage of BA.5 that hasn't taken off in the rest of the world so far.

Wastewater

Wastewater is a very important source of data on what variants are active and when we might see covid surges. Unfortunately I don't think the CDC data presentations for wastewater are very helpful, and the data sources are scattered sporadically throughout the country. This is because reporting has been on a voluntary basis; if you live in a blue state area, you have a better chance of early alerts from wastewater testing. Several national agencies are working on a better network for wastewater testing, but the legal and ethical issues are significant. For example, one could also choose to test collection sites for drugs of abuse and then target police actions to a specific region - those working on a better process want to restrict wastewater testing to just public health uses that do not stigmatize or otherwise target communities for other reasons. I attended a nice summary of the situation provided by the National Academies of Sciences, Engineering, and Medicine (NASEM) which is studying the issue and has produced a preliminary report.

Is My Spice Rack Going to Kill Me?

No, but the closest I come to hoarding behavior is my spice armamentarium. I did a quick count and noted 105 unique spices in my kitchen cupboard, and that doesn't count the maybe 40 or so extra large bags plus maybe 6 different kinds of salt I have on hand.

Last week the lay press picked up on a study that first appeared last September. It looked at contamination rates for people making turkey patties and lettuce salad. The participants were told they were evaluating new recipes, but in fact the turkey meat was laced with a harmless bacteriophage that was then tracked to see where it ended up after the food preparation. It turned out the spice jars were a prime source of contamination. The study didn't seem to address the amount of contamination, but at least it should serve as a good reminder that hand and dish washing during food preparation should be thorough.

I don't plan to wash all of my spice jars, as you might imagine I'm a stickler for food hygiene when I'm cooking!

Fear the Snail

Well, not really. But a recent issue of the Journal of Infectious Diseases reported new trematodes found to be carried by snails in California and elsewhere. These agents have the potential to infect humans, with transmission most likely in a manner seen with angiostrongyliasis in Hawaii. Bottom line, don't eat raw snails on a dare (yes, some people have done this and become infected), and make sure your produce is washed well - you never know when a snail has slimed its way across that piece of lettuce.

Looking Forward to This Week

CDC will release new guidelines for covid testing that will likely de-emphasize routine screening of asymptomatic individuals. The draft is being reviewed now, so expect something fairly soon, perhaps this week.

Also, FDA/VRBPAC will meet on January 26 to start planning covid vaccine strategy going forward. As of today (January 22) the agenda still has not been posted but "the discussion will include consideration of the composition and schedule of the primary series and booster vaccinations" for covid vaccines. I plan to listen in though I don't expect any final decision to be made at this meeting.

By my rough estimate, I've been in my private rabbit hole of infectious diseases and microbiology for over 50 years. Certainly covid has prolonged my stay. This past week I saw a number of new publications that are worth mentioning, I'll try to be succinct!

Tripledemic Tracking

After pausing for data entry to somewhat catch up after the holiday lull, let's look at the landscape.

Influenza

According to FLUVIEW, the country as a whole is seeing continued decline in flu cases. Remember I'm showing you just the hospitalizations confirmed to be flu, as a most accurate tally. Note that the dashed line is to call attention to the lag in reporting the past few weeks. Let's hope we don't see a rebound.

COVID-19

Percent positivity continues to rise, but a little tougher to determine accurate infection rates given all the nuances we've discussed recently.

The XBB.1.5 variant continues to hold the lion's share of the variant proportion in the US. I was interested to see that, at least so far, this variant is not a big deal in the UK. I expect that to change.

RSV

RSV-NET shows a continued decline in RSV infections, with the caveat that we might still be experiencing delayed reporting from the holidays. I don't expect RSV to trouble us any more this winter.

More on Long Covid

A new analysis from Israel suggests that most symptoms of long covid tend to resolve at 1 year follow-up for those individuals who had mild covid illness originally. This is an analysis from a large database which can have its own misleading reporting issues, but in the past this same database has had a good track record for being correct.

Bivalent Covid Vaccine Boosters No Better Than Monovalent?

Two small studies (here and here) in last week's NEJM suggest this is the case, from comparisons of antibody responses. I first commented on these studies last October when they were only in preprint form. Note these studies did not include children, so we could see some different results when those analyses are performed. The accompanying editorial by Paul Offit is a good read. It is essentially an "I told you so" discussion. Some may recall that he was the only member of the FDA VRBPAC panel last summer who voted against moving forward with the bivalent boosters. His main argument was that we didn't know if they were any better than monovalent boosters against the emerging variants, and these small studies appear to confirm his suspicions.

Please be aware this doesn't mean that bivalent boosters are worse, just that they may be no better than boosting with the monovalent vaccine, at least for now. Stay tuned for what should be a very stimulating discussion of future vaccine plans at the next FDA VRBPAC meeting on January 26.

A Clue to Myocarditis Mechanism Following Covid Vaccine?

Researchers in Boston reported results from 61 adolescents and young adults (16 who developed myocarditis and 45 who did not) who had received either the Pfizer or Moderna mRNA vaccines. They found an association of circulating spike protein in blood samples with the myocarditis group. They also looked at immune and cytokine patterns in the subjects. The discussion portion of the article brings up many possible explanations for how intact spike protein might be involved in the pathogenesis of myocarditis, but this is all very preliminary. Now we need more studies to confirm this association and further explore the immunologic phenomena accompanying it.

Note that nothing in this study changes the bottom line for vaccine advice: benefits of covid vaccination outweigh risks when we are considering myocarditis or any other endpoint for COVID-19.

Everything Old is New Again

No one seems to know definitely who first coined this phrase, but I mention it here to remind all healthcare providers to be on the lookout for those "old" vaccine-preventable diseases such as measles, mumps, rubella, and even diphtheria. This week the CDC gave us figures for vaccination rates in kindergarteners during the 2021-22 school year: not encouraging, but also not surprising. Another publication provided some some explanation for why we see problems with mumps outbreaks even in fully vaccinated adolescents and young adults. (Spoiler alert, it is waning immunity.) If any healthcare provider is a little fuzzy on diagnosis and management of these diseases, please review!

Speaking of old, I found that Alice's Adventures in Wonderland was published in 1865, and Down the Rabbit-Hole is the title of the first chapter. Maybe I'll reread it one of these years.

I tried, but not hard enough, to ignore the drama in the House of Representatives this week. At least now we can step back for a bit before we find out what the House looks like when the dust clears. I hope we still have a somewhat functional legislative branch of government.

This past week characteristically is the least reliable in terms of public health epidemiology. This is because our winter holidays naturally result in some delayed data collection and reporting. Even with likely under-reporting, the covid map doesn't look too good. Rather than boring you with unreliable numbers today, instead I will focus on a question about last week's blog.

Flu vs. Covid

Last Monday Michael Schwartz asked 2 questions:

1. Why do we continue to pursue universal testing and recommend isolation for a minimum of 5 days for COVID , but do neither for influenza ?
2. Should we be trying for universal testing and longer isolation for influenza or should we be treating COVID as endemic and treat it like influenza , or some other answer ?

We still have many questions left unanswered, but it may be that covid could become more like influenza in terms of disease management. Influenza and SARS-CoV-2 are both RNA respiratory viruses, but they have significant differences. Still, the history of influenza pandemics might help inform the path forward with covid.

Not much is known about flu pandemics in the 19th century, mostly because the science and reporting wasn't well-developed at that time. Subsequently our flu pandemics all have been influenza A, because it is able to change and "jump" from one species to another. Influenza B does not have an animal reservoir outside humans, plus it is well adapted to us, so it basically behaves like a regular seasonal flu virus rather than causing pandemics which require a large non-immune population. (Note there is an influenza C virus group, but relatively little is known about its epidemiology. Mostly it just doesn't cause problems, which is why most people have never heard of influenza C.)

Everyone knows something about the 1918 flu pandemic, caused by an A H1N1 subtype that jumped from animals to humans. About 40 million deaths occurred worldwide. The next flu pandemic was in 1957 with an H2N2 subtype that had some leftover elements of H1N1 combined with a bird strain of flu. It was a bad time, estimated several million deaths, but not on the order of 1918. With the start of the H2N2 pandemic, circulation of H1N1 flu went away for awhile and just H2N2 persisted as the main seasonal influenza A strain circulating.

Then we experienced an H3N2 pandemic in 1968, but it shared some elements of the 1957 H2N2 strain so not as severe. I have no memory of a pandemic in 1968 even though I was a teenager and thus partially sentient. (Certainly other historical events that year occupied my attention.) H3N2 persisted as seasonal flu, but in the late 1970s H1N1 reappeared as another seasonal A strain. This setting remained until 2009 when we had our most recent flu pandemic of H1N1, a pretty complex reassortment from human, pig, and avian strains. It was actually somewhat similar to the 1918 strain that persisted for a while, so the elderly didn't have as much problem with the 2009 pandemic as might have been expected. Also, folks like me who received the 1976 "swine flu" vaccine (I do remember all that kerfuffle at the time) also had some leftover immunity active against the 2009 H1N1 strain.

All of us should be getting annual flu vaccines, mostly to guard against the common minor changes in circulating flu strains (antigenic drift) as well as to control the relatively uncommon major changes (antigenic shift). SARS-CoV-2 also has minor and major changes ongoing, but the biggest difference is that so far they both occur much more frequently than for influenza. Ergo our moving target or "whack-a-mole" strategies with vaccines and monoclonal antibody treatments the past couple years.

Here are some other comparisons, assuming normal hosts:

InfluenzaSARS-CoV-2
Incubation period2-3 days~3 days1
Reproduction number1.3-1.7 (seasonal)?2
Asymptomatic rate5-30%>40%3
Duration of contagion1 day before -
5-7 days post symptom onset
2 days before -
> 5 days post symptom onset4
All SARS-CoV-2 estimates are highly variable.

1Varies with viral variant, prior SARS-CoV-2 immune status, age

2Widely variable based on multiple factors

3Varies with age and prior SARS-CoV-2 immunity, still not well established

4Varies with multiple factors including disease severity

Lots of footnotes and disclaimers, but perhaps you'll agree there are similarities between flu and covid. If SARS-CoV-2 does progress to behave more like a seasonal respiratory virus, we will be managing it more like we do flu: annual vaccination with composition determined by the most recent variants and (I hope) avoiding school and work attendance when ill, plus lessening of the mandatory testing and quarantine guides still in effect. Of course, if we do veer off to another major variant change that demonstrates increased severity, we are back where we started (except with a now pandemic-exhausted public). Time will tell, but I'm hoping we soon will revert to Michael's second option of settling into an endemic response mode.

More on Invasive Group A Streptococcal Infections (iGAS)

A couple of reports in the online journal Eurosurveillance offer a bit more information. British authorities describe the pattern of iGAS in children over the past few years, clearly showing an increase in absolute numbers. No specific emm types (the gene coding for specific M proteins that could confer enhanced virulence) were identified. The investigators document some association with respiratory viruses such as human metapneumovirus and RSV, but it isn't clear that this is significant since it is the season for both streptococcal infections and many respiratory viruses. In the Netherlands, investigators describe iGAS cases in children, particularly streptococcal toxic shock syndrome and necrotizing fasciitis. The latter showed an association with varicella infection, a known risk factor. Again, no specific emm type jumped out. In retrospect, it seems odd to me that the British study didn't even mention varicella co-infection.

Neither of these studies involved a control group looking at viral co-infections, so it's still hard to know what's behind these trends. The one potentially modifiable factor for prevention is varicella immunization.

1968

If there was a time period that forever changed the type of person I am, it was probably this year. I find it mildly amusing that I have no memory of the flu pandemic, clearly I was distracted by the Tet offensive, the tragic assassinations, the Democratic convention, Smith and Carlos at the olympics, and even the pictures of Earth from Apollo 8. My fascination with infectious diseases was yet to come.

First, some of you may notice I'm posting unusually late for my regular Sunday routine. I wish I could say it was because I was out all night partying New Year's Eve, but anyone who knows me would realize that's a total fabrication. The truth of the matter is that I've been locked out of my blog account all day and unable to reach anyone at GWU to help me, but now all of a sudden my access reappeared. So, I'm writing this at night in case the Gods of Blog decide to exile me again tomorrow.

We have definitely entered a new phase of the pandemic. I know this because the "A" section of the January 1, 2023 Washington Post (yes, I still get the home-delivered version of our local newspaper) had no original news articles about anything related to medical aspects of covid or the other respiratory viruses circulating. The only acknowledgement that this could still be newsworthy was an editorial bemoaning the situation in China.

Let's dive in.

Tripledemic Tracking

RSV

Continued good news from RSV-NET, further definite decrease in RSV activity nationally.

As you can see from the green line, things appear to be coming down to less drastic levels this year.

Influenza

FLUVIEW also has good news.

We have a very definite downward trend on the red line for this year, very encouraging.

COVID-19

The news is not as good with our old friend covid.

The weekly cases don't show a surge, but percent positivity continues to rise.

In the meantime, a new variant appears to be taking over, particularly in the northeast and mid-Atlantic US.

Those big blue pieces of pie represent XBB.1.5, a subvariant in the omicron BA.2 lineage. It has exploded in the last couple of weeks. It likely has similar immune evasion properties as other recent subvariants, but too early to determine if it has increased ability to cause more severe disease.

What does all of this mean for the future of the tripledemic? That again would require an accurate crystal ball, but hey it's a new year, so why not stick my neck out? With the consistent downward trends in RSV and influenza, I think the tripledemic is over. I do not expect a rebound for either flu or RSV this winter because it's already run through most of the susceptibles who now have considerable immunity. I can't say the same for covid, however, because changing variants are still able to infect those who have been recently infected or immunized. The good news is that pre-existing infection and/or vaccination with boosting likely protects somewhat against severe disease, at least for a number of months, but not so much against new infection. So, I think covid will continue to increase though I doubt at levels we saw last winter, unless a more formidable variant appears.

Long Covid News

We still know very little about long covid, but what is increasingly apparent is that we need to have adequate control groups of uninfected people and people infected with other viruses for comparison. A recent example is an article just accepted for publication in Clinical Infectious Diseases. Long covid is likely a mixture of symptoms resulting from direct organ damage from the virus, such as severe pneumonia or cardiac or renal disease, along with some more poorly understood entities such as "brain fog" and other "myalgic encephalitis" symptoms that are known to follow multiple different types of infections. I am hopeful that the many longitudinal studies that are ongoing will shed more light on this confusing grab-bag of illnesses.

Another Effective Oral Anti-Covid Drug?

I was encouraged by the NEJM article showing non-inferiority of VV116 to Paxlovid, with fewer side effects. Development of resistance to antiviral agents is an ongoing concern for any antiviral treatment, so having more options is always preferable. Let's hope more studies support its efficacy.

It Could Have Been Worse

I came across a somewhat uplifting presentation about Epidemics That Didn't Happen. Take a few minutes to look at it; public health principles, when followed, actually work!

If You'll Be Rounding the Corner With Me, How About Doing It With a Silly Walk?

Every year at this time I enjoy reading the Christmas issue of the BMJ which contains some real but tongue-in-cheek research studies. I was particularly drawn to the study alleging to show the health benefits of the "silly walk" shown in the Monty Python skit in 1970. Try it out - it will bring a smile to your face, and we could all use more of that in 2023.

I wish everyone a safe, healthy, and fun 2023!