Better Data on Risks of Myocarditis and Pericarditis from COVID-19 Vaccines
The ACIP/CDC held their meeting, postponed from June 18 due to the new federal Juneteenth holiday, on June 24. It was worth the wait, and fortunately I was able to attend the meeting online. You can see all of the presentation slides on their website, in particular I'd recommend the risk-benefit discussion by Drs. Wallace and Oliver. I had 2 major take-aways from the approximately 5-hour presentation.
First, as more time and cases have accumulated, the link between vaccines and myocarditis/pericarditis in adolescents and young adults (primarily male) seems much more convincing. The timing after the second dose, the striking age distribution, and the mostly mild clinical features strongly suggest a link even though the rates are very rare. It is worth mentioning this potential risk to people considering vaccination, though in these same demographic groups the risk of adverse sequelae from COVID-19 disease itself is much higher. Also note that this association was seen with both of the mRNA vaccines, Pfizer and Moderna, but I don't think we have enough information yet to know if this will occur with other COVID-19 vaccines. The mechanism of injury is still unknown and is the subject of much research.
Second, recognize that the only reason this was brought to light so quickly is that we have very massive and effective surveillance of adverse events with these vaccines. Please encourage all of your patients to sign up for V-safe when they are vaccinated, and everyone should report any suspected vaccine adverse events to the VAERS system.
Delta Variant is a Real Problem Everywhere
Evidence continues to mount that the SARS-CoV-2 delta variant is a major problem worldwide. It is unquestionably more easily transmissible than other variants by a long shot. Both mRNA vaccines seem to provide very good protection against severe disease caused by the delta variant, though preliminary data suggests that a single dose, rather than the recommended 2 doses, is not very protective. The jury is still out about whether delta causes more severe disease than other variants, but clearly this is the strain responsible for the vast majority of hospitalizations in developed countries, primarily impacting children and young adults who represent a disproportionate number of unvaccinated individuals. It likely will be the dominant strain in the US in a matter of weeks. Please encourage everyone to be vaccinated.
Somewhat more in the rumor category, a "delta-plus" variant has cropped up in the lay press. It is a strain that carries an additional mutation, K417N, that was known to be present in the beta variant and has been associated with poor response to treatment with monoclonal antibody preparations. We still need more information about this new sub-lineage strain to know its clinical significance.
Well, vaccines are starting to turn the tide and even the cicadas are retreating now. I'm hoping to recommit to Pediatric Infection Connection this summer and try to post weekly commentary that will be at bit more concise than my traditional rambling style. I will try to limit myself to just 2 topics a week, but starting off I'm already breaking that pledge with 3 topics.
1. A Conflict of Interest
For the first time in maybe a couple decades, I need to declare a conflict of interest up front. I am overseeing the Pfizer COVID-19 vaccine trial at Children's National Hospital for children 6 months through 11 years of age. While I don't think this will color any of my commentary here, implicit bias has been recognized as a confounder in scientific and Evidence Based Medicine circles for many years. I will do my best to recognize that and be objective.
2. Keeping Straight with SARS-CoV-2 Variants
In case you hadn't noticed, the terminology for variants has changed yet again, I think for the better but also adding to the public confusion. The purpose is laudable: eliminating the possibly pejorative naming of variants by site of first detection and also doing away with confusing codes. I'm very much in favor of getting rid of the geographic references to outbreak agents. Some of you know that the 1918 H1N1 influenza A pandemic was also known as the Spanish Flu, but in fact the evidence would suggest that a better name is the Kansas flu. Such nomenclature opens the door to discriminatory practices.
Now we are just using Greek letters for SARS-CoV-2 variants, though I fear we will run out very soon! The CDC has a summary of these.
I want to focus on the delta variant which has been the focus of much attention in the lay press. This variant is officially a "variant of concern" and is very much worthy of concern. I don't think it is oversimplifying to focus principally on 3 features of variants. First is transmissibility, or how easily the variant can spread in a population. As the pandemic has evolved, probably the most accurate early sign of transmissibility is how quickly a new strain becomes predominant in a population. The delta variant is striking in its spread, now the most common variant in the UK and soon to achieve that status in the US. It is clearly more contagious than the original strain and early variants.
The second feature is virulence, or whether the variant causes higher rates of severe disease and death. In my opinion, the jury is still out on this for the delta variant. Certainly we have seen appalling severity of disease with this variant in India, but I cannot sort out from the reports how much of this could be due to properties of the virus itself versus healthcare access and other issues.
The third, and perhaps most fearsome to those residing in highly-vaccinated communities, is whether the variant is able to evade host immunity and cause a higher rate of infection in those who have immunity from either natural infection from another SARS-CoV-2 strain or from immunization. In this regard, the delta variant clearly can evade immunity to some extent. Thankfully full vaccination seems to protect from severe disease, but partial vaccination is much less effective. It really causes concern for all those people who skipped the second dose of the Pfizer or Moderna vaccines.
Also remember that every person who is infected with SARS-CoV-2 represents a new opportunity for new variants to appear.
Myocarditis and COVID-19 Vaccines
We must be certain that these new vaccines are safe, and in particular that the risk/benefit ratio is favorable. This is especially important for children where, although severe COVID-19 and MIS-C cases occur, the rates are much lower for complications than for adults.
The CDC had planned an update on myocarditis cases associated with COVID-19 disease for June 18, but this was postponed for a week due to the new Juneteenth national holiday. Now it is to be incorporated into the regular meeting of the ACIP scheduled for June 23-25.
However, based on the data that have been released so far, it does seem increasingly plausible that one or more of the COVID-19 vaccines can cause myocarditis. They are still so rare that it is difficult to be certain that it is happening above the expected rate of myocarditis from other causes in the population. It is unlikely to be anywhere near as common as the rates of myocarditis from natural SARS-CoV-2 infection and thus at this time suggests a clear benefit from vaccination. If you're interested, check out a nice study of COVID-19 myocarditis in Big 10 conference athletes.
It's been another whiplash week in covid-land, with crushing numbers of hospitalizations and deaths juxtaposed against the first vaccine administrations to healthcare providers and a second vaccine granted Emergency Use Authorization by the FDA followed by a positive vote from the ACIP/CDC. Presumably we will see the Moderna vaccine shipped this week, along with ongoing distribution of the Pfizer vaccine. I won't spend any time detailing the basics of the Moderna vaccine; it is an mRNA vaccine very similar to the Pfizer vaccine and much detail is available at FDA and CDC websites. However, I did want to mention a few nuances.
First, evidence to date is insufficient to compare safety and efficacy of the two vaccines. The study findings were very similar, and given the minor differences in study design it would be improper to consider any head-to-head comparison at this time. Eventually we should know about any significant differences such as duration of immunity.
Note that a good deal of the discussion at the FDA/VRBPAC meeting concerned how to continue the ongoing Pfizer and Moderna trials: ethics and practical considerations of how to manage the placebo recipients in those trials who do have the ability to drop out of further follow up in the trials as well as seek their own antibody testing and immunization. The logistics of continuing a double-blinded crossover design trial (placebo recipients receive vaccine, vaccine recipients receive placebo) are large. Many have advocated continuing with an open-label trial where placebo recipients receive vaccine but agree to continue in some modified follow up within their study.
A few more details about side effects have emerged. As in the Pfizer study, a few people developed Bell's palsy in the Moderna trial, too few to determine if this is above expected rates in the general population or greater in vaccine versus placebo recipients. Also, as in the Pfizer trial a handful of women were pregnant in both groups. These pregnancies are being followed by study investigators.
Of interest are a few cases of facial swelling following vaccine, all in individuals who underwent cosmetic injections in lips and similar areas. Apparently this has been reported with other vaccines such as flu vaccine, as well as with natural viral infections. It appeared these reactions resolved with no permanent sequelae but again are being watched.
In the meantime, a few more healthcare providers have developed anaphylactic-like reactions that may be tied to the Pfizer vaccine, even though this wasn't seen in the clinical trials. Note that a far greater number of people have received vaccine in the past week, over 500,000 in the US, than received vaccine in the trials. Rare events sometimes are noted after approval of any drug or vaccine due to larger numbers of people receiving the product.
I'm hoping I will be called to receive my COVID-19 vaccine soon, but regardless of vaccine status remember we all must continue safe public health practices and promote them to our patients.
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.
I spent most of my day December 10 trying to catch as much of the FDA Center for Biologics Evaluation and Research (CBER) meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) discussion of the Pfizer/BioNTech COVID-19 vaccine. Although I had some interruptions and much multi-tasking, I was able to watch most of the proceedings, plus I did have a chance to review the detailed briefings from FDA and Pfizer as well as all of the presentation slides, posted online for everyone. Overall I came away feeling that we now have a very clear picture of the data, certainly enough to make decisions about this vaccine for the short term. Obviously they covered a ton of information, but I'll try to distill down to the essentials.
First, the overview and major take-home messages. As you may already know, this is a messenger RNA vaccine; the technology and science for making these vaccines has been around for quite a while and been tested in small numbers of humans for different purposes. However, this is the first mRNA vaccine to undergo widespread testing and presumably use in people. The cartoon below is from the Pfizer slides and I think shows you how this works. The modified mRNA is contained in lipid nanoparticles (LNP) and when injected ends up in cells where the mRNA instructs the cell to make the SARS-CoV-2 spike protein. The protein then triggers an inflammatory response such that the recipient makes antibody to the protein as well as memory T and B cells, then lies in wait to attack anything possessing the spike protein to enter the body.
In terms of safety, bottom line is that no serious concerns were raised in the 20,000+ individuals who received the vaccine (the other half of the subjects received saline placebo injections). Local side effects such as pain and swelling at the injection site occurred but nothing dramatic there. Systemic reactions like fatigue and chills were reported by a few percent of vaccine recipients; fever also occurred and usually of short duration. Side effects were more common after the second vaccine dose. Efficacy was as you have heard in news reports, in the mid-90s% range and much higher than I had hoped originally.
Now for the nuances and special populations. You've probably heard about the 2 vaccine recipients in England who may have experienced severe allergic reactions to the vaccine. Pfizer presented what little is known so far about this, and the best I can say is that it is still pretty murky. It didn't really sound like true anaphylaxis to me, but we'll just need to wait for more details, I'm hoping in the next few days. The current trial did not include individuals with severe allergy profiles, unlike the 2 British recipients this week.
A couple other caveats from the safety aspect. Regional lymphadenopathy occurred in 64 individuals in the vaccine group versus 6 in the control group, nothing worrisome but certainly plausible as an uncommon side effect. Bell's palsy occurred in 4 vaccine recipients versus none of the controls, but that level is within the rate of Bell's palsy that would be expected in the general population not receiving any vaccine, so difficult to know if any connection to the Pfizer vaccine.
The immune response to this vaccine is what is termed "Th-1 biased." That's a good thing, because in the past (e.g. an RSV vaccine trial in the 1970s), vaccines have the capability to produce an exaggerated immune response by the host when exposed to the virus. The immunology of that process is now understood, and a Th-1 biased immune profile protects against this. The few vaccine recipients in the Pfizer trial who did develop subsequent infection with SARS-CoV-2 did not show evidence of severe disease; in fact it was very mild.
In terms of special populations, the trial did not enroll immunocompromised individuals though this is planned for the future. They might need a different vaccine dose; this will take a while to figure out. Similarly, pregnant women were not enrolled. However, 23 women subsequently became pregnant, 12 in the vaccine group and 11 in the placebo group. The only known outcome so far is 2 women in the placebo group experienced a spontaneous abortion. The remainder of the pregnancies are still ongoing so we'll hear more about that later. In the meantime, the language of what to do about guidance for pregnant women will come from the FDA. My guess, and it's only that, is pregnancy will not be an absolute contraindication to vaccination and women will be directed to discuss individually with their physician to weigh benefits versus potential risks. In terms of racial and ethnic distribution, the study group included a little under 10% Black or African Americans (about 4000 total) and a little over 25% Hispanic/Latinx participants.
The final special group, the one this audience cares most about, is children. The bulk of the study participants were adults 18 years and older, with a small number of 16- and 17-year olds. Pfizer has begun enrolling younger subjects down to age 12 years, a total of 2000, but no data on that yet. If no problems in that population, they will move to the 5-11 year-old age group, perhaps around April 2021, but they may need to determine if vaccine dose should be different in this younger population. I was surprised that there was some hesitancy from VRBPAC voting members about recommending use of the vaccine for the 16-17 year age group but ultimately the panel voted to recommend authorizing the vaccine for ages 16 and older, with 17 votes in favor, 4 against, and 1 abstention.
Two other important caveats from the FDA meeting: first, extensive post-authorization tracking is planned and already in place. This is called pharmacovigilance and will use both existing and newer vaccine tracking measures. I am very reassured about the quality of this pharmacovigilance plan, and this is where we begin to get some idea of how long immunity from the vaccine will persist. Second is the tricky ethical issue of what to do about the placebo recipients from this trial. Should they all be offered vaccines, which would make some of the long-term follow-up more difficult to assess? It would be great to invite all the trial participants to participate in a "blind crossover" trial, where prior vaccine recipients receive 2 doses of placebo and prior placebo recipients get 2 doses of the vaccine, everyone still remaining blinded but now everyone has the benefit from the vaccine. However, the logistic difficulties of performing what is essentially a new clinical trial for 40,000+ people is significant.
Next steps for this vaccine include what we hope will be a statement the evening of December 11 from FDA regarding recommendation for emergency use authorization. ACIP/CDC meetings are scheduled the afternoons of December 11 and 13, culminating in a vote to decide on whether the data warrant a recommendation for going forward assuming FDA recommends authorization. Then, on December 17, FDA VRBPAC will meet to discuss the Moderna vaccine data, with meeting materials to be posted soon on the web link earlier in this post.
In closing, I need to answer the many questions I've received from friends and colleagues: if offered, will I choose to receive this vaccine? My answer is unquestionably yes. Although we don't have long-term follow up of recipients, most significant side effects from vaccines appear in the first 6 weeks after immunization, and we have lots of information about that time period. Of course we don't know about any extremely rare side effects, but we never have that information about new drugs or vaccines until they are in widespread use. I'm perhaps a bit biased ahead of time in favor of vaccination: my age and occupation puts me in a high-risk group, I'm very familiar with the FDA review process and know several of the reviewers (no, I don't have any inside information about what they are doing with this or any other vaccine), and it turns out one of the senior vice presidents at Pfizer who presented most of the clinical data is an old friend of mine. I don't think any of these potential biases is coloring my decision, however.
