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.
Short answer: it's very encouraging news, but it's also very preliminary.
Pfizer's messenger RNA-based COVID-19 vaccine was always scheduled for interim analyses after prespecified numbers of COVID-19 infections an study volunteers. The plan had been to perform interim efficacy analyses analyses after 32, 62, 92, 120, and 164 cases of COVID-19 in the study population, including both vaccine and placebo recipients. Today's announcement was at the 92 case count, though it actually turned out to be 94 cases. The protocol had set success criteria for this stage at 62.7% efficacy; they also set futility criteria, if efficacy was 38.6% or less it could indicate that it was futile to continue the study since they would be unlikely to reach 50% efficacy after final evaluation.
As an aside, note that it's a pretty complicated issue to perform interim analyses in blinded randomized controlled trials. These "peeks" at the data essentially violate some of the assumptions of standard statistical testing and require correction factors. The statisticians I hang out with like to call this "spending alpha:" each time you look at the data you must correct the statistical analysis, effectively lowering the p value making it tougher to achieve statistical significance. Also note that the investigators and trial volunteers are still blinded as to whether placebo or vaccine was given to an individual. It is a separate data monitoring committee that is actually unblinded for these peeks to see what the infection rates are in vaccine and placebo groups.
So, we'll need to see if this early hint of high efficacy is actually sustained to the end of the study. If so, this will be terrific. Also, we'll eventually know more about the range of disease severity in volunteers as well as some indication of how the vaccine performs in different age groups.
This is also good news for the Moderna COVID-19 vaccine because it uses a similar messenger RNA construct for its vaccine.
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.
