Setback

Dora Anne Mills, MD, MPH

Not-So-Brief COVID-19 Update

Friday, April 16, 2021

Setback

I am very disappointed that the J&J (Janssen) vaccine is being put on hold for at least another seven days. That was the advice Wednesday to the US CDC from its ACIP (Advisory Council on Immunization Practices). They want to wait for more data.

Although a number of the ACIP members are esteemed academic achievers, as others have noted, their questions and dialogue at Wednesday afternoon’s meeting sounded much like a panel of experts discussing the latest academic issue at a public lecture series. Their pondering was interesting and intellectual.

However, I kept wanting to shout, “the house is on fire!” The context of this global pandemic fire seemed lost except for some brief nodding of acknowledgement. I read the official charge of ACIP (linked to below), and I then understood why they may not have more fully taken into account the context of a rapidly expanding pandemic. ACIP’s basic charge is to “develop recommendations on how to use vaccines”. Further verbiage mostly reflects routine use of vaccines. There is no part of the charge that discusses the possibility of ACIP providing emergency advice on how to acutely control an outbreak, an epidemic, or a pandemic.

The front and center issue on their plate is that out of about 7 million doses of J&J administered so far, there are reports of six (now seven) women ages 18 - 48 who have been identified with clots (thrombi) within 1 - 3 weeks after receiving the J&J vaccine here in the U.S. There was also a 25-year-old man during the clinical trials with a similar presentation.

This particular type of clot is extremely rare, since it is paradoxically associated with low platelets (thrombocytopenia), which normally help clots form. Most of the clots have been found in an unusual place - in one of the sinuses of the brain - causing a stroke-like syndrome called a cerebral venous sinus thrombosis (CVST). The cerebral venous sinuses are channels that drain blood from the brain. They are not the same as the nasal bony sinuses (cavities) that commonly get infected after a bad cold or become inflamed due to allergies.

This constellation of CVST or other clots among mostly younger women is very similar to what has been seen in Europe (though also seen extremely rarely) among a few after receiving the AstraZeneca vaccine. Both vaccines use different non-replicating adenoviruses as a vehicle to get our muscle cells (just those cells in the vicinity of the injection) to produce the SARS-CoV-2 spike protein, which in turn triggers our immunity to COVID-19. Additionally, several of the cases here in the U.S. associated with the J&J vaccine have tested positive for antibodies to the PF4 (platelet factor 4) protein, something also observed in the European cases associated with the AstraZeneca vaccine.

This same set of symptoms and test results have also been seen in rare patients who have been administered the blood thinner heparin, causing what is known as heparin-induced thrombocytopenia (or HIT).

The key to successfully treating someone with these types of blood clots - whether induced by heparin or possibly a vaccine - is to not treat with heparin (a traditional treatment for clots), and to treat instead with another type of blood thinner (anti-coagulant) or high-dose immune globulin (see US CDC health alert linked to below for more info).

The good news is that these clotting events have not been seen after the mRNA vaccines. The other good news is that vaccine safety monitoring systems have been able to detect these very rare events possibly associated with the J&J vaccine.

However, there is plenty of not-so-good news. First, the pandemic in the U.S. is at very high levels and rising. Over 5,500 people are hospitalized for COVID-19 each day. It continues to be the third leading cause of death. In the Midwest and northeast corridor, the pandemic is surging. We’re seeing levels of cases approaching that which we saw during the winter surge, though among much younger people. Vaccine supplies are very short and not nearly enough to vaccinate everyone who wants one. The vast majority of these hospitalizations and deaths could be prevented if we had more vaccine.

Ironically, COVID-19 is a major cause of clots, including strokes, and at much higher rates than seem to be possibly associated with the vaccine. Comparisons are challenging and imperfect in an evolving situation. However, if one takes the current incidence of CVSTs in the U.S. associated with the J&J vaccine, it is approximately 6 cases among the 1.4 million doses of J&J vaccine administered to women ages 18 to 50 years old. This is 0.4 cases per 100,000. This is in the ballpark of the incidence seen among those receiving the AstraZeneca vaccine in Europe. By comparison, COVID-19 itself is estimated to cause 4.5 - 20 cases of CVST per 100,000 cases. This indicates a 10 - 50-fold risk for CVST as a result of COVID-19 over the J&J vaccine. In other words, one’s risk of developing CVST appears to be 10-50 higher if you contract COVID-19 over taking the J&J vaccine.

Clots are also not uncommonly associated with oral contraceptives (OCPs, birth control pills). The specific and rare type of clot, CVST, is identified in approximately 2.7 - 40 cases per 100,000 taking OCPs. This is about a 100-fold higher than the preliminary incidence associated with the J&J or the AstraZeneca vaccines. OCPs are still prescribed, though with a warning. In some cases, OCPs are not recommended when people have additional risk factors that may outweigh the benefits, such as older age.

Additionally, many parts of the world are on fire with this pandemic, including much of Europe, South America, and India. Even as the U.S. and the EU vaccinate, as long as the virus continues to transmit somewhere in the world, the virus will continue to spit out mutations that will threaten us. That’s one reason why it is critical we need to come together as a world and assure vaccines are available everywhere.

Yes, disease anywhere is a threat everywhere. And vaccine everywhere is the answer.

The mRNA vaccines (Pfizer and Moderna) are very delicate and must be maintained at very low temperatures. This makes these vaccines improbable solutions for much of the world. However, the adenovirus vaccines, such as J&J, AstraZeneca, and Sputnik V, have been hopeful contenders. They do not require such low temperatures and they generate good immunity, including (in the case of J&J and likely AstraZeneca) after one dose.

What is likely to happen in the next few days? We may see more cases of people with these rare clots. That is because about half of the J&J vaccine administered in the U.S. has been given in the last three weeks, the time period within which these rare complications are seen. Anyone who received the J&J vaccine within the last three weeks and who develops severe headache, abdominal pain, leg pain, or shortness of breath should seek medical care and let them know about their vaccine history.

We also know one thing that for certain will happen in the next few days. More people will continue to get sick from COVID-19, be hospitalized, and even die. Increasingly, these are young people. That’s because the variants are more transmissible (and perhaps especially among young people) and because there is not enough vaccine.

I hope the pause on the use of the J&J vaccine is lifted very soon, as soon as possible. Perhaps a warning can be added, as we see with oral contraceptives. Or perhaps its use can be limited to those over a certain age, e.g., 50 or 60 years old. Most European countries are offering the AstraZeneca vaccine, though some have limited it to older people, in whom the risk for severe COVID-19 is very high and the apparent risk for clots is much lower.

I realize there is always a delicate and imperfect balance of weighing risks versus benefits, and these decisions carry extraordinary responsibilities. I hope that very soon the context of the raging pandemic is more fully considered and incorporated into the deliberations. That includes the billions of people around the globe who currently have no access to vaccine as well as those in our own country who are homebound or living in isolated rural areas who are patiently waiting for this feasible one-dose vaccine while the pandemic fire surges around them.

US CDC Health Alert on J&J Vaccine

https://emergency.cdc.gov/han/2021/han00442.asp

US CDC ACIP Roles

https://www.cdc.gov/vaccines/acip/committee/charter.html

US CDC ACIP April 14, 2021 slides/meeting materials

https://www.cdc.gov/vac.../acip/meetings/slides-2021-04.html